Living Donor Transplantation

Living Donor Transplantation

Living Donor Transplantation Edited by

Henkie P. Tan

Thomas E. Starzl Transplantation Institute Pittsburgh, Pennsylvania, USA

Amadeo Marcos

Thomas E. Starzl Transplantation Institute Pittsburgh, Pennsylvania, USA

Ron Shapiro

Thomas E. Starzl Transplantation Institute Pittsburgh, Pennsylvania, USA

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 © 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3766-6 (Hardcover) International Standard Book Number-13: 978-0-8493-3766-6 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data Living donor transplantation / [edited by] Henkie P. Tan, Amadeo Marcos, Ron Shapiro. p. ; cm. Includes bibliographical references. ISBN-13: 978-0-8493-3766-6 (hardcover : alk. paper) ISBN-10: 0-8493-3766-6 (hardcover : alk. paper) 1. Organ donors. 2. Transplantation of organs, tissues, etc. 3. Donation of organs, tissues, etc. I. Tan, Henkie P. II. Marcos, Amadeo. III. Shapiro, Ron, 1954 – [DNLM: 1. Organ Transplantation. 2. Cell Transplantation. 3. Living Donors. WO 660 L785 2007] RD129.5.L5883 2007 617.5’5620592--dc22

Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

2007005324

To our families for their love and support. To our live donors for their altruistic acts. To our recipients for their courage and faith in us. To Dr. Starzl for providing challenges, inspiration, and a vision.

Preface

Living Donor Transplantation discusses all aspects of living donor solid organ and cellular transplantation in current clinical practice, including kidney, liver, pancreas, lung, small bowel, islet, and hematopoietic stem cell transplantation. Each organ/cell-specific chapter includes sections on the medical evaluation, technical aspects of the operation, and donor and recipient outcomes. Special topics also include the history of living donor organ transplantation, the psychosocial aspects of donation and the transplant process, anesthetic management, prevention and control of infections, pregnancy in transplant recipients, the financial impact of living donation, transplantation tolerance, transplantation for malignancy, the ethics of paid living donation (pro and con), and living donor transplantation in pediatric recipients. This book describes in detail the state of the art and practice of live donor organ transplantation. Although many of the chapters are from the Thomas E. Starzl Transplantation Institute at the University of Pittsburgh, it represents a broad-based attempt to present, as clearly as possible, a comprehensive guide to the practice of live donor organ transplantation and includes important contributions from many other transplant centers in the United States. Chapters 1 to 3 are introductory overviews. Chapter 1 is a discussion of the history of living donor organ transplantation by Dr. Thomas E. Starzl, the “father” of modern transplantation and winner of both the Medawar Prize and the National Medal of Science. Chapter 2 examines the psychosocial aspects of living organ donation and the transplant process, emphasizing the well-being of donors both before and after transplantation. Chapter 3 describes the general medical evaluation of the living donor. Chapters 4 to 13 are specific to living donor kidney transplantation. Chapter 4 focuses on issues related to the medical evaluation of live kidney donors. Chapter 5 is about the different technical aspects of live donor nephrectomy. This extensive chapter covers open, minimal incisional open, laparoscopic, hand-assisted laparoscopic, and robotically hand-assisted laparoscopic donor nephrectomy techniques. Chapters 6 and 7 consider the perioperative and long-term risks to the live kidney donors. These chapters also present a live donor nephrectomy complication classification scheme. Chapter 8 is a discussion of the long-term outcomes for live kidney donors by Dr. Arthur Matas of the University of Minnesota, examining the long-term consequences of living with a single kidney (survival, renal function, cardiovascular disease, proteinuria, risk factors of end-stage renal disease, and quality of life) and the limitations of the current data. Chapter 9 covers donor and recipient outcomes after laparoscopic live donor nephrectomy. Chapter 10, by Drs. Lloyd Ratner and R. John Crew of Columbia Presbyterian Hospital in New York, reviews immunologically incompatible living donor kidney transplants in the highly sensitized, positive crossmatch, and ABO-incompatible recipients. In Chapter 11, Drs. Dorry Segev, Robert Montgomery, and colleague at Johns Hopkins in Baltimore, Maryland, focus on expanding live donor renal transplantation through paired and nondirected donation. Chapter 12 discusses a limited experience with living donor kidney transplantation in HIVpositive recipients. Chapter 13 examines pediatric living donor renal transplantation. Chapters 14 to 20 are specific to living donor liver transplantation. Chapter 14 analyzes issues related to the evaluation of the live liver donor and recipient. Chapter 15 investigates the technical aspects of live donor hepatectomy. Chapter 16 explores live liver donor outcomes. Chapter 17 is a discussion of recipient outcomes after living donor liver transplantation by Drs. James Pomposelli, Elizabeth Pomfret, and Roger Jenkins of the Lahey Clinic. Chapter 18 describes recipient outcomes from the Pittsburgh experience with alemtuzumab preconditioning and tacrolimus monotherapy. Chapter 19 focuses on pediatric living-donor liver transplantation. Chapter 20 examines living donor liver transplantation for hepatocellular carcinoma.

vi

Preface

A discussion of live donor pancreas transplantation by Drs. Miguel Tan, Raja Kandaswamy, Rainer Gruessner, and David Sutherland of the University of Minnesota is undertaken in Chapter 21. This chapter spotlights the preoperative donor evaluation, operative technique (including hand-assisted laparoscopic donor distal pancreatectomy), the recipient operation, and donor and recipient outcomes. Chapter 22 is an examination of living-donor islet cell transplantation by Drs. Emamaullee and J. Shapiro of the University of Alberta, Edmonton, Canada. This chapter describes the evaluation of the live donor and recipient, technical aspects of the islet transplantation procedure, and donor and recipient outcomes. Chapter 23 is a discussion of living lobar lung transplantation by Drs. Mark Barr and Vaughn Starnes of the University of Southern California. It covers evaluation, technical aspects, and donor and recipient outcomes. In Chapters 24 to 26, Dr. Luca Cicalese and colleague of the University of Massachusetts discuss live-donor small intestinal transplantation. Chapter 24 reviews specific issues related to the donor and recipient evaluation. Chapter 25 analyzes the surgical technique, and Chapter 26 examines donor and recipient outcomes. A discussion of hematopoietic stem cell transplantation by Dr. Andrew Yeager and colleagues from the Arizona Cancer Center takes place in Chapters 27 to 29. Chapter 27 investigates the collection, processing, and infusion of adult hematopoietic stem cells (bone marrow and peripheral blood stem cells). Chapter 28 is an examination of the applications and outcomes of autologous and allogeneic hematopoietic stem cell transplantation, and Chapter 29 is a discussion of umbilical cord blood cell transplantation. Chapters 30 to 36 are special topics related to living donor organ transplantation. Chapter 30 examines anesthetic management for living donor organ transplantation. Chapter 31 focuses on the management of infections in living donor transplant recipients. Chapter 32 is a discussion of pregnancy after living donor organ transplantation by Drs. Vincent Armenti and colleagues of the National Transplantation Pregnancy Registry. Chapter 33 covers the financial impact of living donor organ transplantation. Chapter 34 describes transplantation tolerance. In this chapter, the mechanisms of immunological tolerance and the barriers to its induction are depicted. Chapters 35 and 36 consider the ethics of paid living donation. The case for a regulated system of kidney sales is made by Dr. Arthur Matas, and the case against organ sales is taken up by Dr. Arthur Caplan of the University of Pennsylvania. Chapters 37 and 38 are sample live kidney- and liver-donor consent forms created by the editors at the Starzl Transplantation Institute. We hope that this book proves to be a useful guide for individuals interested in living donor transplantation. Henkie P. Tan Amadeo Marcos Ron Shapiro

Acknowledgments

This multiauthored book represents the work of many individuals. We would like to thank all the authors (and their families) who contributed their time and energy to produce the specific chapters of this book. As we all know, the care of transplant donors and recipients is possible only with the help and commitment of a large number of physician consultants, transplant coordinators, nurses, social workers, and other staff personnel. Specifically, we would like to thank Annie M. Smith, RN, CCTC, and Eileen Stanford, RN, BSN, our two very proud live kidney donors. We also thank Gerri James, RN, CCTC; Cindy Anderson, RN, CCRN, CCTC; Diane Connors RN, MPH; Linda Boig, RN, CCTC; Theresa Caponi, RN, CCTC; Deborah Good, RN, BSN, CCTC; Jareen Flohr, RN, BSN, CCTC; Shirley Grube, MSW, ACSW, BCD, LCSW, MPH; and many others who are part of the transplant teams at the Thomas E. Starzl Transplant Institute at the University of Pittsburgh. We would like to thank Dana Bigelow, development editor at Informa Healthcare, for her patience and guidance as well as Alan Kaplan, project editor at Informa Healthcare, and Paula Garber, editorial supervisor at the Egerton Group. Thanks also to Chris DiBiase for the cover illustrations. We would also like to thank Judy Canelos, M.A., Communications Specialist II, and Miranda G. Rosen, Web Editor/Medical Writer, for their help in proofreading and editing the manuscripts. Without their valued help and participation, this book could not have been completed. We also want to thank Diana Smith, Administrative Assistant, for her help in preparing the manuscripts. Finally, we would like to thank our families, especially our wives (Robin, Cristina, and Mary), for their love and support; our live donors, for their altruistic acts; our recipients, for their courage and faith in us; and Dr. Thomas E. Starzl, for providing challenges, inspiration, and a vision.

Contents

Preface …. v Acknowledgments …. vii Contributors …. xiii Part I: Overview 1. Live-Donor Organ Transplantation: Then and Now 1 Thomas E. Starzl and Amadeo Marcos 2. Psychosocial Aspects of Living Organ Donation 7 Mary Amanda Dew, Galen E. Switzer, Andrea F. DiMartini, Larissa Myaskovsky, and Megan Crowley-Matoka 3. General Medical Evaluation of the Living Donor 27 Jerry McCauley, Thomas Shaw-Stiffel, and Henkie P. Tan Part II: Living-Donor Kidney Transplantation 4. Evaluation: Specific Issues for Living-Donor Kidney Transplantation 33 Mark Unruh, Christine Wu, Henkie P. Tan, and Jerry McCauley 5. Technical Aspects of Live-Donor Nephrectomy 49 Amit Basu, Ron Shapiro, John L. Falcone, and Henkie P. Tan 6. Perioperative Donor Risk 69 Henkie P. Tan, Zebulon Z. Spector, and Ron Shapiro 7. Long-Term Risks of Living Donation Connie L. Davis 8. Long-Term Outcomes for the Donor Arthur J. Matas and Hassan Ibrahim

77

87

9. Donor and Recipient Outcomes After Laparoscopic Live-Donor Nephrectomy 101 Henkie P. Tan, David J. Kaczorowski, Amit Basu, Joseph Donaldson, and Ron Shapiro 10. Immunologically Incompatible Renal Transplants: Highly Sensitized Recipients, Positive Crossmatches, and ABO Blood Group Incompatibility 113 Lloyd E. Ratner and R. John Crew 11. Expanding Live-Donor Renal Transplantation Through Paired and Nondirected Donation 125 Dorry L. Segev, Sommer E. Gentry, Henkie P. Tan, and Robert A. Montgomery 12. Living-Donor Renal Transplantation in HIV Positive Recipients 137 Henkie P. Tan, David J. Kaczorowski, Amadeo Marcos, and Ron Shapiro

x

Contents

13. Pediatric Living-Donor Kidney Transplantation 149 Vivek Sharma, Ron Shapiro, Demetrius Ellis, and Henkie P. Tan Part III: Living-Donor Liver Transplantation 14. Evaluation: Specific Issues 159 Vladimir Bogin, Henkie P. Tan, Amadeo Marcos, and Thomas Shaw-Stiffel 15. Technical Aspects of Live-Donor Hepatectomy 169 Vivek Sharma, Henkie P. Tan, J. Wallis Marsh, and Amadeo Marcos 16. Donor Outcomes 185 Henkie P. Tan, Abigail E. Martin, Arman Kilac, Roberto Lopez, and Amadeo Marcos 17. Recipient Outcomes After Living-Donor Liver Transplantation 197 James J. Pomposelli, Elizabeth A. Pomfret, and Roger L. Jenkins 18. Adult Recipient Outcomes: The Pittsburgh Experience with Alemtuzumab Preconditioning and Tacrolimus Monotherapy—Two-Year Outcomes 207 Henkie P. Tan, Kusum Tom, Ngoc L. Thai, Paulo Fontes, Michael DeVera, Joseph Donaldson, Igor Dvorchik, and Amadeo Marcos 19. Pediatric Living-Donor Liver Transplantation 217 Kyle Soltys, Geoffrey Bond, Rakesh Sindhi, Henkie P. Tan, Amadeo Marcos, and George V. Mazariegos 20. Living-Donor Liver Transplantation for Hepatocellular Carcinoma 227 J. Wallis Marsh, Matthew P. Holtzman, and Igor Dvorchik Part IV: Living-Donor Pancreas Transplantation 21. Living-Donor Pancreas Transplantation 235 Miguel Tan, Raja Kandaswamy, David E. R. Sutherland, and Rainer W. G. Gruessner Part V: Living-Donor Islet-Cell Transplantation 22. Islet-Cell Transplant: Evaluation, Technical Aspects, and Donor and Recipient Outcomes 245 Juliet A. Emamaullee and A. M. James Shapiro Part VI: Living-Donor Lung Transplantation 23. Living Lobar-Lung Transplantation Mark L. Barr and Vaughn A. Starnes

259

Part VII: Living-Donor Intestinal Transplantation 24. Intestinal Transplantation from Living Donors: Specific Issues and Donor/Recipient Evaluation 269 Luca Cicalese 25. Living-Donor Intestinal Transplantation: Surgical Technique 281 Luca Cicalese 26. Living-Donor Intestinal Transplantation: Clinical Outcomes 297 Luca Cicalese and Shimul A. Shah

xi

Contents

Part VIII: Hematopoietic Stem-Cell Transplantation 27. Collection, Processing, and Infusion of Adult Hematopoietic Stem Cells (Bone Marrow and Peripheral Blood Stem Cells) 309 Leslie A. Andritsos, Candace Paprocki, and Andrew M. Yeager 28. Applications and Outcomes of Autologous and Allogeneic Hematopoietic Stem-Cell Transplantation 319 Gregory Gerstner, Jennifer Christian, and Andrew M. Yeager 29. Umbilical-Cord Blood-Cell Transplantation 329 Michael L. Graham, Martin Andreansky, and Andrew M. Yeager Part IX: Special Topics in Living-Donor Transplantation 30. Anesthesia for Living-Donor Transplantation Raymond M. Planinsic

341

31. Management of Infections in Living-Donor Transplant Recipients 363 Fernanda P. Silveira and David L. Paterson 32. Pregnancy After Living-Donor Transplantation 379 Vincent T. Armenti, Michael J. Moritz, and John M. Davison 33. Financial Impact of Living-Donor Organ Transplantation 395 Liise K. Kayler, Abigail E. Martin, and Henkie P. Tan 34. Transplantation Tolerance Fadi G. Lakkis

405

35. Ethics of Paid Living-Unrelated Donation: The Case for a Regulated System of Kidney Sales 417 Arthur J. Matas 36. Do No Harm: The Case Against Organ Sales from Living Persons Arthur L. Caplan

431

Part X: Sample Consent Forms to Living Kidney and Liver Donation 37. Consent to Living Kidney Donation 435 Henkie P. Tan, Amadeo Marcos, and Ron Shapiro 38. Consent to Living Partial-Liver Donation 441 Henkie P. Tan, Ron Shapiro, and Amadeo Marcos Index …. 449

Contributors

Martin Andreansky Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, and Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona, U.S.A. Leslie A. Andritsos Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, Tucson, Arizona, U.S.A. Vincent T. Armenti Department of Surgery, Abdominal Organ Transplant Program, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Mark L. Barr Department of Cardiothoracic Surgery, University of Southern California Keck School of Medicine and Children’s Hospital Los Angeles, Los Angeles, California, U.S.A. Amit Basu Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Vladimir Bogin

Internal Medicine, Longview, Washington, D.C., U.S.A.

Geoffrey Bond Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Arthur L. Caplan Department of Medical Ethics and Center for Bioethics, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. Jennifer Christian Blood and Marrow Transplantation Program, University Medical Center, Tucson, Arizona, U.S.A. Luca Cicalese Liver and Intestinal Transplantation, Department of Surgery, University of Massachusetts, Worcester, Massachusetts, U.S.A. R. John Crew Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A. Megan Crowley-Matoka Departments of Medicine and Anthropology, University of Pittsburgh School of Medicine and Medical Center, and Veterans Administration Center for Health Equity Research and Promotion, Pittsburgh, Pennsylvania, U.S.A. Connie L. Davis Division of Nephrology, University of Washington School of Medicine, Seattle, Washington, U.S.A. John M. Davison Department of Obstetrics and Gynecology, University of Newcastle Medical School of Surgical and Reproductive Sciences, Newcastle Upon Tyne, U.K. Michael DeVera Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

xiv

Contributors

Mary Amanda Dew Departments of Psychiatry, Psychology, and Epidemiology, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Andrea F. DiMartini Departments of Psychiatry and Surgery, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Joseph Donaldson Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Igor Dvorchik Departments of Surgery and Biostatistics, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Demetrius Ellis Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Juliet A. Emamaullee Alberta, Canada

Department of Surgery, University of Alberta, Edmonton,

John L. Falcone Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Paulo Fontes Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Sommer E. Gentry United States Naval Academy and Division of Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, Maryland, U.S.A. Gregory Gerstner Section of Hematology/Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona, U.S.A. Michael L. Graham Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, and Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona, U.S.A. Rainer W. G. Gruessner Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A. Matthew P. Holtzman Department of Surgical Oncology, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Hassan Ibrahim Department of Medicine, University of Minnesota, Minneapolis, Minnesota, U.S.A. Roger L. Jenkins Division of Hepatobiliary Surgery and Liver Transplantation, Lahey Clinic Medical Center, Burlington, Massachusetts, U.S.A. David J. Kaczorowski Department of Surgery, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Raja Kandaswamy Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A. Liise K. Kayler Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Arman Kilac Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

xv

Contributors

Fadi G. Lakkis Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Roberto Lopez Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. J. Wallis Marsh Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Abigail E. Martin Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Arthur J. Matas Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A. George V. Mazariegos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Jerry McCauley Renal-Electrolyte Division, Department of Medicine, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Robert A. Montgomery Division of Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, Maryland, U.S.A. Michael J. Moritz Department of Surgery, Lehigh Valley Hospital, Allentown, Pennsylvania, U.S.A. Larissa Myaskovsky Departments of Medicine and Psychiatry, University of Pittsburgh School of Medicine and Medical Center, and Veterans Administration Center for Health Equity Research and Promotion, Pittsburgh, Pennsylvania, U.S.A. Candace Paprocki

University Medical Center, Tucson, Arizona, U.S.A.

David L. Paterson Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Raymond M. Planinsic Department of Anesthesiology, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Elizabeth A. Pomfret Division of Hepatobiliary Surgery and Liver Transplantation, Lahey Clinic Medical Center, Burlington, Massachusetts, U.S.A. James J. Pomposelli Division of Hepatobiliary Surgery and Liver Transplantation, Lahey Clinic Medical Center, Burlington, Massachusetts, U.S.A. Lloyd E. Ratner Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A. Dorry L. Segev Division of Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, Maryland, U.S.A. Shimul A. Shah Liver and Intestinal Transplantation, Department of Surgery, University of Massachusetts, Worcester, Massachusetts, U.S.A.

xvi A. M. James Shapiro

Contributors

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada

Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Vivek Sharma Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Thomas Shaw-Stiffel Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Fernanda P. Silveira Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Rakesh Sindhi Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Kyle Soltys Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Zebulon Z. Spector University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Vaughn A. Starnes Department of Cardiothoracic Surgery, University of Southern California Keck School of Medicine and Children’s Hospital Los Angeles, Los Angeles, California, U.S.A. Thomas E. Starzl Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. David E. R. Sutherland Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A. Galen E. Switzer Departments of Psychiatry and Medicine, University of Pittsburgh School of Medicine and Medical Center, and Veterans Administration Center for Health Equity Research and Promotion, Pittsburgh, Pennsylvania, U.S.A. Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Miguel Tan Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A. Ngoc L. Thai Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Kusum Tom Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A. Mark Unruh Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Christine Wu Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Andrew M. Yeager Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, Tucson, Arizona, U.S.A.

Part I

1

OVERVIEW

Live-Donor Organ Transplantation: Then and Now Thomas E. Starzl and Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION The concept of live-volunteer organ donation has been controversial ever since the first such operation was performed in 1953 in Paris by the team of Jean Hamburger. In the much-publicized inaugural case, a mother’s kidney was transplanted to the extraperitoneal pelvic location of her non immunosuppressed son. The allograft functioned for three weeks before being rejected (1). The recipient operation, which had been developed by Rene Kuss (2), was essentially the same procedure as that employed for the historical identical twin cases of Murray and Merrill (3) and up to the present day. The donor operation also has changed only in its details. During the ensuing 20 years (1953–1973), the conceptual framework of clinical renal transplantation that exists today was put in place in a succession of steps. The first of these steps (4) was largely dependent on kidney donation by live volunteers. In fact, it is unlikely that the modern era of kidney and other kinds of organ transplantation could have evolved as it did between 1953 and 1970 without the observations and advances made possible by the use of these early live donors. The reason was that organs from deceased donors during most of this time could be obtained only after cessation of heart beat and respiration. The clinical results using the ischemically compromised grafts were so poor and the clinical observations were so widely variable that deceased-donor organ transplantation had come to an impasse, both as treatment and as an instrument of discovery. The practice of live donation was no secret and aroused surprisingly little negative reaction from the public. However, live donation was, from the beginning, an intractably divisive issue within the medical profession because it potentially placed healthy persons in harm’s way and; therefore, appeared to violate the deep-rooted physician’s tradition of primum non nocere (first, do no harm). Before support for live kidney donation could be solicited from religious leaders, government agencies, and ultimately the public, it was essential to develop agreement within the medical profession about the probity of this practice. A kidney transplant-specific consensus was reached by the early 1970s in a series of ethical–medical conferences and publications (5,6) in which one of the authors of this chapter, Thomas E. Starzl (TES), was a foremost supporter of live donation. The seminal issue that had to be addressed was the doctor–patient relationship in which the physician assumes a specific kind of responsibility for the welfare of another human individual. Before the advent of transplantation, the doctor–patient agreement had been entered into without regard for its social or other ramifications. Because the “contract” between doctor and patient was so simple and clean, it had shielded the ill from evolving philosophical, religious, and legal caprices. Historically, the sole beneficiary of the “medical care umbrella” was the patient. What conceivable benefit was there for the healthy and well-motivated live donor? A defensible way out was found at ethics conferences and in law courts with the argument that the fullness of the donor’s emotional life and holistic welfare was very often dependent on that of the recipient. This argument was particularly persuasive under circumstances of intrafamilial organ transplantation. The long-term benefits to the donor could then be viewed as parallel, or even equivalent, to those of the recipient. Acceptance of this concept was a great relief to renal transplant surgeons whose early contributions to the new field had been so heavily

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dependent on live donors. The work up and care of these donors had been provided exclusively by the recipient team (7), which also assumed a long-term responsibility for their follow-up. By the time consensus was reached, two important events had improved the prospects for kidney transplantation. The first was acceptance in the late 1960s of the concept of brain death. This resulted in the immediate availability of better kidneys and other organs from dead but heart-beating donors. Second, the federally mandated end-stage renal disease (ESRD) amendment to the U.S. Social Security act of 1972, and similar legislation in several European countries, provided fiscal support for organ procurement from heart-beating deceased donors. The American ESRD legislation caused an additional sea change. It also bolstered live kidney donation by underwriting for the first time the cost of work-up and operative care of the volunteer patients. A predictable effect of the federal financial incentive was peripheralization of the work up and other aspects of donor care. For example, kidney recipients and their donors frequently were referred from outlying hospitals as a pair, usually with a donor renal angiogram in hand. Now, the question arose whether the resulting division of responsibility for donor welfare could erode protection of these volunteers from coercion or even undermine safety standards of work up. At first, such concerns were minimal in Europe because live kidney donation was employed uncommonly, if at all, in most programs. In the United States, where live donation had become widespread, it became difficult in some cases to identify who was looking after the donors’ welfare. In the programs directed by one of the authors (TES) at the Universities of Colorado (until 1980) and Pittsburgh (1980–1992), live-donor kidney transplantation remained continuously available, but with the understanding that faculty and staff with ethical qualms could opt out of the performance of the donor operations. The consequence of this policy in Denver and Pittsburgh was the concentration of surgical experience by a subset of the total team. However, all members of the team were expected to participate in the event of complications. As before, the commitment to the donor as it related to complications from nephrectomy was construed to be for a lifetime. The team leader of the Colorado and Pittsburgh programs (TES) discontinued participation in these operations in 1972 after a vascular accident during the work up of a donor in a referring hospital resulted in a foot amputation. Anxiety generated by this case was compounded by donor deaths at other centers, most of which were never formally reported. In fact, donor deaths occurring during work up (e.g., due to angiography complications), or from late complications of donor nephrectomy (e.g., intestinal obstruction) have never been included in donor mortality compilations. For the record, there have been no known deaths related to donor nephrectomy in either the Colorado or Pittsburgh experience; but because of incomplete late follow-up in some cases, a clean slate cannot be claimed with certainty. THE HELSINKI DEBATE: LIVE ORGAN DONATION CIRCA 1986 The shifting ground of live kidney donation was evident in a formal debate at the 11th Congress of the International Transplantation Society, convened in Helsinki, Finland, in the waning days of August 1986. The program committee assigned Felix Rapaport the task of defending the procedure, with one of the authors (TES) as the designated opponent. Rapaport began by describing how scientific and medical advances had resulted in changed guidelines for live donation. The inference was that both the ethical issues and practical policies of live donation were moving targets, and that positions taken in 1986 would very likely be viewed as obsolete 20 years hence. Like a document in a time capsule, the debate was preserved in the pages of the journal, Transplantation Proceedings (8,9). Now that the 20 years have passed, Rapaport’s prophecies have come to pass. His primary justification for live kidney donation in 1986 was an eminently practical one: i.e., the rapidly growing unmet need for transplantable kidneys. Rapaport associated the shortfall with the improved survival and better quality of life with the advent of cyclosporine, and predicted that further refinements in immunosuppression would only increase the demand. He emphasized the safety of renal donation (citing estimates of one death per 2000 cases). Looking forward, he predicted that future strategies to induce tolerance would be fully applicable only under the circumstances of live donation: i.e., sufficient time for pretransplant recipient immune modulation. The centerpiece argument by TES against live donation was concerned with the physical and emotional health risk to the donor under the increasingly commercial circumstances of the

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emerging field. The risk already had been demonstrated by extensive experience: e.g., there had been 20 known deaths of kidney donors. A secondary concern was the difficulty of ruling out the psychological or economic coercion of donors. Finally, the possibility was raised that the convenience of performing prescheduled transplant operations could dampen enthusiasm, or even be a negative incentive, for deceased donor organ procurement. All of these issues continue to concern us today. What was remarkable about the pro and con positions of 1986, however, was not the divergence but rather the commonality of the two points of view. There was concurrence that living donors provide better grafts, better biologic matches, and a higher quality of recipient life than can be achieved with deceased donors. Moreover, TES was even more specific than Rapaport in suggesting how live-donor blood products in advance of the kidney transplantation could be used to facilitate tolerance. The nonconfrontational nature of the debate was reflected in the final statements of the two presenters. From the con perspective, it was stated that … No one would ever operate on a living donor without being convinced in his deepest conscience that he or she was doing the right thing. What we do when we agree to engage in public discussions like this is to expose the deepest crevices of our consciences for criticism and sometimes ridicule. Thus, I want to conclude by honoring Felix Rapaport for coming here as he has done today to give his views about a decision that must be between the surgeon and the living donor, and between them alone (7).

In his pro summary, Rapaport recapitulated his conviction that even with 100% retrieval of all deceased donor kidneys potentially available in 1986 in the United States, there would be a shortage of grafts, with many deaths of recipients who otherwise could have returned to a useful place in society. He concluded: This consideration raises the very real question as to whether the continuing resistance to livingdonor kidney transplantation is ethically or medically justifiable today. The time may well have come for us to determine … whether … to advance the policy of preserving life, or to stand paralyzed by its taboos (8).

If there was an ethical divide between the 1986 Helsinki debaters, it was because the focus on one side (TES) was almost entirely on a perceived erosion of donor safety. On the other side, Rapaport’s defense of live donation went well beyond the original “mutual donor–recipient benefit” argument, about which consensus had been achieved a decade earlier. Rapaport’s position was that live kidney donation would be necessary to prevent pivotal societal problems, including the breakdown of the national ESRD program, which already was heavily weighted by transplant candidates on long-term dialysis who were vainly waiting for grafts. Moreover, the fiscal viability of many transplant centers depended on live donor organs. In Rapaport’s view, the failure to exploit live donation would result in closure of these programs and thereby inhibit the homogeneous diffusion of renal transplantation into the national health care system. From the perspective of “group ethics,” the death of one volunteer per 2000 donations was a statistical nonevent relative to the life years saved. It is noteworthy that neither of the Helsinki debaters ever published again on the subject of live donation and that both scrupulously avoided public expressions of opinion. It was not merely a matter of mutual respect. There was really no right or wrong answer. In the 1990s, and for reasons he never explained, Rapaport opted out of personal participation in live donor cases at his own institution. LIVE ORGAN DONATION 2006 History’s judgment on the ethics of live donor organ transplantation probably will not be finalized for many more years. The ultimate verdict is apt to be harsh if genuinely effective alternative methods of treating organ failure such as, artificial organs, xenotransplantation, or stem cell-based strategies are developed. For the time being, however, live organ donation is an ethical fait accompli, including at the Universities of Colorado and Pittsburgh, for precisely the reason given by Rapaport. Because of the decreasing availability of deceased donor kidneys, live kidney donation has increased in Pittsburgh over the last 15 years to about the same extent

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as that nationally. Moreover, the trail blazed by live donation of the kidney has expanded in selected centers throughout the world to all of the other transplantable organs except the heart. Living donation of organs other than the kidney was mentioned only once in the 1986 Helsinki debate, and then with the unchallenged expression of hope that … more complex donor operations such as partial pancreas removal or removal of portions of the liver for transplantation will not be extensively carried out in living volunteers since here the risk to the donor will be even greater (9).

The increased risk is best exemplified by the worldwide experience with live-donor liver transplantation (LDLT). Support for LDLT in the United States and Europe was built on the socio-ethical base constructed by regulatory and oversight committees at the University of Chicago, where discussions were initiated at the urging of the surgeon, Christopher Broelsch (10). The first cases of the Chicago LDLT series were reported to the American Surgical Association in 1990 with a generally benign discussion from the floor (11). From the beginning, however, it was estimated that the mortality with these procedures would be approximately one in every 200–250 cases. Based on the world’s known experience of nearly 6000 LDLTs, the prophecy has proved to be accurate, or possibly even an underestimate because some deaths have not been reported and very few have been described in detail (12). Nevertheless, it is clear that the mortality rate to date has been 10 or 15 times greater than that of kidney donation. Most of these losses attracted minimal public attention. However, some set off a frenzy of media attention and subsequent recriminations directed at specific institutions and individuals. Recognizing that these incidents had brought LDLT to the brink of peer- and/or societalimposed abandonment, liver transplant surgeons and hepatologists have taken determined steps to assure complete reporting of such cases to an audited registry of donor as well as recipient outcomes. It is hoped that analyses of these data will provide answers about risks and also clarify important unresolved issues (e.g., what are the relative merits of the right- and leftliver lobe operations?). Moreover, at meetings of registry participants such as the summit conference convened in Vancouver, Canada, on September 15th–16th, 2006, measures to increase donor safety could be discussed in a collegial and nonjudgmental manner. The procedure with the highest mortality has been removal of the right lobe. In contrast to the multicenter case collection, right lobe donation has been safe and effective in single-center or single-surgeon series. For example, between 1998 and date, one of the authors, Amadeo Marcos (AM), performed 307 live donor liver operations at three successive university centers (Commonwealth University of Virginia, University of Rochester, and the University of Pittsburgh). In 289 (94%) of the cases, the right lobe was used. The incidence of early or late donor death, hepatic failure, or aborted operation was zero. This experience is described in Chapter 16. Here, we are concerned, first, with the influence on donor safety of recipient case selection; and second, with the ethical ramifications of the donor and recipient screening policies. The donors in the single-surgeon series described in Chapter 16 were surrounded from the beginning with a highly protective ring against coercion, emotional damage, and technical or management errors. Unlike the diffusion of donor responsibility that took place 30 years ago in kidney transplantation, all liver donors in our program must be worked up and cared for at our transplant center. As the personal experience and that acquired in other LDLT centers was compiled, layers of security were added: for example, a pretransplant liver-needle biopsy has been an obligatory condition for donation. In addition, a constant element throughout the acquisition of this experience was the exclusion from LDLT candidacy of recipients whose chronic end-stage hepatic failure was unstable and of patients who had fulminant hepatic failure. We believe that this restrictive policy is a key factor in avoidance of live donor mishaps. The urgency of donor work up for a recipient who is unstable may lead to errors of commission or omission. Urgent circumstances also can result in the performance of a futile donor operation, as has been exemplified by the experience reported by Broelsch et al., (13) from Essen, Germany. In the German experience, four recipients died intraoperatively after the donor operation had reached the stage of liver division into right and left lobes including transaction of the hilar

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ducts (“hepar divisum”). Although the right lobes could be left in place after biliary reconstruction (two duct-to-duct, two hepaticojejunostomy), three of the four donors had significant early complications from the right lobe, and one of the three had a bout of septic cholangitis at 43 months that was relieved by dilatation of an anastomotic stricture. Because unstable recipient disease can convert a meticulously-planned donor operation into a shamble, our opinion is that volunteer liver donation is an operation that should be used electively to treat patients who are not terminally ill. It could be argued that this policy is based on a medical–ethical syllogism. Even though their life may be miserable, most patients with stable end-stage liver disease have a survival prognosis of many months or even years. Therefore, it can be argued that the preferential target population for an organ allograft should theoretically be the one in which early deaths are most likely. This is, in fact, the basis for the UNOS deceased donor liver allocation system with which we are in unequivocal agreement. However, LDLT requires a very different set of decisions across the full spectrum of health care stakeholders because it involves a double relationship for the doctor: with the donor as well as that with the recipient. Elective LDLT to a nonurgent recipient ostensibly is at odds with the “sickest first” philosophy behind the UNOS deceased donor liver allocation policy, but it is consistent with two higher priorities. First, it improves the safety of donor care as described above. Second, it meets the standard of long-term holistic health and welfare benefit for the donor with which live donor kidney transplantation was justified in the 1960s (see earlier). It is well known that grave illness is the single most negative recipient survival factor with liver transplantation. There is no way to assess the despair caused by a futile LDLT, or for that matter, by a failed live organ donation of any kind. Avoidance of this disillusioning outcome begins with recipient case selection. As discussed earlier, Rapaport considered the benefits of a successful live organ donation in a larger context than that of the welfare of a specific donor and of a specific recipient. He envisioned the looming nightmare of a half-million patients waiting on dialysis. Because chronic artificial-liver support technology does not exist, waiting lists of liver transplant candidates inevitably will be kept small in the foreseeable future by “deaths while waiting.” However, from Rapaport’s “group ethics” viewpoint, the domino benefits of LDLT could relieve the overall liver graft shortage, prevent slippage of liver transplant candidates from elective into the grave disease categories, and assure a higher rate of return of recipients to a genuinely functional role in society. A WILD CARD: PRETRANSPLANT IMMUNE MODULATION Until recently, much of the progress in organ transplantation has depended on the development of increasingly potent immunosuppressants. Following the discovery in 1992 of donor leukocyte microchimerism in long surviving kidney, liver, and other kinds of human organ recipients (14,15), the leukocyte-chimerism-associated mechanisms were elucidated that directly linked organ and bone marrow cell engraftment, and eventually clarified the meaning of acquired transplantation tolerance (16,17). The resulting paradigm shift mandated revisions of many cherished dogmas, revealing how immunosuppression could be better timed and dosed, and suggested ways to effectively prepare recipients for organ transplantation by exposing them to donor leukocytes prior to arrival of the organ graft. The foregoing insight was not fully developed until almost two decades after the 1986 Congress of the Transplantation Society. However, both participants in the Helsinki debate recognized that there would be sufficient time for the pretransplant recipient immunomodulation only under the circumstances of live donor transplantation. Consequently, both men emphasized that the incentive for live donor organ transplantation would be ratcheted up once the principles of effective immunosuppression-aided tolerance induction were delineated and exploited. The objective of efficient tolerance induction was ultimately accomplished in 2005 in patients undergoing LDLT with a protocol that can be generalized for transplantation of all kinds of organs. Immunosuppression is begun three weeks before organ transplantation, followed by an infusion of precursor and stem cell-enriched donor leukocytes. The organ transplantation subsequently is carried out in a patient who already is well on the way to a donorspecific tolerant state.

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Preliminary results of the first five cases of LDLT were presented by one of us (AM) at an international conference in Pittsburgh, Pennsylvania, on March 11, 2006. The follow-ups are still too short to know whether this precise protocol is a definitive end to the search for the Holy Grail of organ tolerance or is only another step toward this objective. However, it is already clear that a high degree of at least partial tolerance can be reliably produced. This has opened a horizon for the more efficient use of the most precious resource of all, namely the allograft taken from a live volunteer donor. To avoid tragedies involving live donors, no matter of what organ, it will be necessary to heed those technical, management, and ethical lessons about live donation that have been learned in the past from bitter experience. A gold rush is gratifying only if the gold is not sullied. REFERENCES 1. Michon L, Hamburger J, Oeconomos N, et al. Une tentative de transplantation renale chez l’homme. Aspects Medicaux et Biologiques. Presse Med 1953; 61:1419–1423. 2. Kuss R, Teinturier J, Milliez P. Quelques essais de greffe rein chez l’homme. Mem Acad Chir 1951; 77:755–764. 3. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins. JAMA 1956; 160:277–282. 4. Starzl TE. History of Clinical Transplantation. World J Surg 2000; 24:759–782. 5. Wolstenholme, GEW, O’Connor M, eds. Ethics in Medical Progress: with Special Reference to Transplantation. Boston: Little, Brown, and Co., 1966: 1–249. 6. Elkinton JR, Huth EJ, eds. The changing mores of biomedical research. A colloquium on ethical dilemmas from medical advances. Ann Intern Med 1967; 67(suppl 7):1–83. 7. Starzl TE. Experience in Renal Transplantation. Philadelphia: WB Saunders Company, 1964. 8. Rapaport FT. Pro: Living donor kidney transplantation. Transplant Proc 1987; 19:174–175. 9. Starzl TE. Con: Living donors. Transplant Proc 1987; 19:174–175. 10. Singer PA, Siegler M, Whitington PF, et al. Ethics of liver transplantation with living donors. New Engl J Med 1989; 321:620–622. 11. Broelsch CE, Emond JC, Whitington PF, Thistlethwaite JR, Baker AL, Lichtor JL. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg 1990; 212:368–377. 12. Middleton PF, Duffield M, Lynch SV, et al. Living Donor Liver Transplantation—Adult Donor Outcomes: A Systematic Review. Liver Transpl 2006; 12:24–30. 13. Nadalin S, Malagó M, Testa G, et al. Hepar divisum” As a rare donor complication after intraoperative mortality of the recipient of an intended living donor liver transplantation. Liver Transpl 2006; 12:428–434. 14. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339:1579–1582. 15. Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology 1993; 17(6):1127–1152. 16. Starzl TE, Zinkernagel R. Antigen localization and migration in immunity and tolerance. New Engl J Med 1998; 339:1905–1913. 17. Starzl TE, Zinkernagel R. Transplantation tolerance from a historical perspective. NATURE Reviews: Immunology 2001; 1:233–239.

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Psychosocial Aspects of Living Organ Donation Mary Amanda Dew Departments of Psychiatry, Psychology, and Epidemiology, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Galen E. Switzer Departments of Psychiatry and Medicine, University of Pittsburgh School of Medicine and Medical Center, and Veterans Administration Center for Health Equity Research and Promotion, Pittsburgh, Pennsylvania, U.S.A.

Andrea F. DiMartini Departments of Psychiatry and Surgery, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Larissa Myaskovsky Departments of Medicine and Psychiatry, University of Pittsburgh School of Medicine and Medical Center, and Veterans Administration Center for Health Equity Research and Promotion, Pittsburgh, Pennsylvania, U.S.A.

Megan Crowley-Matoka Departments of Medicine and Anthropology, University of Pittsburgh School of Medicine and Medical Center, and Veterans Administration Center for Health Equity Research and Promotion, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Optimizing the psychosocial status and well-being of donors, both before and after transplantation, is among the foremost goals of transplant centers that have living-organ donation programs for kidney, liver, lung, intestine, and/or pancreas transplantation. The psychosocial issues that are of greatest concern in the context of living organ donation (for example, prevention of psychological harm, ensuring that donors are fully informed and that they decide to donate without coercion, and monitoring donor psychosocial outcomes) are intimately linked to the factors that historically served as barriers to use of organs from living donors. These barriers include an understandable aversion to the prospect of injuring one person (the potential donor) in order to save the life of another (the recipient); concern about the potential donor’s motives and whether such an act of apparent altruism might reflect a lack of psychological stability; worry that potential donors may be unable to give truly informed consent or are coerced into donating; and apprehension about long-term, as-yet unidentified post-donation complications (1–7). These long-time barriers to widespread use of living organ donation, and the resulting desire of transplant professionals to ensure that undesirable risks to donors are minimized, have led to a major focus in most transplant programs on extensive predonation psychosocial evaluation of potential donors, as well as a growing research literature on post-donation psychosocial costs and benefits to living organ donors. This chapter reviews the predonation evaluation issues that are critical when considering the psychosocial eligibility of potential donors, as well as the post-donation data on donor psychosocial outcomes. (See other chapters in this text for discussions of ethical issues in living donor evaluation, financial issues, and medical outcomes in living donors.) Before addressing the central psychosocial issues, we provide a brief overview of the broad social and psychological context in which the donation of living organs takes place, considering both the key elements of the unique gift-giving relationship between the donor and recipient, and the nature of the medical altruism that allows this relationship to develop.

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THE CONTEXT OF DONATION: THE GIFT RELATIONSHIP AND THE NATURE OF MEDICAL ALTRUISM Given the historical barriers to living organ donation, it is legitimate to ask whether there are indeed any circumstances in which it is truly appropriate to ask an individual to donate a body part to another person. In large part, the fact that growing numbers of transplant centers have living donation programs has stemmed from the recognition that the risks to donors—linked to the historical barriers noted above—must be not only minimized but carefully balanced against other compelling needs for living organ donation. These needs include, first, the escalating demand for organs to save lives that would otherwise be lost because of an increasingly inadequate deceased donor organ supply (8). In addition, there are often medical advantages to the recipient of a living donor (as opposed to deceased donor) transplant (9–13). Finally, it is critical to recognize that competent potential donors should have the right to consider and decide to offer a gift of life to another human being (4,5,12). In other words, the decision and the right to donate cannot be based solely on transplant teams’ views about whether a living donation should take place: it is increasingly viewed as unduly paternalistic for transplant teams to judge that they alone know best (i.e., better than the potential donor) about whether the donor should donate. Even when the best possible balance of risks and benefits is achieved [“equipoise” (14,15)], living organ donation entails significant sacrifice on the part of the donor. It is a unique and important form of gift giving. There are features of organ donation that distinguish it from other types of gift giving, including no expectation of reciprocity and the unparalleled consequences of the gift to prolong life (16,17). Donors undergo significant discomfort, inconvenience, and physical risk to provide such gifts, suggesting potentially unique psychological issues surrounding the decision to donate, and unique factors that impact on donors’ postdonation physical and psychological experiences. Most important, it is critical to bear in mind that the context of donation is one of a relationship: regardless of whether the donor and recipient are biologically or emotionally connected; and even in the case of anonymous, nondirected donation, the donation itself does not occur in a vacuum. Instead, as illustrated in Figure 1, it occurs in a context in which both the donor and the recipient bring their own concerns, hopes, and expectations. The act of donation itself forms a permanent connection, even if donor and recipient never meet, and there are both costs and benefits to having engaged in this interchange. These costs and benefits encompass quality of life (QOL) and related psychosocial outcomes for both parties. In addition, for the donor, there may be psychological consequences including, for example, gaining a sense of “mattering” or feeling that one has done something important to help a fellow human being. For the recipient, sheer survival as well as QOL may be at stake. A key source of concern about the entry of the potential living donor into this gift-giving relationship is the set of motives that the donor brings. Indeed, a large literature has been devoted

The donor

The recipient

Motives, expectations

Hopes, expectations

The gift relationship Costs and benefits of engaging in this interchange Quality of life, “mattering”

Survival, quality of life

FIGURE 1 The context of donation: the gift relationship in living organ donation.

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not only to examining this special case of medical altruism, but also to understanding the act of helping another individual (with limited or no benefit to oneself) in a variety of contexts. Altruistic behavior—and medical altruism in particular—has been defined as including several components: it (i) seeks to improve another’s welfare without conscious regard for one’s selfinterest, (ii) is voluntary, (iii) is intentional, that is, engaged in with the specific goal of helping someone else, and (iv) is done without expectation of external reward (18–20). Altruistic behavior that appears to exemplify these qualities is not uncommon in humans, but it appears to be “a spectacular outlier in the animal world” (21, p. 784). As a result, considerable energy in the fields of evolutionary biology and neurobiology, economics, developmental psychology, social psychology, and sociology has been devoted to studying when and why people help others. Theories have been offered that explain altruism in terms of humans’ need for genetic preservation, physiological rewards achieved through activation of neural circuits during help-giving, developmental mechanisms related to temperament and family upbringing, societal motivations related to social norms and role identity as an altruist, and social psychological hypotheses regarding the circumstances that promote or inhibit altruistic behavior (18,19,21–23). A noteworthy debate has concerned whether gift-giving behavior, including organ donation, is truly altruistic [i.e., driven by selfless compassion and care for others (18)], or is driven largely by self-serving motives. For example, it has been argued that almost all ostensible altruism hides egoistic and self-serving motives, even if the aim is only to increase one’s happiness or relieve one’s own negative emotional state (24,25). This debate is important because it mirrors a concern among many transplant professionals that the potential donors’ motives for donating must be completely examined, and that evidence that self-serving motives are present may be an unfavorable sign. However, it is likely most living donors’ motives reflect a complex interweaving of selfless and self-serving desires. This is illustrated by the following quotes from living donors: Kidney donor: “Hey! I feel wonderful seeing Mom walk around and doing so much. I know I really did something for somebody, and I feel good about it” (20, p. 5). Kidney donor: “I had no choice [about whether to donate]; if I didn’t give my kidney, the patient would have died, and I couldn’t have lived with myself” (26, p. 246). Liver donor: “It’s simple . . . I’m afraid to lose my mother” (27, p. 1511).

We suggest that, as discussed further below, the particular combination and expression of multiple motives in the potential donor is likely to be much more important than the fact that any self-serving desires are present. In short, theories of altruism and the goal of understanding the nature of medical altruism provide the underpinnings for many current clinical and research imperatives focused on the predonation evaluation of donors’ psychosocial status. Predonation Psychosocial Issues and the Psychosocial Evaluation of Potential Donors In this section, we review (i) empirical data on the nature and range of living donors’ professed motives for donation, (ii) studies showing the predominant ways in which donors arrive at the decision to donate, (iii) data on donors’ psychological status and its relationship to their fitness as donors, and (iv) what the findings from these areas suggest for what should be routinely included in the psychosocial evaluation of potential donors. With respect to the latter, we provide a summary and guidelines for the essential components of the predonation psychosocial assessment. In reviewing existing data on donor motives, decision-making, and psychological status, we draw on research not only on living organ donors but also on bone marrow donors for several reasons. First, much of the recent research literature on medical altruism has focused on bone marrow donors, and many of the issues concerning psychosocial and psychological costs and benefits of donation are quite similar to those for living solid organ donors (28). Second, from an historical perspective, the early work on psychosocial issues in living kidney donors in the 1960s and 1970s led directly to the research on altruism in bone marrow donors, which itself proliferated during the years in which living kidney donation declined in favor of deceased donor donation. As living organ donation rates have increased in the past 10 years, the work on

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psychosocial issues in bone marrow donors has, in turn, contributed to our understanding of today’s living organ donors. Donors’ Motives We suggested above that, in most cases, donors are likely to be motivated by a variety of factors. These include both intrinsic factors (e.g., desires to relieve the suffering of another, or to act in accord with religious convictions) and extrinsic factors (e.g., social pressures or perceived norms) that may operate simultaneously. Furthermore, the particular combination of motivational forces will differ depending on whether and how the donor is related to the recipient. In the early years of living organ donation, virtually all donors were genetically related to their recipient, whereas many of today’s living donors are related emotionally but not genetically (e.g., spouses, friends). In kidney donation, for example, only approximately 2% of kidney donors were unrelated (genetically and emotionally) to their recipient in 1994, whereas 21% were unrelated in 2003 (8). In addition, nondirected living donation (NDLD), in which an individual donates an organ to a patient whom the donor did not select and to whom the donor is neither genetically nor emotionally related, is also becoming more prevalent and accepted (29,30). Among living related donors, it has long been assumed that family members or emotional partners are naturally motivated primarily by the prospect of saving the life of a loved one (31). Such motives are indeed the most commonly expressed feelings, as noted in a variety of empirical studies over the past 30 years. For example, in studies conducted during the 1970s, Simmons et al., (32) found that 83% of their sample of living related kidney donors cited “helping to save the recipient’s life” as the primary reason for donating. However, 78% also felt that the donation would make their own lives more worthwhile. In addition, other motives were frequently and simultaneously present, including a desire to donate because of guilt for past actions (25%), fear of future disapproval if the potential donor did not donate (14%), and a desire to acquiesce to either direct or subtle family pressure to donate (43%). Subsequent studies have repeatedly documented similar distributions of key motives, with a desire to help the recipient being most common, but usually present in combination with personal beliefs that the donor will feel like a better person, feelings of moral or religious duty, and external pressure to donate from family, friends, and/or medical personnel (27,33–40). Motives of NDLDs reflect an even greater emphasis on the potential benefits to the recipient and also for the donor, and a lesser role for external pressure to donate (although external pressure not to donate begins to play a role). The first studies of the motives of NDLDs took place in the context of bone marrow donation. In a cohort of 343 of the first donors enrolled in the National Marrow Donor Program, Switzer et al., (41) found that the most common type of motive was “exchange-related” (45%), in which donors emphasized the low costs to themselves and/or the high potential benefits to the recipient (e.g., “I got something freely, and if I can give it back, let’s do it.”). Other commonly reported motive types included “idealized helping” (37%), in which donors indicated helpful attitudes without specific reasons (e.g., “I [wanted] to try to help somebody out, give somebody a chance for a normal life.”). Donors also expressed motives related to moral or social responsibility (26%), or were motivated by the positive feelings that it gave them to donate (25%) (e.g., “From the beginning I felt very privileged I could do this”). Other donors expressed empathy-related motives (18%), in which they had mentally and emotionally placed themselves in the recipient’s position, and motivations related to past life experiences (8%) (e.g., blood donation, or having had an ill relative). Some donors (9%), without giving specific reasons for wanting to donate, expressed incredulity at not volunteering (e.g., “why would anyone not donate?”). In general, the nature and distribution of these motive types is similar to those described for other types of medical and social service volunteers (42–44). Among solid organ NDLDs, recent studies have also found a preponderance of altruistic/humanitarian motives, in combination with beliefs that the donor’s self-worth would be increased, and feelings of moral and religious obligation or identity (45–47). Although pressure from others to donate is not noted in studies of NDLDs’ motives, these donors (and, especially, individuals who decide not to donate) sometimes remark that they faced or acted in opposition to the views of their family or friends (45,48). In sum, the empirical data show that donors are motivated to donate for a variety of psychological and social reasons. There is a high degree of similarity in professed motives

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across related donors and unrelated donors (including NDLDs), with the exception that external pressure regarding the donation operates differently in these two classes of donors. In general, the predominant motives expressed by living donors are similar to those expressed by other types of medical and social volunteers. Donors’ Decision Making Donors’ motives contribute directly to their decisions to donate, but the process by which living donors reach those decisions is not uniform and is influenced by factors such as their relationship to the recipient. Understanding the decision-making process is important because of its potential to lead to the development of better donor educational techniques and, in turn, more positive postdonation outcomes. In addition, it can help to educate transplant teams to have more accurate expectations about whether certain donor decision-making styles play any role in donors’ ultimate reactions to the donation experience. Most studies of donor decision-making have focused on the rapidity with which individuals decided to become potential donors. Decision-making swiftness may indicate the type of decision being made. There appear to be two dominant decision-making approaches that capture the strategies used by most living donors to make their decisions. Simmons et al., (32) described them as “moral” versus “rational” decision making. Moral decision-making involves awareness that one’s actions can affect another, ascription of responsibility to oneself, acceptance of the social/moral norm governing the behavior, and taking action consistent with that norm (32). Because moral decision-making does not involve weighing the costs and benefits of a given behavior, but is based on perceived norms governing that behavior, it is likely to lead to nondeliberative, instantaneous decisions (32). In contrast, rational decision-making includes multiple steps that focus on gathering relevant information, evaluating alternatives, selecting an alternative, and implementing the decision. Under this strategy, the decision-making process involves deliberation and therefore will not be swift. Overwhelmingly, the empirical data on living donors’ decision-making yields support for “moral,” nondeliberative, instantaneous decision-making. This is especially the case for biologically and/or emotionally related donors. Thus, even in the earliest studies, practically all donors were found to have made voluntary and immediate decisions characteristic of moral decision-making (49–51). Simmons et al., (32) found that, in response to the question “when did you first consider donating,” 88% of living related kidney donors endorsed the response, “as soon as I found out about the need.” In addition, 78% indicated that they “knew right away that they would donate,” whereas only 22% said that they had needed to “think it over first.” More recent studies continue to mirror this pattern (33,35,39,52–57). For example, qualitative interviews with living-liver lobe donors show that not only was decision-making spontaneous in almost all cases, but the donors themselves specifically commented on the fact that they did not stop to consider and weigh elements of the decision [e.g., “(the decision) was nothing we really talked about. We never said, well here are the pros and cons to this;” “I think I was on automatic pilot . . . It happened, it happened fast, and we did it” (53, p. 745)]. It is noteworthy that the vast majority of studies finding a predominance of the spontaneous “moral” decision-making pattern were conducted in the United States or Western European countries. In one study in which qualitative interviews were conducted with 14 living kidney donors in Korea (all of whom were genetically or emotionally related to the recipient), a majority reported that their decisions involved deliberation and were heavily influenced by what they perceived as family obligations (58). Similarly, ethnographic research in Mexico found that living kidney donors in that setting also often arrived at the decision to donate as a result of careful consideration of the overall risks and benefits to the family as a whole (59). Additional research is clearly needed to determine the extent to which decision-making processes are influenced by culture and any effect that this may have on postdonation outcomes (60). One limitation of almost all studies in this area is that by the time individuals are questioned about the process by which they reached their decisions to donate (or not to donate), they have already arrived at a decision. Therefore, memory biases may lead them to see their decisions, in retrospect, as spontaneous. Although such a conclusion is belied by the Korean living donor findings (58), there are no prospective studies to date that have directly compared decisionmaking in individuals who ultimately became donors with nondonors (cf. Borgida et al. (61).

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Dew et al.

However, Simmons et al., (32) did at least retrospectively compare donors and nondonors based on extensive qualitative interviews, and found marked differences in their decision-making processes: 68% of donors were classified as following a moral, instantaneous decision-making pattern, whereas only 21% of potential kidney donors who ultimately decided not to donate followed this model. The decision-making studies discussed thus far pertain to living-related donors. Little information is available on unrelated donors. Work in unrelated, anonymous bone marrow donors suggests that the decision to donate occurs well before an individual is actually asked to donate for a specific patient. For example, Switzer et al., (62) asked unrelated donors shortly before the marrow donation when they decided that they would definitely go through with donation; 60% stated that it was either when they first learned of the national need for bone marrow donors or when they joined the National Marrow Donor Program registry. Another 23% decided when they first learned that they were a preliminary match for a specific patient. Only 17% continued to weigh the decision even after they had been found to be a preliminary match. In sum, despite the limitations in research to date, empirical findings strongly support a spontaneous rather than deliberative decision process in most living donors. This approach to making decisions is often of concern to transplant professionals, who want to ensure that potential donors have carefully (and perforce deliberately) weighed the risks and benefits of the donation and can therefore give appropriately informed consent. Yet it is important to realize that rapid decision-making does not mean that donors necessarily fail to understand the risks and benefits or other issues involved. Moreover, as we discuss further below, deliberative decision-making has been found linked to other factors (e.g., ambivalence about the donation) that are themselves strongly associated with poorer postdonation psychosocial outcomes. Psychological Status of Potential Donors Potential donors’ psychological stability has been one of the areas of greatest concern for transplant programs that allow living donation. Concerns have been particularly high in the context of unrelated donation (either directed to a specific patient, or NDLD): the willingness or desire to donate to a stranger has been historically viewed with marked suspicion and as likely to reflect significant psychopathology (4,31,63,64). However, public opinion surveys conducted in the United States and elsewhere indicate that attitudes toward nondirected living donation are much more favorable than the transplant community had previously anticipated, and that substantial proportions of even apparently “ordinary” community residents are willing to entertain the possibility of donating to a stranger (31,57,65–68). A growing number of studies that have examined the psychiatric status of potential donors (both related and unrelated) also suggest that the great majority of individuals who come forward as potential donors do not suffer from mental illness (35,45,47,64,69–72). In the largest systematic study to date on this issue, Olbrisch et al., (73) reported on 139 potential liver donors who underwent complete psychiatric and psychosocial evaluations. Of these, 77 were genetically related to the patient who needed the transplant (80% of these related potential donors were siblings or adult children), and 62 were genetically unrelated (of whom 18% were “Good Samaritans” (74), that is, strangers who heard that the patient needed an organ and came forward as a potential donor). As shown in the left panel of Figure 2, the 139 candidate donors showed no differences in their distribution of lifetime rates of psychiatric or substance use disorders from rates found in the larger U.S. population (75). Interestingly, the right panel in Figure 2 shows that unrelated candidate donors were significantly less likely than related donor candidates to have a lifetime history of psychiatric disorder. In addition, unrelated donors showed significantly greater evidence of psychosocial stability (they were more likely to be married or have a significant other), and they were more likely to have a history of volunteerism. Unrelated and related donors did not differ significantly in lifetime rates of any substance use disorders (data not shown). In this cohort of 139 candidate donors, six (4%) were ultimately not recommended to serve as donors, and 23 (17%) were recommended with caution. Psychopathology or substance use were the most common reasons for caution or lack of a recommendation. The remaining 110 individuals (79%) were recommended without reservation as suitable living donors.

13

Psychosocial Aspects of Living Organ Donation

Percentage

Liver donor candidates

U.S. norm75

Related donor candidate

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

An yp

sy c

Ad MD j us D/D oho tme yst l-re hia nt d hym l a ted tric iso ia dia dia rde gn o gno r si s sis Alc

Lifetime psychiatric disorder in candidate donors versus U.S. rates (no significant group differences; Adjustment Disorder assessed only in donors.)

FIGURE 2

0

An yp sy

ch iat ric

Unrelated donor candidate

Lif Ma elo rrie ng d* vo l un tee dia r* gn os is*

Psychiatric and psychosocial status in related versus unrelated candidate donors (*p < .05 between groups)

Psychiatric and psychosocial status in 139 candidate liver donors. Source: From Ref. 73.

There is no doubt that some potential donors will be psychologically poor candidates to serve as donors, and anecdotal examples have been described in the popular press and in commentaries on this topic (7,76,77). As we discuss below, there is also uniform recognition of the fact that an assessment of the psychiatric status of potential donors should be an important component of their general predonation psychosocial evaluation. But it is important to keep psychiatric issues in perspective: empirical evidence on the rates of psychiatric disorders in potential donors provides no indication that the pool of potential donors (either related or unrelated) shows unduly high levels of psychopathology. This should reassure any members of the medical community who remain suspicious of all potential donors’ psychological stability. Psychosocial Evaluation of Potential Living Donors It is widely agreed, and now mandated by a variety of transplant-related organizations, that living donors (both related and unrelated; among unrelated, both directed and nondirected) receive careful psychosocial evaluation before final decisions are made by the transplant team to proceed with donation (78–81). General guidelines for the nature and content of the psychosocial evaluation have been offered by both individual transplant professionals working in the field (7,14,45,69,74,81–85) and by conferences and workgroups organized to focus on both the medical and psychosocial care of the living organ donor (29,79,80). Yet there remain no widely adopted standards for the exact procedures or content of the psychosocial evaluation. A recent survey of programs in the United States that facilitate NDLDs found that some centers do not yet use a systematic approach to the psychosocial evaluation of potential donors (30). Content of the Psychosocial Evaluation

Table 1 lists seven components of psychosocial status and functioning that are relevant when individuals are considering becoming (and being considered as) organ donors. We have already discussed issues and empirical data related to potential donors’ motivations. Here, we note that it is particularly important to ascertain whether candidate donors appear to be ambivalent about whether to proceed with the donation (which can often be detected when donors report that they deliberated extensively about whether to come forward or that they continue to deliberate about the decision to donate). High levels of ambivalence predict poorer postdonation psychosocial outcomes, as discussed later in this chapter. Additional issues to be considered under the component of motivation assessment include whether and the extent to which family

14 TABLE 1

Dew et al.

Core Components of Predonation Psychosocial Evaluation of Living Organ Donors

Component Motivation for donation Relationship between donor and recipient Attitudes of significant others toward the donation Knowledge about the surgery and recovery Work- and/or school-related issues Mental health history and current status

Psychosocial history and current status

Areas addressed Reasons for donation; how decision to donate was made; evidence of coercion/inducement; expectations; ambivalence about donation Nature of relationship (biological, emotional, unrelated directed, or unrelated nondirected); if related, quality of the relationship Support, pressure, and/or opposition by family, friends; availability of emotional and practical assistance during recovery Understanding of risks of surgery, possible complications, expected recovery and recuperation time; understanding of basic insurance issues Arrangements made with employer or school; financial resources Psychiatric disorders (mood disorders, anxiety disorders, psychosis, suicidal ideation and/or attempts); personality disorders; substance use history (symptoms of abuse and/or dependence; quantity and frequency of current use of alcohol and other substances); cognitive ability, and competence and capability to make informed decisions Marital status and relationship stability, living arrangements; religious beliefs and orientation; community or religious activities; concurrent stressors (work-related, home-related, other); strategies used to cope with health-related and other life stressors

pressure was exerted for the living related donor to come forward. The nature of the related donor’s relationship to the recipient must be carefully examined, including identification of the strengths as well as past conflicts or difficulties in this relationship. Financial ties between the related donor and recipient should also be discussed in order to identify any potential problems or areas that could be affected by the donation. For NDLDs, it is important to determine that these individuals are not seeking or anticipating that they will receive any financial benefits, publicity, or other public recognition from the donation. They must also understand that they will donate for the benefit of any transplant candidate on the wait list; they may not in any way designate the recipient. A related area to evaluate concerns donors’ perceptions of their families’ and/or friends’ opinions about the donation and whether donors feel that they have the support of these individuals. Donors’ knowledge and understanding of the donation process, including the actual surgery and its consequences for their own health, must be explored in order to determine whether their views are realistic and accurate, and whether they may need additional education. For NDLDs, it is important that they understand what information, if any, they will be given regarding recipient health outcomes in the short- and long-term after the donation. Consideration of the practical arrangements that donors plan to make for missed work, school, or other responsibilities will also help to gauge their understanding of the potential consequences of the surgery and their preparation for it. In particular, it is important to identify any major financial hardships that could arise from the donation and what plans donors will have in place to address financial issues (see Chapter 33 on financial issues). We have already emphasized the importance of a careful evaluation of potential donors’ mental health history and current status. It is critical to ascertain that current psychiatric conditions, if any, are well-managed and are unlikely to be exacerbated by donation, and that there is a low risk that the donation will provoke a recurrence of past disorders (83). Assessment of substance use disorders and determination of stable abstinence is important because recurrence of these disorders could directly harm the donor’s long-term health (e.g., alcohol abuse in the case of the liver donor and use of nicotine in the case of lung donors). It is important to determine that potential donors harbor no expectations that the donation experience will remedy any psychological malady, such as depression (14). Potential donors’ psychological and cognitive competence, determined by the psychiatric assessment (and additional cognitive testing if needed) is ultimately critical for donors’ ability to make informed decisions and provide informed consent. Finally, general consideration is needed for other elements of potential donors’ psychosocial background, including current marital status, stability of living arrangements, whether the

Psychosocial Aspects of Living Organ Donation

15

donation is consistent with donors’ religious beliefs, and their styles of coping with physical and emotional stressors. With regard to religious beliefs, it has been noted that evaluators must take care not to inappropriately “pathologize” desires to donate on the basis of religious altruism (86). With respect to donors’ coping styles, sensitive questioning about strategies and levels of adherence to health care recommendations for any previous medical problems can provide insight into donors’ willingness to follow medical recommendations during the donation process. Use of Information Collected in the Psychosocial Evaluation

In many ways, the depth, value, and purpose of the complete psychosocial evaluation of donors are analogous to those of the similarly extensive evaluation of candidates to receive organ transplants. In both situations, the ultimate goals are to ensure that the individuals are psychologically and psychosocially likely to come through the transplant experience well, and to have fewer long-term costs (if any) than benefits. In the context of candidates for organ transplantation, we have argued strongly that the psychosocial evaluation should be used not necessarily to rule out someone as an organ recipient (87,88). For the donor, we also argue that it should not be used primarily as a “veto” tool. Instead, it should be used to identify areas in which interventions might be offered that could enhance potential donors’ well-being and hence their ability and suitability to serve as donors. Our position is consistent with other recommendations regarding the role of the donor psychosocial evaluation (79). This suggests, then, that the psychosocial evaluation itself should be considered to be a process rather than a one-time event. The corollary to this view is that there may be few permanent, absolute contraindications to donation. Rather, just as for organ recipient candidates, (i) there will exist relative contraindications that vary on a case-by-case basis, and (ii) a factor that serves as an absolute contraindication at one point in time may be removed as a concern at a subsequent time. An example of a relative contraindication arose in one U.S. living liver-donor program, in which a parent with symptomatic bipolar disorder (that was at best partially managed by medication) wanted to donate. The parent was the only available match for the child. The child was mortally ill and not expected to survive without an immediate transplant. Symptomatic bipolar disorder would, under most circumstances, be considered an exclusionary criterion in a potential donor. However, after formal assessment, the transplant team judged that the risks of surgery to the psychiatric stability of the parent were lower than the psychological suffering that would be experienced by the parent if the donation was not allowed and the child then died. The donation thus took place. An example of a situation that would be an absolute contraindication to living organ donation at one time, but that could be addressed and modified through intervention would be a potential donor with active substance abuse (e.g., alcohol or illicit drugs). If the candidate donor participated in rehabilitation and maintained abstinence as required by the transplant team, a psychosocial re-evaluation could indicate that it was reasonable to then proceed toward donation. Procedures for Collecting Living Donor Psychosocial Information

Living donor programs must attend not only to the content of the psychosocial evaluation but procedural issues related to when the evaluation will be completed during the overall medical work-up of potential donors, and who will conduct it. We suggest that the multistep procedure already in place in some programs (especially those for NDLDs (69,70)) be followed: an initial, brief telephone interview can be conducted (usually by a transplant coordinator) to ascertain the reasons why the potential donor wishes to donate, the donor’s understanding of the patient’s situation, whether the donor has insurance coverage, and whether there appears to be significant risk of financial hardship for the donor due to the donation. Next, an information packet is mailed to the potential donor to provide a broad orientation to the donation process. This is followed by scheduling an appointment for the potential donor at the center in order to collect basic medical history, and have a more complete discussion of the reasons for interest in donating, and the risks and benefits of donation. This appointment would involve meeting with a transplant team physician and a transplant coordinator or social worker. The complete medical evaluation and full psychosocial evaluation would then be scheduled and conducted. Because of the sensitive issues involved and the need for an accurate psychiatric assessment, the psychosocial evaluation should be performed by a trained mental health professional

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Dew et al.

(e.g., psychiatrist, psychologist, or clinical social worker). This individual may be a member of the medical team responsible for donor evaluations or an external consultant to the team. Unless the transplant patient is mortality ill and death is imminent, the potential donor should be given a 1- to 2-week “cooling-off period” and then recontacted to ensure that the donor still wishes to donate. Finally, especially in the case of unrelated donation, the review of evaluation materials and the decision to accept the donor (or to defer acceptance until needed psychosocial interventions have been offered and reevaluation can be undertaken) should be made by a transplant team that is separate from the team caring for the recipient. This is critical in order to avoid conflicts of interest with the recipient’s needs and best interests (70,79,82). In completing each step of the complete psychosocial evaluation process, it is important to bear in mind that psychosocial assessments—just as any other medical test or procedure— are not infallible. As Olbrisch et al., (74, p. 44) commented, “the demands of the situation that drive potential living donors to offer themselves may be so powerful as to preclude the possibility of an accurate assessment” by even skilled clinicians. All clinical evaluations create a context in which individuals being evaluated must be concerned with how they are being perceived and how they are describing themselves and their history. These concerns are likely to be heightened among prospective donors. Although less common than such attempts at impression management, deliberate deception (e.g., with the purpose of engaging in organ vending or other financial arrangements) is of great concern as well. Finally, it is to be expected that some potential donors will actively attempt to conceal important information, including past medical or psychiatric problems, out of fear of being rejected as donors. Because of these inherent difficulties in conducting the psychosocial evaluation, it is essential for transplant teams to ensure that they have carefully trained clinicians whose efforts can be dedicated to these assessments. Moreover, treating the psychosocial evaluation as a process (as we suggested above), in which information unfolds across multiple encounters with the potential donors, is also likely to increase the probability that accurate information from potential donors is ultimately obtained. Post-Donation Psychosocial Outcomes Careful psychosocial evaluation before donation can help to ensure that potential donors understand all of the potential consequences of their decisions to donate and that they are competent to make those decisions. It can reassure transplant teams regarding the nature of donors’ motivations and psychological stability. But, as Elliott (1, p. 93) has argued, these are not “the most worrying part[s] of living organ donation … The worrying part is the chance of harm to a healthy donor …” Indeed, because postdonation health and psychosocial outcomes are critical to the balancing of potential risks and benefits of living organ donation, a growing research literature has sought to carefully document the full range of potential consequences to the donor in both the short- and long-term after the transplant surgery. Evidence regarding medical complications and consequences is discussed elsewhere in this text. Here, we focus on empirical findings on psychosocial and QOL outcomes. These outcomes can be conceptualized as encompassing donors’ perceived physical well-being, psychological status, social functioning, and global views of QOL (89). In addition to summarizing descriptive information on these outcomes, we review what is known about risk factors and correlates of relatively poorer psychosocial outcomes. Descriptive Information on Psychosocial and QOL Outcomes Between 1966 and 2005, there were at least 42 independent investigations of kidney donors’ psychosocial outcomes (26,33,34,36,38–40,47,49–51,56,57,64,72,81,90–121). Fifteen studies of living liver donors (35,53,55,97,98,122–132), and one report briefly noting QOL outcomes in living lung donors (133) have been published. Studies vary dramatically in sample size from as few as seven to well over 500 donors. Altogether, over 4,800 kidney donors and over 500 liver donors were surveyed across these studies. The vast majority of donors were either genetically or emotionally related to their recipients. Most studies were conducted in North American or Northern European countries, although Japan and Australia are also well represented. Most studies employed retrospective follow-up designs, in which donors were recontacted at some point after the donation. Follow-up periods range from one week to 34 years after

17

Psychosocial Aspects of Living Organ Donation 100

Percentage of respondents

90 80 70 60 50 40 30 20 10 0

1

4

7

Median percentage 3

95

72

10

8

20

No. of studies

12

10

21

7

9

2

11

23

10

5

7

p hi ds ar lh ia p nc hi ly na ns mi Fi tio fa la r o re e se us or po p hi W hs t ns wi tio nt la ie re cip th s e re al or th W wi he t ou ab e d rs rie wo or W th al on i he nat ss al re ic do st ys ce di Ph sin g. lo ion ho at yc on ps d r gh fte Hi a gs in el n fe atio ive on sit d Po rom f te na do ld in ou ga n W a tio na do et gr Re

a

13

each datapoint represents an independent empirical investigation

FIGURE 3

Living kidney donors’ perceptions of the consequences of donation.a

donation, with most in the range of 1 to10 years. There have been only a few investigations using more rigorous prospective designs, in which donors were assessed before donation and then at one or more time points postdonation (32,72,94,97,98,117–119,131,132). Donor assessments have most often involved paper-and-pencil survey questionnaires, although semi-structured psychiatric interviews and more qualitative interviews are also common. Key results from this literature are summarized in Figures 3–6. Figures 3 and 4 show, for kidney and liver donors respectively, a series of nine psychosocial outcomes that have been examined in a relatively large number of investigations. For example, 13 studies of kidney donors (Fig. 3) and four studies of liver donors (Fig. 4) have reported the percentages of donors who came to regret having donated. Among kidney donors, from 0% to 10% have been found to regret their donation, with a median of 3% across all studies. Similarly low percentages are reported across the studies of liver donors. In contrast, a median of 95% of kidney donors (across 12 reports), and 100% of liver donors (across six reports) would still donate if they had it to do over again. Figures 3 and 4 show that large percentages of donors have reported positive feelings about the donation. This reflects a diverse set of responses: studies have asked about donors’ feelings of self-esteem and self-worth, feelings of being a better person for having donated, and feelings that their lives are more worthwhile. In contrast, percentages of respondents who have reported feelings of psychological distress (most commonly depression or anxiety) are relatively low: with the exception of an early report on seven kidney donors that described all of them as experiencing high distress (109), studies show low distress rates that are similar to or lower than those observed in the general population (134). In addition, Figures 3 and 4 show that relatively low percentages of donors feel that their physical health is worse as the result of the donation, or report that they are worried about their health. Regarding family relationships, low percentages of donors report that their relationship with either the recipient or with their spouses or families has been negatively affected. Instead, the majority report that these relationships are unchanged or improved. One area of concern is the percentage of donors who have reported financial hardship as a result of the donation: although it is encouraging that the percentages constitute a minority of donors, it remains unfortunate that across studies, a median of almost one-quarter of donors have reported such difficulties.

18

Dew et al. 100

Percentage of respondents

90 80 70 60 50 40 30 20 10 0

Median percentage 0 No. of studies

4

100

96

7

12

36

4

29

33

6

3

4

2

2

1

3

3

p hi ds ar lh ia p nc hi ly na ns mi Fi tio fa la r re e o se us or po W hs p hi t ns wi tio nt la ie re i p c lth s e re or th ea W wi th ou ab d e rs rie or wo h W n t l o ea ati lh n o ss re ica d ist ys nce .d n Ph si log atio ho n yc d o ps ter f gh a Hi gs in el n fe atio ive on sit d Po m fro nate do ld in ou ga W a n tio na do

et gr Re

a

each datapoint represents an independent empirical investigation

FIGURE 4

Living liver donors’ perceptions of the consequences of donation.a

We noted earlier that the psychological stability of potential donors has been a major concern historically, often coupled with pessimistic predictions about the potential for negative psychological outcomes following donation. Figure 5 displays findings from the only studies to have examined period prevalence rates of diagnosable psychiatric disorders after donation. The rates of diagnosable major depression and anxiety disorders are similar to or even lower than those found in the U.S. population (75), probably as a result of careful evaluation of potential donors before surgery. Nevertheless, several reviews and commentaries (83,84,135) have noted that there have now been three cases of suicide reported in the living donor literature (136,137), and one additional report of attempted suicide (111). In one case, the original authors stated that the suicide was determined by the transplant team to be unrelated to the donation, although they note that details on the suicide were not available (136). The other two suicides and the single attempt have often been described in a context that implies that there was an established relationship to the organ donation experience (84,106,124,135). In fact, however, the published case descriptions show that each person’s interpersonal situation was very complex. It is

50

Percentage

45

US Norm (75)

40

Kidney donor (n=65) (98)

35

Kidney donor (n=48) (72)

30

Liver donor (n=31) (98)

25 20 15 10 5 0

M ajor depression

Anxiety disorder

FIGURE 5 Prevalence of psychiatric disorder during first year post-donation.

19

Psychosocial Aspects of Living Organ Donation 100

Mean

90 80

Kidney donors

70

(7 studies)

60 50 100

Mean

90 80

Liver donors

70

(5 studies)

60 50 Vi

a he al er en in G pa ly di Bo hys -p le nc Ro fu ys Ph

la

lity

So

cl

Solid line indicates M norm for U.S. en t a fu nc em l he general population ot al th Ro

le

lth

FIGURE 6 Living organ donors’ quality of life after donation.

ultimately impossible to determine the role that the donation experience played, if any, in the suicide. It is also important to bear in mind that there is a non-zero base rate of suicide in the general population (138). Thus, even in living donors, there unfortunately will be some probability, albeit very small, that at least some suicides will occur. Clearly, careful psychosocial evaluation before donation can help to minimize this risk. As we discuss later, postdonation follow-up for donors may be needed as well. But it is unlikely that the risk will ever drop to zero. Data on donors’ perceptions of broad domains of QOL are shown in Figure 6, which includes all studies to date that have used the SF-36 survey (139) or its derivatives in examining these areas. On this measure, a higher score in each domain indicates better QOL. Normative data from the general U.S. population (139) are shown in Figure 6 for comparison purposes. In all studies, donors’ perceptions of their physical functioning, psychological well-being, and social well-being were found to be either nonsignificantly different from or significantly better than levels reported in the general population. (One report in liver donors that shows somewhat lower values than the U.S. norms in some domains was based on a small sample of 18 donors in Turkey (120); it is difficult to know whether these differences, although nonsignificant, could be due to cultural differences or whether they could be due to true QOL decrements.) The only published report on living lung donors obtained by the findings on the SF-36 were also similar to normative values (133). In sum, the empirical data strongly indicate that psychosocial and QOL outcomes for donors are good to excellent in a broad range of areas. Most donors do not perceive their health to have been adversely affected by donation; instead, the majority report a variety of personal and interpersonal benefits. The few prospective studies have found the benefits to persist for many years following the donation (32,110,118). As has been amply documented by qualitative reports (32,39,52,64), these benefits seem to accrue in large part because donors were able to offer critical help to a person in need, at what was perceived as little, if any, cost to themselves. Yet, some donors, albeit a minority, do report costs, including psychological distress, worries about their health, and/or financial hardship. Thus, it becomes critical to identify key risk factors for these poorer outcomes so that steps can be taken (either pre- or post-donation) to further reduce their occurrence. Predictors of Living Donor Psychosocial and QOL Outcomes There has been only limited work to date that has attempted to identify robust predictors or correlates of donor psychosocial outcomes. Table 2 summarizes the major findings. The most striking feature about the Table is that the evidence regarding most potential predictors/ correlates is inconsistent: studies appear to find evidence that refutes putative relationships as often as they find evidence that supports them. Thus, donor psychosocial outcomes are not

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TABLE 2 Evidence on Potential Predictors and Correlates of Psychosocial and Quality of Life Outcomes in Living Organ Donors Donor outcome

Factors found to be predictors or correlates of outcome

Factors found to be unrelated to outcome

Regret or would not donate again

Recipient lost graft or died (96,106) Donor physical health complaints or medical complications (96,115) Donor financial hardship (115) Donor was a non-first degree relative (106)

Recipient lost graft or died (53,100,115,116,124,129) Donor physical health complaints or medical complications (99)

Psychological distress and negative reactions

Recipient lost graft or died (27)

Recipient lost graft or died (72,99,103,124) Donor physical health complaints or medical complications (127,131) Mood or psychiatric history before donation (72,97,98,111,131) Poor pre-donation relationship with recipient (131)

Donor physical health complaints or medical complications (72,99) History of mood problems or unhappiness (117,118) Poor pre-donation relationship with recipient, spouse, or family (111,117,118) Ambivalent about donation (117,118) “Black sheep” donora (115,116) Physical complaints or worries about health

Recipient died or lost graft (26) Donor financial hardship (40) Donor medical complications after donation (99)

Recipient died or lost graft (124,129) Donor financial hardship (129) Donor medical complications after donation (127)

Donor was non-first degree relative (93) aSee

text for definition.

clearly related to (i) whether recipients lost their grafts or died, (ii) the occurrence of donor perioperative medical complications, (iii) whether donors had predonation histories of psychiatric disorder, or (iv) the nature of donors’ past relationship with the recipient. Other variables have been examined relative to specific donor outcomes in only one to two investigations each, so conclusions must remain tentative. However, it appears that related donors who are not firstdegree relatives, donors who are more ambivalent prior to the donation, and “black sheep” donors [e.g., who donated in order to compensate for or repair past wrongs, or to restore their position in the family (32)] may be at heightened risk for poorer postdonation psychosocial outcomes. With respect to predonation ambivalence and “black sheep” donors, the fact that Simmons et al., (32) utilized a strong, prospective research design and replicated their findings in multiple samples suggest that these variables may indeed play critical roles in the donation experience. In addition, predonation ambivalence has been found to be a powerful predictor of poorer postdonation outcomes in unrelated bone marrow donors (140). Ambivalence before living organ donation has long been recognized clinically as a poor prognostic sign, and detection of high levels of ambivalence in prospective donors are generally taken to indicate that the donation must either not be undertaken, or must be postponed pending further discussion, education, or counseling (7,74,79,84). The empirical data (32,140) support these clinical decisions. The inconsistent evidence on whether recipient graft loss and/or death affect donor outcomes is also noteworthy because of longstanding views that living donation is unwise because donors could be greatly harmed by such recipient outcomes. However, qualitative studies [see, e.g., (64)] provide additional insight into why recipient graft loss and death may not have the universally negative impact on donors that had been feared. Donors of recipients who die clearly experience bereavement, but they frequently comment that they are grateful that they had the chance to do as much as they could for the recipient. Similar views have been expressed by both related and unrelated bone marrow donors following the death of the recipient (141,142). There remain other important variables that have as yet received little to no attention as potential predictors of donor outcomes. For example, whether donors who are neither genetically nor emotionally related to their recipient (including NDLDs) have similar, better, or worse

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outcomes than related donors is very poorly understood. One recent report on kidney NDLDs noted that “no adverse psychological effects occurred in any of the donors” (47, p. 1113), but provided no further information as to the type or degree of psychosocial follow-up that had been undertaken. Interestingly, a very early report of a case series that included unrelated donors who came forward for particular patients found very positive psychosocial outcomes for these donors: regardless of the transplant recipients’ medical outcomes, donors uniformly felt that their donation had been worthwhile, they had no regrets, and they felt that they had benefited psychologically from the experience (64). Finally, although rarely studied because of marked moral objections and medical and social prohibitions to organ vending in most countries, one study of 100 kidney vendors sheds light on the very negative repercussions of such activity for the donor (143,144). These individuals ultimately experienced financial hardship even greater than that which led them to sell their kidneys, as well as very poor psychological, social, and physical outcomes. The majority reported hate and anger at the recipient after donation, feelings that they had not received what they were promised (either economically or emotionally), and marked distress over a perceived lack of gratitude from the recipient. These findings strongly suggest that the gift relationship and donors’ altruistic motivations provide the bedrock needed to ensure that living organ donation yields a favorable balance of risks to benefits for donors. CONCLUSIONS AND ISSUES FOR THE FUTURE Living organ donation is becoming increasingly prevalent. Despite the lack of uniform protocols to evaluate the psychosocial status and background of potential donors, there is wide recognition that such evaluation is critical in order to ensure that donor outcomes postdonation remain favorable in both the short- and long-term. We suggest that such evaluations continue to move in the direction of comprehensiveness, and that they be viewed as opportunities not so much to rule out potential donors as to enhance individuals’ eventual suitability as donors. Of course, there will be individuals who will be identified during this process as poor candidates to serve as donors, and these individuals need to have a clear understanding of why it is in their best interests that they not donate. The psychosocial evaluation process will help to increase this understanding. Clinical and empirical evidence suggests that these individuals will themselves often be ambivalent about donating, are likely to have deliberated extensively about the donation (rather than reaching a more rapid decision), and may sometimes have psychiatric illnesses that preclude the possibility of donation. Yet, empirical data also show that most individuals who step forward to donate should not be regarded with undue suspicion regarding their motives or psychological stability, and such findings should be reassuring to transplant teams, especially if they are contemplating the development or expansion of living donor programs. With regard to postdonation donor outcomes, studies to date show that there are clearly both psychosocial benefits and costs, although the majority of donors experience the former rather than the latter. Nevertheless, the fact that some individuals do have poorer postdonation outcomes points to the need to incorporate routine psychosocial follow-up into donor medical care after surgery. We suggest that such follow-up involve in-person assessments on several occasions during the first few months after surgery, with either telephone or mailed follow-up questionnaires to be completed annually. This is not currently standard practice at most transplant centers (30,145), although recent United Network for Organ Sharing requirements for the completion of very brief assessments of donor functional status at six and 12 months after donation has been a positive step toward more routine follow-up. Indeed, a common donor complaint has been the lack of postsurgical attention and follow-up care by the transplant program (53,55,93,123). Moreover, the routine collection of psychosocial and QOL follow-up data is critical for improving our understanding as to which factors do and do not predict psychosocial outcomes. Without information concerning the role of such factors, it is not possible to refine predonation evaluations or postdonation care in order to maximize outcomes for all donors, including those at risk for psychosocial problems in one or more areas. A variety of additional issues require clinical and empirical attention in the future. These include the need to document psychosocial outcomes in understudied groups including, for example, lung donors. In addition, there has been little direct comparison of donor psychosocial

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outcomes according to type of donation (e.g., kidney versus liver), type of donor–recipient relationship (e.g., genetic versus emotional; related versus NDLD), or even according to basic demographic characteristics. For example, do older and younger donors differ in their psychosocial outcomes? Are there ethnic group differences? Are there unique concerns that certain subgroups bring to the donation experience that increase their likelihood of better versus poorer outcomes? Findings regarding these issues will, in turn, allow the process by which potential donors are evaluated, educated, and counseled before donation to become more useful and more likely to ensure positive donor psychosocial outcomes. REFERENCES 1. Elliott C. Doing harm: Living organ donors, clinical research and “The Tenth Man.” J Med Ethics 1995; 21(2):91–96. 2. Northup PG, Berg CL. Living donor liver transplantation: The historical and cultural basis of policy decisions and ongoing ethical questions. Health Policy 2005; 7(2):175–185. 3. Rapaport FT. Living donor kidney transplantation. Transplant Proc 1987; 19:169–173. 4. Spital A. Ethical and policy issues in altruistic living and cadaveric organ donations. Clin Transplant 1997; 11(2):77–87. 5. Spital, A. When a stranger offers a kidney: Ethical issues in living organ donation. Am J Kidney Dis 1998; 32(4):676–691. 6. Starzl TE. Living donors: Con. Transplant Proc 1987, 19:174–175. 7. Surman OS, Fukunishi I, Allen T, et al. Live organ donation: Social context, clinical encounter, and the psychology of communication. Psychosomatics 2005; 46:1–6. 8. United Network for Organ Sharing (UNOS) and U.S. Department of Health and Human Services, Health Resources, and Services Administration, Office of Special Programs, Division of Transplantation. 2003 Annual Report of the U.S. Scientific Registry for Transplant Recipients and the Organ Procurement and Transplantation (OPTN). Rockville, Md and Richmond, Va: HHS/HRSA/OSP/DOT and UNOS, 2004. 9. Bowdish ME, Barr ML, Starnes VA. Living lobar transplantation. Chest Surg Clin N Am 2003; 13(3):505–524. 10. Curran C. Adult-to-adult living donor liver transplantation: History, current practice, and implications for the future. Prog Transplant 2005; 15(1):36–42. 11. Fryer J, Angelos P. Is there a role for living donor intestine transplants? Prog Transplant 2004; 14(4):321–329. 12. Levey AS, Hou S, Bush HL. Kidney transplantation from unrelated living donors: Time to reclaim a discarded opportunity. N Engl J Med 1986; 314(14):914–916. 13. Terasaki PI, Cecka JM, Gjertson DW, et al. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995; 333(6):333–336. 14. Delmonico FL, Surman OS. Is this live-organ donor your patient? Transplantation 2003; 76(8): 1257–1260. 15. Ingelfinger JR. Risks and benefits to the living donor. N Engl J Med 2005; 353(5):447–449. 16. Fox RC, Swazey JP. The Courage to Fail: A Social View of Organ Transplants and Dialysis. Chicago, Il: University of Chicago Press, 1974. 17. Titmuss RW. The Gift Relationship: From Human Blood to Social Policy. New York, NY: Vintage Books, 1972. 18. Batson CD. Altruism and prosocial behavior. In: Gilbert DT, Fiske ST, Lindzey G, eds. The Handbook of Social Psychology, 4th ed. Vol. 2. New York, NY: McGraw-Hill, 1998:282–316. 19. Schroeder DA, Penner LA, Dovidio JF et al. The Psychology of Helping and Altruism. New York, NY: McGraw-Hill, 1995. 20. Simmons RG. Presidential address on altruism and sociology. Sociol Quarterly 1991; 32(1):1–22. 21. Fehr E, Rockenbach B. Human altruism: Economic, neural, and evolutionary perspectives. Curr Opin Neurobiol 2004; 14:784–790. 22. Penner LA, Dovidio JF, Piliavin JA, et al. Prosocial behavior: Multilevel perspectives. Ann Rev Psychol 2005; 56:365–392. 23. Stevens JR, Hauser MD. Why be nice? Psychological constraints on the evolution of cooperation. Trends Cogn Sci 2004; 8(2):60–65. 24. Cialdini RB, Schaller M, Houlihan D, et al. Empathy-based helping: Is it selflessly selfishly motivated? J Pers Soc Psychol 1987; 52:749–758. 25. Mansbridge JJ, ed. Beyond Self-Interest. Chicaco, Il: University of Chicago Press, 1990. 26. Eisendrath RM, Guttmann RD, Murray JE. Psychologic considerations in the selection of kidney transplant donors. Surg Gynecol Obstet 1969; 129(2):243–248. 27. Papachristou C, Walter M, Dietrich K, et al. Motivation for living-donor liver transplantation from the donor’s perspective: An in-depth qualitative research study. Transplantation 2004; 78: 1506–1514.

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General Medical Evaluation of the Living Donor Jerry McCauley Renal-Electrolyte Division, Department of Medicine, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Thomas Shaw-Stiffel Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Living organ donation has been the central issue of transplantation from its inception, with the first successful renal transplant from identical twins in 1954. The advantages of living organ donation are many, but the act of donation may pose risk to the donor both in the short and the long term. ETHICAL CONSIDERATIONS The evaluation of potential donors is based upon several principles. The first and overriding principle is to do no harm to the donor or recipient. The concept of harm in bioethics is complex and is open to many interpretations. We will, for the purpose of this discussion, accept a narrow focus, which is defined as setbacks to the physical and psychological interests of the donor (1). As many have noted, the process of organ donation always involves harm when a broad definition is employed. The operative pain, loss of wages, and potential loss of the intact physical self are unavoidable when broad definitions are used. In the narrow view, these are not harms, because they are not setbacks but predictable consequences of donation. Harm in the narrow view includes sufficient loss of donated organ function that would place the donors at risk of needing organ replacement themselves. It also includes the initiation of new morbidities that were not present at the time of donation. This could include a myocardial infarction leading to chronic congestive heart failure in a kidney transplant donor, transmission of blood transfusion-derived viral hepatitis to the donor, or donor-derived viral infection (e.g., hepatitis) to the recipient. Although the medical evaluation of potential donors is not capable of absolutely preventing all harm, a well-constructed evaluation should reduce the risk of doing harm to the donor or recipient to a minimum level acceptable to both the patients and the physician. THE VALUE OF LIVING DONOR ORGANS The scarcity of organs for all types of transplantations has prompted the need for living organ donation. For most forms of transplantation, recipient patient survival and graft survival is not superior to that associated with deceased donors, and the therapeutic goal is to achieve parity of living and deceased organ donation. This is true for liver, lung, intestine, and pancreas living organ donation (Chapters 4, 14, 17–19, 21, and 23–26). For renal transplantation, however, superior patient and graft survival, and reduced morbidity is the expected outcome. Living donor-related or unrelated renal transplantation can legitimately be advanced as a superior alternative to deceased donation regardless of the supply of deceased organs. For extrarenal

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organ transplantation, the scarcity of organs leads to high mortality on the waiting lists, making living donation advantageous when compared with no transplantation. The major advantage of extrarenal living donor transplantation is that it may actually save the life of a patient awaiting a vital organ. When viewed in this context, living extrarenal donation is vastly superior to the only other alternative, that is, death. Traditionally, very close relatives have been the source of extrarenal living donor organs, given the importance of preserving the life of a loved one. Parents, in general, have been the source for liver and lung transplants. In many cases, the donors have been willing to undergo extreme risk for the sake of their family members. It is not uncommon to hear a family member or other loved one say that they would be willing to die so that their loved one can live or stop dialysis treatments. This sensitive context makes the evaluation of emotionally committed donors particularly difficult. When members of the transplant team are not willing to tolerate the level of risk the donor accepts, the prospect of certain death or life-long dialysis is understandably poorly tolerated by the potential donor and recipient. The psychosocial issues involved and the ethics of decision-making in these complex situations continues to evolve. (Chapters 2, 35, and 36) The level of risk acceptable to donors by transplant programs has slowly increased over the past two to three decades, but it will likely always be the responsibility of transplant teams to restrain excessive risk taking by donors. MEDICAL SUITABILITY Regardless of the organ to be donated, the ideal potential donor is one who is young and in perfect health. Such a donor will have little-to-no prior medical illnesses, will be taking no medications, and is near ideal body weight, with no laboratory test outside the range of normal. The growing shortage of deceased donors has prompted most transplant programs to extend their criteria for inclusion of potential living donors to encompass individuals who do not fit the ideal. The criteria for acceptance of donors with medical conditions unrelated to the organ to be donated varies widely by organ and by transplant center. Some renal and liver transplant programs are now accepting donors who would have been rejected without question a decade ago. Donor with Medical Problems Donor age has increased over the past decade for all organs. With the aging donor population has come an increasing number and complexity of medical problems [United Network of Organ Sharing (UNOS) Annual Report 2005]. For most organs, this includes a decline in function. Renal function predictably declines with age, hepatic regenerative capacity slows, and pulmonary function may be reduced because of age, a prior history of smoking, and pollution. In addition to the decline in function of the primary organ to be donated, these patients develop an increased risk for other illnesses that may limit their capacity to donate any organ. Hypertension is an excellent example of such problems. The prevalence of hypertension is known to increase with age (Joint National Committee report-7) (2). Although many of these problems are related to aging, others are directly related to the increasing prevalence of obesity in the nation and the world. Obesity significantly complicates the operative management of donors, and may also be associated with a constellation of other medical conditions. The metabolic syndrome, which is a direct consequence of obesity, has become a rapidly growing public health problem in the United States and other developed countries. Potential Transmission of Infectious Diseases to the Recipient In all forms of living organ donation, identification of diseases that can be transmitted from the donor to the recipient forms an important part of the evaluation (Chapter 31). Infectious diseases, such as viral hepatitis and HIV, are routinely included in any assessment as they may preclude donation. Other infections, such as the herpes viruses, cytomegalovirus (CMV) or Epstein–Barr virus (EBV) are not absolute contraindications, but would increase the risk to the recipient and may require special measures in the perioperative state (3). Human herpes virus-8 has been associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric

General Medical Evaluation of the Living Donor

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Castleman’s disease in transplant recipients. Human T-cell lymphotropic virus (HTLV) has been reported to cause T-cell leukemia in renal and bone marrow transplant recipients (4). The above viral diseases may develop as a primary infection derived from the donor or as reactivation of previously acquired recipient disease. More unusual infectious such as West Nile virus and rabies have generated great interest in the deceased donor population, but could also pose a risk in the living donor situation. Routine screening for these problems has not become the standard of care, as these infections are rare. Malignancy Transmission of cancer to the recipient is also a potential threat during living organ donation. All living donor evaluations include an attempt to detect pre-existing cancers. For some donors, a well-documented history of prior cancer treatment may be available. For others, occult cancers may be discovered during the evaluation. In the deceased donor situation, transplantation of organs with cancers has occurred. Examples include occult renal cell carcinoma in renal transplant recipients and primary hepatic cancer in liver transplant recipients. Donors with known or occult melanoma pose a particularly important problem in both deceased and living organ donation. Reports of donor-derived melanomas in transplant recipients date back to the late 1960s (5). There is currently no consensus on whether living donors with prior histories of melanoma should be allowed to donate organs. Obviously, potential donors with recent invasive melanomas should be avoided. Those with remote and/or in situ lesions may be considered by some centers. This problem highlights the importance of careful examination of the skin in all potential donors. Age-appropriate screening for cancers as recommended by the American Cancer Society is usually employed as the first line in cancer detection in all living organ donor evaluations (6). Many potential donors will present for evaluation without having completed the appropriate studies. The evaluation process provides an opportunity to improve the health of donors, in addition to preventing transmission of disease to the recipients. ORGAN RESERVE Organ donation is performed with the implicit understanding that the donor has sufficient reserve of their organ function to allow donation without concern that insufficient function will be left to support the donor for the remainder of their lives. Determination of organ function and the reserve available differs by organ and the organ’s ability to regenerate or compensate. The details of these assessments are included in the organ-specific chapters in this book. The liver is unique in its ability to regenerate hepatic mass. The kidney, however, develops compensatory hypertrophy and is capable of increasing single nephron glomerular filtration rate (GFR) by 85%. Age Organ reserve is a function of donor age and prior or ongoing injury. All organs tend to experience deterioration of function with aging. For most organs, there remains considerable question as to whether the observed decline is related to the normal aging process or if the decline is largely a function of environmental factors leading to injury of the organ over time. Although the liver is unique in its ability to regenerate, predictable age-associated deterioration in its function also occurs. Recent reviews suggest that decreases in hepatic volume, resistance to oxidative stress, drug metabolism, hepatobiliary function, and regenerative capacity can be expected of the aging liver (7). Busuttil and Tanaka in a recent review suggested that the deleterious effects of the aging donor could be eliminated when careful selection is observed and donors of extreme age (>70 years) are avoided in the deceased donor population (8). Living donors of extreme ages are likely to be very rare in the living donor situation. Renal function may also decline with aging. Rowe and colleagues suggested that renal function declines by 10% per decade after age 30 in most patients, but 30% experienced no

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decline in function (9,10). This study was a longitudinal study that followed patients for about 20 years and ended in 1976. It obviously predated our current attempts at improved blood pressure control and other measures planned to reduce the risk of renal injury, so that a greater proportion of aging individuals may retain excellent renal function. Donation of a kidney requires not only acceptable static renal function but also the ability to undergo adaptive hyperfiltration. A recent study by Saxena et al., suggests that older (>55 years) uninephrectomy patients (from organ donation or cancer surgery) experienced a similar magnitude of adaptive hyperfiltration, although the older patients had lower baseline glomerular filtration rates. Selected older individuals may have stable renal function and sufficient reserve to allow organ donation. The elderly with declining renal function should be avoided as they will have insufficient reserve and blunted adaptive hyperfiltration. Pulmonary reserve also declines with advancing age. By age 10 to 12, the maximal number of alveoli is attained, and at approximately 20 years of age for females and 25 years for males, maximal pulmonary function is achieved (11,12). Thereafter, pulmonary function declines. Reported changes include dilatation of alveoli, airspace enlargement, decreased exchange surface area, and loss of tissue support for peripheral airways, resulting “senile emphysema.” Inferior graft survival has been associated with increased deceased donor age (13). Most lung transplant programs concede the loss of pulmonary function to age and restrict potential donors between 18 and 55 years of age (Chapter 23). Age restrictions are used in all other living donor programs, including pancreas and intestinal transplants. Living donor transplantation from these organs are much less common than kidney and liver transplantation, so that extensive experience is not available about the contribution of age to donor and recipient outcomes. Most programs exercise age restriction with upper limits of 55 to 60 years of age (Chapters 21 and 24). OTHER COMORBID ILLNESSES With the aging of donor population has come the requirement to assess the contribution of pre-existing illnesses or those discovered during the evaluation, for the potential risk to the donor or recipient. In the kidney transplant population, previously rejected donors with definable illness are now being accepted (Chapter 4). Some programs now accept donors with pre-existing hypertension. Short-term follow-up suggests that blood pressure control is actually improved after organ donation; this is likely related to more aggressive adherence to antihypertensive agents and closer medical supervision. The requirement that donors have no illnesses is cautiously receding in nonrenal living donor programs as well. In all programs, the illnesses should be completely correctable or managed such that they do not pose undue additional risk to the donor in the long or short term. Conditions such as hyperlipidemia are highly prevalent in the population and can be easily managed with diet and medication. Donation of an organ should not increase the risk of cardiovascular disease in this setting and should not exclude potential donors. Compliance with medical treatment is, however, an absolute requirement in most programs that allow such patients to donate. STAGING OF THE EVALUATION The donor evaluation should be performed so that it minimizes risk to the donor and is cost effective. In general, this will mean moving from relatively simple tests to more complex as the evaluation proceeds. Low risk studies that might eliminate potential donors early in the process should be performed first during the evaluation. These include blood tests such as HIV, hepatitis screening, and other studies such as electrocardiogram and chest X-rays. More advanced studies that would only be performed if the donor is otherwise acceptable should be performed last. This includes CT-angiograms and procedures that are performed only if the transplant is to be allowed to proceed. Likewise, the most expensive studies should be performed late during the evaluation to minimize cost. In practice, most of the higher-risk studies also are most expensive.

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REFERENCES 1. Beauchamp T, Childress JF. Nonmaleficence. In: Principles of Biomedical Ethics. Oxford University Press, New York, 1994:193. 2. Phillips B. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560–2571. 3. Yoshikawa T. Significance of human herpes viruses to transplant recipients. Curr Opin Infect Dis 2003; 16(6):601–606. 4. Villafruela Mateos A, Arruza Echevarria A, Martin Bazaco J, Azurmendi Arin I, Zabala Eugurrola JA, Pertusa Pena C. HTLV infection after renal transplant. Arch Esp Urol 2005; 58(10):1064–1068. 5. Cotter MA, Tristani-Firouzi P. Unsuitability of organ donation from a patient with a history. J Am Acad Dermatol 2006; 54(6):1096–1098. 6. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer 2006. CA Cancer J Clin 2006; 56:11–25. 7. Schmucker DL. Age-related changes in liver structure and function: implications for disease? Exp Gerontol 2005; 40(8–9):650–659. 8. Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transpl 2003; 9(7):651–663. 9. Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol 1976; 31(2):155–163. 10. Denshaw RM, Unruh ML. Kidney disease in the elderly. UPMC Renal Grand Rounds. http:// www.dom.pitt.edu/renal/ 11. Janssens JP, Pache JC, Nicod LP. Physiological changes in respiratory function associated with ageing. Eur Respir J 1999; 13(1):197–205. 12. Janssens JP. Aging of the respiratory system: impact on pulmonary function tests and adaptation to exertion. Clin Chest Med 2005; 26(3):469–484, vi–vii. 13. Bryan AW, Dilip SN, Adam CJ, et al. Risk factors for primary graft dysfunction after lung transplantation. J Thorac Cardiovasc Surg. 2006; 131(1):73–80; Epub 2005 Dec 5.

Part II

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LIVING-DONOR KIDNEY TRANSPLANTATION

Evaluation: Specific Issues for Living-Donor Kidney Transplantation Mark Unruh and Christine Wu Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Jerry McCauley Renal-Electrolyte Division, Department of Medicine, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Perioperative morbidity and mortality are rarely the prohibitive issues in the generally healthy potential living kidney donor population. However, in order to obtain truly informed consent from potential kidney donors, it is important to understand and explain the potential long-term effects that can accompany a reduction in renal mass (1,2). This chapter will focus on the preoperative assessment of kidney function and the predictors of long-term health consequences of kidney donation, both in terms of renal and overall patient health. It will discuss the medical evaluation of donors and will focus on what is currently known regarding the risks of both End-Stage Renal Disease (ESRD) and overall morbidity associated with common medical problems identified during the medical evaluation of potential kidney donors. It will review the available data regarding the effects of nephrectomy in the setting of comorbidity or illness that may modify the risk of renal failure, specifically discussing issues of aging, lower estimated glomerular filtration rate (GFR), proteinuria, hematuria, stone disease, hypertension, glucose intolerance, and obesity. Finally, it will offer suggestions regarding the long-term follow-up care of the kidney donor. In situations for which long-term data are lacking, we have tried to avoid setting arbitrary cut offs to define acceptability for donor nephrectomy, because multiple individual factors need to be weighed when determining the overall advisability of kidney donation. The ultimate goal of the medical evaluation is to arrive at a decision made jointly in a spirit of cooperation by the transplant center and a well-informed donor candidate. The approach to a potential donor with a risk factor that modifies the risk of renal failure is displayed in Figure 1. When the donor presents for evaluation, he or she has a complete history and physical by both the surgical and nephrology teams. As discussed in Chapters 5 to 8, this will allow the teams to advise the possible donor on the general risks of living donor nephrectomy and any risks unique to that individual uncovered by the assessment. If the donor is found to have a condition that increases the risk of renal failure, the donor will be informed during the visit (Table 1). For example, a patient was evaluated for nondirected donation and found to be markedly hypertensive at the initial medical examination. At this point, the nondirected donor was withdrawn from consideration and was directed to seek further medical care from a primary physician. In some cases, such as borderline hypertension or family history of autosomal dominant polycycstic kidney disease (ADPKD), the potential donor requires further medical testing. In the case of ADPKD, this would often be a renal ultrasound or in the case of hypertension, ambulatory blood pressure (BP) monitoring. After receiving the results of further testing, an appropriate

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FIGURE 1

Unruh et al.

Flowchart for living donor kidney evalution.

decision can be made regarding the donor evaluation. Often, potential donors with hypertension or obesity are advised to address the problem with lifestyle changes and then return for another visit with the surgical or medical teams. At that point, after the additional data are collected, the team conveys the potential long-term increased risk of kidney disease. If the donor accepts a potentially higher lifetime risk of kidney problems or other health consideration (e.g., hypertension), the candidate is presented to a multidisciplinary transplant committee. If the committee feels that the potential donor has adequate information regarding the risk of nephrectomy, and if the committee is also satisfied that the candidate will not be exposed to unreasonable risk, then the donor is approved, and the candidate may proceed with donor nephrectomy. As an example, a fifty-year-old African-American potential donor was found to have untreated hypertension (135–159/80), and the urine dipstick was negative for albumin. This donor was advised of an increased risk of kidney failure in the long term. The candidate met with both the medical and surgical teams for further risk assessment after validating the finding of hypertension with a series of outpatient BP measurements. The donor was given an estimated lifetime risk of 3% to 7% of kidney failure. The recipient had no other available donors and was likely to require three years of dialysis prior to receiving a deceased donor transplant. The donor elected to undergo living donor nephrectomy and has done well postoperatively

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Evaluation: Specific Issues for Living-Donor Kidney Transplantation

TABLE 1

Summary of Medical Screening, Testing, and Intervention for Potential Live Kidney Donors

Risk factors Kidney function Hypertension

Proteinuria

Screening tests 24-hour urine, serum creatinine Clinic blood pressure using aneroid unit by nephrologists; history 24-hour urine total protein

Hematuria

Urine dipstick; history

Kidney stone

History, CT angiography, renal ultrasound

Diabetes and glucose intolerance

History and fasting plasma glucose (FPG)

Obesity

Body mass index; physical examination Renal ultrasound

Family history of PKD Family history of glomerulonephritis

Urinalysis

Follow up testing

Clinical intervention to continue donor candidacy

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I-iothalamate, Tc-DTPA 10 outpatient blood pressures by health care practitioner Ambulatory BP testing 99m

Split 24-hour urine total protein. Assessment of proteinuria after cessation of aerobic exercise 1. Urological evaluation for stones and malignancy: a. IVP and U/S or CT if indicated b. Urine cytology or cystoscopy depending on risk factors c. If cystoscopy is initial test and is positive, need to evaluate upper tract 2. Glomerular evaluation. Nephrologist evaluation of urine sediment. 24-hour urine oxalate and creatinine; serum calcium, creatinine and albumin, and parathyroid hormone level if hypercalcemia is present; urinalysis and urine nitroprusside test for cystine and urine culture; analysis of prior stone if available; helical CT

A 75g 2-hour oral glucose tolerance test if: a. impaired FPG (FPG >110mg/dL and less than 126mg/dl), b. first degree relative with history of diabetes, c. second degree relative with history of diabetes in a donor, candidate <40 years old, d. history of gestational diabetes or infant with >9 pound birth weight e. BP >140/90,fasting triglycerides > 250 mg/dl, BMI > 30, or HDL < 35. Evaluation for associated comorbid conditions Genetic screening if <30 years old or equivocal ultrasound, Urine microscopy

Control of blood pressure with lifestyle modifications and/or antihypertensive agent

Renal biopsy

If a stone former elects to undergo donor nephrectomy, testing to guide treatment should be completed: serum electrolytes, calcium, uric acid; 2 24-hour urine collections for volume, calcium, uric acid, citrate, oxalate, pH, sodium, creatinine and supersaturations of calcium oxalate, calcium phosphate and uric acid

Recommended weight loss

Serologic or genetic testing, if applicable

Abbreviations: BP, blood pressure; DPTA, diethylene triamine pentaacetic acid; FPG, fasting plasma glucose; IVP, intravenous pyelogram; PKGD, polycycstic kidney disease; U/S, ultrasound.

on a low dose of an angiotensin converting enzyme (ACE) inhibitor. As discussed below, there are data available to guide recommendations, but more data on the long-term risk of donor nephrectomy are needed. Current data available to physicians and potential donors on the long-term risk of nephrectomy have been estimated from a number of sources. Long-term data from follow-up of World War II soldiers who underwent uninephrectomy for trauma suggests that there are no

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major consequences from uninephrectomy performed in young, healthy adults (3). However, the mostly male military population cannot fully represent the living donor population that consists of a greater proportion of women than men. Northern European registries also offer long-term patient follow-up data. Fehrman-Ekholm et al., analyzed survival and causes of death in 430 living donors and compared their findings with expected survival in the general Swedish population (4,5). The expected donor cohort mortality rates were calculated from age, sex, and calendar year-specific (1964–1992) mortality rates for the general population. Donors had a twenty-year survival rate of 85% compared with an expected rate of 66%. Twenty years after donation, one-third of donors were hypertensive, and 1% had proteinuria with protein excretion >1 g/d. No donor death was reported from renal disease; most deaths were caused by cardiovascular disease. At least 56 prior living donors have been listed for deceased-donor kidney transplantation in the database of the United Network for Organ Sharing (UNOS) (6). The donors’ ages at time of donation ranged from 17 to 61, with an average age of 31, and the time from donation to listing ranged from 2 to 32 years, with a mean and median of 15 years. Based on the number of living donors who have subsequently been listed for deceased-donor kidney transplantation, the estimated incidence of ESRD in living donors since 1987 is 0.04%, similar to the incident rate of ESRD in the general U.S. population of 0.03% (USRDS 2001 Annual Data Report). However, this select group of former living donors listed for transplantation may underrepresent the risk to kidney donors, as it fails to capture those donors who were listed prior to the establishment of the OPTN registry, those who developed ESRD and were not listed, and those who suffered a significant decline in renal function but died before reaching ESRD. Finally, data from individual centers are available, but need to be interpreted with caution because of relatively short follow-up times and the potential lack of sufficient resources to maintain complete records, as well as the disincentive to find poor outcomes. In one series, 464 of 773 individuals who donated a kidney between 1963 and 1979 were assessed for outcomes; 84 patients had died, and three patients were on dialysis therapy at the time of death (7). Of the 380 surviving donors, mean creatinine values were 1.2 ± 0.04 mg/dL (106 ± 3.5 μmol/L) in the 20- to 29-year group and 1.3 ± 0.1 mg/dL (115 ± 8.8 μmol/L) in the >30-year group (7). Proteinuria rates were 11% and 5%, and hypertension was present in 36% and 38%, respectively. Overall, the prevalence of ESRD in the donor population was five of 464 donors, or 1%. Because genetic predisposition is known to play a role in the development of ESRD (8), a better comparison group might be the siblings of kidney donors. Najarian et al., compared the renal function, BP, and presence of proteinuria in 57 donors from 20 to 30 years after nephrectomy with those of 67 siblings (9). There were no differences in mean serum creatinine levels, proteinuria, or hypertension between donors and their siblings. Thus, donor nephrectomy appears to result in maintained renal function over 20 to 30 years if the subject has normal renal function, no hypertension, and no proteinuria at the time of nephrectomy. Although there are crude methods to estimate the risk of kidney donation, these methods are particularly difficult when donors have multiple potential risk factors for kidney disease. As the number of living donors has increased and surpassed the number of deceased donors in the United States, transplant centers have also begun to adjust their definition of the acceptable donor to include those with pre-existing medical conditions such as hypertension. In the remainder of this chapter, we will discuss the long-term risks attendant to specific isolated comorbidities and medical conditions. AGE A steady decline in GFR has generally been considered a part of the general aging process. Following kidney donation, a similar, but not accelerated, rate of decline is seen in kidney donors (5). The percentage of nephrosclerosis in donor biopsies appears to be more in older donors (10–16), and the early experience with living donors suggested a poorer outcome for recipients of kidneys from older donors (17). However, not all individuals demonstrate a decline in GFR with advancing age (18,19). Comparable one-year outcomes in recipients of older living donor kidneys with those in recipients of kidneys from younger donors (<55–60 years old) can be expected. Long-term data on both allograft function as well as survival are less clear, with some studies suggesting no

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difference in either survival or function, others demonstrating impaired but stable function and comparable survival, and others demonstrating worse graft survival and function in recipients of older donor kidneys(10–16). There is no definite age limit beyond which kidney donation can be considered unacceptable. We have used donors as old as 76 years with excellent donor and recipient results. The decision to allow an older patient to donate a kidney should be made on an individual basis, but older donors and their recipients should be informed of the potential for decreased kidney function and graft survival. LOWER CANDIDATE GLOMERULAR FILTRATION RATE Most centers agree that potential kidney donors should demonstrate “normal” kidney function or at least sufficient function to provide both donor and recipient with an adequate GFR following nephrectomy and transplantation. However, the definition of “normal” is somewhat elusive, because of the imprecision of various methods of estimating GFR. Whereas some centers accept selected donors with a lower creatinine clearance, a GFR >80ml/min, corrected to body surface area (BSA) of 1.73/m2 is generally considered to be acceptable for kidney donation. However, Thiel et al., advocate calculating a ‘minimal creatinine clearance required’ for each individual donor (20). The calculation involves a minimal creatinine clearance of 40 ml/ min/1.73/m2 at an age of 80 and then adjusts for an abrupt loss of 25% of the GFR with nephrectomy and a more gradual decline with age (20). Using this calculation, transplantation from older living donors with lower creatinine clearances have been performed, and the donors have had good outcomes with short-term follow-up. Despite the apparent safety of ‘low’ GFR donors, the increased relative risk for recipient graft loss of 2.28 has been reported for kidneys from living donors with a baseline predonation GFR <80 ml/min, when compared to kidneys from donors with higher baseline GFR (21), and the potential increased risk to donor health requires additional consideration. The most widely used measure of GFR in clinical practice is based on the 24-hour creatinine clearance and serum creatinine concentration. The 24-hour creatinine clearance may under- or overestimate GFR in patients with normal or near normal renal function because of factors such as adequacy of collection or dietary protein intake. The urinary clearances of exogenous radioactive markers (125I-iothalamate and 99mTc-DTPA) provide excellent measures of GFR and could be considered in cases of borderline 24-hour urine findings before excluding a potential donor on the basis of low GFR. However, these tests are not always widely available. In healthy individuals, GFR cannot be estimated accurately using the abbreviated Modification of Diet in Renal Disease (MDRD) or Cockcroft-Gault prediction equations(22). The classic method of inulin clearance requires an intravenous infusion and timed urine collections over a period of several hours, making it costly and cumbersome. Plasma clearance of exogenous substances including iohexol and 51Cr-EDTA require estimates of body size, which decreases their precision. Serum cystatin C has been used to estimate GFR, but data are conflicting as to whether it provides a sufficient improvement to warrant widespread clinical use. HYPERTENSION Hypertension is a common and often unrecognized disorder in the general population and is often associated with impaired renal function. Until recently, high BP has been considered to be a contraindication to kidney donation. The questions regarding to what extent living kidney donation contributes to subsequent high BP and the precise risk to donors who have family history of hypertension, borderline hypertension, or mild hypertension adequately controlled on a single agent remain incompletely answered. BP increases with age in the normal population (23) (Fig. 2), and those related to patients with kidney diseases have a higher risk of high BP. It has been suggested that those undergoing nephrectomy for living-donor kidney transplantation may expect an increase in BP (5,7,24). The difficulties of measuring BP at the time of evaluation have been well described in living kidney donors (25). In this study, 238 potential donors between 18 and 72 years of age

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FIGURE 2

Unruh et al.

Increasing prevalence of hypertension with aging. Source: From Ref. 95.

were prospectively studied, comparing “clinic” BP values measured in the outpatient clinic with an oscillometric recorder, ambulatory BP monitoring (ABPM) findings, and standardized BP values determined by nurses using American Heart Association criteria. Using as criteria for systolic BP values of >140 mmHg or diastolic BP values of >90 mmHg, 36.7% of subjects were initially considered hypertensive in the clinic; this decreased to 11% with awake ABPM findings. It is critical to note that a substantial number of subjects with excellent kidney function were misclassified as hypertensive with clinic oscillometric measurements alone. Despite issues with sensitivity, the clinic BP and medical history are used in clinical practice to screen for hypertension. A BP of >140/90 at the visit supports a diagnosis of hypertension, and the patient with a history of hypertension or use of antihypertensives is considered hypertensive. In either case, the candidate subsequently undergoes outpatient BP checks at the primary physicians’ clinic or with ambulatory BP monitoring. It is preferred to have a candidate with borderline clinic hypertension get ABPM, particularly if the candidate is >50 years old, given the improved sensitivity of ambulatory BP monitoring. Candidates who are found to be normotensive after subsequent testing proceed with the donor evaluation. Patients found to be hypertensive or with known and treated hypertension have a modified risk of donation, and these patients should have follow-up counseling from the surgical and nephrology team regarding the risk of donation. Patients with difficult-to-control hypertension or evidence of target organ damage are usually excluded. The data support considering candidates for living donor nephrectomy if the BP is easily controlled and they meet other criteria (>50 year old, GFR > 80 ml/min, urinary albumin <30 mg/d), as this group should be low risk for development of subsequent kidney disease. In the hypertensive candidates, the potential donors are asked to undergo lifestyle modifications and are monitored to determine if the hypertension improves. Prior to the nephrectomy, the potential donors with hypertension are advised that they will need regular follow-up with a primary physician and control of the BP within the target levels outlined by Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (26). Two separate groups reported their experience with hypertension in the Amsterdam Forum (27). Thiel et al., reported seven-year follow-up on 18 donors who were hypertensive at the time of nephrectomy. Of those donors, 56% were receiving antihypertensive therapy (five on single agent, three on dual therapy, two on three medications). However, eight donors who had been hypertensive at the time of nephrectomy were normotensive at follow-up. Of note, renal function did not differ between the hypertensive and normotensive groups (71 + 19 mL/ min/1.73 m2 in the initially hypertensive group versus 75 + 17 mL/min/1.73m2 in the initially normotensive group). This group has extended these findings to 29 hypertensive donors in the SOL-DHR kidney donor registry. This finding was confirmed when Stegall reported the recent Mayo Clinic experience using iothalamate clearance to estimate GFR (27). The kidney function of 25 hypertensive donors was not statistically different than that of 150 normotensive donors prior to nephrectomy and at one year following donor nephrectomy, and none of the

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hypertensive donors were found to have proteinuria at follow-up. In their experience, hypertension was easily controlled with an angiotensin receptor blocker and diuretics. PROTEINURIA The association between albuminuria and the development of both renal and cardiovascular disease has been well established in the diabetic population, and the association has been increasingly noted in nondiabetics (28). In the PREVEND cohort, > 6000 patients with a baseline creatinine clearance of 90ml/min were examined after a mean follow-up of 4.2 years (29). De novo renal impairment, defined as a GFR < 60ml/min, developed in 4.2% of patients. Urinary albumin excretion was an independent risk factor for renal impairment, with an unadjusted odds ratio of 1.63 and adjusted odds ratio of 1.3 (29). The risk of developing renal impairment increased as baseline urine albumin concentration increased, with a steep increase in the incidence of renal impairment to >25% in patients with a baseline urine albumin concentration of >300mg/24h compared to <10% in patients with lower levels of baseline albuminuria (29). Although a 24-hour urine protein of >300 mg is generally considered to be a contraindication to kidney donation, the significance of lesser amounts of urinary albumin has not been clearly established. Microalbuminuria is a sensitive indicator of glomerular pathology in patients with diabetes and may also be the first sign of glomerular pathology both before and after nephrectomy (30). Although the evaluation of microalbuminuria is not consistently recommended as a part of the preoperative assessment of kidney donors, its detection may be important in prognostic and therapeutic recommendations in the long-term follow-up of kidney donors. The Kidney Disease and Outcome Quality Innitiative (KDOQI), American Diabetes Association (ADA), and National Kidney Foundation (NKF) guidelines regarding assessment of proteinuria recommend a first morning urine specimen, but consider random urine specimens acceptable if first morning urine specimens are not available. A first morning urine specimen correlates best with 24-hour protein excretion and is required for the diagnosis of orthostatic proteinuria. Among the over 2500 participants of the PREVEND study, both sensitivity and specificity of first morning urine albumin concentration in predicting microalbuminuria on a 24-hour urine collection were reported as 85%. Sensitivity and specificity for spot urine albumin to creatinine ratios were approximately 87% (31). Therefore, for ease and consistency of collection, a random urine specimen for protein or albumin to creatinine ratio is acceptable if a first-morning urine specimen is not available. Not all proteinuria is the result of glomerular disease. Increased protein excretion can be the result of altered renal hemodynamics in conditions, such as fever, exercise, and extreme cold. Proteinuria related to changes in renal hemodynamics is transient and, if suspected, can be confirmed with repeat testing. The condition of orthostatic proteinuria should also be considered, particularly in young donors. Approximately 2% to 5% of adolescents have orthostatic proteinuria, and this condition accounts for 60% to 75% of proteinuria in adolescents. However, this condition is rare in those >30 years of age (32). Twenty-four hour protein excretion is usually <1g/day but can exceed 3g/day. Published series summarizing over 50 years of follow-up have documented the benign nature of this condition, demonstrating a good long-term prognosis and lack of association with underlying glomerular disease (33). The diagnosis of orthostatic proteinuria can be made by either a split-timed collection or by two separate spot urine samples. In order to perform a split timed collection, the patient should be instructed to discard his first morning void, and then collect urine for the next 16 hours while engaging in usual upright activities. The patient should assume a recumbent position two hours prior to beginning the supine collection to avoid contaminating the overnight specimen. A separate eight-hour overnight collection is then performed. Because a modest decrease in protein excretion with recumbency can also be seen in glomerular disease, the simple observation of a decrease in supine versus upright protein excretion is insufficient to make the diagnosis of orthostatic proteinuria. The diagnosis requires that the eight-hour sample contain <50mg of protein. Alternatively, a spot urine protein to creatinine (P:C) ratio from a first morning void can be compared to a spot P:C ratio obtained in the upright position. The second specimen

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should yield a higher ratio, and the first morning specimen should show a P:C of <0.2mg/mg (<20mg protein/mmol of creatinine). Orthostatic proteinuria has been associated with the Nutcracker syndrome (left renal vein compression between the aorta and superior mesenteric artery) and preoperative vascular imaging should help to rule out this condition (25,34). In summary, the urine dipstick testing alone is inadequate screening for proteinuria in living donor nephrectomy candidates. The first morning urine albumin concentration is the preferred screening test, but a random urine albumin to creatinine ratio is an acceptable alternative. If either screening test suggests an albumin concentration of >110 mg/dl or 30 mg/24 hours, a timed specimen is indicated. In practice, we use 24-hour urine for both creatinine clearance and proteinuria. A 24-hour urine protein of >300 mg that is not due to orthostatic proteinuria (which can be determined by a split urine collection) is considered by most centers to be a contraindication to kidney donation. However, there are little data to guide the recommendations regarding the degree of risk modification from isolated proteinuria in the setting of donor nephrectomy. Although microalbuminuria may be more sensitive for glomerular pathology, the assay is more expensive and lacks laboratory standardization. URINARY TRACT INFECTIONS According to the Amsterdam forum, the donor urine should be sterile prior to donation to avoid the dissemination of a urinary tract infection (UTI) and resultant sepsis in the recipient. Therefore, asymptomatic bacteruria should be treated prior to living donor nephrectomy. In addition, unexplained recurrent pyelonephritis was felt to be a contraindication to donation (27). Recurrent UTIs from childhood may indicate reflux, and candidates should undergo a voiding cystourethrogram (VCUG) to rule out an anatomic problem prior to kidney donation. HEMATURIA Isolated microscopic hematuria is not, in itself, a contraindication to kidney donation. A survey of transplant centers in the United States indicated that over one-third of centers were willing to accept donor candidates with isolated microscopic hematuria and a negative urologic evaluation and renal biopsy (35). Asymptomatic hematuria is a relatively common finding as shown in a study of 1000 young men aged between18 and 33 undergoing yearly urine dipstick with hematuria detected on at least one occasion in 39%, and on greater than one occasion in 16% (36,37). Hematuria has also been reported in 13% of adult men and postmenopausal women, but only 2.3% of those with hematuria were subsequently found to have serious disease (38). Another study examining 231 men over the age of 50, who were tested weekly for three months, detected hematuria in 10% of their subjects (38). The sensitivity of the urine dipstick is comparable to the evaluation of the urine sediment, and a negative result reliably excludes the presence of hematuria (39). However, the test is prone to false positive results from contaminated samples, myoglobinuria or hemoglobinuria, and should be confirmed by examination of the urine sediment. The differential diagnosis of hematuria, including microscopic hematuria defined as three to five red blood cells per high power field is large. It includes benign conditions, such as exercise, endometriosis, menstruation, and benign prostate hypertrophy. It can also include potentially manageable conditions that may not preclude kidney donation if evaluated and treated appropriately, such as arterio-venous malformations, infections or stone disease. Finally, it can be associated with significant disorders that should exclude kidney donation, such as polycystic kidney disease, renal or genitourinary malignancy, sickle cell disease, and glomerular disease. Evaluation should begin with a thorough history and physical. In a low-risk patient with a clearly defined history of exercise or trauma, a repeat negative urine dipstick may be sufficient to complete the evaluation. Other important historical features include a personal or family history of stone or glomerular disease, flank pain, cyclical bleeding, environmental or occupational exposures, and bleeding diatheses. However, hematuria should not be attributed solely to anticoagulation (40,41). In addition, the other components of the donor evaluation will necessarily include testing for obvious glomerular disease by evaluating serum creatinine, urine protein, and urinary sediment. If the serum creatinine and urinary protein

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excretion are normal, most transplant centers will typically exclude stone disease and malignancy prior to pursuing a renal biopsy. The appropriate sequence of urological investigations is debatable; however, an intravenous pyelogram (IVP) is a reasonable first test as it can detect conditions such as medullary sponge kidney or lesions of the renal pelvis and ureter that would be missed by ultrasound. In older patients, a negative IVP should be followed by imaging with either ultrasound or CT for the detection of small tumors that may have been missed on IVP (42–44). In patients under the age of 40 with no risk factors for uroepithelial cancer and negative radiographic studies, the literature supports noninvasive monitoring, and a negative urine cytology exam is probably sufficient to complete the urological evaluation (45–47). In men >40 to 50 years of age or in patients with a history of prolonged analgesic abuse, tobacco smoking, high-risk occupational exposures, prior receipt of cyclophosphamide, or history of gross hematuria, a cystoscopy is indicated. If a cystoscopy is chosen as the initial test, and a bladder tumor is found, evaluation of the upper urinary tract is mandatory because of the field cancerization effect of uroepithelial cancers. If all tests are negative, the urological evaluation can be considered complete; however, up to 1% of older patients with intermittent hematuria and a negative evaluation will present with a malignancy after three to four years (48), and, at minimum, yearly follow-up evaluation for hematuria with a local physician should be recommended. If the urological examination is negative, a renal biopsy can be considered. In the general population, a renal biopsy is not usually recommended in the evaluation of isolated hematuria of suspected glomerular etiology because the differential diagnosis is composed of conditions for which there are no specific therapies, for example, thin basement membrane, IgA nephropathy, and Alport’s syndrome (49,50). However, in the potential kidney donor, a biopsy would be helpful as the renal prognosis can vary significantly among these various diagnoses. In summary, the urine dipstick is adequate for screening hematuria in the living donor nephrectomy candidate. A positive result in the urinalysis should be confirmed by a nephrologist examining the urinary sediment. Of note, the persistence and degree of hematuria are not necessarily predictive of the severity of its cause. The recommended evaluation includes a history and physical, if the history is highly suggestive of a benign transient etiology, and the repeat urine dipstick is negative, no further evaluation is needed. However, in the case where the candidate is at risk for either stones or malignancy, the candidate should undergo a urological evaluation that includes an intravenous pyelogram (IVP) and ultrasound (U/S), or computed tomography (CT), if indicated, and a urine cytology or cystoscopy depending on risk factors. If cystoscopy is the initial test and is positive, there remains the need to evaluate the upper tract. For the glomerular evaluation, the nephrologists should evaluate the urinary sediment. If the evaluation is completely negative, regular follow-up is recommended. STONE DISEASE Stone disease is relatively common in the general population. Data from the National Health and Nutritional Examination Survey, revealed a prevalence of 5.2% from 1988–1994 (51). Older estimates report an incidence of at least one episode of nephrolithiasis by age 70 in 12% of men and 5% of women (52). The risk of stone recurrence depends on the etiology of stone formation. For all first-time stone formers, the estimated risk of recurrence for calcium stones has been estimated at 5% per year for the first five years, or cumulative risks of approximately 15% at one year, 35% at five years, and 50% at 10 years. The reported mean time to recurrence is approximately eight years (52–54). However, the risk of recurrence diminishes with time, and the morbidity from kidney stones is relatively limited with careful monitoring, and can usually be managed with relatively noninvasive techniques. Although no data exist directly comparing the renal outcome in stone formers with two kidneys against those with a solitary kidney, data from patients undergoing unilateral nephrectomy for stone disease suggests that renal function is generally well-preserved with close follow-up in patients at high risk for nephrolithiasis (55,56). Thus, despite the significantly increased risk of morbidity from nephrolithiasis in the setting of a solitary kidney, an asymptomatic kidney donor candidate with a history of a single uncomplicated episode of nephrolithiasis >10 years previously may still be a suitable kidney donor.

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The number of prior events, rather than the metabolic risk profile, is more predictive of future events. However, laboratory studies, including serum electrolytes, uric acid, and calcium, urinalysis to examine the sediment for crystals, urine nitroprusside test for cystine, and 24-hour urine collections for volume, calcium, uric acid, citrate, oxalate, pH, sodium, and creatinine (to assess adequacy of the sample) are helpful in ruling out metabolic stone forming abnormalities, such as primary hyperparathyroidism, hyperuricemia, cystinuria, hyperoxaluria, or metabolic acidosis. Urinary tract infection should be excluded. CT should demonstrate the absence of multiple stones or nephrocalcinosis. Acute transplant renal failure due to donor nephrolithiasis has been reported. Because the grafted kidney is denervated, the classic symptoms of renal colic may be absent (57–60). However, ex vivo ureteroscopy to remove stones from donor kidneys at the same time preserving graft integrity and function has been successfully accomplished (61). Therefore, potential donors with a current single stone may be acceptable candidates for kidney donation if they meet the above criteria, and the current stone is either <5 mm in diameter (with high likelihood of spontaneous passage) or potentially removable (27). Lifelong follow-up with periodic stone risk assessment and medical treatment including targeted advice to address identified risk factors, and general recommendations regarding maintenance of adequate hydration, is recommended. Routine screening with kidneys, ureters, and bladders (KUB) or ultrasound has been found to be cost effective in the general population following the first occurrence of nephrolithiasis (62,63). In conclusion, stone disease is common, but in most instances has limited associated morbidity. A single uncomplicated past episode >10 years prior to candidacy is not necessarily a contraindication to donation. Stone formers with cystine or struvite stones, with stone disease related to inherited or systemic disorders (hyperoxaluria, distal renal tubular acidosis, sarcoidosis, inflammatory bowel or short gut disease) or with evidence of nephrocalcinosis should not donate. However, stone disease related to primary hyperparathyroidism that has resolved following parathyroidectomy is not a contraindication to kidney donation. Stone formers with a history of bilateral stones or recurrence on appropriate preventive therapy probably should not donate. Older donors with a history of a single stone between 5 to 10 years in the past, and those found to have an asymptomatic stone, potentially removable or <5mm, at the time of donor evaluation may still be appropriate donor candidates. The candidates need to be informed of an increased risk of acute renal failure with the obstruction of a single kidney. If a stone former elects to undergo donor nephrectomy, testing to guide treatment should be completed: serum electrolytes, calcium, uric acid, and two 24-hour urine collections for volume, calcium, uric acid, citrate, oxalate, pH, sodium, creatinine and supersaturations of calcium oxalate, calcium phosphate and uric acid. The donor candidates should be informed that lifelong follow-up is required, with periodic stone risk assessment and medical treatment, including targeted advice regarding any identified risk factors and general recommendations regarding maintenance of adequate hydration. DIABETES AND GLUCOSE INTOLERANCE Diabetes is currently one of the main etiologies of renal failure in the United States. Unfortunately, there is currently no unique qualitative biological marker of diabetes. In 1999, a World Health Organization (WHO) study group, in consultation with an International Expert Committee convened in 1997, re-examined the classification and diagnostic criteria for diabetes that was first established by the National Diabetes Data Group in 1979 and revised by the WHO study group in 1985 (64). Based on an increase in the prevalence and incidence of diabetic retinopathy, the use of fasting plasma glucose (FPG) cut point of >126 mg/dl was recommended for the diagnosis of diabetes. Normal FPG was defined as <110 mg/dl (6.1 mmol/l). FPG is the recommended first test because of its better reproducibility, lower cost, and increased convenience compared to alternative tests. Because of lack of laboratory standardization, the use of HbA1c as a diagnostic test was not recommended. The use of the oral glucose tolerance test, which consists of a FPG and two-hour plasma glucose was not recommended, for reasons of cost and convenience. However, a two-hour plasma glucose > 200 mg/dl (11.1 mmol/l) was defined as diabetes and a level of 144 to199 mg/dl (7.8–1.0 mmol/l) was accepted as representing impaired glucose

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tolerance. Because of the currently established cut-off values, the two-hour glucose tolerance test is the more sensitive assay for the detection of diabetes in most populations. The study group recognized that the two tests were not completely interchangeable, but both were useful in terms of their ability to identify disordered glucose metabolism and risk for subsequent microvascular and perhaps macrovascular consequences. As currently defined, the category of impaired glucose tolerance may be a stronger predictor of cardiovascular risk than impaired fasting glucose, but current data are insufficient to declare either test superior. Although diabetes is accepted as a risk factor for the development of renal disease, not all diabetic patients will develop nephropathy. The United Kindgom Prospective Diabetes Study (UKPDS), which examined over 5000 patients with type II diabetes, reported the following prevalences 10 years following the diagnosis of diabetes: microalbuminuria in 25%, macroalbuminuria in 5%, and serum creatinine >2 mg/dl, or renal replacement therapy in 0.8% (65). Based on the UKPDS data, the yearly rate of progression from diagnosis to microalbuminuria, microalbuminuria to macroalbuminuria, and macroalbuminuria to renal insufficiency defined as serum creatinine >2 mg/dl, or requirement of renal replacement therapy has been estimated at 2%, 2.8%, and 2.3%, respectively. Glycemic control has been established as the most important risk factor for the development of diabetic nephropathy, but less than 35% of patients develop kidney disease, regardless of glycemic control, suggesting a role for genetic predisposition (66,67). Familial clustering of both diabetic nephropathy and cardiovascular disease has been observed in studies of both types I and II diabetes (68,69). Diabetes mellitus is generally considered to be a contraindication to kidney donation. The diagnosis of diabetes is established by fasting plasma glucose (FPG) > 126 mg/dl on two occasions, or a 75 g two-hour oral glucose tolerance > 200 mg/dl. A 75 g two-hour oral glucose tolerance test should be performed if any of the following are present: impaired FPG (FPG > 110mg/dL and < 126mg/dl), first-degree relative with history of diabetes, second degree relative with history of diabetes in a donor candidate < 40 years old, history of gestational diabetes or infant with > 9 pound birth weight, BP > 140/90, fasting triglycerides >250 mg/dl, body mass index (BMI) >30, and high-density lipoprotein (HDL) < 35. A patient with impaired fasting or impaired two-hour glucose tolerance may be an acceptable donor candidate, but should be advised of the possible increased renal and overall health risk following donation. A persistent urine albumin excretion of > 30 mg/24 hours or 20 mg/g of creatinine should be considered relative contraindications to kidney donation in the setting of glucose intolerance. Because of the familial clustering of nephropathy and cardiovascular disease, an evaluation for comorbid conditions, including heart disease, should be pursued, and follow-up postdonation should include yearly urinary albumin measurements and evaluation for appropriate risk factor modification such as intensive BP and lipid management. OBESITY Although obesity may play a role in the development and progression of some glomerular lesions, such as focal segmental glomerulosclerosis and IgA nephropathy (70–77), the risk of renal disease attributable to obesity itself, rather than its associated comorbidities, such as impaired glucose tolerance, hypertension, hyperlipidemia, cardiovascular disease, and sleep apnea, is difficult to quantify. In particular, the effect of nonmorbid obesity alone in the development of renal disease is not defined, although it appears to be increased after nephrectomy (78,79). In one small study examining 73 patients after unilateral nephrectomy, 13 of 14 (98%) patients with a BMI >30, compared with seven of 59 (12%) patients with a BMI <30, had evidence of proteinuria and renal insufficiency at a follow-up of 13.6 + 8.6 years (80). The estimated odds ratio of proteinuria or renal insufficiency attributed to a BMI of >30 at the time of nephrectomy by multiple logistic regression was found to be 1.34 (1.03–1.76). The experience at a single center with obese donors suggests that the rate of major surgical complications and length of hospital stay are not significantly increased for obese donors (81,82). Renal function was similar, but follow-up was limited to 12 months, and long-term renal effects are not known. Although obesity alone may not be a contraindication to kidney donation, potential donors should be evaluated for obesity-related comorbidities (including hypertension, cardiovascular disease, obstructive sleep apnea, cancer, and diabetes), informed

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of the possible increased risks of donation, and should be offered regular, long-term follow-up. Kidney donation should probably be discouraged in donors with a BMI >40, although definitive evidence is lacking. POLYCYSTIC KIDNEY DISEASE Transplant programs will frequently evaluate donors at risk for polycystic kidney disease, as the incidence of autosomal-dominant polycystic kidney disease (PKD) is approximately one in 700 live births. Fortunately, screening for ADPKD using ultrasound is effective, as ultrasound criteria have a near 100% specificity after the age of 30 (83). Accepted ultrasound criteria for the diagnosis of ADPKD1 are as follows: 1. < 30 years of age, at least two cysts, either unilateral or bilateral 2. 30 to 59 years of age, at least two cysts in each kidney 3. > 60 years of age, at least four cysts in each kidney The above ultrasound criteria do not apply for ADPKD2, which tends to present with cysts later in life; however, the incidence of renal disease and rate of progression are significantly less than in ADPKD1, while its diagnosis is, arguably, somewhat more difficult in the potential living donor (83). The role of CT and MRI imaging in screening younger donors remains to be defined. Preliminary evidence suggests increased sensitivity with these modalities when compared to ultrasound, and the lack of cysts in the liver and kidney may reliably exclude ADPKD1 in patients as young as 20 years of age (84). Direct sequencing of the PKD1 and PKD2 genes is commercially available, and for patients under the age of 30, can be considered. However, because of the large size of the PKD1 gene, in particular, and the difficulty in determining the clinical significance of isolated mutations, the results of direct sequencing are generally difficult to interpret. If at least two other family members are available, linkage analysis, which provides diagnostic reliability of greater than 99%, can be performed (85). HEREDITARY NEPHRITIS (ALPORT’S SYNDROME) In individuals with a family history of nephritis, living donors should be advised regarding risk of developing nephritis. In men and women with a family history of nephritis but who do not have hematuria, the risk of progression to disease is unlikely, and they should be reasonable candidates. Screening for Alport’s disease can be performed with immunohistochemical analysis of skin biopsies using monoclonal antibodies directed at the collagen α-5(IV) chain (86–88). If protein expression is negative in men or mosaic in women, the diagnosis of X-linked Alport’s syndrome or carrier status is confirmed. If expression is positive, the possibilities of the rarer form of autosomal recessive disease, non-Alport’s nephritis, or antigenically normal but functionally abnormal protein expression exist. Further diagnostic testing could include renal biopsy. Molecular genetic testing is not currently available commercially in the United States. Women with a family history of nephritis and hematuria may have an increased risk of renal disease, but potentially could still be allowed to donate. Of concern for these women is the reported incidence of ESRD for the X-linked carrier that has been estimated at 12% before age 40 and 30% by age 60, although the percentages are generally considered to be high and the result of disproportionate loss to follow-up of study participants with a benign renal course (89). RENOVASCULAR DISEASE Renovascular disease is detected in up to 10.9% of kidney donor candidates during routine preoperative imaging (90). Even as the most common findings of the vascular disease in the donor candidates are either fibromuscular dysplasia (FMD) or atherosclerotic disease, other anatomic concerns such as renal artery aneurysms may be demonstrated on imaging studies. The selection of which imaging study to use is often driven by local expertise, and there are data supporting the use of CT angiogram (CTA), MR angiogram (MRA), or angiography. However, concerns

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have been raised that CTA or MRA may overlook mild cases of FMD (91). A case has been reported of fibromuscular dysplasia undetected by CTA prior to donation, which progressed to severe symptomatic stenosis with hypertension and acute renal failure (92). If the donor with abnormal vascular anatomy undergoes nephrectomy, it is standard practice to use the kidney with the abnormal vasculature, in spite of a potentially higher risk of vascular and urologic complications in the recipient. Given the risks of hypertension and renal failure, candidates with moderate to severe FMD and bilateral FMD are at high risk for renal complications. Some centers will accept donors with mild FMD and have demonstrated good graft outcomes (93). With the aging of potential donors, the likelihood of an increasing number of donor candidates with atherosclerotic renovascular disease is high. Limited data exist regarding kidney donor outcomes with isolated atherosclerosis, but one report suggests that living donors with renovascular disease can safely undergo nephrectomy “provided that careful selection, informed consent, and a normal remaining kidney are ensured” (94). CONCLUSION In conclusion, living donor candidates should be advised regarding potential modifying risks of developing chronic kidney disease. The presence of a modifying factor may need to be evaluated by testing outside of routine checklists, such as genetic testing in those with a family history of polycystic kidney disease. Once additional data are collected, the transplant team may fully address the concerns raised by modifying risk factors. The follow-up evaluations may eliminate putative risk factors found on initial presentation, such as the case when ambulatory BP findings demonstrate a normotensive candidate after a high BP finding in the evaluation clinic. In most cases, the living kidney donors with modifying risk factors may choose not to undergo nephrectomy, or the team may not find the potential donor to have an acceptable risk profile. However, in those donors with modifying risk factors, close follow up with a primary physician is required, with at least an annual history and physical with BP measurement, cardiovascular risk assessment, urinalysis, serum creatinine, and spot urine albumin/creatinine ratio. Those who choose to undergo living donor nephrectomy should be advised to adopt healthy lifestyles including tobacco cessation, maintenance of a target weight, and physical exercise. Finally, the risk of renal disease in donors with multiple potential risk factors remains uncertain. Given the increase in living donor transplantation and the expansion of the criteria for acceptable kidney donors, this area merits further investigation and very close follow-up of outcomes by transplant centers. REFERENCES 1. Kasiske BL, Ma JZ, Louis TA, Swan SK: Long-term effects of reduced renal mass in humans. Kidney Int 1995; 48:814–819. 2. Steiner RW. Risk appreciation for living kidney donors: Another new subspecialty? Am J Transplant 2004; 4:694–697. 3. Narkun-Burgess DM, Nolan CR, Norman JE, Page WF, Miller PL, Meyer TW. Forty-five year follow-up after uninephrectomy. Kidney Int 1993; 43:1110–1115. 4. Fehrman-Ekholm I, Elinder CG, Stenbeck M, Tyden G, Groth CG. Kidney donors live longer. Transplantation 1997; 64:976–978. 5. Fehrman-Ekholm I, Duner F, Brink B, Tyden G, Elinder CG. No evidence of accelerated loss of kidney function in living kidney donors: Results from a cross-sectional follow-up. Transplantation 2001; 72:444–449. 6. Ellison MD, McBride MA, Taranto SE, Delmonico FL, Kauffman HM. Living kidney donors in need of kidney transplants: A report from the organ procurement and transplantation network. Transplantation 2002; 74:1349–1351. 7. Ramcharan T, Matas AJ. Long-term (20-37 years) follow-up of living kidney donors. Am J Transplant 2002; 2:959–964. 8. Freedman BI, Volkova NV, Satko SG, et al. Population-Based Screening for Family History of End-Stage Renal Disease among Incident Dialysis Patients. Am J Nephrol 2005; 25:529–535. 9. Najarian JS, Chavers BM, McHugh LE, Matas AJ. 20 years or more of follow-up of living kidney donors. Lancet 1992; 340:807–810. 10. De La Vega LS, Torres A, Bohorquez HE, et al. Patient and graft outcomes from older living kidney donors are similar to those from younger donors despite lower GFR. Kidney Int 2004; 66:1654–1661.

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41. Van Savage JG, Fried FA. Anticoagulant associated hematuria: a prospective study. J Urol 1995; 153:1594–1596. 42. Mokulis JA, Arndt WF, Downey JR, Caballero RL, Thompson IM. Should renal ultrasound be performed in the patient with microscopic hematuria and a normal excretory urogram? J Urol 1995; 154:1300–1301. 43. Lang EK, Thomas R, Davis R, et al. Multiphasic helical computerized tomography for the assessment of microscopic hematuria: a prospective study. J Urol 2004; 171:237–243. 44. Lang EK, Macchia RJ, Thomas R, et al. Improved detection of renal pathologic features on multiphasic helical CT compared with IVU in patients presenting with microscopic hematuria. Urology 2003; 61:528–532. 45. Sarnacki CT, McCormack LJ, Kiser WS, Hazard JB, McLaughlin TC, Belovich DM. Urinary cytology and the clinical diagnosis of urinary tract malignancy: a clinicopathologic study of 1,400 patients. J Urol 1971; 106:761–764. 46. Konety BR, Getzenberg RH. Urine based markers of urological malignancy. J Urol 2001; 165:600–611. 47. Konety BR, Metro MJ, Melham MF, Salup RR. Diagnostic value of voided urine and bladder barbotage cytology in detecting transitional cell carcinoma of the urinary tract. Urol Int 1999; 62:26–30. 48. Murakami S, Igarashi T, Hara S, Shimazaki J. Strategies for asymptomatic microscopic hematuria: a prospective study of 1,034 patients. J Urol 1990; 144:99–101. 49. McGregor DO, Lynn KL, Bailey RR, Robson RA, Gardner J. Clinical audit of the use of renal biopsy in the management of isolated microscopic hematuria. Clin Nephrol 1998; 49:345–348. 50. Hall CL, Bradley R, Kerr A, Attoti R, Peat D. Clinical value of renal biopsy in patients with asymptomatic microscopic hematuria with and without low-grade proteinuria. Clin Nephrol 2004; 62:267–272. 51. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney Int 2003; 63:1817–1823. 52. Johnson CM, Wilson DM, O’Fallon WM, Malek RS, Kurland LT. Renal stone epidemiology: a 25-year study in Rochester, Minnesota. Kidney Int 1979; 16:624–631. 53. Uribarri J, Oh MS, Carroll HJ. The first kidney stone. Ann Intern Med 1989; 111:1006–1009. 54. Sutherland JW, Parks JH, Coe FL. Recurrence after a single renal stone in a community practice. Miner Electrolyte Metab 1985; 11:267–269. 55. Lee YH, Huang WC, Chang LS, Chen MT, Yang YF, Huang JK. The long-term stone recurrence rate and renal function change in unilateral nephrectomy urolithiasis patients. J Urol 1994; 152: 1386–1388. 56. Worcester E, Parks JH, Josephson MA, Thisted RA, Coe FL. Causes and consequences of kidney loss in patients with nephrolithiasis. Kidney Int 2003; 64:2204–2213. 57. Qazi YA, Ali Y, Venuto RC. Donor calculi induced acute renal failure. Ren Fail 2003; 25:315–322. 58. Lerut J, Lerut T, Gruwez JA, Michielsen P. Case profile: donor graft lithiasis—unusual complication of renal transplantation. Urology 1979; 14:627–628. 59. Kar PM, Popili S, Hatch D. Renal transplantation: donor with renal stone disease. Clin Nephrol 1994; 42:347–348. 60. Van Gansbeke D, Zalcman M, Matos C, Simon J, Kinnaert P, Struyven J. Lithiasic complications of renal transplantation: the donor graft lithiasis concept. Urol Radiol 1985; 7:157–160. 61. Rashid mg, Konnak JW, Wolf JS, et al. Ex vivo ureteroscopic treatment of calculi in donor kidneys at renal transplantation. J Urol 2004; 171:58–60. 62. Lotan Y, Cadeddu JA, Roerhborn CG, Pak CY, Pearle MS. Cost-effectiveness of medical management strategies for nephrolithiasis. J Urol 2004; 172:2275–2281. 63. Lotan Y, Cadeddu JA, Pearle MS. International comparison of cost effectiveness of medical management strategies for nephrolithiasis. Urol Res 2005; 33:223–230. 64. Genuth S, Alberti KG, Bennett P, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003; 26:3160–3167. 65. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63:225–232. 66. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999; 341:1127–1133. 67. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int 1995; 47:1703–1720. 68. Rudberg S, Stattin EL, Dahlquist G. Familial and perinatal risk factors for micro- and macroalbuminuria in young IDDM patients. Diabetes 1998; 47:1121–1126. 69. Canani LH, Gerchman F, Gross JL.: Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients. Diabetes 1999; 48:909–913. 70. Jennette JC, Charles L, Grubb W. Glomerulomegaly and focal segmental glomerulosclerosis associated with obesity and sleep-apnea syndrome. Am J Kidney Dis 1987; 10:470–472. 71. Bonnet F, Deprele C, Sassolas A, et al. Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis. Am J Kidney Dis 2001; 37:720–727.

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72. Kasiske BL, Cleary MP, O’Donnell MP, Keane WF. Effects of genetic obesity on renal structure and function in the Zucker rat. J Lab Clin Med 1985; 106:598–604. 73. Kasiske BL, Napier J. Glomerular sclerosis in patients with massive obesity. Am J Nephrol 1985; 5:45–50. 74. O’Donnell MP, Kasiske BL, Cleary MP, Keane WF. Effects of genetic obesity on renal structure and function in the Zucker rat. II. Micropuncture studies. J Lab Clin Med 1985; 106:605–610. 75. Kasiske BL, Crosson JT. Renal disease in patients with massive obesity. Arch Intern Med 1986; 146:1105–1109. 76. Weisinger JR, Kempson RL, Eldridge FL, Swenson RS. The nephrotic syndrome: a complication of massive obesity. Ann Intern Med 1974; 81:440–447. 77. Verani RR. Obesity-associated focal segmental glomerulosclerosis: pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia. Am J Kidney Dis 1992; 20:629–634. 78. Praga M. Obesity—a neglected culprit in renal disease. Nephrol Dial Transplant 2002; 17:1157–1159. 79. Praga M, Hernandez E, Herrero JC, et al. Influence of obesity on the appearance of proteinuria and renal insufficiency after unilateral nephrectomy. Kidney Int 2000; 58:2111–2118. 80. Praga M, Perez JCR, Rodicio JL, et al. The Spanish Society of Nephrology Forum—Hyperfiltration nephropathy. Nefrologia 2000; 20:311–335. 81. Heimbach JK, Taler SJ, Prieto M, et al. Obesity in living-kidney donors: Clinical characteristics and outcomes in the era of laparoscopic donor nephrectomy. Am JTransplant 2005; 5:1057–1064. 82. Chow GK, Prieto M, Bohorquez HE, Stegall MD. Hand-assisted laparoscopic donor nephrectomy for morbidly obese patients. Transplant Proc 2002; 34:728. 83. Parfrey PS, Bear JC, Morgan J, et al. The diagnosis and prognosis of autosomal dominant polycystic kidney disease. N Engl J Med 1990; 323:1085–1090. 84. Gabow PA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 1990; 11:1033–1037. 85. Breuning MH, Reeders ST, Brunner H, et al. Improved early diagnosis of adult polycystic kidney disease with flanking DNA markers. Lancet 1987; 2:1359–1361. 86. Kashtan CE, Michael AF. Alport syndrome. Kidney Int 1996; 50:1445–1463. 87. Yoshioka K, Hino S, Takemura T, et al. Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody. Am J Pathol 1994; 144:986–996. 88. van der Loop FT, Monnens LA, Schroder CH, et al. Identification of COL4A5 defects in Alport’s syndrome by immunohistochemistry of skin. Kidney Int 1999; 55:1217–1224. 89. Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol 2000; 11:649–657. 90. Hiramoto JS, LaBerge JM, Neymark E, Hirose R. Live-donor renal transplants using kidneys with arteriographic evidence of mild renovascular disease. Clin Transplant 2002; 16:24–29. 91. Andreoni KA, Weeks SM, Gerber DA, et al. Incidence of donor renal fibromuscular dysplasia: does it justify routine angiography? Transplantation 2002; 73:1112–1116. 92. Parasuraman R, Attallah N, Venkat KK, et al. Rapid progression of native renal artery fibromuscular dysplasia following kidney donation. Am J Transplant 2004; 4:1910–1914. 93. Kolettis PN, Bugg CE, Lockhart ME, Bynon SJ, Burns JR. Outcomes for live-donor renal transplantation using kidneys with medial fibroplasia. Urology 2004; 63:656–659. 94. Serrano DP, Flechner SM, Modlin CS, Streem SB, Goldfarb DA, Novick AC. The use of kidneys from living donors with renal vascular disease: expanding the donor pool. J Urol 1997; 157:1587–1591. 95. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003; 290:199–206.

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Technical Aspects of Live-Donor Nephrectomy Amit Basu and Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

John L. Falcone Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION The first donor operation ever performed for successful clinical vascularized solid organ transplantation was a live open donor nephrectomy. It remains the most commonly performed donor operation today, but the technical aspects have evolved considerably. There are a number of possible techniques that are being utilized currently, and they include the following: 1. Traditional open donor nephrectomy (ODN) by a flank incision or anterior approach. 2. Minimal incisional open donor nephrectomy (MIODN) using a posterior or anterior approach. 3. Laparoscopic live donor nephrectomy (LLDN), or hand-assisted LLDN (HALDN). 4. Robotic hand-assisted laparoscopic live donor nephrectomy (RHALDN). The technical aspects of these various alternatives are discussed in this chapter. OPEN DONOR NEPHRECTOMY All other factors being equal, the left kidney is recovered preferably because it has a longer renal vein. The right kidney is removed in the case of multiple renal arteries on the left side, or in the situation where there is some slight abnormality of the right kidney with a normal left kidney (e.g., a significantly smaller right kidney, a small nonobstructive calculus, or a stenotic arterial ostium of the right kidney). After appropriate preoperative donor evaluation [including the determination of medical suitability of the donor, immunological compatibility between the donor and recipient, and obtaining written informed consent (see Chapter 37)], the donor is brought to the operating room. Sequential compression devices are placed on both legs prior to induction of general endotracheal anesthesia, and a Foley catheter is inserted for close monitoring of urine output. The patient is placed in a nearly right lateral position (the donor is actually a bit anterior), the table is flexed, and the kidney rest is raised to open up the left flank (Fig. 1). The left arm is placed on an armrest. The right leg is flexed and the left leg kept extended with a pillow between the two, and the patient is kept in position using broad adhesive tapes. After preparation and draping a wide area of the left flank, an incision is made in the skin extending from the tip of the 11th rib anteriorly and toward the umbilicus for 12 to 14 cm, ending at the lateral border of the left rectus abdominis. Alternatively, the incision can be made just below the 12th rib to minimize the risk of pneumothorax. The incision is deepened through the subcutaneous fat and muscles to expose the tip of the 11th rib for about 4 cm. The periosteum is mobilized along the upper and lower margins of the 11th rib and on its posterior surface. The incision is deepened through the muscle layers of the external oblique, internal

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FIGURE 1 Position of patient for flank approach to open donor nephrectomy; note the axillary pad. Source: From Ref. 18.

oblique, and transversus abdominis and extended anteriorly. The peritoneum is identified and mobilized medially, by blunt dissection posteriorly, some of the perinephric fat is removed and the kidney identified by palpation within the Gerota’s fascia. The Gerota’s fascia is incised and the plane developed between the fat and the capsule of the kidney. A Bookwalter retractor is set up with a round ring (alternatively, the iron intern is utilized). The right-angled Richardson retractor blade is used to retract the particular part of the wound where dissection is being performed. Dissection is generally carried out within the Gerota’s fascia, in a plane between the fat and the capsule of the kidney. The kidney is mobilized by dissection of the aerolar tissue between the fat and the kidney capsule with electrocautery. This dissection is continued to the superior pole of the kidney as well as on the anterior, posterior, and lateral aspects. Next, by elevating the posterior and inferior part of the kidney forward, and by dissecting outside the Gerota’s fascia, the ureter and left gonadal vein are identified. The ureter and left gonadal vein are isolated, dissected out, and a vessel loop placed around them. Once the upper pole of the kidney has been mobilized, the kidney drops down into the region of the incision, making further dissection easier. The aerolar tissue is released from the anterior surface of the kidney close to the medial aspect of the hilum. By careful dissection, the left renal vein is identified. The gonadal vein is traced upward to its junction with the left renal vein. The gonadal vein is doubly ligated in continuity close to its junction with the renal vein and divided between the ligatures. A right angle clamp is passed around the left renal vein and a vessel loop passed around it. The renal vein dissection is extended, and vein tributaries, including the lumbar and adrenal veins, are divided between ligatures. Prior to dissecting free the renal artery, periarterial papavarine is infiltrated to minimize the risk of arterial spasm. The artery is dissected free, and the rest of the hilum is mobilized to free up the kidney completely. During the dissection of the vessels, intravenous Furosemide is given in 5 to10 mg increments intravenously two or three times, and Mannitol is given in 12.5 gm increments intravenously two or three times. During the procedure, between 6 and 8 L of crystalloid are given. The ureter is clamped at the level of bifurcation of the iliac artery and is divided. The distal ureter is ligated with 0-chromic catgut (or 0-vicryl). Urine output from the end of the divided ureter should be observed; urine from the contralateral kidney should continue to collect in the urine bag via the Foley catheter. Hendren clamps are applied to the renal artery (ies) and vein(s), and then divided sequentially. The kidney is removed from the field and perfused using cold lactated Ringer’s solution containing 100 mg Procaine and 10,000 units of heparin per liter (University of Wisconsin or other preservation solution can also be used). The ends of the renal artery and renal vein are oversewn with running 4-0 polypropylene, and undertied with 0-silk ligature sutures (if there is no hard atherosclerotic plaque). After ensuring hemostasis and absence of pleural defects, the kidney rest is lowered and the table is reflexed. Closure of the muscle layers is done in two layers with 0-polypropylene or 0–PDS (polydioxanone) sutures (sometimes it is easier to place the innermost layer of sutures before reflexing the table and then tie them after reflexing the table). The subcutaneous layer and skin are closed with Vicryl, and steristrips are applied to the wound. While doing a right ODN, a similar approach and technique is used. The right renal vein is shorter and thin-walled. To maximize vein length, a larger Hendren clamp is applied to occlude partially the inferior vena cava (IVC), and the vein is divided almost flush with the IVC. In this setting, only a two-layer polypropylene closure is possible. Lumbar veins are found

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FIGURE 2 Patient positioning, anatomic landmarks, and retractor system used in anterior retroperitoneal live donor nephrectomy. Source: From Ref. 1.

infrequently on the right side, and the gonadal vein generally drains directly into the IVC. Hilar dissection of the right kidney also involves dissecting the duodenum away from the IVC. ODN using an anterior, retroperitoneal approach has been described by Jones and colleagues (1) (Figs. 2 and 3). Here, the incision extends from the mid-rectus in the subcostal region, and laterally to beyond the midaxillary line. “MINIMAL INCISIONAL” OPEN DONOR NEPHRECTOMY “Minimal incisional” open donor nephrectomy has been performed using a posterior transcostal (2) or supracostal (3) approach. The surgeon uses 3.5 x loupe magnification and a head-light with a high-intensity light source for the procedure. The donor is placed in the lateral decubitus position with the kidney rest raised between the iliac crest and the lower border of the rib cage (Fig. 4). The lower extremity resting on the table is flexed 30 degrees at the hip and 90 degrees at the knee. The donor is tilted 10 to 15 degrees forward to provide better access to the back. The table is flexed until the flank skin is stretched to spread the ribs and the flank musculature. The arm resting on the table is extended with an axillary roll placed to relieve pressure on axillary structures. The other arm is placed on a Mayo stand or a Kraske holder. The 12th rib and its relationship to the kidney are determined on a preoperative angiogram. A 6 to 8 cm long (this may be longer in obese patients) incision is marked along the course

FIGURE 3 Anterior retroperitoneal living donor nephrectomy with retractor system in position. Source: From Ref. 1.

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FIGURE 4 Donor position for minimally invasive open donor nephrectomy. Source: From Ref. 2.

of the 12th rib, 2 to 3 cm anterior to the sacrospinalis muscle. If the rib is absent or short, a subcostal incision is placed in the same location using the 11th rib as a guide. A Wheatlander retractor is used to expose deeper tissues and the latissimus dorsi and serratus posterior inferior muscles are divided to expose the 12th rib (Fig. 5). An extraperiosteal rib resection is done and the 12th rib divided at the lateral border of the sacrospinalis. The vertical post of a Bookwalter retractor, along with a large ring, is set up. Following division of the lumbodorsal fascia, extraperitoneal fat is encountered. Excision of the fat pad allows creation of a working space around the kidney. Following this, longitudinal incision of the Gerota’s fascia is done and excision of perinephric fat is commenced at the middle of the kidney. Dissection extends posteriorly and then superiorly to release the upper pole. A self-retaining right-angle blade retracts the upper cut edge of the abdominal wall to facilitate dissection of the upper pole (Fig. 6). A handheld Sweetheart retractor blade is used to displace the kidney caudally to help in dissection. Perinephric fat in the posterior-inferior part of the kidney is excised. A Sweetheart blade is used to retract the peritoneum medially. After retracting the kidney upward with a selfretaining Dever blade, a plane is developed between the gonadal vein and ureters preserving the periureteric plexus of vessels (Fig. 7). The ureter is encircled with a vessel loop and, by using gentle traction on this loop, the ureter is dissected to a point 2 cm beyond where it crosses the external iliac vessels. The perinephric fat pad anterior to the kidney is excised, and the peritoneum is retracted medially by repositioning the self-retaining Sweetheart blade. The gonadal vein is divided between medium-sized ligaclips near its insertion, leaving a generous stump on the renal vein. Retracting the upper pole of the kidney downward and medially using a Dever blade and using a Sweetheart blade to retract the peritoneum medially allows complete exposure of the renal vein (Fig. 8). The adrenal vein is isolated, clipped, and divided. The renal artery

FIGURE 5 Incision and position of retractor for minimally invasive open donor nephrectomy. Source: From Ref. 2.

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FIGURE 6 Retraction to facilitate dissection of the upper pole in minimally invasive open donor nephrectomy. Source: From Ref. 2.

FIGURE 7 Dissection of the ureter for minimally invasive open donor nephrectomy. Source: From Ref. 2.

FIGURE 8 Dissection of the hilum in minimally invasive open donor nephrectomy. Source: From Ref. 2.

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is dissected to its origin, and the plexus of nerves and lymphatics between the artery and vein are divided. All lumbar tributaries are then visualized straight ahead, as this is a posterior approach, and these are then clipped and divided. The kidney is then medially retracted with a Sweetheart retractor. Fat and areolar tissue on the posterior aspect of the kidney is divided. Intravenous heparin is administered at a dose of 80 units/kg. The ureter is divided first using medium ligaclips or large Hemolock clips to occlude the distal ureter. A self-retaining Sweetheart blade is used to retract the peritoneum medially, even as a hand-held or self-retaining Dever retractor blade retracts the kidney downward and medially to expose the renal vein and renal artery. Vascular clamps are applied on the renal vein and renal artery, and they are divided sequentially. After removing the Dever blade, a ring forceps is used to grab the upper pole of the kidney to deliver it vertically upward through the incision. The renal vein stump is closed with a 5-0 polypropylene continuous suture followed by closure of the renal artery in a similar fashion. A laparoscopic knot pusher is used to slide the knots down. The retroperitoneum is inspected for hemostasis and for violation of the peritoneum or pleura. A peritoneal opening is closed with a 4-0 absorbable suture. If a pleural opening is identified, the rent in the diaphragm is closed around a red rubber catheter. The catheter is removed simultaneously with closure of the diaphragmatic defect and expansion of the lungs. The lumbodorsal fascia is closed with continuous sutures as a first layer. The serratus posterior inferior and latissimus dorsi are closed with interrupted 0-Vicryl figure of eight sutures. Subcutaneous tissue is closed with 3-0 continuous Vicryl, and a subcuticular skin closure is done with 4-0 absorbable monofilament or Vicryl sutures. While performing a right nephrectomy, the gonadal vein directly enters the IVC, and the renal vein is short. The retrocaval arterial dissection and division of short lumbar tributaries of the IVC are easier with this posterior approach. In the MIODN procedure, there is division of only the lateral portion of the latissimus dorsi and part of the serratus posterior inferior muscles, so there is minimal postoperative discomfort. As only a small amount of retrocostal extraperitoneal fat is encountered with this posterior approach, it is an acceptable procedure even for donors with increased body mass index. The modified use of the Bookwalter retractor allows adequate exposure to the area of dissection; the upper pole, lower pole, ureter, hilum, and posterior portion of the renal pelvis are dissected sequentially to complete mobilization of the allograft. One or two blades are placed on the Bookwalter ring on the same or adjacent sides of the incision to skew it to the area of the dissection. The posterior approach provides a direct view of the lumbar and adrenal tributaries. The small incision provides little room for hand ties. Use of automated surgical clips reduces the need for hand ties. When hand ties are needed for closure of vessels, a laparoscopic knot pusher is used. The transcostal technique is a modification of the conventional retroperitoneal approach, and is designed to reduce morbidity. Surgeons familiar with the retroperitoneal approach can easily adopt this technique with a short learning curve. Additional investment in expensive equipment is not required. Furthermore, the transcostal incision can be easily and safely extended, if necessary, for the emergent control of bleeding. This does not require additional equipment or a change in the position of the donor. Using a modified Turner-Warwick approach, a minimal incisional posterior supracostal technique has been developed for live donor nephrectomy (3). This approach takes advantage of the fact that, if the superior ligamentous attachment of the 11th or 12th rib is secured, the rib can be hinged inferiorly to give maximal exposure of the renal bed. Following induction of general endotracheal anesthesia and placement of a Foley catheter, the patient is placed in the standard lateral decubitus position. The arteriogram is examined to determine the level of the kidney and the 11th or 12th rib is chosen for the initial incision. The incision begins at the tip of the 11th or 12th rib and extends posteriorly over the rib for 10 to14 cm. The subcutaneous tissue is divided with electrocautery, and the attachments of latissimus dorsi and serratus anterior are divided for a short distance along the rib. Superior attachments of the intercostal muscles to the rib are divided by electrocautery. Ligaments of the vertebral column posteriorly are divided bluntly, and the rib is hinged inferiorly. The diaphragmatic attachments to the rib are taken down using electrocautery, and exposure to the field is maintained with a hand-held retractor. After incising Gerota’s fascia, its attachments to the kidney are taken down. The superior pole of the kidney is dissected free from the surrounding tissue first, followed by the lower pole. The

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ureter is identified and dissected down to the level of the iliacs. Two large clips are placed on the distal ureter, and the proximal part brought up into the operative field. Arterial and venous blood supplies of the donor kidney are dissected free from the surrounding tissue. Branches to the renal vein and from the artery are clipped twice proximally and distally, and then divided. At the beginning of the hilar dissection, 0.5 gm/kg of Mannitol and 20 mg of Furosemide are administered intravenously to the donor. Three minutes before removing the kidney, 50 to 60 units per kg of heparin is given intravenously. The kidney is flushed on the prepared backtable with 300 to 400 cc of Eurocollins solution immediately after removal. After completion of the nephrectomy, the previously retracted rib is allowed to assume its normal position. The muscles are closed in two layers. Subcutaneous tissue is approximated and the skin is closed with a subcuticular suture. The minimal incisional posterior supracostal approach was found to be superior to the conventional ODN, allowing shorter incision length, minimizing postoperative analgesia, reducing the hospital stay, and enhancing return to full activity. The length of stay with the supracostal approach is significantly shorter than with conventional ODN. The use of this incision also avoids the uncommon but recognized complication of a bulge on the ipsilateral side that can occur with conventional ODN. In the study reported, several outcome parameters, including the length of stay and return to activity, were comparable to those observed in published series of laparoscopic donor nephrectomy (3). Although difficult vascular dissection and potential loss of control must be handled with immediate extension of the incision, the kidney is easily accessible, even in obese donors, without extending the length of the incision. According to its advocates, because the supracostal approach is a modification of conventional ODN, it should not require special training and the use of costly laparoscopic instrumentation; surgeons performing conventional ODN can easily adopt the procedure. LAPAROSCOPIC LIVE DONOR NEPHRECTOMY The flank incision for ODN is associated with considerable morbidity in terms of postoperative pain, slow recuperation, pneumothorax, and a substantial incidence of long-term wound complications, such as diastasis, hernia, and chronic pain or discomfort. Limitations of the extraperitoneal approach to donor nephrectomy combined with advances in laparoscopic surgery, such as high-quality video systems, vascular stapling devices, and the harmonic scalpel, provided the impetus for developing the minimally invasive approach to live renal donation. Benefits of a laparoscopic donor procedure include less postoperative pain, shorter hospitalization, less incisional morbidity, more rapid return to normal activity, and improved cosmesis. The potential advantages of a minimally invasive operation have led to an increased acceptance of the donor operation and perhaps an expansion of the pool of potential kidney donors (4,5). A helical/spiral CT angiogram with 3D reconstruction is done preoperatively to assess the vasculature of the kidneys. LLDN is performed through a transperitoneal approach (6). Sequential compression devices are placed on both legs, and general endotracheal anesthesia is induced. A Foley catheter and an orogastic tube are placed. The patient is placed in a modified flank position with the torso in a 30-degree lateral decubitus position with the right side down and secured to the table (Fig. 9). The hips are rolled slightly posteriorly to allow exposure of the lower abdominal midline. The arms are flexed and placed at chest level with appropriate axillary roll, padding, egg crates, and pillows to protect the brachial plexus as well as the lower extremity from any compression. The arms and pillow assembly, the head, and the lower limbs are affixed to the Skytron Elite 6500 Operating Table with several rolls of adhesive tape to prevent dislodgement of the patient. The table is then flexed. Pneumoperitoneum to a pressure of up to 15 mm Hg is established using a Veress needle at the lateral margin of the left rectus sheath. Three transperitoneal laparoscopic ports are placed under direct visualization. The first port is a 12 mm port placed lateral to the rectus, about twothirds of the distance between the umbilicus and the left anterior superior iliac spine using a Visiport optical trocar. A second 10/12 mm port is placed infraumbilically in the midline and a third 5 mm port placed in the midline approximately two to three fingersbreaths below the xiphoid process. The umbilical port is used as a camera port throughout the dissection, and a 30-degree lens is used for visualization.

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FIGURE 9 Patient positioning for left laparoscopic donor nephrectomy. Source: From Ref. 7.

After pneumoperitoneum is achieved, the laparoscopic curved DeBakey-Crile forceps and Metzenbaum scissors are used to incise the left lateral peritoneal reflection (Fig. 10). The descending colon is reflected medially from the beginning of the splenic flexure down to the level of the sigmoid colon, incising the phrenocolic ligaments completely. This dissection is performed with the suction tip and Harmonic Scalpel (Ethicon). Great care is taken to ensure there is no bowel injury and that no mesenteric defect is created. A 5 cm long Pfannenstiel’s incision is made centered on the midline about two finger breadths above the pubic symphysis. The linea alba is incised in a longitudinal fashion and the peritoneum entered after placing a purse-string suture with 3-0 PDS. An Endocatch bag is then inserted through the purse-string while maintaining pneumoperitoneum. The Endocatch is used as a retractor for the descending colon (Fig. 11). The lieno-renal and spleno-colic ligaments are divided at the inferior border of the spleen, allowing the spleen to be retracted superiorly and to mobilize the splenic flexure medially (Fig. 12). The Gerota’s fascia is exposed by mobilizing the descending colon medially (7). A plane is developed between the Gerota’s fascia and the mensentery, adjacent to the lower pole of the kidney. Dissection is done medial to the gonadal vein and thus medial to the ureter. The ureter can be identified by demonstrating peristalsis. The plane medial to the gonadal vein and thus medial to the ureter is developed, and these structures are dissected off the psoas muscle. Great care is taken not to devascularize the ureter (7). This dissection is carried down to the left iliac fossa to maximize the length of the ureter available. Dissection is carried out at the medial aspect of the upper pole of the kidney, which is then dissected out carefully and mobilized until the upper pole is completely free. The left renal vein is then freed from its adventitial attachments, the adrenal and lumbar veins are identified, doubly clipped on both sides, and divided between clips (Fig. 13). After elevating the kidney, further dissection is performed, usually posteriorly to the renal vein to identify and isolate the renal artery after dividing the fibro-fatty and lymphatic tissue around the vessels. The renal

FIGURE 10 Incision of left lateral peritoneal reflection in left lateral donor nephrectomy. Source: From Ref. 19.

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FIGURE 11 Use of Endocatch bag introduced by a suprapubic incision to aid in colonic retraction in left laparoscopic donor nephrectomy. Source: From Ref. 19.

FIGURE 12 Division of the colorenal ligaments and exposure of the Gerota’s fascia. Inset shows mobilization of the upper pole of the kidney. Source: From Ref. 7.

FIGURE 13 Application of hemoclips on the adrenal vein prior to division in left laparoscopic donor nephrectomy. Source: From Ref. 7.

artery is dissected out for only a short distance after its take-off from the aorta to avoid arterial vasospasm. Care is taken to note that adequate space has been made to pass the endovascular GIA stapler (United States Surgical, Norwalk, Connecticut) around the artery and vein. While dissection of the hilum is being performed, 40 mg of Furosemide and 12.5 mg of Mannitol are given to the patient. Intravenous fluids alternating normal saline and lactated Ringer’s, with a total volume of 6 to 10 L, are given to minimize the side effects of pneumoperitoneum (7) and to avoid significant electrolyte imbalance, such as hypokalemia and hypomagnesemia.

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FIGURE 14 Division of the ureter at the level of the iliac vessels after triple clipping with 10 mm Hemoclips. Source: From Ref. 19.

The entire kidney is then freed of all its adventitial attachments, including the lateral, posterior, and inferior attachments. The patient is given a second dose of 40 mg of Lasix and 12.5 gm of Mannitol. Three thousand units of heparin are administered intravenously. The gonadal vein is followed distally toward the pelvis, clipped doubly on both sides, and divided at the level of the pelvis, where it crosses anterior to the ureter. The ureter is also transected at the level of the left iliac vessels after triple clipping with 10 mm clips distally (Fig. 14). After three minutes of systemic heparinization, the renal artery (Fig. 15) and vein (Fig. 16) are transected individually and sequentially with the endovascular GIA stapler. The kidney is placed into the Endocatch bag under direct laparoscopic vision and extracted from the peritoneal cavity via the Pfannenstiel incision. The kidney is flushed using cold preservation solution (we use lactated Ringer’s solution containing 100 mg Procaine and 10,000 units of heparin per liter) on the back table (8).

FIGURE 15 Division of the left renal artery with the endovascular GIA stapler in left laparoscopic donor nephrectomy. Source: From Ref. 7.

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FIGURE 16 Division of the left renal vein in laparoscopic donor nephrectomy using the endovascular GIA stapler. Source: From Ref. 19.

Thirty milligrams of protamine sulfate are given intravenously to reverse the effect of heparin. The abdominal fascia of the suprapubic wound is closed with interrupted #1 Vicryl in a figure of eight fashion. The renal bed and the stapled ends of the artery and vein are inspected for hemostasis. The mesentery is also inspected for defects. The fascia of the 12 mm port sites are closed with #1 Vicryl using the Carter-Thomason needle. Local anesthetic is injected into the fascia/skin prior to closure of the skin incision. Mandal and colleagues (9) reported on 14 (6.2%) patients with a retroaortic or circumaortic renal vein in a series of 227 kidneys recovered laparoscopically; there were no vascular complications noted. Right Laparoscopic Live Donor Nephrectomy Laparoscopic harvesting of the right kidney is technically more challenging than that of the left kidney because of the short right renal vein and the need to retract the liver away from the right kidney (10). There is an increased risk of thrombosis after right laparoscopic donor nephrectomy because of the shortening of the right renal vein related to the use of endoscopic vascular staples (10). The majority of surgeons performing right LLDN have used the presence of multiple left renal arteries (>3), a dominant left kidney, or a complex cystic lesion of unknown histology in the right kidney as relative contraindications to left LLDN. The donor is positioned in the left lateral decubitus position on the operating table with the kidney rest fully elevated and the bed in a flexed position. An axillary roll is placed beneath the donor’s arm and the right arm is maintained on an armrest in a flexed position. The donor is fixed in position using an inflatable beanbag with a convection blanket in place. The donor is prepped from nipples to pubis, from midline to spine. Initial port placement is modified from the left-sided operation by caudal placement from the costal margin. The ports are placed 2 to 4 cm lower on the right to allow visualization under the liver. Four operative trochar ports are used. A 12 mm port is placed through the umbilicus for the laparoscope; a 10 mm port is placed in the midline in the epigastrium, and a 5 mm port is placed in the right lower quadrant above and medial to the anterior superior iliac spine. A fourth 5 mm port is placed in the midline cephalad to the epigastric port to place a laparoscopic Kitner, grasper, or expandable fan for retracting the right lobe of the liver (Fig. 17). These methods of retraction require intermittent elevation of the right lobe of the liver when the superior pole of the kidney is mobilized. Exposure of the IVC is a major challenge in right LLDN. The right renal vein differs from the left in occasionally having several small anterior venous branches that can easily be avulsed

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FIGURE 17 Patient positioning and port placement for right laparoscopic living donor nephrectomy. Source: From Ref. 19.

during mobilization of the duodenum and colon. Several surgeons advocate the use of a laparoscopic hand-assist device to facilitate this part of the dissection (11) (Fig. 18). The intraabdominal hand facilitates surgical dissection, manually retracts the colon, facilitates duodenal mobilization and, when necessary, applies digital pressure on bleeding sites. Gonadal vein division is either avoided in right living donor nephrectomy or, if necessary, divided at a site distant from the renal vein. This strategy prevents a potentially obtrusive clip on the staple line. During stapling, maximal renal vein length can be achieved utilizing a caudal approach parallel to the IVC at the same time everting the vein above the IVC (Fig. 19). Division of short lumbar veins when present can be challenging because their lengths and limited mobility prohibit double clipping and division. Use of the hand-assist ports can facilitate the dissection by permitting an anterior rotation of the kidney and improving access to the posterior right renal artery and posterior lumbar vessels. Arterial mobilization in right LLDN requires dissection of the right renal artery from the posterior aspect of the right renal vein. After dividing the short lumbar veins, the right renal artery can be mobilized posterior to the IVC. Ratner and Kavoussi (12) have also described a technique to maximize right renal artery length by an interaortocaval approach. A drawback of this technique is that major mobilization of the vena cava can lead to vascular avulsion or division if anatomical landmarks are misidentified. The renal artery is divided first. To gain adequate length of the right renal artery, the kidney must be rotated medially (“flipped”) to allow posterior dissection between the anterior aspect of the renal artery and the IVC. Laparoscopic vascular staples are used to divide the renal artery and vein. Maximal renal arterial length can be obtained by placing the endovascular stapler on the renal artery at the same time as retracting the IVC medially away from the anterior

FIGURE 18 Position of hand-assist port to facilitate right laparoscopic living donor nephrectomy. Source: From Ref. 10.

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FIGURE 19 Division of right renal artery using endovascular GIA stapler introduced via a caudal port. Source: From Ref. 10.

aortic wall. With the kidney in its normal anatomic position, arterial division can proceed with superior traction, allowing an endovascular stapler to be placed from a caudal port (Fig. 20). Where inadequate renal artery exposure is obtained, the kidney can be retracted medially (“flipped”), and the renal artery stapled following introduction of the laparoscopic vascular stapler from a cephalad port (Fig. 21). Application of the standard GIA endovascular stapler on the right renal vein results in an obligatory loss of about 1.0 cm of renal vein. This is postulated to increase the risk of thrombosis after right laparoscopic donor nephrectomy. Among the methods introduced to increase the length of vein removed from the donor and overcome the short renal vein length are the following: 1. Placement of an extraction port over the right kidney, thus allowing open division of the renal vein. In a manner analogous to ODN, this allows harvesting a 1to 2 mm cuff of vena cava to maximize donor vein length. 2. The use of the hand-assist device is another variation of right living donor nephrectomy that can maximize vein length by enabling lateral retraction of the right kidney, allowing retraction of the renal vein and division of the renal vein at the level of its insertion into the vena cava. 3. Yet another technique is to place a stapling device (vascular cartridge of the Endo-TA stapler, United States Surgical, Norwalk, Connecticut) that places three rows of staples without dividing the vein. Before stapling, traction on the renal vein draws the adjacent caval wall into the jaws of the stapler. After firing, the staple line is carefully inspected to check that it is complete (Fig. 22). The vein is then divided with endoscopic scissors, close and parallel to the staple line. This maximizes renal vein length, leaving a staple line flush on the vena cava. When the operation is performed with attention to potential complications, right laparoscopic donor kidneys can provide kidneys without increased risk for thrombosis or other potential complications. Some groups have preferentially performed HALDN of the right kidney. This provides a margin of comfort when performing lateral retraction of the kidney, which improves the length of renal vein obtained. Some groups of surgeons, especially urologists, advocate the retroperitoneal approach, especially for right donor nephrectomies. This approach allows direct visualization of the renal vein-caval junction, ensuring the recovery of maximal renal vein

FIGURE 20 Division of the right renal vein using endovascular GIA stapler introduced via a caudal port. Source: From Ref. 10.

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FIGURE 21 Division of the right renal artery using an endovascular GIA stapler introduced by a cephalad port after “flipping” the kidney medially. Source: From Ref. 10.

length. Gill and colleagues (13) have had success in maximizing the right renal vein length at the same time minimizing the operative time and blood loss. In their initial experience of right LLDN at the Johns Hopkins Hospital (9), three (37.5%) of eight renal allografts were lost because of vascular complications. With modifications of the donor and recipient operations below, further graft losses were avoided (9). Three modifications of the donor operation were developed to preserve maximal right renal vein length: (i) passing the GIA stapler through a right lower quadrant port at the lateral border of the rectus abdominis muscle in a plane parallel to the IVC, (ii) relocation of the incision for extracting the kidney to the right subcostal region for open division of the right renal vein, and (iii) lengthening the right renal vein by using a panel graft constructed from the recipient greater saphenous vein (9). The recipient operation was also modified to provide a tension-free venous anastomosis. To do so, the left iliac vein is mobilized completely by dividing all posterior branches and transposed lateral to the left iliac artery. At the University of Pittsburgh Medical Center, of the over 400 LLDNs now performed, the vast majority are performed in about two hours of operating time, with a warm ischemia time less than five minutes, and blood loss <50 mL. The incidence of complication is now <2%, no delayed graft function, blood transfusion <0.5%, ureteral stenosis <0.5%, and the average hospital stay is 2.9 days. The one-year patient and graft survival rates are 99% and 98%, respectively, under alemtuzumab preconditioning, steroid free tacrolimus monotherapy (14). Hand-Assisted Laparoscopic Live Donor Nephrectomy LLDN demands technical proficiency and was associated with prolonged delayed graft function and increased ureteral complication rates in early series. Application of the hand-assist

FIGURE 22 Placement of three rows of staples on the right renal vein using the endo-TA stapler. Source: From Ref. 10.

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FIGURE 23 Position of hand-assist port in left hand–assisted laparoscopic living donor nephrectomy. Source: From Ref. 15.

device can provide a less steep learning curve for nonlaparoscopic-trained surgeons. Manual palpation, dissection, and digital control of bleeding help to avoid the need for conversion to an open procedure. A more controlled ureteral dissection avoids stripping the periureteral vasculature during mobilization, which can result in ureteral stenosis. Lastly, manual extraction allows a very short extraction time, resulting in excellent initial graft function (11,15). With a left nephrectomy, the patient is placed in the right lateral decubitus position, and then prepped and draped to allow access to the midline, flank, or lower abdomen, in case of a need for emerging open conversion. The operating table is flexed and the kidney rest elevated. The bladder is catheterized and orogastric suction is used to prevent gastric and small bowel distension. Pneumoperitoneum is obtained by the open Hasson technique; a single 10 mm port is placed highest in the subcostal margin to provide access for a 30 degree video laparoscope and the two 12 mm ports are used as working parts. The hand-assist port is positioned parallel to the iliac crest, centered over the lateral edge of the rectus muscle in the region over the left ureter (Fig. 23). A 7 to 8 cm incision is made dividing the anterior and posterior rectus sheaths, at the same time preserving the rectus and transversus muscles. A wound protector is placed on the abdominal wall and a protractor is placed through the abdominal wall to prevent dissection into the soft tissue of the abdominal wall. After placement of the hand-assist protractor, an open ureteral dissection is performed at the level of the iliac vessels. A vessel loop is placed around the ureteral and periureteral fat, which is dissected free from the gonadal vein. The assistant surgeon stands at the patient’s back and places his left hand in the abdomen through the wound protector and abdominal wall protractor (Fig. 24). The camera is operated either through the medial port by a second assistant or the operating surgeon, or through the lateral port operated by the assistant, enabling the operative surgeon to use both hands. Either hand of the assistant surgeon can be used as the intra-abdominal hand to maintain pneumoperitoneum. A nonwhite

FIGURE 24 Position of hand-assist port in left hand–assisted laparoscopic donor nephrectomy. Source: From Ref. 15.

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FIGURE 25 Pneumo-sleeve hand retracts the renal vein while the renal artery is dissected at the aorto-renal junction in left hand–assisted laparoscopic donor nephrectomy. Source: From Ref. 15.

glove is used to decrease light reflection. The assistant’s intra-abdominal hand is used to retract and aid in dissection of the colon and splenorenal attachments. The intra-abdominal hand is advantageous in palpating the renal artery and vein. Dissection proceeds with a combination of manual and laparoscopic dissection using a laparoscopic Kitner and the ultrasonic dissector. The assistant’s hand enables rapid dissection by manually retracting and reflecting the renal vein to identify the renal artery. The left renal vein is identified, and the gonadal vein and adrenal branches are doubly clipped and divided. The pneumo-sleeve hand retracts the vein inferiorly when the artery is dissected at the aortorenal junction (Fig. 25). The ureteral dissection is completed with the ultrasonic scalpel, and the assistant’s hand retracting the ureter to the bifurcation of the common iliac artery. Once the anterior aspect of the artery is dissected, the kidney is retracted anteriorly by the pneumo-sleeve hand, and the posterior attachments are freed, exposing the posterior aspect of the renal artery. Once the kidney is completely mobilized, 25 gm of Mannitol and 10 mg of Furosemide are given. An articulated vascular stapler is placed through the medial port with the device articulated parallel to the aorta. The renal artery is divided close to the aortorenal junction always leaving a stump of several millimeters on the aorta. The renal vein is then divided using the articulated vascular stapler below the adrenal and gonadal branches. The renal allograft is extracted through the hand-assist port by direct manipulation of the assistant’s hand without placement in an extraction bag. The allograft is removed and placed in an ice bath held on the abdominal wall just outside of the hand-assist protractor, where the mobilized ureter can be divided after clamping, and then ligated under direct vision. The kidney is then placed on the back table where, after excision of the staple lines, the organ is flushed with University of Wisconsin Solution (Viaspan, Madison, Wisconsin). The abdomen is reinsufflated and the amputated vascular pedicle is inspected. The incisions are then closed at the fascia and at the skin. Right Laparoscopic Retroperitoneal Live Donor Nephrectomy Right laparoscopic retroperitoneal live donor nephrectomy has also been performed (13). Briefly, the patient is secured to the operating table in the standard full flank position with kidney rest elevated and the table flexed. A three-port retroperitoneal laparoscopic approach is used. Following balloon dilation and placement of three retroperitoneal ports (two 12 mm ports and one 5 mm port), the renal hilum is identified (Fig. 26). The renal artery is circumferentially mobilized from the renal hilum up to its retrocaval location. The renal vein and a segment of the adjacent IVC are similarly mobilized. The ureter with adequate periureteral tissue is laparoscopically dissected distally into the pelvis, endoclipped distally, and divided proximally. The superior, posterior, and lateral kidney surfaces are mobilized inside Gerota’s fascia, leaving the adrenal intact. The anterior kidney surface is mobilized only minimally to prevent the kidney falling posteriorly. A modified, muscle splitting, Gibson transplant incision is made over the right iliac fossa with the patient in the flank position. The incision is developed to the transversalis fascia

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FIGURE 26 Patient position and placement of ports in retro-peritoneal right laparoscopic living donor nephrectomy. Source: From Ref. 13.

without entering the pelvic extraperitoneal space, thereby avoiding compromising the pneumoretroperitoneum. Laparoscopic visualization is used to confirm that only a thin intervening layer of fascia separates the Gibson incision from the pneumoretroperitoneum. Mannitol and Furosemide are given intravenously to promote and maintain a brisk diuresis throughout the dissection. Five thousand units of heparin are administered intravenously before ligation of the renal vessels. The renal artery and vein are sequentially secured and divided five minutes later with the vascular endo-GIA anastomosis stapler. The anterior surface of the kidney is completely freed and the intact fascial layer at the Gibson incision dissected. The retroperitoneum is entered to extract the kidney with the hand. On the backbench table, the kidney is cooled in ice and flushed with University of Wisconsin solution. Vascular dissection is performed to prepare the renal artery and vein for transplantation. Additional venous length is made available by meticulous mobilization of the vein in the hilum. ROBOTIC HAND-ASSISTED LAPAROSCOPIC DONOR NEPHRECTOMY The University of Illinois started performing RHALDN in 2000 and their experience has included >100 RHALDN for kidney transplantation (16). The daVinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, California) offers many potential benefits when performing minimally invasive surgery. The system affords six degrees of freedom plus grip. This includes in-and-out motion, rotation of the shaft, pitch (up-down) and yaw (left-right) at the instrument’s tip (Endowrist; Intuitive Surgical) plus pitch and yaw at the port site. The surgeon can replicate well-established open surgical maneuvers in the laparoscopic environment. The system allows for adjustable motion scaling and the ability to translate large hand movements to smaller instrument movements. The system incorporates software that filters tremor from the surgeon’s movements. The surgeon places his or her forehead on a console (Fig. 27) that has two independent monitors serving as eyepieces, thereby restoring three-dimensional vision lost in the standard laparoscopic approach. Camera movement as

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FIGURE 27 Surgeon console for robotic hand-assisted laparoscopic donor nephrectomy. Source: From Ref. 20.

well as zoom and focus functions are controlled by hand movements disengaged from the operative instruments. The system allows for excellent magnification. The use of a hand-assisted device may increase the confidence of the surgeon, safety of the operation, and facilitates removal of the kidney. The hand inside the abdomen allows rapid control in the case of bleeding. The room setup (Fig. 28) has to be considered before bringing the patient into the room. The room setup takes up considerable time and is a significant drawback of the robotic procedure. After administering general anesthesia, the patient is placed in the right lateral decubitus position, and the operating room table is flexed to facilitate exposure of the left kidney. The abdomen is then prepped and draped in a standard sterile manner. A 7 cm long infraumbilical incision is made in the midline, beginning at the umbilicus, taken down through the fascia and into the abdominal cavity. A lapdisc hand port (Ethicon, Piscataway, New Jersey) is inserted, and pneumoperitoneum is achieved with 14 mm Hg CO2 insufflation. Under direct visualization, a 12 mm trocar is placed in the left lateral abdominal wall, two 8 mm trocars are placed in the subxiphoid and left lower lateral abdomen, and another 12 mm trocar placed in the left inguinal region. The daVinci robot is then brought in position and the arms are connected to the trocars. The operation starts by mobilizing the descending colon from the lateral peritoneal attachments using electrocautery. The ureter is dissected free circumferentially in a cephalad direction, beginning at the level of the left common iliac artery. The posterior attachments of the kidney are taken down. The robot is very helpful in the dissection of the upper pole of the kidney from the retroperitoneal fat and the spleen, because the articulated arm reproduces the action of the human wrist. The gonadal vein is identified medially and followed superiorly to its junction with the left renal vein. The renal vein is then dissected free and its tributaries (gonadal, lumbar, and left adrenal veins) are divided using the Ligasure device (Valley Lab, Boulder, Colorado). The kidney is then retracted medially, and the main renal artery and any accessory renal artery are identified and dissected free up to the level of aortic takeoff. The ureter is clipped twice distally at the level of the iliac artery and sharply transected. Eighty units per kg of heparin are given intravenously. A locking clip (Hem-O-Lok; Weck Closure Systems, Research Triangle Park, North Carolina) is placed at the takeoff of the renal artery, and the artery is divided with the stapling device. The stapling device alone is used to transect the renal vein. The left kidney is removed through the lower midline incision and taken to the back table, where it is flushed with cold University of Wisconsin solution. Laparoscopic inspection of the renal bed is performed to ensure hemostasis. Intravenous protamine is given

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FIGURE 28 Room set-up for robotic hand-assisted laparoscopic donor nephrectomy. Source: From Ref. 16.

to counter heparin. After evacuation of the pneumoperitoneum and removal of trocars, the lower midline fascia is closed with running No. 1 monofilament absorbable sutures. CONCLUSION The development of LLDN has invigorated an area of transplantation that was dormant for a long period. LLDN has increased patient willingness to donate, thereby increasing the donor pool (16) and the number of living related and unrelated renal transplants being performed. ODN remains a time-tested procedure, and is still being performed for right donor nephrectomy at centers where right LLDN is not done. An additional role for ODN is in donors with coagulopathy, such as hemophiliacs, and in donors with bleeding disorders like Von Willebrand’s disease, Kidney donors who are Jehovah’s witness should also undergo ODN. In this chapter, we have presented the various technical aspects of donor nephrectomy on the right or left side, open, laparoscopic, or hand-assisted laparoscopic. Finally, RHALDN has been found to be a safe and effective procedure in a small number of centers. In advanced minimally invasive surgical centers routinely performing robotic-assisted procedures, RHALDN may become more common in the future. REFERENCES 1. Jones KW, Peters TG, Walker GW. Anterior-retroperitoneal living donor nephrectomy: techniques and outcomes. Am Surg 1999; 65:197–205. 2. Shenoy S, Lowell JA, Ramachandran V, Jendrisak M. The ideal living donor nephrectomy “mini-nephrectomy” through a posterior transcostal approach. J Am Coll Surg 2002; 194:240–246. 3. Jarowenko MV, Yang HC, Shapiro R, Holman MJ, Ahsan N. Minimally invasive donor nephrectomy using a posterior supracostal approach—A comparison with conventional open donor nephrectomy. Digital Urology Journal. http://www.duj.com/Article/Ahsanarticle.html. 2003. Accessed 2.11.2007. 4. Tan HP, Maley WR, Kavoussi LR, et al. Laparoscopic live donor nephrectomy: evolution of a new standard. Curr Opinions Organ Transplant 2000;12:312–318.

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5. Tan HP, Orloff M, Marcos A, et al. Laparoscopic Live-Donor Nephrectomy: Development of a New Standard in Renal Transplantation. Graft 2002; 5:405–416. 6. Ratner LE, Montgomery RA, Kavoussi LR. Laparoscopic live donor nephrectomy. Urol Clin North Am 2001; 28:709–719. 7. Tan HP, Ratner LE. Surgical techniques for Kidney and Pancreas Procurement. In: Manzarbeitia C, ed. Practical Manual of Abdominal Organ Transplantation. New York, NY: Kluwer Academic/Plenum Publishers, 2002: 81–92. 8. Tan HP, Vyas D, Basu A, et al. Cold heparinized lactated ringers with procaine (Help) preservation fluid in 266 living donor kidney transplantation. Transplantation 2007; in press. 9. Mandal AK, Cohen C, Montgomery RA, Kavoussi LR, Ratner LE. Should the indications for laparoscopic live donor nephrectomy of the right kidney be the same as for the open procedure? Anomalous left renal vasculature is not a contraindication to laparoscopic left donor nephrectomy. Transplantation 2001; 71:660–664. 10. Buell JF, Hanaway MJ, Potter SR, et al. Surgical techniques in right laparoscopic donor nephrectomy. J Am Coll Surg 2002; 195(1):131–137. 11. Slakey DP, Wood JC, Hender D, et al. Laparoscopic living donor nephrectomy: Advantages of the hand-assisted method. Transplantation 1999; 681:581–583. 12. Chaw GK, Chan DY, Ratner LE, Kavoussi LR. Interaortocaval renal artery dissection for right laparoscopic donor nephrectomy. Transplantation 2001; 72:1458–1460. 13. Gill IS, Uzzo RG, Hobart MG, Streem SB, Goldfarb DA, Noble MJ. Laparoscopic retroperitoneal live donor nephrectomy for purposes of allotransplantation and autotransplantation. J Urol 2000; 164:1500–1504. 14. Tan HP, Kaczorowski DJ, Basu A, et al. Steroid-free tacrolimus monotherapy following pretransplant thymoglobulin or Campath and laparoscopy in living donor renal transplantation. Transpl Proc 2005; 37:4235–4240. 15. Buell JF, Alverdy J, Newell KA, et al. Hand-assisted laparoscopic live-donor nephrectomy. J Am Coll Surg 2001; 192(1):132–136. 16. Horgan S, Benedetti E, and Moser F. Robotically assisted donor nephrectomy for kidney transplantation. Am J Surg 2004; 188:45S–51S. 17. Kuo PC, Johnson LB. Laparoscopic donor nephrectomy increases the supply of living donor kidneys: a center-specific microeconomic analysis. Transplantation 2000; 69:2211–2213. 18. Walsh PC, Retik AB, Darracott Vaughan E Jr.,Wein AJ, eds. Campbell’s Urology, Philadelphia, WB Saunders, 2002. 19. Bishoff JT, Kavoussi LR, eds. Atlas of Laparoscopic Retroperitoneal Surgery. Philadelphia, WB Saunders, 2000. 20. Horgan S, Vanuno D, Sileri P, Cicalese L, Benedetti E. Robotic-assisted laparoscopic donor nephrectomy for kidney transplantation. Transplantation 2002; 73:1474–1479.

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Perioperative Donor Risk Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Zebulon Z. Spector University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION With the increasing gap between the number of end-stage renal disease (ESRD) patients requiring kidney transplantation and the number of available deceased donor allografts, living donation has become the principal means of increasing the number of kidney transplantations performed in the United States. As of August 2005, 62,889 patients were on the waiting list for a kidney transplant, and 16,004 kidney transplants were performed in 2004 (1). Access to a living kidney donor has shortened the recipient waiting period from two to six years to less than three months (2,3). In addition to reducing the discrepancy between the number of recipients and donor organs, kidneys from living donors perform better than and outlast grafts from deceased donors (1). The transplant community has thus promoted live kidney donation as a safe and viable alternative to deceased donor grafts. In fact, since the year 2000, the number of living donors has exceeded the number of deceased donors for kidney transplantation (Table 1) (1). Given the benefits of living donor kidney transplantation, it is easy to overlook the risks undertaken by the donor in such operations. Live kidney donors are healthy individuals, and therefore, any donor operation must be associated with minimal donor morbidity and no donor mortality (4,5). Open donor nephrectomy (ODN) and laparoscopic live donor nephrectomy (LLDN) are the two major donor surgery techniques, and have fortunately been associated with a relatively low and progressively decreasing morbidity rate as a result of ongoing technical refinements and experience of the surgical team (6–8). Perioperative mortality reported for living kidney donors is estimated to be about 0.03% (9,10). Most recently, a survey of 171 transplant programs, including 10,828 live donor nephrectomies between January 1, 1999 and January 7, 2001, found a 0.03% risk of mortality from the donor operation associated exclusively with LLDN (10), similar to that of ODN (11). Given five decades of experience with ODN, long-term studies with large patient series are available for a detailed review of perioperative donor risk. LLDN, introduced in 1995 (12), has become an established technique for retrieval of living donor grafts and is now practiced at most major transplant centers. In this time, LLDN techniques have evolved, and the operation has, to a large extent, fulfilled its promise of decreased postoperative pain, improved cosmesis, reduced hospital stay, and reduced time away from work for donors, and has further increased the size of the living donor pool (2–5). Many large patient series are now also available for the study of perioperative risks to the donors (8,13–17). This chapter discusses perioperative outcomes, including donor morbidity after ODN and LLDN from these large patient series. OPEN DONOR NEPHRECTOMY ODN has been viewed as the traditional gold standard for retrieving kidneys from living donors, with which more recent techniques have been compared. Several large patient series

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Kidney Transplantation in the United States

Till date 2005 (incomplete) 2004 2003 2002 2001 2000 1999

All donor types

Deceased donor

Living donor

157,561 5399 12,973 12,227 11,878 11,566 10,983 10,110

87,303 2781 6326 5753 5638 5528 5489 5386

70,258 2618 6647 6474 6240 6038 5494 4724

have demonstrated the low donor risk associated with ODN. Morbidity rates for these ODN compared with the LLDN series are presented in Table 2. Fabrizio and colleagues (11) reviewed the historical donor risk for ODN by pooling data from 10 studies encompassing 3,657 patients. The analysis showed an overall complication rate of 16%, with rates ranging from 8% to 47%. The most commonly reported complications were urinary tract infection and pneumothorax. The authors noted several serious complications that were more common in the early literature, including adrenalectomy, enterotomy, pulmonary embolism, re-exploration for bleeding, and splenectomy, altogether still occurring in less than 1% of donors. The reported mortality rate for ODN was low, and was estimated to be about 0.03%. A decrease in the complication rate over time was observed among the studies reviewed. A retrospective study was conducted at the University of Wisconsin detailing a 20-year experience with ODN in 681 patients from January 1971 to December 1991 (18). The authors reported a total complication rate of 17%, with no donor mortality. They used a flank incision for the procedure that often required the excision of the 11th rib in the exposure of the kidney. The most common associated complication was pneumothorax, occurring in 13% of patients (7% required a chest tube; the 6% not requiring a chest tube were excluded from the calculation of the total complication rate). In addition, 5% of patients had a urinary tract infection, 4% a wound infection, and 0.3% required blood transfusion. The authors noted a slight deterioration in renal function in some donors after donation with function returning to normal levels by about six months after surgery.

TABLE 2 Published Large Series Morbidities of Laparoscopic Live Donor Nephrectomy, Hand-Assisted Live Donor Nephrectomy, and Open Donor Nephrectomy LLDN/HALDN References Tan (2005) (16) Su (2004) (8) Jacobs (2004) (15) Leventhal (2004) (13)b Leventhal (2000) (25) Posselt (2004) (14) Left Right Kuo (2000) (17) Matas (2003) (10) Fabrizio (1999) (11) Johnson (1997) (6) Waples (1995) (18)

n 196 381 738 500 80 387 333 54 68 2929 — — —

ODN

Major (%)

Minor (%)

OCa (%)

Total (%)

n

Major (%)

Minor (%)

Total (%)

2.6 7.6 23.9

4.2 8.9 6.8+

2.0 2.1 1.6 1.8 — 0.3 0.3 0.0 3.0 — — — —

6.8 16.5 30.7+ 6.2 13.8 5.9 6.3 3.7 5.9 1.7 — — —

— — — — 50 — — — — 5660 3657 871 681

— — — — — — — — — — — 0.2 —

— — — — — — — — — — — 8.0 —

— — — — 9.0 — — — — 0.7 16.0 8.2 17.0

a

a

5.0 — — — — — — — —

8.8 — — — — — — — —

1 = 3.6%, Grade 2 = 2.2%, Grade 3 = 0.4%, does not include intraoperative morbidities. 3.4% HALDN. Abbreviations: HALDN, hand-assisted live donor nephrectomy; LLDN, laparoscopic live donor nephrectomy; n,number of patients; OC, open conversion; ODN, open donor nephrectomy. aGrade

bIncludes

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A study by Johnson and colleagues at the University of Minnesota described a more recent 10-year experience with ODN (6). This series of 871 patients from January 1985 to December 1995 had an overall complication rate of 8.2% (two major complications and 69 donors with 86 minor complications). The most common morbidities were wound infection (2.4%) and pneumothorax (1.5%). One of the major complications was a re-exploration following discovery of a retained surgical sponge postsurgery, and had no associated consequences. The second major complication was lower extremity weakness attributed to femoral nerve compression by a retroperitoneal hematoma, with lingering symptoms at six-month follow-up. The authors note that by univariate analysis, there was a significantly increased risk of complications in males, those patients with a body mass index (BMI) > 30, and in operations extended beyond four hours in length. In the multivariate analysis, only the male gender remained a significant risk factor. An overall reduction in complications over time was reported. As demonstrated by the above studies, donor risks involved with ODN have decreased with improvement of the technique and accumulated experience. Furthermore, most of the reported morbidity consisted of complications that were easily managed [0.2% major versus 8.0% minor morbidity (6)]. The incidence of acceptable risk must be determined by the donor and by the transplant community endorsing the operation, but ODN remains as a relatively safe procedure. LAPAROSCOPIC LIVE DONOR NEPHRECTOMY As an improvement to ODN, the goal of LLDN was to offer the benefits of less postoperative pain, shorter recovery time, and better cosmetic outcome for the donor. LLDN donors, in comparison with historical ODN donors, have required less analgesia (34 versus 124 mg morphine), and have had a shorter hospital stay (2.9 versus 5.5 days), a faster return to full activity (2.2 versus 4.2 weeks), and a faster return to work (3.9 versus 6.4 weeks) (3). It was also hoped that LLDN would offer comparable or decreased donor morbidity with the use of minimally invasive techniques, high technology instrumentation, and robotics, including the harmonic scalpel, laparoscopic vascular stapling devices, and AESOP/Hermes. However, many surgeons were initially quick to question its safety in comparison with ODN, and were slow to implement LLDN before longer-term studies could be conducted. Currently, several large donor series (8,13,14,16,17) have been examined, and morbidity rates appear to be comparable to or better than those from historical ODN patient groups (Table 2). No LLDN mortality was reported in any of these single center reports. However, Matas and colleagues (10), in a summary of 171 programs and 10,828 live donor nephrectomies, reported a mortality rate of 0.03% for LLDN, including one patient in a persistent vegetative state. This mortality rate is comparable to that reported for ODN, estimated to be 0.03% (11). They also found a reoperation rate of 0.9% for LLDN, primarily because of bleeding [there was an additional 1.0% rate for hand-assisted laparoscopic donor nephrectomy (HALDN)] and a 0.8% rate of other complications (1.0% for HALDN), compared with a 0.4% reoperation rate, and 0.3% rate of other complications for ODN. Su and colleagues from Johns Hopkins described a series of 381 consecutive LLDN (95% left-sided) over a six-year period (8). Patients were divided into four groups based on the chronology of surgery [groups A, B, and C = 95 patients each, group D = 96 patients (most recent)] in order to examine trends in donor morbidity/outcome over time. The authors reported a 7.6% and 8.9% major and minor complication rate, respectively, with 2.1% open conversions, a 1.8% reoperation rate, and a 3.4% need for blood transfusion. The total complication rate was 16.5%. In addition, the authors noted a significant decrease in donor complications over time (Group A = 21%, Group B = 19%, Group C = 14%, Group D = 10%). Major complications included three renal artery injuries and three renal vein injuries leading to open conversions, five bowel injuries (one colonic, four small bowel), eight retroperitoneal hematomas, two elective open conversions, two cases of pneumonia, two readmissions for dehydration and ileus, and one case each of epigastric artery injury, incisional hernia, testicular ischemia, and subrectus seroma. The most frequent minor complications (n = 34) were nine wound infections, five transient neuromuscular injuries, five urinary tract infections/epididymitis, four cases of orchalgia, and three retroperitoneal hematomas not requiring transfusion or re-exploration. No deaths occurred in the series.

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Leventhal and colleagues (13) from Northwestern University reported on a series of 500 LLDN (99% left-sided, 3.4% hand-assisted) between October 1997 and September 2003. All laparoscopic procedures were staffed by two dedicated faculty members. The authors noted a 2.8% intraoperative complication rate with 1.8% open conversions and a 6.2% total complication rate. Complications were graded as 18 Grade 1 complications, 11 Grade 2 complications, and two Grade 3 complications. Grade 1 complications were defined as nonlife-threatening complications, Grade 2 complications as those with no residual disability, and Grade 3 complications as those with some residual disability. Complications resulting in renal failure/ patient death would have been classified as Grade 4, but none were observed. Intraoperative complications included three splenic capsular tears, three renal and two lumbar vein injuries requiring open conversion, two cases of transient CO2 pneumomediastinum, one diaphragmatic tear, one adrenal hematoma, and one bowel injury. In addition, in one of the earliest cases in the series, one partial occlusion of the aorta was reported because of a misalignment of the vascular stapler. The patient required reoperation and aortic reconstruction. The Grade 3 complications were related to chylous ascites requiring recurrent hospitalization. No deaths were reported in the series. In addition to general morbidity outcomes, the authors noted that six of nine open conversions occurred in the first 100 patients, and that there was no significant difference in outcome between obese (BMI > 30, n = 110) and nonobese patients (n = 390). Posselt and colleagues (14) from the University of California San Francisco reported on a series of 387 LLDN (14% right-sided) from November 1999 to February 2004. The left-sided LLDN had a complication rate of 6.3%. Complications included eight wound infections, five blood transfusions, two readmissions, one open conversion because of a stapler malfunction, one bowel injury, one pulmonary embolus, one hernia at a port site, one deep venous thrombosis, and one case of rhabdomyolysis caused by a prolonged operative time. The rightsided LLDN had a complication rate of 3.7% with no open conversions. Complications included one bowel injury and one wound infection. The authors reported no statistically significant difference in the incidence of donor complications between left-sided and right-sided LLDN. A University of Maryland study (15) presented a series of 738 LLDN (96% left-sided) over six years. The major and minor intraoperative complication rates were both 6.8%, respectively, and the major postoperative complication rate was 17.1%. Of note, the authors demonstrated a generally decreasing trend in complication rates over the six years, from 28% in year 1 to 13% in year 4, with a slight rise to about 17% in year 6. Twelve open conversions were required, primarily because of vascular injury. The authors also reported 15 vascular injuries, which comprised the bulk of the major intraoperative complications. These included four injuries to the aorta, three to the renal vein, two to the renal artery, two to the mesenteric veins, one to the vena cava, and one to the common iliac artery. Two bowel injuries also occurred. Minor complications were repaired/controlled laparoscopically, and the most common included 15 splenic lacerations, seven pneumothoraces, four stapler misfires, three controllable vascular injuries, and two injuries to the diaphragm. In addition, the authors noted a slow return of bowel function in some donors undergoing LLDN leading to longer hospitalizations. Tan and colleagues (16) at the University of Pittsburgh Medical Center, Thomas E. Starzl Transplantation Institute, presented donor outcomes in a series of 196 unselected consecutive LLDN from October 9, 2002 to December 31, 2004. In this patient series, a 2.6% major complication rate and 4.2% minor complication rate were reported. Major complications included one colonic injury and four open conversions for intraoperative bleeding. Three of the open conversions were related to malfunction or misalignment of the GIA stapler. Two patients required blood transfusion. Minor complications included two urinary tract infections, two transient brachial plexopathies, one wound infection, one case of nausea with emesis and urinary tract infection, one umbilical incisional hernia, and one case of severe constipation with an emergency room visit. No deaths occurred in this series. There were no cases of reoperation and delayed graft function. All LLDN surgeries in this series were performed by a single surgeon in an academic center with a large transplant surgical fellowship training program. Davis and Delmonico (19) reviewed donor risk factors for living kidney donors. The authors cited low operative risk rates for ODN (n = 5,660), LLDN (n = 2,929), and HALDN (n = 2,239), in terms of reoperation (0.4%, 0.9%, and 1.0%, respectively), readmission (0.6%, 1.6%,

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TABLE 3

Proposed Live Donor Nephrectomy Complication Classification Schemea

Techniques: Open (ODN), laparoscopic (LLDN), hand-assisted (HALDN), robotic hand-assisted (RHAN) Type: Definition of complication I. Intraoperative complications A. NO interventions (i) Hematomas (subrectus, retroperitoneal), no blood transfusions (ii) Complications unrelated to surgical site (e.g., intubation complication, thrombophlebitis not requiring antibiotics) (iii) Cardiac arrhythmias (iv) Surgery longer than twice the average operation (e.g., >7 hrs) (v) Aborted donor operation (e.g., intended recipient not transplanted) (vi) Donor nephrectomy completed but kidney not used for intended recipient (excluding donor swap program) B. Minimal interventions (i) Minor splenic/liver injury (<10% subcapsular, nonexpanding hematoma) (ii) Cardiac arrhythmias, cardiology intervention (e.g., new medications) (iii) Elective open conversion for patient management (e.g., adhesions, unable to safely perform laparoscopically, bleeding but no blood transfusion) (iv) Pneumothorax, diaphragmatic injury (needle or intraoperative surgical repair) (v) Minor bowel injury (e.g., reinforcement of a small bovie burn) C. Moderate interventions (i) Emergent open conversion for patient management (e.g., bleeding ≤2 uPRBCs) (ii) Pneumothorax (chest tube placement) (iii) Moderate bowel injury (e.g., perforation requiring closure but no resection) D. Major interventions (i) Major splenic injury (≥10% laceration), or splenectomy (ii) Major bowel injury (resection, osteomy) (iii) Unintentional adrenalectomy (iv) Major vascular injury (e.g., aorta, vena cava, renal, iliac, mesenteric) (v) Bleeding (> 2 uPRBCs) E. Donor kidney injury (i) Perinephric hematoma, capsular tear (ii) Parenchymal laceration (bleeding versus nonbleeding) (iii) Renal vascular injury (vein versus artery, surgical repair) (iv) Delayed graft function, requiring dialysis ≤7 days post-transplant (v) Primary nonfunction II. Minor postoperative complications requiring no/minimal interventions A. NO interventions postoperatively during initial hospitalization (i) Atelactasis, postoperative fever ≤48 hrs with no evidence of infection (ii) Pneumothorax (no surgical intervention) (iii) Scrotal edema and pain B. Minimal interventions postoperatively during initial hospitalization (i) Infections (e.g., UTI, epididymitis, wound, pneumonia, bacteremia), requiring ≤7 days antibiotics (ii) Urinary retention, requiring Foley >3 days (iii) Ileus, >5 days, or requirement of NGT (iv) Nausea/emesis >5 days requiring antiemetics, or dehydration requiring IV fluids C. Prolongation of hospital stay (LLDN >5 days, ODN >8 days) D. Emergency room visits for any reason but no rehospitalization E. Rehospitalization with minimal interventions (e.g., IV hydration) III. Postoperative complications with no residual disability, requiring moderate/major interventions, generally ≤4–6 months duration A. Moderate interventions, rehospitalization for any reason (i) Infections (e.g., intra-abdominal abscess, pneumonia, pyelonephritis), >7 days antibiotics (ii) Chylous ascites, requiring paracentesis or TPN (≤4 months in duration) (iii) Pancreatitis (IV hydration >7 days, TPN) (iv) Deep venous thrombosis, pulmonary emboli B. Additional nonsurgical therapeutic intervention (e.g., drainage of abscess, paracentesis of chylous ascites) C. Re-explorations or additional surgery for any reasons (e.g., bowel obstruction, perforation, retained sponge, incisional hernia repair) D. Neuropathy/paresthesias/pain (brachial, femoral, testicular) < 6 months (Continued )

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Proposed Live Donor Nephrectomy Complication Classification Schemea (Continued )

IV. Postoperative complications with residual disability, or type III complications generally >4–6 months duration A. Nonprogressive disability (i) Reversal of ileostomy/colostomy B. Progressive or difficult to manage disability (i) Chylous ascites (> 4 months) (ii) Pancreatitis requiring long-term TPN, pseudocyst (iii) Ileostomy/colostomy (iv) Development of hepatitis B, C/HIV (from blood transfusion) (v) CVA, MI B. Chronic stable neuropathy/parathesias/pain (brachial, femoral, testicular) > 6 months V. Postoperative complications with renal insufficiency/failure A. Acute renal insufficiency/failure (26) (e.g., rhabdomyolysis, undetected ureterocele) (i) Injury: increased Screat x2 or GFR decreased >50%, or UO <0.5 mL/kg/h × 12 hrs (ii) Failure: increased Screat x3 or GFR decrease 75%, or Screat ≥ 4 mg/dL, or UO < 0.3 mL/kg/h × 24 hrs or anuria × 12 hrs (iii) Loss: persistent acute renal failure = complete loss of kidney function > 4 to 6 weeks B. CKD, defined by kidney damage persisting more than three months, with structural or functional abnormalities of the kidney (per National Kidney Foundation K/DOQI Guidelines (27)]: (i) GFR (mL/min per 1.73 m2) ≥ 60 AND evidence of structural damage (e.g., hematuria, proteinuria, abnormalities in imaging studies) (stage 1 and 2 CKD) (ii) GFR 30 to 59 (stage 3 CKD) (iii) GFR 15 to 29 (stage 4 CKD) (iv) GFR < 15 (stage 5 CKD) C. Late serious complications due to being uninephric (e.g., trauma, obstruction of the contralateral kidney/ureter) D. Leads to dialysis or renal transplantation in the donor VI. A. Intraoperative life-threatening interventions or death (i) Sternotomy, cardiac arrest/massage (ii) Bleeding ≥ 6 U packed red blood cells (iii) Death B. Postoperative complications leading to donor death (i) Primarily attributed to intraoperative events (e.g., major hemorrhage, MI) (ii) Secondarily attributed to intraoperative events (e.g., hepatitis C/HIV from blood transfusion) (iii) ESRD (iv) Persistent vegetative state Add NOS for “not otherwise specified” in the above classification. aThis table was reviewed and approved by the American Society of Transplantation 2006 Kidney Pancreas Committee (Tan H, Bloom R, Hoffman M, Conti D, Becker B, Delaney V, Egidi F, Ko D, Loss G, Murray B, Najafian N, Ranga K, Serur D, Almeshari K, Bresnahan B, Darras F, Djamali A, Florence L, Heilman R, Meier-Kriesche H, Golconda M). Abbreviations: CKD, chronic kidney disease; CVA, cerebral vascular accident; ESRD, end stage renal disease; GFR, glomerular filtration rate; HALDN, hand-assisted laparoscopic donor nephrectomy; LLDN, laparoscopic live donor nephrectomy; MI, myocardial infarction;

and 1.6%), deep venous thrombosis and pulmonary embolism (0.02%, 0.1%, 0.09%), and bleeding (0.1%, 0.2%, 0.45%) (10,19). An Australian systematic review examining 25 reports on LLDN and ODN between 1993 and 2000 (20) came to several conclusions. First, ODN complications in general were underreported, but those reported frequently included hemorrhage and blood transfusion. Second, for LLDN, the most frequent complications included hemorrhage, vascular injuries, incisional hernia, bowel obstruction, and pneumonia. Third, no significant difference in the rate of complications between LLDN and ODN was found, with much variation among studies. In LLDN, the complication rate was found to decrease markedly after the first 20 to 30 cases, indicating a defined learning curve for the laparoscopic procedure. Finally, Vats and colleagues (21) examined the effects of LLDN on the donor’s remaining kidney using a group of 39 LLDN donors and 53 ODN donors from January 2000 to December 2002. The glomerular filtration rate (GFR) and serum creatinine (SCr) were measured at baseline (prior to surgery), at postoperative day 1 and at postoperative day 3. It was found that GFR decreased significantly more in the LLDN group than the ODN group on postoperative day 1,

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but that the difference was gone by postoperative day 3. The SCr was elevated in both groups postoperatively, but no significant difference was noted between the LLDN and ODN donors. The difference in GFR was attributed to the effects of pneumoperitoneum in the patient; however, when the authors examined the length of pneumoperitoneum and the extent of the drop in GFR, no correlation could be found. PROPOSAL OF A LIVE DONOR NEPHRECTOMY COMPLICATION CLASSIFICATION SCHEME LDN is a unique operation with unique complications. The revised Clavien classification (13,22,23) provides a good start to judge the results of new operations and set benchmarks of quality, but the proposed system suffers from variability in interpretation and may not apply to LDN. First, the present system does not address specific intraoperative complications unique to donor nephrectomy (e.g., aborted donor operation, the quality of the donor kidney, elective versus emergent conversion). Second, the degree of possible development of renal insufficiency/ failure is unique to these live donors, and is a very important long-term outcome measure, especially when more aggressive transplant programs are using extended criteria live kidney donors. Third, this proposed classification attempts to encompass all possible complications unique to LDN, so that it can be classified easily with minimal variability in interpretation. A large center recently published a 23.9% (intraoperative 6.8% and postoperative 17.1%) major complication rate in 738 LLDN patients (15). Not only is this relatively alarming, but it is unclear if live kidney donors are actually aware of these complication rates prior to donation. There is currently no consensus on how to define and grade LDN complications. The need for a national donor registry is extremely urgent. The transplant community needs to know the combined experience of complications and long-term outcomes in live organ donors rather than short-term reports from single institutions. All new techniques should be developed, investigated, and improved at a few centers of excellence prior to widespread use. With our combined experience (1500 laparoscopic and 1000 open) in donor nephrectomies, we proposed an LDN complications classification scheme (24). A slight modification as revised by the 2006 AST Kidney Pancreas Committee is presented in Table 3. We hope this may serve as a template for the classification of complications in a national living donor kidney registry, and be used by the national and international transplant organizations [e.g., American Society of Transplantation (AST), American Society of Transplant Surgeon (ASTS), United Network for Organ Sharing (UNOS) and the Transplantation Society] to develop a definitive scheme that can be adopted universally. REFERENCES 1. United Network Organ Sharing Data. http://www.optn.org (accessed August 26th, 2005). 2. Tan HP, Maley WR, Kavoussi LR, Montgomery RA, Ratner LE. Laparoscopic live donor nephrectomy: evolution of a new standard. Curr Opin Organ Transplant 2000; 12:312–318. 3. Tan HP, Orloff M, Marcos A, Mieles L, Kavoussi LR, Ratner LE. Laparoscopic live-donor nephrectomy: Development of a new standard in renal transplantation. Graft 2002; 5:405–416. 4. Novick AC. Laparoscopic live donor nephrectomy: con. Urology 1999; 53:668–670. 5. Tan HP, Kavoussi LR, Sosa JA, Montgomery RA, Ratner LE. Laparoscopic live donor nephrectomy: debating the benefits. Nephrol News Issues 1999; 13:90–95. 6. Johnson EM, Remucal MJ, Gillingham KJ, Dahms RA, Najarian JS, Matas AJ. Complications and risks of living donor nephrectomy. Transplantation 1997; 64:1124–1128. 7. Ratner LE, Smith P, Montgomery RA. Laparoscopic live donor nephrectomy: pre-operative assessment of technical difficulty. Clin Transplant 2000; 14:427–432. 8. Su LM, Ratner LE, Montgomery RA, et al. Laparoscopic live donor nephrectomy: Trends in donor and recipient morbidity following 381 consecutive cases. Ann Surg 2004; 240:358–363. 9. Najarian JS, Chavers BM, McHugh LE, Matas AJ. 20 years or more of follow-up of living kidney donors. Lancet 1992; 340:807–810. 10. Matas AJ, Bartlett ST, Leichtman AB, Delmonico FL. Morbidity and mortality after living kidney donation, 1999-2001: Survey of United States transplant centers. Am J Transplant 2003; 3:830–834. 11. Fabrizio MD, Ratner LE, Kavoussi LR. Laparoscopic live donor nephrectomy: pro. Urology 1999; 53:668–670.

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12. Ratner LE, Ciseck LJ, Moore RG, Cigarroa FG, Kaufman HS, Kavoussi LR. Laparoscopic live donor nephrectomy. Transplantation 1995; 60:1047–1049. 13. Leventhal JR, Kocak B, Salvalaggio PRO, et al. Laparoscopic donor nephrectomy 1997 to 2003: Lessons learned with 500 cases at a single institution. Surgery 2004; 136:881–890. 14. Posselt AM, Mahanty H, Kang SM, et al. Laparoscopic right donor nephrectomy: A large single-center experience. Transplantation 2004; 78:1665–1669. 15. Jacobs SC, Cho E, Foster C, Liao P, Bartlett ST. Laparoscopic donor nephrectomy: The University of Maryland 6-year experience. J Urol 2004; 171:47–51. 16. Tan HP, Kaczorowski DJ, Basu A, et al. Steroid-free tacrolimus monotherapy following pretransplant thymoglobulin or campath and laparoscopy in living donor renal transplantation. Trasplant Proc 2005; 37:4235–4240. 17. Kuo PC, Johnson LB, Sitzmann JV. Laparoscopic donor nephrectomy with a 23-hour stay: A new standard for transplantation surgery. Ann Surg 2000; 231:772–779. 18. Waples MJ, Belzer FO, Uehling DT. Living donor nephrectomy: A 20-year experience. Urology 1995; 45:207–210. 19. Davis CL, Delmonico FL. Living-donor kidney transplantation: A review of the current practices for the live donor. J Am Soc Nephrol 2005; 16:2098–2110. 20. Merlin TL, Scott DF, Rao MM, et al. The safety and efficacy of laparoscopic live donor nephrectomy: A systematic review. Transplantation 2000; 70:1659–1666. 21. Vats HS, Rayhill SC, Thomas CP. Early postnephrectomy donor renal function: Laparoscopic versus open procedure. Transplantation 2005; 79:609–612. 22. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications. A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240:205. 23. Clavien PA, Camargo CA Jr, Croxford R, Langer B, Levy GA, Greig PD. Definition and classification of negative outcomes in solid organ transplantation: application in liver transplantation. Ann Surg 1994; 220:109–120. 24. Tan HP, Shapiro R, Montgomery RA, Ratner LE. Proposed live donor nephrectomy complication classification scheme. Transplantation 2006; 81:1221–1223. 25. Leventhal JR, Deeik RK, Joehl RJ, et al. Laparoscopic live donor nephrectomy—is it safe? Transplantation 2000; 70:602–606. 26. Bellamo R, Ronco C, Kellum JA, et al., and the ADQI workgroup. Acute renal failure-definition, outcome measures, animal model, fluid therapy and information technology needs: the Second International Concensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8:R204. 27. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 2002; 39(2 suppl 2):S1–S246.

7

Long-Term Risks of Living Donation Connie L. Davis Division of Nephrology, University of Washington School of Medicine, Seattle, Washington, U.S.A.

LONG-TERM DONOR RISKS Long-term medical and psychological risks for the living donor are generally minimal. However, the data supporting such claims come from a relatively small sampling of the total number of donors and almost exclusively from donors of northern European heritage (1,2). Thus, although most nephrologists feel that a donor who is normal at donation has very little risk of future renal disease or impairment of other organ systems as a consequence of donation, the real answer is unknown, especially for donors of color or with minor medical abnormalities. In order to define more specifically the risks of living donation, large registry data are needed. This is particularly important at a time when not all donors are considered completely “normal.” OVERVIEW The largest reports of uninephrectomy and long-term outcome (>20 years after nephrectomy) are from Narkun-Burgess, Fehrman-Ekholm, Najarian, and Ramcharan (1–4). All of these reports concluded that living donation is safe with little mortality or renal impairment (Figs. 1 and 2, Table 1). The major limitations of these reports are the lack of complete population follow-up and little ethnic diversity. Additionally, there is no report of donor renal histology at death to determine if prolonged hyperfiltration that ultimately occurs with donation causes any adverse effect such as pronounced glomerulosclerosis or interstitial fibrosis. However, a follow-up report from Sweden (n = 348/407 surviving donors, 2 to 33 years after nephrectomy) did not find accelerated declines in donor glomerular filtration rate (GFR); declines in GFR were not above that expected for the general population(5). In this study, the serum creatinine along with reagent strip determined urinary protein, and urinary blood cells were evaluated. The GFR was estimated using a serum creatinine-based calculation. Iohexol clearance was performed in 43 of the donors. The mean age of the donors was 61 years, average time since donation was 12 years, and the average estimated GFR was 72% of age predicted values. However, five donors had a GFR less than 30 cc/min, three developed renal disease, and one was on dialysis. No donor died in uremia. Goldfarb and colleagues reported on 70 of 180 living donors who donated from 1963–1975 (6). These donors, 20 to 32 years after donation, were evaluated by urine and blood samples sent to the Cleveland Clinic and a blood pressure (BP) reading taken by a local physician. The 24-hour urinary creatinine clearance was 72% of the predonation value, and the average serum creatinine and systolic BP were higher than predonation but still within the normal range at follow-up. The overall rate of hypertension was the same as that seen in the age matched general population. Protein excretion was over 150 mg/d in 19% of the subjects who performed a 24-hour urine collection. Urinary albumin excretion over 10 ug/min was seen in 36% of donors. Renal disease developed in six [glomerulonephritis n = 1, nephrolithiasis n = 2, atheroemboli n = 1, and endstage renal disease n = 2 (1.1%)] and 24 died. Finally, Ramcharan and Matas identified 773 individuals who had donated a kidney between 1963–1979 (1). They were able to locate information on 464; 84 had died and three were on dialysis at the time of death. The surviving 380 donors were contacted and asked to fill out a survey, have a physical, and perform a urinalysis and serum creatinine measurement. Of this group, 124 said they had no kidney problems but did not participate in the study; 198 participated who had donated 20 to 29 years earlier, and 58 who had donated >30 years before the survey. The serum creatinine was available in 74 of those who donated 20 to 29 years prior to study and 29 who donated over 30 years before the study. The mean creatinine value was 1.2 ± 0.04 mg/dL in the 20 to 29 year group and 1.3 ± 0.1 mg/dL in the over 30-year group. The rate of proteinuria was 11% and 5%, respectively, with most proteinuria

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Davis 1.00

Nephrectomy

Survival

0.75 Control 0.50

0.25

0 24

36

48

60

72

84

Age

FIGURE 1 The survival of U.S. servicemen undergoing unilateral nephrectomy during WWII in the field for trauma compared with servicemen in WWII who did not undergo nephrectomy. Source: From Ref. 3.

measured at the 1+ level by dipstick; hypertension was apparent in 36% and 38%, respectively. The incidence of hypertension was no different from that reported in a population study published in 1995. Postdonation 19/250 responding donors developed diabetes; nine of these donors (47%) had a negative family history for diabetes. Five of the responding donors had a serum creatinine over 1.7 mg/dl; two had developed end-stage renal disease (ESRD) and undergone transplantation. Overall, the prevalence of ESRD in the donor population was 5/464 or 1% (two living donors had received renal transplants, three of the 84 donors who had died were on dialysis at the time of death). A meta-analysis of reduced renal mass in humans was undertaken by Kasiske et al. (7). Multiple linear regressions were used to combine studies and adjust for differences in the duration of follow-up, reason for reduced renal mass, type of controls, age, and gender. There were 48 studies with 3124 patients (renal mass reduction due to organ donation in 60.5%, cancer in 10.1%, infection in 8.1%, nephrolithiasis or obstructive uropathy in 6.8%, unilateral agenesis in 3.4%, trauma in 2.5%, other in 6.8% and unknown in 1.6%) and 1703 controls. Renal mass reduction, gender, and age were associated with decreases in GFR. The glomerular filtration rate was estimated based upon an isotopic determination in 13.7%, creatinine clearance in 45.8%, or calculated using the Cockcroft-Gault equation in 40.4%. Unilateral nephrectomy caused, on average, a decrement of 17 cc/min in the GFR that tended to improve with each 10 years of follow-up (average increase 1.4 cc/min/decade). A small progressive increase in proteinuria was also noted (average 76 mg/decade), but was negligible after nephrectomy for trauma or kidney donation and most pronounced in those with renal agenesis or if there was more than a 50% reduction in renal mass. Nephrectomy did not affect the prevalence of hypertension, but

observed and exopected survival

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

5 10 15 20 time (years) since donation

25

FIGURE 2 The observed (in black) compared with expected (dotted line) survival of living kidney donors in Sweden. The expected survival was calculated from the general Swedish population. Source: From Ref. 2.

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TABLE 1

Over 20 Years After Donation Preoperative (n = 78)

Age mean (range) Serum creatinine mg/dl (SD) Creatinine clearance cc/min (SD) Urinary protein per day mg/d Blood pressure mean mmHg

36.8 1.0 (0.1) 103 (4) 118/76

Postoperative (n = 57) 61 (40–83) 1.1 (0.01) 82 (2) N = 12 over 150 mg/dL 134/80 32% on antihypertensives

Siblings (n = 50) 58 (29–83) 1.1 (0.03) 89 (3.3) N = 10, over 150 mg/dL 130/80 44% on antihypertensives

Numbers in parentheses are standard deviations. Living donor and nondonor sibling outcomes 20 or more years after living donation. Abbreviation: SD, standard deviation Source: From Ref. 4.

was associated with a small increase in the systolic blood pressure that rose further with duration of follow-up. Thus, the majority of those living with one kidney survive without complications; however, it is becoming apparent that the risk of ESRD, even though small, needs to be re-examined. END-STAGE RENAL DISEASE Next to death or crippling disability, the most severe potential consequence of living donation is end-stage renal disease (ESRD). ESRD developing over many years after donation has been reported in 0.04% of living renal donors compared with 0.03% of the general U.S. population (8). Ellison and colleagues reported this value after reviewing the Organ Procurement and Transplantation Network (OPTN) database for live kidney donors who were subsequently listed for a kidney transplant. This report did not include living donors who exclusively received dialysis or who died with ESRD, but did not receive renal replacement therapy. The renal diagnosis in these patients was hypertension (n = 24), focal sclerosis (n = 9), chronic glomerulonephritis (n = 7), familial nephropathy (n = 2), diabetes (n = 2), and other (n = 12). In the report by Ramcharan and Matas detailed above, five of 464 (1%) of located donors had developed ESRD, and three others had abnormal renal function. The etiology of renal disease was not determined (1). Fehrman-Ekholm identified ESRD in one of 402 (0.2%) surviving donors (5). One other donor from Sweden recently developed renal cell cancer in the remaining kidney and started dialysis. Altogether 2/402 (0.5%) of studied or 2/737 (0.27%) of all donors have developed ESRD (9). Holdaas and colleagues reported from their program in Norway that seven of 1800 (0.4%) living donors had developed ESRD (10). An unpublished review of United Network for Organ Sharing (UNOS) data for the American Transplant Congress 2005 showed at least 104 donors have now been registered for transplantation since 1995 (Fig. 3) (11). If these donors had all donated from 1988 onward (the first year UNOS collected data), then the worse-case calculation for ESRD would be 0.15% (104/68623 donors through February 2005). This account, as the report by Ellison states, did not capture donors developing ESRD who were not listed for transplant. The causes of donor ESRD from the OPTN database are listed in Table 2. In order to

FIGURE 3 Kidney registrations with United Network for Organ Sharing from January 1995 to October 2004 indicating prior living donor status. Source: From Ref. 11.

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TABLE 2 Donor End-Stage Renal Disease: Etiology—United Network for Organ Sharing Jan 1995–Oct 2004 (n = 104) Renal disease

Total cases

Membranous IgA Pyelonephritis FSGS PKD Nephritis Nephrolithiasis Diabetes type 1 Diabetes type 2 Trauma Unknown Vasculitis Fibromuscular dysplasia Hypertension SLE RCC Familial nephropathy Chronic GN unknown type Analgesic nephropathy

2 1 2 12 1 1 1 2 10 1 27 1 1 25 2 2 2 9 1

Abbreviation: PKD, polycycstic kidney disease. Source: From Ref. 11.

capture more donors who developed ESRD, Ojo and Davis performed a preliminary evaluation of the Scientific Registry of Transplant Recipients (SRTR) and Centers for Medicare and Medicaid Services ESRD databases (12). A total of 46 ESRD patients were found linked to a donor ID in the SRTR living donor file (determined by dialysis date, ESRD service date or date of kidney waitlist) and an additional 62 ESRD patients were found to have been waitlisted for a kidney transplant with an indicator for previously donating an organ. These final patients, however, could not be matched to a donor ID number in the SRTR. The overall incidence of ESRD in white donors was estimated to be 0.10% and in African-American donors 0.52% (Table 3). This assumes that all of the donors donated from 1988 onward; if they did not (i.e., donated before 1988), then the rates would decrease. Of the living donors developing ESRD, 46% were White, 44% African American, and 6% Hispanic. The mean age at donation for the African American donors was 32 years and for White donors 45.1 years. The cause of renal disease reported to the SRTR in African American donors was glomerulonephritis (n = 9), diabetes (n = 2), hypertension (n = 1), and other (n = 7); the cause in White donors was glomerulonephritis (n = 5), diabetes (n = 1), hypertension (n = 2), and other (n = 24). The mean time from donation to ESRD in those with the date of donation available was 8.1 years. Verification of this information is now in progress. Supporting the concern over increased risk for ESRD in African American donors was data also presented at the American Transplant Congress in 2005 from Ahmed and colleagues (13). They reviewed 34 African American donors donating from 1999 through 2004 and compared the results with 23 Caucasian donors. Although the serum creatinine was not different at

TABLE 3

End-Stage Renal Disease in Living Kidney Donors General population incidence of ESRD

Age

White (%)

African American (%)

30–39

0.008

0.04

40–49 50–59 60–69

0.016 0.038 0.067

0.086 0.18 0.28

Abbreviation: ESRD, end-stage renal disease. Source: From Ref. 12.

Incidence of ESRD in living donors overall White

African American

50/48760 (assuming donation from 1988) 0.10%

47/9053 (assuming donation from 1988) 0.52%

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TABLE 4 Increase in Creatinine After Donation in African Americans Compared to White Living Kidney Donors Variable Precreatinine Postcreatinine ΔScr > 50% Post HTN

African American

White

P value

1 ± 0.1 1.5 ± 0.3 75% 2

0.8 ± 0.2 1.2 ± 0.2 25% 0

NS NS <0.05 NS

Abbereviations: NS, not significant; HTN, hypertension. Source: From Ref. 13.

donation between donors of different ethnicities, the number of donors with a serum creatinine that increased over 50% was higher in African American donors (Table 4). Given the fact that data appear to support a higher risk of ESRD after donation than previously recognized (even if the absolute numbers are small), the donor renal evaluation needs to be undertaken with special care. This may be especially true for prospective African American donors. MORTALITY Donor death is not only related to surgical complications. Common medical conditions may develop, such as cancer or vascular disease, but of special concern is the contribution of donation to the psychological state of the donor and the impact on accident, homicide, and suiciderelated deaths (5,12). Review of the OPTN database revealed in an as yet unpublished report that donor mortality (for donors from October 1999 to October 2005) >180 days from donation is often from an unknown cause (Tables 5 and 6). However, it is also not uncommonly due to suicide, homocide, or accidents especially in the young donor (Table 6). Jordan and colleagues recently reported that 3% of donors had a psychopathological illness related to donation and that younger donors had more characteristics associated with psychosis than older donors (14). Corley and colleagues reported that 20% of donors thought that they had done something prior in their lives that their families disapproved of, 6% had recently done something that their families disapproved of, 25% felt they had given up something by donating without getting TABLE 5 Living-Kidney Donor Deaths (Donors Oct. 25, 1999–Oct. 31, 2004)—Cause of Death Where Death >180 Days After Donation Cause of death

N

%

Unknown Suicide/homicide/gunshot Accident (auto/drowning/work) Cancer Donation related/hemorrhage Other medical reason Total

22 4 2 2 1 4 35

62.9 11.4 5.7 5.7 2.9 11.4 100.0

Source: From Ref. 11.

TABLE 6 Living Donor Deaths (Donors Oct. 25 1999 to Oct. 31 2004)— Cause of Death Where Donor Was 18–29 Years of Age at Donation Cause of death Unknown Suicide/homicide/gunshot Accident (auto/drowning/work) Predonation coma Donation related/hemorrhage Other medical reason Total Source: From Ref. 11.

N

%

2 3 3 1 1 1 11

18.1 27.3 27.3 9.1 9.1 9.1 100.0

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anything in return, and several donated in order to get societal approval (15). Although donors overall are less likely to have depression, anxiety or somatisation, and have higher self-esteem than the general population, they still do have psychological characteristics and stresses that might put them at risk for accidental or self-determined death. In particular, younger donors need to be evaluated for thought processes that might put them at increased risk for self-destructive behavior following donation (14,15). ASSOCIATED MEDICAL CONCERNS The metabolic syndrome is the current and future plague of living donors. Donors who develop the metabolic syndrome are likely to be at increased risk for future renal disease, the most glaring risk being the development of diabetic nephropathy (16–18). Obesity, a major risk factor for diabetes, is increasing worldwide and will become an increasing impediment to donor safety. The renal injury seen with obesity and the metabolic syndrome is related to abnormal glucose metabolism, hypertension, hyperlipidemia, and increased levels of inflammatory factors (19). Donor teams need to discuss the possible risks of current or future obesity on renal outcome. This is especially true if donors have a family history of diabetes, renal disease, or the metabolic syndrome, even if they are clear at the time of donation. Unfortunately, no specific numerical value can be given to the risk of obesity. Special studies of the obese donor need to be undertaken, given the association of obesity not only with diabetes and the metabolic syndrome but also with nephrolithiasis, renal cell cancer, and focal segmental glomerulosclerosis (16,19–24). Finally, the long-term impact of minor degrees of proteinuria in up to 30% of donors needs to be reviewed. Proteinuria, even small amounts, is a marker for endothelial dysfunction, and is associated with the development of cardiovascular disease (25–27). QUALITY OF LIFE Physical and psychological function in living donors is higher than in the general population (28–30). Donors start the donation process at a higher than average functional state; after surgery, they note declines that remain unchanged or improve again with time (Fig. 4) (14,28,29,31–34). Most studies of donor attitudes and functional status are retrospective, include at most 40% to 75% of the possible donors, include a small total sample size (often <100 donors), are based upon written surveys, and do not assess factors other than those associated with donations that contribute to life satisfaction (e.g., birth of a baby, marriage) (14,15,30–32). Only two reports review the quality of the published literature on donor lifestyle outcomes (14,35). The most in-depth studies have been prospective and involve face-to-face interviews (29,36). However, for all of the flaws in study methodology, the results are, in general, remarkably consistent. The decision to donate is often immediate, a moral imperative without tremendous forethought by the donor in order to help a loved one; frequently, little thought is given to the possible physical and psychological functional changes that may be noted after donation (14). Furthermore, donors often report feeling an obligation to donate and that they are the only potential donor (14). These feelings are not often expressed before donation as the donor is afraid they might result in denying them the opportunity to donate. Physical issues reported by

FIGURE 4 Physical and psychological function scores in living donors before and following donation. Source: From Ref. 28.

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donors following donation frequently include a decrease from baseline in energy, whereas some note a longer time to full recovery (up to four months) than they had anticipated and incisional pain that lasts longer than they were prepared for (beyond one year) (30,34). Interestingly, they rarely are concerned about the level of their remaining kidney function (29). Psychological factors usually include an improved relationship with the recipient, an improved self-image, and frequently a positive effect on their life (14,15,29,30,32). Studies vary, however, in the ability to associate declines in mental component scores with failure of the allograft or death of the recipient (14,28,30). They also vary in the reporting of the impact of era of donation on psychological outcome; some report no difference in responses by year of donation, whereas others note time-sensitive responses (14,15,30,34). Even though most donors have a very positive experience, a small number do regret the decision to donate (0–5%) (30,34). Cultural or ethnicity-centered issues are discussed in very few studies (14,15,31,33,34,36). Even in the few reports where ethnicity may be mentioned, little information about or analysis of ethnocentric issues is presented. For instance, Corley and colleagues reported results from 16 African American and 39 Caucasian donors (15). African American donors had higher self-esteem following donation. Pradel and colleagues reported on nine African American and 16 Caucasian donors. None of the African American participants ever talked about any conflict with their close social environment about the decision to donate (37). Isotani and colleagues reported from Japan that the donors scored slightly higher than the general U.S. population for functional ability on the short-form 36-item health survey (34). Thus, even though reports on living donation have come from around the world, ethnic-specific perspectives have not been well-delineated. When reviewing the treatment by the medical team, the donors complained that they felt like nonpatients and, in some cases, felt deserted by the health care team (36). A few indicated that donation brought with it a financial burden for travel and time lost from work, and there have been many anecdotal reports of donors being denied life or health insurance (30,34,38,39). Johnson and colleagues reported that 88% of 524 donors responding felt that the donation provoked little or no financial burden; 8% found it to cause a moderate burden; and 3% an extreme burden (30). The average amount paid by donors for expenses related to donation was $579 (range $0 – $20,000; median amount paid $0). Loss of income during recovery from surgery was somewhat stressful for 9%, very stressful for 4%, and extremely stressful for 1%. Isotani and colleagues reported that 16% of donors had negative donation-related financial consequences (34). McCune and colleagues reported that donors rely on employer-provided vacation time and sick leave to recuperate, but the average donor required 12 days of unpaid leave before returning to work. Although costs of transportation, lodging, and child care cause a financial burden, the major reason for financial distress is because of time off work (40). Time off work is variable, ranging between one to 12 weeks overall and, on average, two to five weeks (32). Concerns about future health insurance were somewhat stressful for 7%, very stressful for 3%, and extremely stressful for 1%. Spital and Kokmen reported in 1996 on a survey of 99 health insurance organizations (41). Of those organizations responding, all said that donation would not affect an insured person’s coverage, and that a healthy donor would be offered insurance. Only 2% said that the premium would be higher, and 5% said that donors would be considered to be at increased risk for future medical problems (41). Spital has also queried life insurance carriers about living-kidney donor candidacy for life insurance (38,39). In his reports, insurance providers overwhelming stated that living donation did not impair access to purchasing insurance, nor did it change the rate at which the insurance was purchased. Future discussions of health care provision for donors need to include the programs where, at a minimum, health care problems related to the donation are covered for the life of the donor (40). Pain and health concerns aside, very few donors regret the decision to donate. Studies indicate that over 95% to 97% of donors would donate again (14,32). Thus, the living donor is motivated by a desire to help, although at times they may feel pressured. Donors come from a segment of the population that is highly functional and has high self-esteem. The donation process seems to add to that esteem for most, even though they frequently feel health care systems ignore them after donation. Donors seem to overcome this and continue, for the most part, to be highly functional individuals. One area, however, that programs should consider is making sure that the younger donor does not have personality characteristics or other signs that might point to self-destructive behavior or an inability to cope with the stress of postdonation life.

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CONCLUSION Living donors are motivated to donate out of a sense of family love and desire for an improved quality of life for the recipient. By donating, they markedly improve the recipient’s survival. In this process, it is up to health care providers evaluating prospective donors to offer them as risk-free a future as possible. The acceptance of those with minor medical abnormalities, especially if a potential donor is African American, should only be done in the setting of continued donor follow-up with early treatment of new risk factors. Fehrman-Ekholm summarized the situation well: “On average, the remaining renal function of kidney donors did not deteriorate more rapidly than what may be expected from aging. However, one-third of the female and half of the male donors developed hypertension, and approximately 10% displayed proteinuria. Nevertheless, our study supports the continued use of living kidney donors if strict criteria are used for acceptance (5).” The study of living donors must continue. Future reports need to incorporate information on donors of all ethnic backgrounds, longitudinally evaluate more specific studies of GFR and protein excretion, track hospital admissions, capture the outcomes of pregnancies, record the development of other disease processes, and follow up on the access to insurance, employment, and general activities. Only then will the medical profession be able to individualize the long-term risk analysis for each prospective donor. REFERENCES 1. Ramcharan T, Matas AJ. Long-term (20–37 years) follow-up of living kidney donors. Am J Transplant 2002; 2:959–964. 2. Fehrman-Ekholm I, Elinder CG, Stenbeck M, Tyden G, Groth CG. Kidney donors live longer. Transplantation 1997; 64:976–978. 3. Narkun-Burgess DM, Nolan CR, Norman JE, Page WF, Miller PL, Meyer TW. Forty-five year follow-up after uninephrectomy. Kidney Int 1993; 43:1110–1115. 4. Najarian JS, Chavers BM, McHugh LE, Matas AJ. 20 years or more of follow-up of living kidney donors. Lancet 1992; 340:807–810. 5. Fehrman-Ekholm I, Duner F, Brink B, Tyden G, Elinder CG. No evidence of accelerated loss of kidney function in living kidney donors: results from a cross-sectional follow-up. Transplantation 2001; 72:444–449. 6. Goldfarb DA, Matin SF, Braun WE, et al. Renal outcome 25 years after donor nephrectomy. J Urol 2001; 166:2043–2047. 7. Kasiske BL, Ma JZ, Louis TA, Swan SK. Long-term effects of reduced renal mass in humans. Kidney Int 1995; 48:814–819. 8. Ellison MD, McBride MA, Taranto SE, Delmonico FL, Kauffman HM. Living kidney donors in need of kidney transplants: a report from the organ procurement and transplantation network. Transplantation 2002; 74:1349–1351. 9. Fehrman-Ekholm I, Thiel GT. Long-term risks after kidney donation. London and New York, NY: Taylor & Francis, 2005. 10. Hartmann A, Fauchald P, Westlie L, Brekke IB, Holdaas H. The risk of living kidney donation. Nephrol Dial Transplant 2003; 18:871–873. 11. Organ Procurement and Transplant as of February 2005. 12. Davis C, Ojo AO. Living Donor Risks. Amercian Transplant Congress, 2005. 13. Ahmed J, Shah V, Malinzak L, et al. Comparison of the increase in serum creatinine post kidney donation between African American and Caucasian donors. Am J Transplant 2005; 5:A416. 14. Jordan JC, Sann U, Janton A, et al. Living kidney donors’ long-term psychological status and health behavior after nephrectomy—A retrospective study. J Nephrol 2004; 17:728–735. 15. Corley MC, Elswick RK, Sargeant CC, Scott S. Attitude, self-image, and quality of life of living kidney donors. Nephrol Nurs J 2000; 27:43–50. 16. Adelman RD, Restaino IG, Alon US, Blowey DL. Proteinuria and focal segmental glomerulosclerosis in severely obese adolescents. J Pediatr 2001; 138:481–485. 17. Csernus K, Lanyi E, Erhardt E, Molnar D. Effect of childhood obesity and obesity-related cardiovascular risk factors on glomerular and tubular protein excretion. Eur J Pediatr 2005; 164:44–49. 18. Iseki K, Ikemiya Y, Kinjo K, Inoue T, Iseki C, Takishita S. Body mass index and the risk of development of end-stage renal disease in a screened cohort. Kidney Int 2004; 65:1870–1876. 19. Abrass CK. Overview: Obesity: What does it have to do with kidney disease? J Am Soc Nephrol 2004; 15:2768–2772. 20. Moore LE, Wilson RT. Lifestyle factors, exposures, genetic susceptibility and renal cell cancer risk: a review. Cancer Invest 2005; 23:240–255.

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21. Ramey SL, Franke WD, Shelley MC. Relationship among risk factors for nephrolithiasis, cardiovascular disease and ethnicity: focus on a law enforcement cohort. AAOHN J 2004; 52:116–121. 22. Ekeruo WO, Tan YH, Young MD, et al. Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol 2004; 172:159–163. 23. Gillen DL, Coe FL, Worcester EM. Nephrolithiasis and increased blood pressure among females with high body mass index. Am J Kidney Dis 2005; 46:263–269. 24. Verani RR. Obesity-associated focal segmental glomerulosclerosis: pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia. Am J Kidney Dis 1992; 20:629–634. 25. Manrique C, Lastra G, Whaley-Connell A, Sowers JR. Hypertension and the cardiometabolic syndrome. J Clin Hypertens 2005; 7:471–476. 26. Tuttle KR. Cardiovascular implications of albuminuria. J Clin Hypertens 2004; 6:13–17. 27. Wu Y, Liu Z, Xiang Z, et al. Obesity-related glomerulopathy: insights from gene expression profiles of the glomeruli derived from renal biopsy samples. Endocrinology 2006; 147(1): 44–50. 28. Smith GC, Trauer T, Kerr PG, Chadban SJ. Prospective psychosocial monitoring of living kidney donors using the SF-36 Health Survey. Transplantation 2003; 76:807–809. 29. Lumsdaine JA, Wray A, Power MJ, et al. Higher quality of life in living donor kidney transplantation: prospective cohort study. Transplant Int 2005; 18:975–980. 30. Johnson EM, Anderson JK, Jacobs C. Long-term follow-up of living kidney donors: quality of life after donation. Transplantation 1999; 67:717–721. 31. Hasegawa A, Oshima S, Takahashi K, Uchida K, Ito K, Sonoda T. Improvement of quality of life in tacrolimus-based pediatric renal transplant recipients and their caregivers, including donors. Transplant Proc 2005; 37:1771–1773. 32. Rudow DL, Charlton M, Sanchez C, Chang S, Serur D, Brown RS Jr. Kidney and liver living donors: a comparison of experiences. Prog Transplant 2005; 15:185–191. 33. Tanriverdi N, Ozcurumez G, Colak T, et al. Quality of life and mood in renal transplantation recipients, donors and controls: preliminary report. Transplant Proc 2004; 36:117–119. 34. Isotani S, Fujisawa M, Ichikawa Y, et al. Quality of life of living kidney donors: the short-form 36-item health questionnaire survey. Urology 2002; 60:588–592. 35. Nolan MT, Walton-Moss B, Taylor L, Dane K. Living kidney donor decision making: state of the science and directions for future research. Prog Transplant 2004; 14:201–209. 36. Pradel FG, Mullins CD, Bartlett ST. Exploring donors’ and recipients’ attitudes about living donor kidney transplantation. Prog Transplant 2003; 13:203–210. 37. Pradel FG, Limcangco MR, Mullins CD, Bartlett ST. Patients’ attitudes about living donor transplantation and living donor nephrectomy. Am J Kidney Dis 2003; 41:849–858. 38. Spital A. A life insurance for kidney donors: an update. Transplantation 1988; 45:819–820. 39. Spital A, Jacobs C. Life insurance for kidney donors: another update. Transplantation 2002; 74:972–973. 40. McCune TR, Armata T, Mendez-Picon G, et al. The living organ donor network: a model registry for living donors. Clin Transplant 2004; 18:33–38. 41. Spital A, Kokmen T. Health insurance for kidney donors: how easy is it to obtain? Transplantation 1996; 62:1356–1358.

8

Long-Term Outcomes for the Donor Arthur J. Matas Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A.

Hassan Ibrahim Department of Medicine, University of Minnesota, Minneapolis, Minnesota, U.S.A.

INTRODUCTION The donor organ shortage continues to be the most pressing issue in kidney transplantation today. It is known that a transplant provides longer survival and better quality of life than dialysis (1–3). Thus, each year more patients with end-stage renal disease (ESRD) opt for a transplant, and each year, more patients go on the deceased donor (DD) waiting list than actually receive a DD graft (4). Therefore, the waiting list continues to grow and, consequently, the waiting time is longer. Currently, the median waiting time for a DD transplant is about five years and is expected to become longer (4); moreover, about 7% of wait-listed patients die annually without having received a kidney transplant (5). For the first time, significant numbers of ESRD patients are dying on the waiting list (5). It is unlikely that increasing the number of DD grafts will be sufficient to meet the growing demand of the ESRD population (6). As a consequence, living donor (LD) transplants are being increasingly emphasized and encouraged. LD transplants, especially if performed pre-emptively, provide better outcome than DD transplants (7,8). With LD transplants, both short- and long-term graft survival rates are better, and exposure to dialysis is minimized. Recently, there has been an increase in LD transplants in the United States. At least three factors have contributed to this increase. First, the outcomes for recipients of LD kidneys have improved steadily over the last two decades. Second, the outcome for recipients of living-unrelated donor (LURD) kidneys has been shown to be equivalent to that of recipients of non human leukocyte antigen (HLA)-identical living related donor (LRD) kidneys (9). The increased acceptance of LURD kidneys has appreciably expanded the potential donor pool. Third, laparoscopic donor nephrectomy is now an option that is associated with less pain and a faster recovery for the donor than conventional open nephrectomy (10). As a result, more potential LDs may be willing to donate, and more recipients are willing to accept a LD kidney. An LD transplant has a significant disadvantage: The donor is required to have a major operative procedure that is associated with morbidity, mortality, and the potential for adverse long-term consequences secondary to living with a single kidney. Perioperative mortality after living kidney donation is 0.03% (11–13) and morbidity, including minor complications, is less than 10% (14). There are only limited studies of the long-term (>15 yrs) consequences of living with a single kidney. A major concern regarding the use of LDs is whether unilateral nephrectomy predisposes to the development of kidney disease and/or premature death. IMPACT OF NEPHRECTOMY ON LONG-TERM SURVIVAL Survival of Kidney Donors Anderson et al. compared the survival rates of 232 patients who underwent nephrectomy for benign disease with the overall Danish population (15). Follow-up ranged from two months to 26 years. If the remaining kidney was normal, survival was identical to that of the overall population. In Sweden, Fehrman-Ekholm et al. found that kidney LDs live longer than the age-matched general population (16). Although Fehrman-Ekholm’s finding may reflect the selection bias of healthy LDs, both studies offer a contradiction to the idea that LD longevity may be limited. Of concern, however, is the recent finding that mild renal dysfunction or proteinuria correlates with cardiovascular risk. All LDs lose more than 20% renal function, and, as discussed below, proteinuria is common after kidney donation.

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Reduced Renal Function and Cardiovascular Disease A number of reports indicate that an elevated serum creatinine (Cr) may be an independent predictor of all-cause and of cardiovascular disease (CVD) mortality (17–33). Many reports have focused on specific groups, such as hypertensive individuals, the elderly, patients with recent stroke, survivors of myocardial infarction, patients undergoing carotid endarterectomy, or those with pre-existing CVD (17–24). In the HTN Detection and Follow-up Program (HDFP) study, the eight-year mortality risk increased progressively with increasing concentration of serum Cr (17). Similarly, data from over 24,000 hypertensive participants who constituted the control groups from eight controlled trials (HDFP, MRFIT, SHEP, among others) showed that a lower level of glomerular filtration rate (GFR) was associated with an increased risk of fatal strokes, fatal coronary events, and cardiovascular mortality (25). The strength of this association was similar to that of high BP and high total cholesterol (25). In the general population, most (26–33) but not all (34) studies have shown that patients with reduced renal function have increased mortality (even after adjustment for adverse prognostic factors associated with chronic kidney disease) (30). For example, Fried et al., studied subjects more than 65 years old (average follow-up = 7.3 years) (26). Renal insufficiency, defined as serum Cr >1.5 mg/dl in men and >1.3 mg/dl in women, was associated with increased risk for cardiovascular disease, congestive heart failure, and death. Of importance to the study of LDs, many of the reports on CVD risk did not differentiate between those with mild renal insufficiency and those with significant dysfunction. More recently, there have been a number of studies (28–33) looking at CVD risk in National Kidney Foundation (NKF) Class 2 or 3 renal insufficiency (35). Muntner et al. reported on CVD-related mortality in patients age 30 to 74 at baseline (followed over 16 years), and who had urinary dipstick protein measurement (n = 8786) or serum Cr level <3 mg/dl (28). After adjustment for potential confounders, the relative hazards for CVD-related death were 1.57 (0.99–2.48) for subjects with urinary protein levels of 30 to 399 mg/dl, and 1.77 (0.97–3.21) for those with levels >300mg/dl versus <30. Similarly, those with GFR < 70 ml/min had higher risk of death from CVD (RR = 1.68) and all causes (RR = 1.51), versus those with GFR >90 mg/min. Manjunath et al., reported on the relationship between renal function and CVD in 15,792 participants from four counties in the United States (31). After a mean follow-up of 6.2 years, subjects with a GFR of 15 to 59 ml/min had a hazard ratio of 1.38 and those with a GFR between 60 to 89 ml/min had a hazard ratio of 1.16 for atherosclerotic CVD, versus subjects with a GFR of 90 to 150 ml/ min. Most recently, Go et al. estimated the longitudinal GFR among 1,120,295 adults within a large health care system, in whom the serum Cr level was measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation (32). After a median follow-up of 2.8 years, the adjusted hazard ratio for death was 1.2 for those with a GFR of 45 to 59 ml/min, and 5.9 for those with an estimated GFR of less than 15 ml/min. The adjusted hazard ratio for cardiovascular events also increased inversely with estimated GFR. Similar findings were also reproduced by Foley et al. in their study of a 5% sample of the U.S. Medicare population in 1998 and 1999 (33). Also of note is that subjects with mild renal dysfunction appear to have both traditional and novel risk factors for CVD (36–38). All of the above findings were noted in patients with two kidneys. It is important to determine if there are similar CVD risks associated with the same GFR or proteinuria levels in donors after uninephrectomy. IMPACT OF NEPHRECTOMY ON LONG-TERM RENAL FUNCTION Experimental Studies The LD’s long-term renal function is also of concern. Uninephrectomy is followed by early compensatory changes: within seven days of donation, the GFR and renal blood flow increase to 70% of prenephrectomy values (39–46). These compensatory hemodynamic changes, although initially beneficial, may ultimately prove deleterious (39–45). In 1932, Chanutin and Ferris demonstrated that rats could survive after removal of one kidney and 50% to 70% of the contralateral kidney; however, the rats quickly developed progressive polyuria, albuminuria, nitrogenous waste retention, renal hypertrophy, HTN, and cardiac hypertrophy (47). Others have

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demonstrated that the extent of glomerular sclerosis and damage are proportional to the mass of renal tissue removed (49,52,53). Shimamura, Morrison, and others showed that after a 5/6 nephrectomy, hyperfiltration occurs in the remaining glomeruli (49,53,54). It was postulated that this adaptive hyperfiltration led to the subsequent deterioration. Hostetter et al. studied renal structure and the single-nephron glomerular filtration rate (SNGFR) one week after an 11/12 renal ablation, and came to similar conclusions (53). Remnant glomeruli show striking structural abnormalities, and a marked increase in SNGFR caused by augmented intraglomerular pressure and renal plasma flow. Both the glomerular structural changes and the increase in SNGFR can be prevented by decreasing the “work” of the remaining nephrons with protein restriction (55). Thus, in the rat, extensive renal ablation leads to adaptive increase in glomerular capillary pressure and flow. Although this adaptive hyperfiltration increases the GFR, it also leads to glomerular injury. Measures that ameliorate the heightened intraglomerular pressure, namely protein restriction and blockade of angiotensin II actions, result in preservation of glomerular structure (56–59). An important observation that has been consistent in animal models of reduction in renal mass is that progressive injury to remnant glomeruli was heralded by increasing proteinuria (39,49,53). A four-fold increase in urinary protein excretion in rats can be demonstrated as early as one week after ablation of 90% of renal mass (60). Because of such findings in the rat model, the reported increased incidence of proteinuria in kidney LDs (discussed below) has been worrisome. The rat model, however, required removal of one kidney plus significant damage to, or removal of, a large portion of the remaining kidney before progressive renal insufficiency ensued. The rat differs from many other species in that its life span is shorter. Also, an agerelated progressive glomerulosclerosis, heralded by proteinuria, is routinely observed in laboratory rats (61–63). In other species, subtotal nephrectomy does not uniformly lead to the same progressive loss of renal function. Dogs undergoing a three-fourths reduction in renal mass had stable renal function for over four years (64). Some long-term survivors, however, did develop proteinuria. Baboons undergoing a five-eighths reduction in renal mass had elevated mean BP and increased protein excretion four months after renal mass reduction, but no additional significant damage after 4 to 12 months; biopsy of the remnant kidney after eight months was normal (65). Moreover, if more than half of the renal mass needs to be removed in the rat before compensatory changes lead to renal insufficiency, why should LD nephrectomy be a concern? One needs to consider seriously the possibility that the “hyperfiltration damage” may be additive to the background of the “normal” loss of kidney function with age. Numerous cross-sectional studies in healthy humans have shown an age-related decrease in GFR. The GFR in men aged 80 to 90 years, for example, is about half the rate in men aged 20 to 30 years (66,67). Histologic studies have also shown that after the fourth decade, the incidence of sclerotic glomeruli increases in otherwise healthy men (68). Striker et al. noted that when unilateral nephrectomy is performed in older rats, glomerulosclerosis was more prominent in the remaining kidney (40). Brenner et al. suggests that “age-related glomerulosclerosis poses no threat to well being …. If, however, extrinsic renal disease or surgical loss of renal tissue adds to the glomerular burden imposed by eating ad libitum, the course of glomerulosclerosis may be hastened considerably (55).” Proteinuria—Cause or Effect of Kidney Disease? Proteinuria has been incriminated as a central mediator of the progression of renal disease rather than just being its consequence (69). Proteinuria in humans is a significant determinant of GFR decline in both diabetic and nondiabetic renal disease, and is also a strong predictor of renal and all-cause mortality (70,71). Reduction of proteinuria, either spontaneously or with pharmacotherapy, is associated with improved renal survival. Although the association of proteinuria with loss of renal function is considered causal by many, the mechanisms are not wellunderstood. For example, it is unclear why substantial proteinuria is relatively benign in minimal change disease, yet seems detrimental in other nephropathies. Numerous mechanisms have been proposed, most of which involve tubular cell injury or proliferation following increased protein trafficking in the proximal tubule (72–81).

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Given the above, the reported increased risk of proteinuria in kidney donors is, therefore, worrisome and needs to be studied more carefully. Uninephrectomy in Nondonors In humans, evidence that a reduction in renal mass may lead to progressive renal failure comes from studies of children born with a reduced number of functioning nephrons (82–84) and reports of focal sclerosis developing in patients with unilateral renal agenesis (85–87). However, in these situations, it has not always been clear that the patient had one normal kidney. Zucchelli et al. reported that during the follow-up of three to 37 years, seven of 24 patients who had undergone unilateral nephrectomy, and who had a normal remaining kidney by intravenous pyelography, developed proteinuria (88). In four of these patients, kidney biopsy showed focal and segmental glomerulosclerosis. Proteinuria developed, on average, 12.2 years after nephrectomy; but after it developed, it did not increase further, and renal function, as measured by serum Cr, remained stable. Other long-term follow-up studies after nephrectomy performed for unilateral disease have not shown progressive deterioration in renal function (89–94). In the study with the longest follow-up, Baudoin assessed patients who had undergone uninephrectomy in childhood (at the time of the study, patients were 18 to 56 years old) (93). In general, their kidney function was maintained. However, those followed for more than 25 (versus less than 25) years had a higher incidence of kidney failure, higher blood pressure (BP), and increased urinary protein excretion. In another study, Narkun-Burgess et al. assessed 56 World War II veterans who had lost a kidney due to trauma during the war (average follow-up, 45 years) and compared them with other World War II veterans of the same age (94). Mortality was not increased in those who had lost a kidney. Of the 28 living veterans (average age, 64 ± 4 yrs; average interval after kidney loss, 45±1 yrs), none had serious kidney insufficiency. Other similar studies, albeit with shorter follow-up, have noted small increases in BP and an increased incidence of mild proteinuria after uninephrectomy. None of these studies suggested that proteinuria (after uninephrectomy) was a precursor of renal insufficiency. Of particular interest are the case reports of patients with partial loss of a solitary kidney. Of 35 such patients studied, 31 were reported to have stable renal function (95–99). However, in the largest series, Novick et al. evaluated 14 patients who were five to 17 years old after partial nephrectomy of a solitary kidney: 12 had stable renal function, but two developed renal failure and nine had proteinuria (98). The extent of proteinuria correlated directly with the length of follow-up and inversely with the amount of remaining renal tissue. IMPACT OF DONOR UNINEPHRECTOMY Follow-Up of Less Than 20 Years Prospective LDs are screened to determine that they have two normal kidneys at the time of nephrectomy. To date, numerous studies have examined renal function, proteinuria, and HTN (12, 42–46, 100–125; reviewed in 125). Although isolated cases of renal failure after donor nephrectomy have been reported (121,122), no large, single-center series has demonstrated any evidence of progressive deterioration of renal function in LDs. In recognition of this benign course, insurance companies do not increase premiums for kidney donors (126). However, a limiting factor in most of these studies is that average follow-up has been less than 20 years. Given that most LDs have a life expectancy of more than 20 years, longer follow-up is necessary. Ellison et al. reported on 56 former LDs who had subsequently listed themselves with the United Network for Organ Sharing (UNOS) for a DD transplant (127). Some had donated before the establishment of the UNOS database, making it difficult to determine a denominator and calculate an incidence rate. Even if such a calculation were possible, it might still underestimate the incidence of ESRD in LDs, because those receiving a LD transplant and those developing ESRD but not listed for transplantation would be missed in the calculation. In Ellison’s report, 86% of the LDs who were later wait-listed had donated to a sibling; the cause of ESRD was hypertensive nephrosclerosis in 36% and focal sclerosis in 16%. Clearly, this study emphasizes the need for long-term follow-up studies of LDs to determine accurately the

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donor risk. Large numbers will be required to determine if the risk differs in different subsets (e.g., siblings versus LURDs). Data from Ongoing Studies at the University of Minnesota Recently, we have begun more detailed studies of renal function in LDs. To date, we have comprehensive information on more than 15% of LDs who donated more than five years ago. We classified these donors according to the chronic kidney disease (CKD) staging system advocated by the NKF (128). The mean time after donation was 19.5 ± 9.6 years. The majority, 67%, of LDs had renal function that could be classified as CKD stage 2 to 3 (given that the CKD system was developed for those with two kidneys and known intrinsic kidney disease, the classification can only be used as a rough guide for LDs; but, if morbidity is related to the level of renal function, the classification may apply). Overall, 32% were hypertensive, 6% were diabetic, and hyperlipidemia was present in 37%. When compared with the National Health and Nutrition Examination Survey (NHANES) III data, our LDs were at least three times more likely than the general population to have renal function that could be classified as stage 2 or 3 CKD. We found that the presence of HTN (but not diabetes nor time after donation) was an independent risk factor for having a lower estimated GFR. To guard against the possibility that the overrepresentation of LDs in CKD stage 2 to 3 is due to the poor performance of the MDRD formula, we performed iohexol GFR on 43 randomly selected former LDs (129). The mean time after donation was 12.1 ± 8.5 years, the serum Cr level was 1.11 ± 0.19 mg/dL, and the mean iohexol GFR was 68.7 ± 11.7mL/min/1.73m2; 26% were hypertensive, 2.3% were diabetic, and 40% were on lipid-lowering agents. Our preliminary data demonstrate that regardless of whether CKD staging is performed by the MDRD prediction model or by measured GFR, a significant proportion of former kidney LDs fall in CKD stages 2 to 3 (130). We then studied the prevalence of microalbuminuria after donation in 140 randomly selected LDs (80% donated more than five yrs ago) (131,132). Of the cohort, 11% were microalbuminuric. Multivariate analysis identified age (p = .056), diastolic BP (p = .0014), current smoking (p = .0018), and increased body mass index (BMI) (p = .0009) as independent risk factors (203). Because these are similar risk factors to those identified in the NHANES III data, we compared the risk of albuminuria in LDs with the general population within strata that contained the eight possible permutations for the presence or absence of the three strongest predictors of albuminuria (in Table 1, two strata had too few LDs in them and therefore are not shown) (204). The data indicate that for any combination of risk factors, kidney donors have an increased risk for the development of albuminuria (204). The combination of BMI > 30 plus either of the other risk factors was associated with a marked increase in albuminuria. Clearly, our data are preliminary (small numbers); large-scale studies need to be done both to verify these findings and to determine their implications. Donor Follow-Up of More Than 20 Years We know of only three published studies reporting ≥20-year follow-up of LDs. In 1991, we studied our LDs ≥20 yrs after donation (range, 21 to 29 yrs) by comparing their renal function, BP, and proteinuria (versus their siblings) (12). Of 130 LDs between January 1963 and December TABLE 1 BMI > 30 No Yes No Yes No Yes

Predictors of Albuminuria in Kidney Donors Smoking

DBP > 85

Albuminuria in donors (%)

Albuminuria in NHANES (%)

Rate Ratioa

No No Yes Yes No No

No No No No Yes Yes

2 13.6 0 60 6.25 80

0.8 1.77 3.11 3.93 0.92 2.78

2.5 7.71 — 15.27 6.79 28.8

a Risk in donors/Risk in general population. Abbreviations: BMI, body mass index; DBP, diastolic blood pressure.

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1970, we were able to locate 125. Of these 125, 78 LDs (or donor families) returned a mailed questionnaire. Of the remaining 47 LDs, 32 were known to be alive, but did not respond. In addition, for each donor, we asked all siblings to participate. Of the 78 LDs (or families) who returned the questionnaire, the mean age at time of donation was 43 ± 1 years (range, 16 to 70 years). Fifteen donors had died two to 25 years after donation; none of these 15 had had kidney disease at death. Fifty-seven LDs (mean age = 61 ± 1 years; range, 40 to 83 yrs) had laboratory tests done. In addition, 65 siblings gave a history and physical (H&P); of these, 50 (mean age = 58 ± 1.3 years; range, 29 to 83 years) underwent laboratory testing. For the 57 LDs, the mean serum Cr level was 1.1 ± .01 mg/dl, the mean BUN was 17 ±0.5 mg/dl, the mean Cr clearance (as determined by 24-hour urine collection) was 82 ±2 ml/min, and the mean BP was 134 ± 2/80 ± 1 mm Hg. We found that 32% of the LDs were taking antihypertensive drugs, and 23% had proteinuria. The 65 siblings did not differ significantly from the 57 LDs in either their demographics or outcomes of interest: mean serum Cr level, 1.1 ± 0.03 mg/dl; BUN, 17 ± 1.2 mg/dl; mean Cr clearance, 89 ± 3.3 ml/min.; and BP, 130 ± 3/80 ± 1.5 mm Hg. Of the siblings, 44% were taking antihypertensive medications, and 22% had proteinuria. Goldfarb et al. studied LDs 20 to 32 years (mean ± SD = 25 ± 3 years) after uninephrectomy (120). Of 180 eligible LDs, 70 (39%) participated in the study. For these 70 LDs, BP and serum Cr levels were increased at the time of the study, compared with levels prior to donation, but the values were still in the normal range. The overall incidence of HTN was comparable to the agematched general population. Of the 70 LDs, 13 (19%) had a 24-hour urinary protein excretion greater than 0.15 gm/24 hours. Donors with, compared with those without proteinuria, did not differ significantly by age, duration of follow-up, Cr, 24-hours Cr clearance, or prevalence of HTN. Of note, ESRD requiring dialysis developed in two LDs. Recently, we again studied all of our LDs more than 20 years after donation (122). We were able to obtain information on 464 (60%) of 773 LDs. Of these 464 LDs, 84 have died. The cause of death was available for 27; 24 had no kidney disease, but three were on dialysis at the time of death. Of these three who died with kidney failure, one developed diabetes and diabetic nephropathy, and started dialysis 10 years after donating a kidney and partial pancreas, one developed kidney failure secondary to hemolytic uremic syndrome at age 76 (32 years postdonation), and one had prerenal failure secondary to cardiac disease. We obtained information on 380 of our LDs who were alive more than 20 years after donation. Of these, 124 reported no kidney problems, but did no other tests; 256 returned our questionnaire and, of these, 125 also sent in records of an H&P examination (done by their local physician), laboratory results, or both. Of 198 LDs who were 20 to 29 years postdonation, 74 had serum Cr levels measured. The average serum Cr level was 1.2 ± .04 mg/dl (range, 0.7 to 2.5 mg/dl). Of these 198 LDs, 92 underwent urinalysis for proteinuria: 82 (89%) had no proteinuria, seven (8%) had trace, one (1%) had 1+, one (1%) had 2+, and one (1%) had 3+ proteinuria. Of these 198 LDs, 72 (36%) stated they have high BP. Another 58 LDs, 30 to 37 years postdonation, returned our questionnaire. Of these, 29 had serum Cr levels measured. The average serum Cr level was 1.3 ± 0.1 mg/dl (range, 0.7 to 2.3 mg/dl). Of these 58 LDs, 21 underwent urinalysis for proteinuria; 20 (95%) had no proteinuria, and one had trace proteinuria: 22 (38%) stated they have high BP. Of LDs providing information, five had serum Cr levels >1.7 mg/dl: (i) 69 years old at the time of the study, developed ESRD secondary to CGN and underwent a kidney transplant 24 years after donation; (ii) age 69, developed renal failure secondary to gout, renal stones, and repeated episodes of pyelonephritis, and underwent a kidney transplant 32 years after donation; (iii) age 87, had a serum Cr level of 2.3 mg/dl (30 years after donation) secondary to prerenal failure; (iv) age 47, had a serum Cr level of 2.5 mg/dl (no biopsy has been done) 25 years after donation; (v) age 66, had a serum Cr level that vacillated from 1.7 to 2.2 mg/dl (22 years after donation); Cr clearance (24-hour urine collection) is 52 ml/min. Kidney biopsy results showed nephromegaly with segmental and global glomerular sclerosis. Of interest, 250 LDs responded to a question about family history of diabetes. Of these, 87 reported a family history (20 Type 1, 43 Type 2, 24 not specified). Postdonation, 19 LDs developed diabetes; nine of them (47%) had no other family members with diabetes.

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RISK FACTORS FOR END-STAGE RENAL DISEASE IN THE GENERAL POPULATION Population studies have shown that smoking, obesity, elevated BP, and elevated blood glucose levels are associated with increased risk for proteinuria (133–140, reviewed in 140); and, as discussed above, proteinuria is an early marker for renal disease. Whereas diabetes and HTN are well-described causes of ESRD, the association of smoking and obesity with proteinuria is a cause for concern. Both are prevalent in the general population. Tozawa et al., in a sequential study of 5,403 men and women in Japan, noted that development of new onset proteinuria was related to smoking and obesity (133). Briganti et al., in a study of Australian adults, also noted an association between proteinuria and smoking (135). Praga et al. studied the impact of uninephrectomy for unilateral renal disease on proteinuria and renal function (139). The preoperative characteristic that determined the development of proteinuria or renal insufficiency was BMI. The probability of proteinuria was 60% in obese subjects (BMI > 30) at 10 years after nephrectomy and 92% at 20 years (versus 7% at 10 years and 23% at 20 years for those with BMI < 30). This finding clearly underscores the need for long-term LD follow-up with stratification for risk factors. Presumably, in Praga et al. series, the patients having unilateral nephrectomy required nephrectomy for their disease. It is unlikely that a minimum Cr clearance was needed before proceeding with the nephrectomy (although serum Cr levels were reported to be normal). LDs may be more extensively evaluated before being approved for nephrectomy. It is important to determine whether Praga’s findings will also be noted in long-term follow-up of LDs. OUTCOME OF INTRINSIC KIDNEY DISEASE IN UNINEPHRECTOMIZED HUMANS A critical question is whether LDs who subsequently develop any form of kidney disease, even years postnephrectomy, will have an accelerated time course to develop kidney failure. As described above, our long-term donor follow-up study identified 19 LDs who developed diabetes six to 34 years postdonation (122). There are little data to answer this question. Of nine diabetic patients with either unilateral agenesis or unilateral nephrectomy, none suffered accelerated kidney failure in the remaining kidney (141,142). Silveiro et al. studied type two non-LD diabetic patients who had undergone uninephrectomy (single-kidney diabetes, n = 20; duration of diabetes, 8.5 ± 7 yrs) comparing renal function with nondiabetics who had undergone uninephrectomy (single-kidney nondiabetic, n = 17) and versus type 2 diabetics having two kidneys (n = 184; duration of diabetes, 10±7 yrs) (143). The single-kidney and two kidney type 2 diabetic patients were matched for age, sex, and BMI. Microalbuminuria was noted in a higher proportion of single-kidney diabetics (40%) than in single kidney nondiabetics (18%) or two-kidney diabetics (20%). Macroalbuminuria was noted in a higher proportion of single- kidney diabetics (30%) than in single-kidney nondiabetics, but there was no difference between single-kidney diabetics (30%) and two-kidney diabetics (23%). Of importance, renal function at the time of the study was not different for single-kidney patients, whether or not they had diabetes (143). Zeier et al. compared 47 patients with polycystic kidney disease who required uninephrectomy with matched controls who did not undergo nephrectomy (144). The uninephrectomy was done for infection, stones, hemorrhage, or trauma. Both the mortality rate and the median time for serum Cr levels to rise from 4 mg/dl to 8 mg/dl were similar in the two groups. QUALITY OF LIFE AFTER KIDNEY DONATION The authors and others, using a variety of standardized instruments (most commonly the SF-36), have studied LD quality of life (QOL) (145–155; reviewed in 155). In general, LDs report a similar, or better, QOL compared to the general population. However, risk factors for less positive outcomes have also been identified, and include poor donor or recipient physical outcome, a negative personal donor-recipient relationship, and financial hardship. In addition, most studies are of LRDs. It needs to be determined whether LURDs and nonrenal donors have similar outcomes, as the surgery, relationship dynamics, and motivation to donate is complex.

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To date, there is no reported difference when comparing QOL scores between LDs with open versus laparoscopic nephrectomy (150). However, it is known that laparoscopic nephrectomy is associated with a quicker recovery and faster return to work. Although, in the above studies, LD QOL was reported to be good, some concerns were raised: negative effects on recovery and future health (149,156,157), amount of time to return to routine daily activities and commitments (145,156), financial consequences and implications (146,149,158), and potential penalization by life or health insurance (145,158,159). In addition, many LDs also report feeling abandoned after surgery by the transplant program, and are disappointed by the lack of any follow-up after hospital discharge (149,159,160). The majority of these studies were done after open nephrectomy. It will be important to learn if the same issues develop after laparoscopic nephrectomy. Such information can help transplant programs design protocols to increase LD satisfaction with the process. EXPANDING ACCEPTANCE CRITERIA FOR LIVING DONORS The organ shortage has become a major crisis in clinical transplantation. In some parts of the United States, the average waiting time now exceeds five years; and, for the first time, a significant number of kidney transplant candidates are dying while waiting for a transplant (4,5). As waiting times for DD transplants have increased, so has acceptance of living donation. This acceptance has two components: (i) transplant candidates are now strongly encouraged to find a LD; (ii) in many centers, LD acceptance criteria have been expanded. To date, all long-term follow-up data (both medical and psychosocial) have focused on LDs who were selected and, most often, related (either genetically or emotionally) to the recipient. As described above, only 40% to 70% of former LDs could be contacted, because no system had been established to track them long term. As a consequence, the data are incomplete. As LD acceptance criteria continue to expand, it is imperative that we establish a system for long-term follow-up. Heimbach et al. reported on 553 consecutive LDs, including 172 with a BMI >30, of whom 58 had a BMI >35 (161). At one-year follow-up, GFR and microalbuminuria did not differ between obese and nonobese LDs. However, obesity has been associated with proteinuria and renal dysfunction in the general population (133,139). Thus, long-term follow-up of LDs with a high BMI will be necessary to determine their risk. Textor et al. reported on follow-up of carefully selected white kidney LDs with essential hypertension. Selection criteria included absence of proteinuria and of microalbuminuria, normal GFR, and modest hypertension (162). The LDs were studied six to 12 months after donation; no adverse effects of donation on BP were found. However, two previous studies comparing normotensive and hypertensive kidney LDs had reported that the latter were at increased risk for worsening hypertension on follow-up (163,164). As noted by Herman et al., long-term follow-up of current LDs with “modest” hypertension is necessary (165). LD acceptance has also increased in situations in which medical criteria for donation have not been relaxed—for example, ABO incompatible and crossmatch-positive transplants—but there is increased risk of early rejection and early graft failure. As described above, a risk factor for decreased LD quality of life has been poor early recipient outcome. However, because ABO- incompatible and crossmatch-positive LDs are counseled predonation about the increased risks of graft loss in such transplants, the psychological consequences of graft failure may not be the same. In the case of nondirected donation or kidney exchanges, LDs without any pre-existing relationship with the recipient have been accepted (166). Long-term follow-up is necessary to determine the effect on LD quality of life. LIMITATIONS OF THE CURRENT EVIDENCE Numerous questions remain regarding long-term outcome for kidney LDs. These include: 1. What is the long-term (≥15 yrs) outcome of donor nephrectomy? Most published studies have a mean follow-up of less than 15 years, and those with longer follow-up have

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2. 3. 4. 5. 6.

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incomplete information. Many examples of renal functional deterioration (e.g., diabetes) in humans require two to three decades to develop. It is important to determine if the incidence of HTN, proteinuria, anemia, or renal dysfunction is higher in LDs than in their siblings or in the age-matched general population. Does proteinuria or mild renal dysfunction in LDs herald the development of renal failure? To date, there have not been sequential studies of LDs more than 15 years from donation. It is unknown whether previously reported mild proteinuria in some LDs is progressive. Are proteinuria or mild renal dysfunction (seen in some LDs) associated with increased risk for CVD or mortality? Are LDs at risk for anemia and, if so, does this contribute to increased risk for CVD? Are the use of expanded criteria LDs (obese, mild HTN) associated with an increased incidence of perioperative complications, proteinuria, or renal dysfunction? If LDs develop native kidney disease or other disease that might affect the kidney (particularly type 2 diabetes), will there be an accelerated time course to develop kidney failure? Is quality of life affected by laparoscopic nephrectomy?

SUMMARY The retrospective nature of the previous studies, the small number of LDs studied, and the poor response rates constitute major limitations to our understanding of long-term outcome. Recall bias on the part of the responding LDs, and frequently, their family members, undoubtedly creates a problem for proper interpretation of the data. To date, no study has had 100% long-term follow-up of LDs. Thus, it remains unclear if kidney LDs are at increased risk of developing ESRD or any other health-related problems. With the current increased emphasis on living kidney donation, it is imperative that accurate long-term information be available to donor candidates. REFERENCES 1. Evans RW, Manninen, DL, Garrison, LP Jr, et al. The quality of life of patients with end-stage renal disease. N Engl J Med 1985; 312(9):553–559. 2. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341(23):1725–1730. 3. Schnuelle P, Lorenz D, Trede M, et al. Impact of renal cadaveric transplantation on survival in endstage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998; 9(11): 2135–2141. 4. Xue JL, Ma JZ, Louis TA, et al. Forecast of the number of patients with end-stage renal disease in the United States to the year 2010. J Am Soc Nephrol 2001; 12(12):2753–2758. 5. Ojo AO, Hanson JA, Meier-Kreische H, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant patients. J Am Soc Nephrol 2001; 12(3):589–597. 6. Sheehy E, Conrad SL, Brigham LE, et al. Estimating the number of potential organ donors in the United States. N Engl J Med 2003; 349(7):667–674. 7. Cosio FG, Alamir A, Yim S, et al. Patient survival after renal transplantation. I. The impact of dialysis pre-transplant. Kidney Int 1998; 53(3):767–772. 8. Meier-Kreische HU, Port FK, Ojo AO, et al. Effect of waiting time on renal transplant outcome. Kidney Int 2000; 58(3):1311–1317. 9. Gjertson DW, Cecka JM. Living unrelated donor kidney transplantation. Kidney Int 2000; 58(2):491–499. 10. Wolf JS Jr, Merion RM, Leichtman AB, et al. Randomized controlled trial of hand-assisted laparoscopic versus open surgical live donor nephrectomy. Transplantation 2001; 72(2):284–290. 11. Bay WH, Hebert LA. The living donor in kidney transplantation. Ann Intern Med 1987; 106(5):719–727. 12. Najarian JS, Chavers BM, McHugh LE, et al. 20 years or more of follow-up of living kidney donors. Lancet 1992; 340(8823):807–810. 13. Matas AJ, Bartlett AT, Leichtman AB, et al. Morbidity and mortality after living kidney donation in 1999-2001: A survey of United States transplant centers. Am J Transplant 2003; 3(7):830–834. 14. Johnson EM, Remucal MJ, Gillingham KJ, et al. Complications and risks of living donor nephrectomy. Transplantation 1997; 64(8):1124–1128.

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15. Andersen B, Hansen JB, Jorgensen SJ. Survival after nephrectomy. Scand J Urol Nephrol 1968; 2(2):91–94. 16. Fehrman-Ekholm I, Elinder CG, Stenbeck M, et al. Kidney donors live longer. Transplantation 1997; 64(7):976–978. 17. Shulman NB, Ford CE, Hall WD, et al. Prognostic value of serum Cr and effect of treatment of hypertension on renal function. Results from the Hypertension Detection and Follow-up Program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension 1989; 13(5 suppl):I80–193. 18. Damsgaard EM, Froland A, Jorgensen OD, et al. Microalbuminuria as predictor of increased mortality in elderly people. BMJ 1990; 300(6720): 297–300. 19. Friedman PJ. Serum Cr: an independent predictor of survival after stroke. J Intern Med 1991; 229(2):175–179. 20. Hamdan AD, Pomposelli FB Jr, Gibbons GW, et al. Renal insufficiency and altered postoperative risk in carotid endarterectomy. J Vasc Surg 1999; 29(6): 1006–1011. 21. Matts JP, Karnegis JN, Campos CT, et al. Serum creatinine as an independent predictor of coronary heart disease mortality in normotensive survivors of myocardial infarction. POSCH Group. J Fam Pract 1993; 36(5):497–503. 22. Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular dysfunction. J Am Coll Cardiol 2000; 35(3):681–689. 23. Anderson RJ, O’Brien M, MaWhinney S, et al. Mild renal failure is associated with adverse outcome after cardiac valve surgery. Am J Kidney Dis 2000; 35(6):1127–1134. 24. Weiner DE, Tighiouart H, Stark PC, et al. Kidney disease as a risk factor for recurrent cardiovascular disease and mortality. Am J Kidney Dis 2004; 44(2):198–206. 25. Gueyffier F, Boissel JP, Pocock S, et al. Identification of risk factors in hypertensive patients: contribution of randomized controlled trials through an individual patient database. Circulation 1999; 100(18): e88–e94. 26. 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The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease, Ann Int Med 2004; 140:9–17. 37. Muntner P, He J, Astor BC, et al. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: Results from the atherosclerosis risk in communities study. J Amer Soc Nephrology 2005; 16:529–538. 38. Shilpak MG, Fried lf, Cushman M, et al. Cardiovascular mortality risk in chronic renal disease. JAMA 2005; 293:1737–1745. 39. Ogden DA. Consequences of renal donation in man: Am J Kidney Dis 1983; 2(5):501–511. 40. Donadio JV Jr, Farmer CD, Hunt JC, et al. Renal function in donors and recipients of renal allotransplantation. Radioisotopic measurements. Ann Intern Med 1967; 66(1):105–115. 41. Krohn AG, Ogden DA, Holmes JH. Renal function in 29 healthy adults before and after nephrectomy. JAMA 1966; 196(4):322–324. 42. Flanigan WJ, Burns RO, Takacs FJ, et al. 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Am J Dis Child 1974; 127(1):17–19. 88. Zucchelli P, Cagnoli L, Casanova S, et al. Focal glomerulosclerosis in patients with unilateral nephrectomy. Kidney Int 1983; 24(5):649–655. 89. Goldstein AE. Longevity following nephrectomy. J Urol 1956; 76(1):31–41. 90. Kohler B. The Prognosis After Nephrectomy: A Clinical Study of Early and Late Results. Stockholm, Sweden, Kungl, Boktryckeriet P.A. Norstedt & Soner, 1944. 91. Higashihara E, Horie S, Takeuchi T, et al. Long-term consequence of nephrectomy. J Urol 1990; 143(2):239–243. 92. Robitaille P, Mongeau JG, Lortie L, et al. Long-term follow-up of patients who underwent unilateral nephrectomy in childhood. Lancet 1985; 1(8441):1297–1299. 93. Baudoin P, Provoost AP, Molenaar JC. Renal function up to 50 years after unilateral nephrectomy in childhood. Amer J Kid Dis 1993; 21(6):603–611. 94. Narkun-Burgess DM, Nolan CR, Norman JE, et al. Forty-five year follow-up after uninephrectomy. Kidney Int 1993; 43(5):1110–1115. 95. Lhotta K, Eberle H, Konig P, et al. Renal function after tumor enucleation in a solitary kidney. Am J Kidney Dis 1991; 17(3):266–270. 96. Foster MH, Sant GR, Donohoe JF, et al. Prolonged survival with a remnant kidney. Am J Kidney Dis 1991; 17(3):261–265. 97. Rutsky EA, Dubovsky EV, Kirk KA. Long-term follow-up of a human subject with a remnant kidney. Am J Kidney Dis 1991; 18(4):509–513. 98. Novick AC, Gephardt G, Guz B, et al. Long-term follow-up after partial removal of a solitary kidney. N Engl J Med 1991; 325(15):1058–1062. 99. Solomon LR, Mallick NP, Lawler W. Progressive renal failure in a remnant kidney. Br Med J (Clin Res Ed) 1985; 291(6509):1610–1611. 100. Penn I, Halgrimson CG, Ogden D, et al. Use of living donors in kidney transplantation in man. Arch Surg 1970; 101(2):226–231. 101. Davison JM, Uldall PR, Walls J. Renal function studies after nephrectomy in renal donors. Br Med J 1976; 1(6017):1050–1052. 102. Ringden O, Friman L, Lundgren G, et al. Living-related kidney donors: complications and long-term renal function. Transplantation 1978; 25(4):221–223. 103. Dean S, Rudge CJ, Joyce M. Live-related renal transplantation: An analysis of 141 donors. Transplant Proc 1982; 14:657. 104. Vincenti F, Amend WJ Jr, Kaysen G, et al. Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects. Transplantation 1983; 36(6):626–629. 105. Weiland D, Sutherland DER, Chavers B. Information on 628 living-related kidney donors at a single institution, with long-term follow-up in 472 cases. Transplant Proc 1984; 16:5. 106. Hakim RM, Goldszer RC, Brenner BM. Hypertension and proteinuria: long-term sequelae of uninephrectomy in humans. Kidney Int 1984; 25(6):930–936. 107. Miller IJ, Suthanthiran M, Riggio RR, et al. Impact of renal donation. Long-term clinical and biochemical follow-up of living donors in a single center. Am J Med 1985; 79(2):201–208. 108. Tapson JS, Marshall SM, Tisdall SR, et al. Renal function and blood pressure after donor nephrectomy. Proc Eur Dial Transplant Assoc Eur Ren Assoc 1985; 21:580–587.

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Lancet 1992; 339(8785):124–125. 116. Smith S, Laprad P, Grantham J. Long-term effect of uninephrectomy on serum Cr concentration and arterial blood pressure. Am J Kidney Dis 1985; 6(3):143–148. 117. O’Donnell D, Seggie J, Levinson I, et al. Renal function after nephrectomy for donor organs. S Afr Med J 1986; 69(3):177–179. 118. Talseth T, Fauchald P, Skrede S, et al. Long-term blood pressure and renal function in kidney donors. Kidney Int 1986; 29(5):1072–1076. 119. Williams SL, Oler J, Jorkasky DK. Long-term renal function in kidney donors: a comparison of donors and their siblings. Ann Intern Med 1986; 105(1):1–8. 120. Goldfarb DA, Matin SF, Braun WE, et al. Renal outcome 25 years after donor nephrectomy. J Urol 2001; 166(6):2043–2047. 121. Dunn JF, Nylander WA Jr, Richie RE, et al. Living-related kidney donors: A 14-year experience. Ann Surg 1986; 203(6):637–643. 122. Ramcharan T, Matas AJ. Long-term (20–37 years) follow-up of living kidney donors. 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Ibrahim H, Rogers T, Humar A, et al. The accuracy of the MDRD and Cockcroft Gault formulas in predicting true GFR years after donor nephrectomy. Am J Transplant 2005; 5:478 (abst). 130. Ibrahim H, Rogers T, Humar A, et al. Prevalence of chronic kidney disease years after donor nephrectomy using measured GFR. Am J Transplant 2005; 5:300 (abst). 131. Ibrahim H, Rogers T, Matas AJ. Prevalence of microalbuminuria in kidney donors years after donation. J Am Soc Nephrol 2005; 16:560A–561A. 132. Rogers T, Matas A, Ibrahim H. Comparison of the risk of albuminuria in kidney donors years after donation and the NHANES III study population. J Am Soc Nephrol 2005; 16:560A. 133. Tozawa M, Iseki K, Iseki C, et al. Influence of smoking and obesity on the development of proteinuria. Kidney Int 2002; 62:956–962. 134. Watnick TJ, Jenkins RR, Rackoff P, et al. Microalbuminuria and hypertension in long-term renal donors. Transplantation 1988; 45(1):59–65. 135. Briganti EM, Branley P, Chadban SJ, et al. 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Donor and Recipient Outcomes After Laparoscopic Live-Donor Nephrectomy Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

David J. Kaczorowski Department of Surgery, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Amit Basu Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Joseph Donaldson Thomas E. Starzl Transplantaion Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Renal transplantation offers patients a life free from dialysis and provides improved survival over dialysis as well (1). Unfortunately, the number of patients with end-stage renal disease (ESRD) continues to grow, while the number of organs available for transplantation has not kept up with the increased demand. As the disparity between organs available for transplantation and the number of potential recipients increases, the number of patients on the waiting list grows rapidly. Currently, there are over 63,000 patients awaiting a kidney transplant in the United States (2). Increased use of living donor renal transplantation is the most immediately available route for alleviating the current shortage of donor organs for transplantation. Live donation improves both graft survival and patient survival in comparison with deceased donor renal transplantation (3). Despite these advantages, organs procured from live donors are still underutilized. A number of barriers to living donor nephrectomy exists, including postoperative pain, time away from work and family, and others. In 1995, Ratner and colleagues introduced laparoscopic live donor nephrectomy (LLDN) as a means of increasing organ donation by minimizing potential disincentives to donors (4). Since then, the use of LLDN has been shown to cause less postoperative pain, permit shorter hospital stays, and allow more rapid recovery when compared with the open operation (5,6). LLDN has also provided equivalent functional results when compared with the open operation as well (7). For these reasons, LLDN has been implemented at transplant centers throughout the world and appears to have increased the number of living donor renal transplantations (8). In this chapter, the current data on outcomes after LLDN are reviewed, and recent data utilizing a novel approach to immunosuppression are presented. DONOR AND RECIPIENT OUTCOMES Outcomes after LLDN have been examined in several large single-center studies. Su et al. reviewed a six-year experience involving 381 consecutive LLDNs between 1995 and 2001 at the Johns Hopkins Medical Institutions (9). In this series, 362 (95%) were left-sided and 19 (5%) were right-sided kidneys. All 381 kidneys were procured and transplanted. The mean operative time in this series was 253 + 56 minutes. The estimated blood loss (EBL) was 334 + 690 mL.

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Warm ischemia time was 4.9 + 3.4 minutes. The average length of stay in the hospital for the donor was 3.3 + 4.5 days. There were no donor mortalities. Conversion to the open operation was necessary in eight (2.1%) cases. Of these, six of the conversions were emergent because of either renal vein (n = 3) or renal artery (n = 3) injuries. Small bowel distention leading to insufficient working space and adhesions were cited as the reasons for elective conversion to the open operation in the other two cases. Reoperation was necessary in seven patients for injury to the epigastric artery (n = 1), postoperative bleeding from other sources (n = 3), incisional hernia (n = 1), ischemia of the left testicle requiring orchiopexy (n = 1), and duodenal injury requiring duodenojejunostomy (n = 1). Four other bowel injuries (three small bowels, one large bowel) were managed at the time of the initial operation. The total donor complication rate in this series was 16.5% (n = 63). Of these, 29 (7.6%) were major complications and 34 (8.9%) were minor complications. Aside from those listed above, other major donor complications included retroperitoneal hematoma (n = 5) that was managed conservatively, pneumonia (n = 2), and readmission for ileus and dehydration (n = 2). Minor complications included wound infection/seroma (n = 9), transient neuromuscular injury (n = 5), urinary tract infection (UTI)/epididymitis (n = 5), orchalgia (n = 4), retroperitoneal hematoma not requiring transfusion (n = 3), and others. It is important to point out that the authors noted a substantial and statistically significant decline in the observed complication rate as greater experience was accumulated and modifications were made to the operative technique. In the first 95 cases in the series, the overall donor complication rate was 21%, compared with 10.4% in the most recent 96 cases in the study. The authors found that the recipients of the grafts procured laparoscopically had functioned similarly on postoperative day 4, and at five-year follow-up when compared with grafts obtained utilizing the open operation. There were a total of 23 (6%) recipient mortalities. Only one of these was in the immediate postoperative period and was related to hemorrhage from a renal artery anastomosis. Of the 381 patients, 24 (6.3%) developed ureteral complications. Eight (2.1%) patients developed vascular thromboses. In five of these cases, renal vein thrombosis occurred, and three of these kidneys were obtained from the right side. Renal artery thrombosis occurred in two patients, and one patient suffered from cholesterol emboli. Also of note is that the rates of ureteral complications and vascular thrombosis declined with greater experience. Graft loss occurred in 22 other patients from acute cellular rejection (ACR) (n = 16), humoral rejection (n = 1), medical noncompliance (n = 3), recurrent focal segmental glomerulosclerosis (FSGS) (n = 1), and hemorrhage (n = 1). The incidence of ACR was 23.9% in the first three months postoperatively. This large six-year study demonstrated that LLDN is clearly not without risks and that the learning curve is steep for this technically demanding operation. However, with greater experience, the operation can be performed safely and result in lower donor morbidity and a high-quality allograft for the recipient. In the largest single-center series to date, Jacobs and colleagues examined outcomes from 738 LLDNs at the University of Maryland over a six-year period (10). In this series, 96% of nephrectomies were left-sided. The mean operative time was 202 + 52 minutes and the EBL was 128 + 194 mL. The mean warm ischemia time was 169 + 91 seconds. Warm ischemia time did not correlate with recipient creatinine or the incidence of delayed graft function (DGF). Donor hospitalization lasted 64 + 38 hours. Of the 738 donors, 12 (1.6%) underwent conversion to the open operation. Vascular injury (n = 10) or obesity and failure to progress laparoscopically were reasons for converting to the open operation. Two cases in this series were aborted. In one case, the patient suffered a colon injury and in another a mesenteric vein injury occurred. Major intraoperative complications occurred in 6.8% and included injuries to the renal arteries (n = 2), renal veins (n = 3), aorta (n = 4), common iliac artery (n = 1), vena cava (n = 1), and mesenteric veins (n = 2). Minor complications, most of which were managed laparoscopically and thought not to pose a significant risk to the donor, included 15 splenic lacerations, one liver laceration, seven cases of pneumothoraces, two diaphragmatic injuries, four stapler misfires requiring control with clips or sutures, three intubations or extubation difficulties, two cardiac arrhythmias, two urethral strictures, and others. The postoperative donor serum creatinine was 1.5 times the preoperative value. Major postoperative donor complications occurred in 17.1% and included five cases of bowel

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obstruction requiring laparotomy, four cases of pancreatitis, four retroperitoneal hematomas, one case of atrial fibrillation, one case of pneumonia, and one splenic laceration requiring splenorrhaphy. A number of minor complications were also reported. In this study by Jacobs et al. the recipient serum creatinine was 2.0 + 1.5 mg/dL at one week post-op and 1.7 + 0.7 mg/dL at four years. DGF occurred in 19 out of 730 cases (2.6%). Factors contributing to DGF included technical problems during the procurement leading to acute tubular necrosis (ATN) in nine cases, technical issues with implantation in five cases, and graft rejection in five cases. Ureteral stricture or necrosis occurred in 33 cases. The majority of these (88%) occurred within the first six months after transplantation. Other recipient urologic complications included two ureteroneocystostomy leaks, two cases of bleeding at the ureteral reimplantation site, two lymphoceoles leading to hydronephrosis, and one perinephric hematoma. This large retrospective review by Jacobs et al. demonstrates again that high-quality allografts can be obtained for recipients. However, strict attention must clearly be paid to donor safety, given the technical complexity of this operation. Donors must be adequately counseled on the potential risks of the procedure. Leventhal et al. from Northwestern University performed a retrospective review of 500 cases of LLDN performed at their transplant center between 1997 and 2003 (11). In this series, the left kidney was harvested in 99% of donors; 3.4% (n = 17) were hand-assisted, and all laparoscopic cases were staffed by two dedicated faculty. The warm ischemia time was 2.6 + 0.5 minutes and the average length of hospital stay was 1.7 + 0.7 days. There was conversion to the open operation in nine cases (1.8%) in this series. Notably, six of these were in the first 100 cases. Lack of exposure, donor obesity, and the need for open management of multiple renal vessels were reasons cited for conversion in three cases. The remaining conversions were related to bleeding, either from lumbar vein injuries or three renal artery injuries. The overall rate of intraoperative complications in this series was 2.8% and also included an aortic injury requiring reoperation, a splenic capsular tear and diaphragmatic injury repaired laparoscopically, an adrenal hematoma, a serosal bowel injury, and a transient carbon dioxide pneumomediastinum. The incidence of postoperative complications was 3.4% and included wound infection, chylous ascites, temporary thigh numbness, urinary retention, and port site granuloma. No postoperative bowel obstructions were noted. Preoperative and postoperative donor serum creatinine levels were 0.9 + 0.2 mg/dL and 1.3 + 0.3 mg/dL, respectively. In this study, all kidneys functioned immediately with the exception of one case. This patient experienced DGF requiring dialysis. The same patient also developed an ureteral stricture requiring radiologic intervention. Overall, recipient serum creatinine was 1.5 + 0.2 mg/dL at one week. Graft survival was 96% at follow-up. No graft losses occurred related to laparoscopic technique. Death with a functioning graft occurred in seven patients. Other grafts were lost to noncompliance, drug toxicity, chronic rejection, and recurrent disease. Vascular complications (two renal artery thromboses, one renal artery stenosis, and one renal infarct) resulted in graft loss. This study highlighted the potential safety and efficacy of LLDN, and demonstrated that the operation can be performed with a low complication rate and low rate of conversion to the open operation. Furthermore, excellent recipient outcomes, with low rates of urologic complications and DGF can also be achieved. Melcher et al. examined a series of 530 LLDNs [four trocar ports (three 11 mm and one 12 mm) and a 7 to 8 cm suprapubic incision] performed at the University of California San Francisco (UCSF) between 1999 and 2004 (12). This study included 86 donors with a body mass index (BMI) > 30, 84 right-sided donors, and 91 donors with complex vascular anatomy. The duration of the procedure and length of donor hospital stay were similar to previously described studies. Of the 530 cases reported here, there was only one conversion to an open operation, which occurred early in the series. Furthermore, there was no donor death and the overall complication rate was low, with an incidence of 6.4%. This included 14 wound infections, two bowel injuries, one case of ileus, three splenic injuries, two bladder infections, one bladder injury, one case of rhabdomyolosis, one case of pneumonia, and two thromboembolic events. This study provides clear evidence that LLDN can be performed safely with a complication rate comparable to that seen with the open operation.

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We recently reported on 196 consecutive unselected LLDNs [three trocar ports (one 5 mm and two 10/12 mm) and a 5 to 6 cm suprapubic incision] performed between October 2002 and December 2004 at the University of Pittsburgh Medical Center (UPMC) by a single surgeon (13). Teaching of fellows and faculty was graded according to experience and difficulty level of the cases. We had no donor mortality. The incidence of major and minor donor morbidities was 2.6% and 4.2%, respectively. Major complications included a delayed colonic perforation requiring colostomy in one patient and open conversion for bleeding in four patients. Three of the open conversions for bleeding were secondary to malfunction of the GIA stapler and one was due to a renal vein injury. Minor complications included two UTIs, two transient brachial plexus neuropathies, one wound infection, one readmission for nausea, emesis, and UTI, one umbilical hernia, and one patient with constipation. In our series, patient and graft survival was 98.5% and 96.9%, respectively, with a follow-up of 401 days. The mean recipient creatinine was 1.5 + 1.1 mg/dL. The incidence of DGF was 0.5%. No vascular thromboses occurred. The incidence of ureteral stenosis was 0.5%. In addition, using preconditioning (differs from induction as it is given prior to reperfusion only) therapy with alemtuzumab followed by tacrolimus monotherapy, we were able to wean immunosuppression in a substantial number of patients with an incidence of ACR of 8.4% at mean follow-up of 401 days. This trial confirms earlier results that LLDN can be performed safely without compromising donor safety, and that excellent recipient outcomes with low rates of DGF and ureteral complications can be achieved at a high-volume teaching hospital. OUTCOMES IN SELECT PATIENT POPULATIONS Right-Sided Grafts Procurement of right-sided donor kidneys via a laparoscopic approach is avoided by some because of concerns regarding technical difficulty and vessel length. Several series comparing outcomes of right and left laparoscopically harvested kidneys, with or without the use of handassist devices, have demonstrated similar overall operative duration as well as graft function and survival (14,15). Posselt et al. from UCSF retrospectively analyzed data on 387 LLDNs without the use of hand-assist devices performed between 1999 and 2004 (16). Of these cases, 54 (14%) were right kidneys. The authors found that the groups undergoing right and left nephrectomy were similar with respect to a number of variables, including EBL, operative time, duration of hospital stay, and rates of complications. Furthermore, the incidence of DGF was similar between the two groups. At one month, post-transplant, graft function was similar in both groups as well. These data demonstrate that right kidneys can be safely recovered laparoscopically (without the use of a hand-assist device) and that the use of right-sided kidneys represents a reasonable alternative to left-sided grafts when necessary. In addition to the purely laparoscopic transperitoneal approach, other approaches, including hand-assisted live-donor nephrectomy (HALDN) and retroperitoneoscopic live-donor nephrectomy (RLDN) have been advocated for procurement of right kidneys. One study by Buell et al. compared the outcomes between patients undergoing HALDN and RLDN to procure right-sided allografts (17). The operative time was longer in the HALDN group when compared with the RLDN group (3.4 + 0.7 hours versus 3.0 + 0.7 hours, respectively; P < 0.04), but the warm ischemia time was shorter in HALDN group (3:55 + 1:47 minutes versus 4:55 + 0:55 minutes, respectively; P < 0.001). Other variables, including the length of renal artery and vein, the incidence of complications, the length of donor hospitalization, and the serum creatinine at one week, one month, and one year were similar. Another retrospective review of 40 hand-assisted right LLDNs confirmed that grafts can be safely and effectively obtained using this approach with good recipient outcomes (18). Older Donors The use of living kidney donors of advanced age remains controversial for a number reasons, including an increased incidence of comorbid conditions and increased operative risk to the

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donor, a decline in glomerular filtration rate (GFR), higher rates of DGF and reduced allograft survival in recipients of deceased donor grafts from older donors. A recent study by Johnson et al. suggests, however, that high-quality allografts can be obtained from older living donors (19). A retrospective review of 78 live donor renal transplants between 2000 and 2003 was performed. Of the 78 donors, 22 (28.2%) were older than 50 years of age. LLDN was performed in 29 (37.2%) patients overall. Of the 22 donors older than 50, 13 (59.1%) underwent LLDN, whereas 16 of the 56 (28.6%) of the younger donors underwent LLDN. When the donors who were older than 50 were compared with those younger than 50, it was noted that the older donors had a reduced preoperative creatinine clearance (107.5 + 3.4 versus 124.2 + 3.1 mL/min). The donor serum creatinine was similar between the two groups at multiple early time points, but was noted to be slightly higher at one-year follow-up in the older donor group (1.26 + 0.26 mg/dL versus 1.01 + 0.18 mg/dL). There were no statistically significant differences between the older and the younger groups in terms of complications and with respect to patient and graft survival at one year or the incidence of ACR. On postoperative day 1, the serum creatinine in the group that had received kidneys from the older donors was higher than in those who received kidneys from the younger donors (5.4 mg/dL versus 4.4 mg/dL). However, this difference did not persist past postoperative day number 7, and there was no significant difference in creatinine at several other time points up to one year. These results demonstrate that the older donors can provide high-quality allografts, with function comparable to those of younger donors. Furthermore, the incidence of complications does not appear to be higher in older living donors. Despite these encouraging results, long-term serum creatinine values in the older donors will have to be followed closely. In a smaller study, Hsu and others examined outcomes of six patients aged 65 years or older who underwent LLDN (20). The median age of the donors in this study was 69.5 years with a range of 65 to 74 years of age. There were no intraoperative complications. One patient developed a superficial wound infection. The median donor serum creatinine at discharge was 1.2 mg/dL (range 0.7–1.7). The overall one-year graft survival rate was 100%. The median serum creatinine clearance of the recipients was 46.5, 42.5, and 38 mL/min at three, six, and 12 months of followup. These data suggest that LLDN is well tolerated in elderly donors. However, long-term donor and recipient follow-up as well as expanded patient numbers will be required for greater certainty. Jacobs et al. from the University of Maryland reviewed 42 cases of donors greater than 60 years of age and compared this group with younger but otherwise matched controls (21). The preoperative baseline creatinine was similar in both groups, but the younger donors had a slightly higher creatinine clearance (106.9 + 19.1 versus 100.0 + 35.5 mL/min). There were no significant differences in length of the operation, warm ischemia time, EBL, length of hospital stay, or complication rates. However, in this study, there was slightly better renal function in the recipients of the younger kidneys, which became statistically significant at six and 12 months, but this difference was not thought to be of clinical significance. Taken together with these other studies, the data suggest that LLDN is well-tolerated by donors of advanced age and that highquality grafts with good function can be obtained. Long-term follow-up of both donors and recipients will be required to confirm these outcomes. Obesity Because of increased technical difficulty and the possibility of increased risk of complications, the use of LLDN in obese patients has been questioned. Several studies have addressed this question. In 2000, Jacobs and colleagues compared a group of 41 obese patients (BMI > 30) with 41 controls who were otherwise matched in terms of sex, age, race, and date of surgery (22). They found that the donor operations were significantly longer in the obese patients and more laparoscopic ports were used in obese patients. In this series, the rate of conversion to the open operation was also greater in the obese donors. The overall length of stay, incidence of complications, and recipient graft function did not statistically differ between the two groups. In another study, Kuo and others reviewed a series of 40 cases of LLDN performed at Georgetown University between 1998 and 1999. Outcomes between obese donors (BMI > 31) or nonobese donors were compared. The authors found no significant increase morbidity or mortality attributed to LLDN in obese patients (23).

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In an effort to determine which anatomic factors, including obesity, or radiologic features can be used to predict the degree of difficulty of LLDN for an individual case, Ratner et al. collected preoperative demographic data, obtained measurements related to body habitus, and performed CT scans on 41 patients undergoing LLDN (24). Postoperatively, components of the operation were graded with respect to difficulty for each patient by the operating surgeon. Other markers reflecting the difficulty of the operation, including operative time, EBL, and fluid requirements were also noted. In this study, only operative time correlated with the difficulty score. Body habitus was not a predictor of difficulty during the case. Leventhal et al. from Northwestern University reported that 110 out of 500 donors were obese with a BMI > 30, and even as high as 48 (11). No technical modifications were made for obese donors. Hospital stay, EBL, open conversion rate, and intraoperative complications were found to be similar between obese and nonobese donors. While donor obesity can add greater technical difficulty to the operation, these data demonstrate that good recipient and donor outcomes can be obtained in obese patients undergoing LLDN. There does not appear to be a substantial increase in preoperative donor morbidity due to obesity. Obesity should not be considered a contraindication to LLDN. Multiple Renal Arteries The presence of multiple renal arteries can also increase the complexity of an already technically demanding operation. Because of this, outcomes in patients undergoing LLDN with multiple renal arteries have been studied by several authors. To evaluate donor and recipient outcomes when multiple renal arteries were present, a retrospective chart review of 353 LLDNs at the Johns Hopkins Medical Institutions was performed by Hsu et al. (25). There was one renal artery in 277 cases (78.5%), two renal arteries in 71 cases (20.1%), and three renal arteries in five cases (1.4%). The authors found that as the number of renal arteries increased, there was a trend toward increasing duration of the operation and warm ischemia time, but the differences did not reach statistical significance. There were no significant differences in EBL, length of stay, complication rate, graft survival, or graft function. Husted et al. compared outcomes between LLDN cases at the University of Cincinnati between 2000 and 2004 involving multiple renal arteries with those with single renal arteries (26). They found that both cold ischemia time (46 + 24 minutes versus 35 + 13 minutes) and warm ischemia time (4:20 + 2:05 minutes versus 3:13 + 0:47 minutes) were longer in the cases with kidneys that had the multiple arteries compared to those with single arteries. Despite these differences, there was no significant difference in recipient creatinine at one week and one-year follow-up. In the series by Leventhal et al. from Northwestern, 115 of the 500 kidneys obtained had multiple renal arteries (11). There were no statistically significant differences in EBL, warm ischemia time, length of stay, or intraoperative complications. However, the authors noted a significant increase in the rate of conversion to open nephrectomy (4.35%) when compared with patients that had a single renal artery (1.04%). Live donors with up to five renal arteries at UPMC have been procured laparoscopically and transplanted successfully (Fig. 1). What is probably more important in determining the success of LLDN and minimizing the conversion rate is the complexity of the tributaries of the renal vein(s). Pediatric Recipients The impact of laparoscopic procurement of living donor renal allografts for pediatric recipients has been examined in several small studies. In a retrospective analysis by Hsu and colleagues from Johns Hopkins, donor and recipient outcomes were reviewed in seven cases in which adult donors underwent LLDN for renal transplantation in pediatric recipients (27). There was no mortality in the pediatric recipients. Graft survival rates at one and two years were 100%. The pediatric recipients had creatinine clearances of 52.1, 52.1, 44, and 41.1 mL/min at three, six, 12, and 18 months, respectively. The authors concluded that LLDN was an acceptable method of providing grafts for pediatric recipients; however, the study population was clearly limited in size.

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FIGURE 1 Four of the five living donor renal arteries were anastomosed to a deceased donor iliac artery graft and the donor iliac artery graft is anastomosed end-to-side to the recipient external iliac artery. The fifth small donor renal artery was ligated. The recipient had immediate graft function and continues to do well.

Troppmann et al. compared the outcomes in 11 pediatric recipients of laparoscopically procured living donor renal allografts with 11 age-matched recipients of open donor grafts (28). The investigators found that the recipients of the laparoscopically procured kidneys had higher serum creatinine levels in the first postoperative week when compared with the control group. However, by one-month post-op, graft function was similar in both groups. Of note, there was no difference in the incidence of DGF or the incidence of ACR. Furthermore, graft survival rates were not significantly different between the groups. In another small study in which nine recipients of grafts procured via laparoscopy were compared with five recipients of open donor grafts, both early and late outcomes were similar (29). Abrahams et al. from UCSF retrospectively analyzed outcomes of 20 recipients younger than 18 years of age who received grafts obtained by laparoscopic donor nephrectomy (30). Compared with 26 other pediatric recipients of grafts procured utilizing the traditional open approach, there were no statistically significant differences in operative parameters, graft function, or recipient complications at 13.6 months follow-up. We at the University of Pittsburgh Medical Center reported similar results in 14 pediatric live donor kidney transplant recipients who received antilymphoid antibody preconditioning and tacrolimus monotherapy (31). From May 2003 to July 2004, 14 live donor kidneys were removed laparoscopically. There was no DGF, and no episodes of rejection with a mean followup of 22 + 4.9 months; patient and graft survival is 100%. However, in a larger study of 995 pediatric recipients of living donor renal transplants in the United Network for Organ Sharing (UNOS) database, Troppmann and colleagues examined data in patients from zero to five years of age and six to 18 years of age (32). The authors noted higher rates of DGF in the groups that received grafts procured laparoscopically when compared with those that received grafts obtained using the open approach. In addition, the rates of ACR at six months and one year for both age groups were higher for the recipients of laparoscopically procured kidneys. These results are in sharp contrast with the results of the several smaller single-center studies; the differences are probably a function of center experience with LLDN. Further studies will be required to address these conflicting results. IMMUNOSUPPRESSION Modern immunosuppressive regimens include multiple immunosuppressive agents and have successfully decreased the incidence of ACR after renal transplantation. However, with the increasing potency of these regimens, patients are subjected to the detrimental side effects of immunosuppression. The risks of infectious complications, malignancy, metabolic side effects, and other immunosuppressive drug toxicities persist. Furthermore, chronic allograft nephropathy remains a significant problem. These observations, coupled with the realization that heavy early post-transplant immunosuppression might inhibit the immunologic mechanisms

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that are seminal to the development long-term graft acceptance (33,34), have prompted us to implement a novel immunosuppressive regimen based on two key principles: recipient pretransplant lymphoid depletion and minimal post-transplant immunosuppression. This regimen is intended to deplete pre-existing donor-specific alloreactive T-cells preoperatively to prevent acute rejection, while minimizing post-transplant immunosuppression in order to permit engagement between donor and recipient leukocytes, thereby facilitating alloengraftment and the development of partial tolerance. Recent trials at our transplant center have demonstrated that the use of pretransplant lymphocyte depletion with either thymoglobulin or alemtuzumab prior to both deceased donor and living donor renal transplantation followed by minimal use of post-transplant immunosuppression using steroid-free tacrolimus monotherapy has resulted in outcomes that are at least equivalent to historical controls in terms of patient and graft survival (13,35,36). Furthermore, these novel regimens have allowed spaced weaning of tacrolimus monotherapy in a significant proportion of the recipients. There have been no cases of post-transplant lymphoproliferative disorder (PTLD) and no cases of tissue invasive cytomegalovirus (CMV). The risk of metabolic complications, such as post-transplant diabetes, has been exceptionally low (0.5% at one-year follow-up). Of particular note, the use of alemtuzumab has substantially lowered the rate of acute rejection that was observed with the use of thymoglobulin (13,36). Alemtuzumab (Campath-1H) is a humanized anti-CD52 monoclonal antibody. It was approved by the Food and Drug Administration in May 2001 for the treatment of chronic lymphocytic leukemia (37,38). Administration of the drug results in marked and prolonged depletion of T-cells from the peripheral circulation upon administration (39,40). B cells, natural killer cells, and monocytes are also depleted, although to a lesser extent. Alemtuzumab is not yet approved for use in transplantation, but experience with the drug is growing, and results to date have been promising. In renal transplantation, Calne et al. first used alemtuzumab as induction therapy, followed by low-dose cyclosporine monotherapy, with good results (41). More recently, a singlecenter five-year follow-up study demonstrated no significant differences in patient mortality (12% versus 17%) or graft loss (21% versus 26%) in renal transplant recipients treated with alemtuzumab induction therapy followed by low-dose cyclosporine monotherapy versus those treated with conventional immunosuppression consisting of cyclosporine, azathioprine, prednisolone (42). The overall incidence of acute rejection was also similar in the two groups (31.5% versus 33.6%), but the pattern of acute rejection was different. In the alemtuzumab group, the incidence of acute rejection at one year was 14%, while no patients in the control group experienced early rejection. A number of subsequent studies have demonstrated that alemtuzumab is an effective induction agent in both living donor and deceased donor renal transplantation with few shortterm side effects (43–45). A recent randomized controlled clinical trial compared induction agents, thymoglobulin, daclizumab, and alemtuzumab in deceased donor renal transplant recipients (46). Induction therapy with alemtuzumab allowed for similar graft survival and function with lower tacrolimus trough levels and a significant percentage of patients remaining steroid-free (46). Furthermore, encouraging preliminary results have been also been obtained with alemtuzumab induction in recipients with the human immunodeficiency virus (HIV). We have previously reported outcomes of four HIV+ patients who received living donor renal transplants after alemtuzumab induction therapy (47,48). To date, patient and graft survival has been 100%. Good graft function has been observed. There have been no opportunistic infections and no evidence of progression of HIV. CD4 cell counts dropped transiently below 200 cells/mm3 in all patients, but are recovering. Bartosh et al. from the University of Wisconsin also reported outcomes in four pediatric patients (ages from 20 months to 16 years) (49). Although one patient who lost two previous grafts to rejection experienced no rejection, three of the patients in this series experienced ACR and two of these were CD4+. As in adults, administration of alemtuzumab appeared to result in prolonged depletion of lymphocytes, but it did not prevent recurrence of focal segmental glomerulosclerosis (FSGS). At UPMC, we have examined the outcomes of 225 living donor renal transplant recipients who have received preconditioning with alemtuzumab followed by low-dose steroid-free

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TABLE 1

Characteristics of 225 Living Donor Renal Transplant Recipients

Patients (%) Transplants Age (yr) Primary graft Retransplants Second retransplants Third or more retransplants HIV+ recipients Pediatric recipients Human leukocyte antigen mismatch Positive crossmatch Panel of reactive antibodies > 20% Mean recipient follow-up (days) Overall recipient survival (%) Recipient survival at one year (%) aThere

Alemtuzumab preconditioning

Historical control

225 (100%) 227a 45.3 ± 16.5 199 (87.7%) 28 (12.3%) 21 (9.3%) 7 (3.1%) 4 (1.8%) 13 (5.8%) 3.2 ± 1.6 4 (1.7%) 21 (12.1%) 422 ± 381 222 (98.7%) 223 (99.1%)

47 (100%) 47 46.2 ± 16.9 40 (85.1%) 7 (14.8%) 7 (14.8%) 0 0 3 (6.4%) 2.9 ± 1.5 0 10 (21.3%) 2101 + 640 39 (83.0%) 44 (93.6%)

were two retransplants in the series.

tacrolimus monotherapy and compared those outcomes with 47 recipients of living donor transplants who received standard triple immunosuppression and no induction. In this complex patient population with 12.3% retransplants, four HIV+ recipients, four patients with a positive crossmatch, 21 patients with a panel of reactive antibodies (PRA) > 20%, and 13 pediatric patients (see Table 1 for baseline patient characteristics), we observed excellent outcomes. Patient and graft survival at one year were 99.1% and 98.2% in patients that received alemtuzumab preconditioning therapy compared with 93.6% and 91.5%, respectively, for the historical controls. Furthermore, serum creatinine levels were 1.5 + 0.7 mg/dL and 1.6 + 1.2 mg/dL in the alemtuzumab and control group, respectively (Table 2). Importantly, at current mean follow-up of 422 days, we were able to wean immunosuppression in 78 patients (34.7%) who received alemtuzumab, and 112 others (49.8%) were maintained on daily tacrolimus monotherapy. Furthermore, of the 225 patients who received alemtuzumab, only 7.5% experienced ACR at one year compared with 17.3% of historical

TABLE 2 Graft Survival and Function of 225 Live Donor Renal Transplants at UPMC with Alemtuzumab Preconditioning and Steroid-Free Tacrolimus Monotherapy No. of recipients No. of grafts Overall graft survival (%) Graft survival at one year (%) Creatinine at 493 days follow-up (mg/dL) Creatinine at one year (mg/dL)

Alemtuzumab preconditioning

Historical control

225 227 217 (95.6%) 223 (98.2%) 1.5 + 0.7 1.5 + 0.7

47 47 35 (74.5%) 43 (91.5%) 1.5 + 0.6 1.6 + 1.2

TABLE 3 Immunosuppression Regimen Status and Frequency of Immunosuppression Dosing of 225 Live Donor Renal Transplants at UPMC with Alemtuzumab Preconditioning and Steroid-Free Tacrolimus Monotherapy Alemtuzumab preconditioning No. of recipients Multi-immunosuppressant therapy Daily monotherapy Spaced dose monotherapy Graft failure or patient death (%) aOn

225 27 (12.0%)a 112 (49.8%) 78 (34.7%) 8 (3.6%)b

Historical control 47 20 (42.5%) 15 (31.9%) Not applicable 12 (25.5%)

multiple immunosuppressive drugs (not just tacrolimus monotherapy), because of multiple rejection episodes or had multiple extra-renal solid organ transplantations. bThree recipient deaths denote graft failure.

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TABLE 4 Frequency of Dosing in Patients Receiving Monotherapy Immunosuppression at Mean Follow-Up of 422 Days Alemtuzumab preconditioning No. of recipients Twice daily Daily Every other day Every third day Three times per week Twice per week Once per week

TABLE 5

225 33 (14.7%) 79 (35.1%) 45 (20.0%) 1 (0.4%) 27 (12.0%) 3 (1.3%) 2 (0.9%)

Incidence of Acute Cellular Rejection Alemtuzumab preconditioning

Patients ACRa ACR at one year Weaning attempted Preweaning rejection Postweaning rejection

Historical control

225 22 (9.7%) 17 (7.5%) 106 (46.7%) 11 (4.9%) 11 (4.9%)

47 13 (27.7%) 8 (17.0%) N/A N/A N/A

aAll episodes of ACR are biopsy proven and at mean follow-up of 422 days. Abbreviations: ACR, acute cellular rejection; N/A, not applicable.

TABLE 6 Severity of Acute Cellular Rejection After Alemtuzumab Preconditioning by Banff Score Banff score Total episodes Banff 1a Banff 1b Banff 2a Banff 2b Banff 3

Number of episodes 30 (100%) 12 (40%) 12 (40%) 4 (13%) 1 (3%) 1 (3%)

controls (Tables 3–5). Of the total 30 rejection episodes in the alemtuzumab group, the majorities were Banff 1a or Banff 1b rejections and were sensitive to steroids (Table 6). There were no instances of CMV infection or PTLD in the group that underwent alemtuzumab preconditioning. One patient (0.4%) developed new onset insulin-dependent diabetes post-transplant. Ureteral stenosis occurred in two patients (0.8%). Both case of stenosis were treated using an uretero-ureteral anastomosis to the native ureter. No vascular thromboses occurred in this series. These results, which represent the largest series of living donor patients to date undergoing preconditioning therapy with alemtuzumab, demonstrate that excellent outcomes, including graft survival and function, can be obtained in patients undergoing living donor renal transplantation under alemtuzumab. Furthermore, preconditioning therapy with alemtuzumab followed by low-dose tacrolimus monotherapy allows immunosuppression to be weaned post-transplant with a low incidence of ACR. While long-term follow-up will clearly be required, these results are exceptionally promising. CONCLUSIONS LLDN has become the new standard for procuring renal allografts from living donors, as it results in shorter hospital stays for donors, less post-operative pain, faster return to work, improved cosmetic outcomes, and high-quality grafts. Several large studies from centers with

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broad experience confirm the effectiveness of this approach. While it is a complex operation that is technically demanding, current data demonstrate that LLDN can be performed safely with minimal risk to the donor. Good outcomes have also been reported with both elderly and obese donors. Current data also demonstrate the successful use of right-sided allografts and grafts with multiple renal arteries. Pediatric recipients of kidneys obtained utilizing the laparoscopic approach also have comparable outcomes to those obtained using the open approach in experienced single centers, although UNOS data suggest an increased incidence of ACR and DGF. Furthermore, when used as preconditioning agent in living donor renal transplantation and combined with postoperative low-dose steroid-free tacrolimus monotherapy, alemtuzumab permits weaning of daily immunosuppression. With this approach, excellent patient survival, graft survival, and graft function can be achieved in the short term. In addition, the incidence of ACR is low, and the majority of these rejections are mild and steroid-sensitive. Long-term follow-up will be required, but current data suggest great promise for this novel approach to immunosuppression in living donor renal transplantation. REFERENCES 1. Krakauer H, Grauman JS, McMullan MR, Creede CC. The recent U.S. experience in the treatment of end-stage renal disease by dialysis and transplantation. N Engl J Med 1983; 308:1558–1563. 2. http://www.unos.org/data/default.asp?displayType=usData. Accessed October 22, 2005. 3. 2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI. 4. Ratner LE, Cisek LJ, Moore RG, et al. Laparoscopic live donor nephrectomy. Transplantation 1995; 60:1047–1049. 5. Tan HP, Maley WR, Kavoussi LR, et al. Laparoscopic live donor nephrectomy: evolution of a new Standard. Curr Opin Organ Transplant 2000; 12:312–318. 6. Tan HP, Orloff M, Marcos A, et al. Laparoscopic live donor nephrectomy. Graft 2002; 5:404–415. 7. Brown SL, Biehl TR, Rawlins MC, Hefty TR. Laparoscopic live donor nephrectomy: a comparison with the conventional open approach. J Urol 2001; 165:766–769. 8. Kuo PC, Johnson LB. Laparoscopic donor nephrectomy increases the supply of living donor kidneys: a center-specific microeconomic analysis. Transplantation 2000; 69:2211–2213. 9. Su LM, Ratner LE, Montgomery RA, et al. Laparoscopic live donor nephrectomy: trends in donor and recipient morbidity following 381 consecutive cases. Ann Surg 2004; 240:358–363. 10. Jacobs SC, Cho E, Foster C, et al. Laparoscopic donor nephrectomy: the University of Maryland 6-year experience. J Urol 2004; 171:47–51. 11. Leventhal JR, Kocak B, Salvalaggio PR, et al. Laparoscopic donor nephrectomy 1997 to 2003: lessons learned with 500 cases at a single institution. Surgery 2004; 136:881–890. 12. Melcher ML, Carter JT, Posselt A, et al. More than 500 consecutive laparoscopic donor nephrectomies without conversion or repeated surgery. Arch Surg 2005; 140:835–839. 13. Tan HP, Kaczorowski DJ, Basu A, et al. Steroid-free tacrolimus monotherapy following pretransplant thymoglobulin or Campath and laparoscopy in living donor renal transplantation. Transpl Proc 2005; 37:4235–4240. 14. Bettschart V, Boubaker A, Martinet O, et al. Laparoscopic right nephrectomy for live kidney donation: functional results. Transpl Int 2003; 16:419–424. 15. Husted TL, Hanaway MJ, Thomas MJ, et al. Laparoscopic right living donor nephrectomy. Transplant Proc 2005; 37:631–632. 16. Posselt AM, Mahanty H, Kang SM, et al. Laparoscopic right donor nephrectomy: a large single-center experience. Transplantation 2004; 78:1665–1669. 17. Buell JF, Abreu SC, Hanaway MJ, et al. Right donor nephrectomy: a comparison of hand-assisted transperitoneal and retroperitoneal laparoscopic approaches. Transplantation 2004; 77:521–525. 18. Boorjian S, Munver R, Sosa RE, Del Pizzo JJ. Right laparoscopic live donor nephrectomy: a single institution experience. Transplantation 2004; 77:437–440. 19. Johnson SR, Khwaja K, Pavlakis M, et al. Older living donors provide excellent quality kidneys: a single center experience (older living donors). Clin Transplant 2005; 19:600–606. 20. Hsu TH, Su LM, Ratner LE, Kavoussi LR. Laparoscopic donor nephrectomy in the elderly patient. Urology 2002; 60:398–401. 21. Jacobs SC, Ramey JR, Sklar GN, Bartlett ST. Laparoscopic kidney donation from patients older than 60 years. J Am Coll Surg 2004; 198:892–897.

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22. Jacobs SC, Cho E, Dunkin BJ, et al. Laparoscopic nephrectomy in the markedly obese living renal donor. Urology 2000; 56:926–929. 23. Kuo PC, Plotkin JS, Stevens S, Cribbs A, Johnson LB. Outcomes of laparoscopic donor nephrectomy in obese patients. Transplantation 2000; 69:180–182. 24. Ratner LE, Smith P, Montgomery RA, et al. Laparoscopic live donor nephrectomy: pre-operative assessment of technical difficulty. Clin Transplant 2000; 14:427–432. 25. Hsu TH, Su LM, Ratner LE, Trock BJ, Kavoussi LR. Impact of renal artery multiplicity on outcomes of renal donors and recipients in laparoscopic donor nephrectomy. Urology 2003; 61:323–327. 26. Husted TL, Hanaway MJ, Thomas MJ, Woodle ES, Buell JF. Laparoscopic living donor nephrectomy for kidneys with multiple arteries. Transplant Proc 200; 37:629–630. 27. Hsu TH, Su LM, Trock BJ, et al. Laparoscopic adult donor nephrectomy for pediatric renal transplantation. Urology 2003; 61:320–322. 28. Troppmann C, Pierce JL, Wiesmann KM, et al. Early and late recipient graft function and donor outcome after laparoscopic versus open adult live donor nephrectomy for pediatric renal transplantation. Arch Surg 2002; 137:908–915. 29. Singer JS, Ettenger RB, Gore JL, et al. Laparoscopic versus open renal procurement for pediatric recipients of living donor renal transplantation. Am J Transplant 2005; 5:2514–2520. 30. Abrahams HM, Meng MV, Freise CE, Stoller ML. Laparoscopic donor nephrectomy for pediatric recipients: outcomes analysis. Urology 2004; 63:163–166. 31. Shapiro R, Ellis D, Tan HP, et al. Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediatr 2006; 148:813–818. 32. Troppmann C, McBride MA, Baker TJ, Perez RV. Laparoscopic live donor nephrectomy: a risk factor for delayed function and rejection in pediatric kidney recipients? A UNOS analysis. Am J Transplant 2005; 5:175–182. 33. Starzl TE, Zinkernagel RM. Transplantation tolerance from a historical perspective. Nat Rev Immunol 2001; 1:233–239. 34. Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003; 361:1502–1510. 35. Shapiro R, Jordan ML, Basu A, et al. Kidney transplantation under a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning. Ann Surg 2003; 238:520–525. 36. Shapiro R, Basu A, Tan H, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with thymoglobulin or Campath. J Am Coll Surg 2005; 200:505–515. 37. Pangalis GA, Dimopoulou MN, Angelopoulou MK, et al. Campath-1H (anti-CD52) monoclonal antibody therapy in lymphoproliferative disorders. Med Oncol 2001; 18:99–107. 38. Liu NS, O’Brien S. Monoclonal antibodies in the treatment of chronic lymphocytic leukemia. Med Oncol 2004; 21:297–304. 39. Hale G, Dyer MJ, Clark MR, et al. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H. Lancet 1988; 2:1394–1399. 40. Knechtle SJ. Present experience with Campath-1H in organ transplantation and its potential use in pediatric recipients. Pediatr Transplant 2004; 8:106–112. 41. Calne R, Friend P, Moffatt S, et al. Prope tolerance, perioperative Campath 1H, and low-dose cyclosporine monotherapy in renal allograft recipients. Lancet 1998; 351:1701–1702. 42. Watson CJ, Bradley JA, Friend PJ, et al. Alemtuzumab (Campath 1H) induction therapy in cadaveric kidney transplantation—efficacy and safety at five years. Am J Transplant 2005; 5:1347–1353. 43. 41. Knechtle SJ, Pirsch JD, H Fechner J Jr, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003; 3:722–730. 44. Knechtle SJ, Fernandez LA, Pirsch JD, et al. Campath-1H in renal transplantation: the University of Wisconsin experience. Surgery 2004; 136:754–760. 45. Ciancio G, Burke GW, Gaynor JJ, et al. The use of Campath-1H as induction therapy in renal transplantation: preliminary results. Transplantation 2004; 78:426–433. 46. Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation 2005; 80:457–465. 47. Tan HP, Kaczorowski DJ, Basu A, et al. Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience. Transplantation 2004; 78:1683–1688. 48. Tan HP, Kaczorowski DJ, Basu, et al. Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience (abstract). Am J Transplant 2005; 5(suppl 11):386. 49. Bartosh SM, Knechtle SJ, Sollinger HW. Campath-1H use in pediatric renal transplantation. Am J Transplant 2005; 5:1569–1573.

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Immunologically Incompatible Renal Transplants: Highly Sensitized Recipients, Positive Crossmatches, and ABO Blood Group Incompatibility Lloyd E. Ratner Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A.

R. John Crew Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A.

INTRODUCTION Historically, immunologic incompatibilities precluded the utilization of many willing and medically suitable potential live kidney donors. These immunologic incompatibilities were the result of donor-specific antibodies (DSA) directed against either human leukocyte antigen (HLA) antigens or the major blood group antigens (ABO). Transplantation across these humoral immunologic barriers resulted in a high incidence of immediate irreversible hyperacute rejection, subsequent acute humoral rejection, or aggressive acute cellular rejection, with unacceptable graft survival rates. Recently, a confluence of developments and advances in the field of renal transplantation has allowed the field to overcome these previously prohibitive humoral immunologic barriers. The first of these developments is the growing disparity between the demand for kidneys for transplantation and the organ supply. Since live donors provide the most immediately available new source of organs for transplantation, overcoming immunologic barriers promised to increase significantly the organ supply. This provided the impetus to devise strategies to abrogate the humoral immune responses that limited the optimal utilization of living kidney donors. Second, the advent of laparoscopic live donor nephrectomy and other less morbid donor operations shifted the “donor/recipient risk benefit ratio” and allowed early investigators to take more risk on the recipient side. Third, effective therapeutic options emerged for the successful treatment of antibody-mediated rejection (AMR), utilizing intravenous immunoglobulin (IVIG) either alone or in combination with plasmapheresis (PP). Fourth, improved histologic techniques were devised that greatly aided in the diagnosis of AMR. Fifth, several immunosuppressive agents became commercially available that provided more robust anti-B cell activity. Sixth, a better understanding has been gained of the pathogenetic processes of the humoral immune response. Finally, strategies emerged for the successful removal or inactivation of DSA prior to transplantation. In this chapter, we review these developments and provide a framework for approaching patients who have immunologic incompatibilities with their live donors. PROBLEM OF THE SENSITIZED PATIENT Waiting time on the deceased donor kidney transplant waiting list presently averages approximately four years, and has been increasing. In some geographic localities in the United States, patients may wait in excess of six to seven years. Unfortunately, the fate of sensitized patients (i.e., patients who have antibodies against the HLA antigens of potential donors) is generally worse. Those patients who are sensitized are usually relegated to prolonged times on the waiting list until a well-matched donor organ is available. Patients with preformed IgG antibodies

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directed against the donor HLA are at risk for hyperacute rejection. A screening test called the “panel of reactive antibodies” (PRA) can identify the range of antibodies present in a patient’s sera by testing against a range of known HLA antigens. The PRA result allows prediction of the frequency with which random donor kidneys will be excluded on crossmatch testing. This does not necessarily mean a broad range of antibodies present in the sera, but is also a reflection of the distribution of specific HLA antigens within the population. For instance, HLA-A2 is present on approximately 28% of the general population; the presence of antibodies directed against this antigen would result in the exclusion of 28% of potential donor kidneys (1). However, the risk of hyperacute rejection is not only dependent upon the presence or absence of IgG DSA, but is also highly dependent upon the titer of the antibody. The presence of low-titer IgG DSA at the time of transplantation is unlikely to result in hyperacute rejection. However, its presence potentially indicates a pre-existing immune responsiveness to the donor, and places the patient at increased risk for AMR and even acute cellular rejection. Donor-specific alloantibodies develop as a result of exposure to foreign HLA from blood transfusions, pregnancies, or prior organ or tissue transplants (2). In some individuals, when exposed to foreign tissue, the immune system is stimulated in a helper T-cell dependent process that results in antibody class switching from IgM to IgG antibodies. This has two implications. First, B-lymphocytes that have been stimulated in this manner proliferate and differentiate, leaving a pool of long-lasting memory B-lymphocytes. Upon re-exposure to an antigen, memory B-lymphocytes proliferate rapidly and differentiate into plasma cells that produce antibodies. The result is that prior exposure to an antigen can result in AMR. This can occur even if the antibody titer has decreased to a level not detectable with current assays prior to transplantation. The second implication is that class switching requires help from T-lymphocytes. Thus, the cellular immune system (by definition) has also been activated against the foreign tissue. Therefore, there is also an increased incidence of acute cellular rejection seen in patients who are sensitized with alloantibodies directed against the donor HLA. It is quite common for antibodymediated and cellular rejection to occur simultaneously, as seen in many renal biopsies (3). The presence of the anti-HLA antibodies has a real effect on the patients waiting for kidney transplants. As of 2003, approximately 33% of patients on the kidney-transplant waiting list had an elevated PRA, defined as >10%, although this is down from 50% of patients on the waiting list in 1994 (4). The decreasing rate has been attributed to improved anemia management leading to fewer blood transfusions in end-stage renal disease (ESRD) patients. Among the 33% of the waiting list with a PRA >10%, approximately 40% of these patients are highly sensitized, with a PRA >80%. The greater diversity of antibodies present, the less likely a patient will have a negative crossmatch against a potential donor. This is reflected in the relative waiting times of patients with and without anti-HLA antibodies (Table 1) (5). In general, patients with a low or moderate degree of sensitization (PRA 10% to 79%) wait twice as long for kidney transplants as those who are not sensitized, while fewer than 50% of patients who are highly sensitized ever get transplanted. While waiting for their transplants, these patients suffer more morbidity and mortality on dialysis. With increasing evidence that the duration of dialysis prior to transplantation worsens posttransplant outcomes, these patients are disadvantaged after transplantation as well (Table 1) (6,7). The impact of an elevated PRA is attenuated in recipients of living donor transplants. There are few options for those patients on the waiting list with multiple antibodies directed against potential donors. The rest of this review focuses on advances in managing these antibodies to allow transplantation from a living donor against whom the recipient has a donor-specific antibody.

TABLE 1 Impact of Sensitization on Deceased Donor Renal Transplant Graft Survival and Waiting Time Panel of reactive antibodies 0–9% 10–79% ≥80% aLess

Five-year allograft survival

Median waiting time (days)

69.7% 65% 60.7%

857 1620 Unable to calculatea

than 50% of patients transplanted, so therefore unable to calculate median.

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ASSAYS UTILIZED FOR THE DETECTION OF DONOR-SPECIFIC ALLOANTIBODY Understanding the uses and limitations of the various assays employed to detect DSA is imperative if one wishes to perform incompatible live-donor renal transplants. Prior to transplantation, the donor’s lymphocytes and the recipient’s serum are used to perform a crossmatch. This test assesses the presence of antibodies currently in the recipient serum that can recognize the allograft. The primary purpose of this assay is to predict the risk of hyperacute rejection. HLA class I antigens are present on all cells in the body, including the endothelium of the donated kidney. HLA class II antigens are constitutively expressed on B-lymphocytes, but expression on vascular endothelium can be upregulated, particularly in response to γ-interferon. Antibodies against those HLA antigens can lead to immediate rejection with activation of complement, initiation of the coagulation cascade, and graft thrombosis, as noted in the earliest reports by Terasaki and Patel in 1968 (8,9). The earliest crossmatch techniques used recipient sera and donor lymphocytes, with the addition of complement components. Antibody bound to cells leads to cell lysis in the presence of complement. This type of crossmatch became widely known as the National Institutes of Health (NIH) complement-dependent cytotoxicity (NIH-CDC) crossmatch. Unfortunately, this assay was not always sensitive enough. Some patients still underwent rapid graft loss despite negative NIH-CDC crossmatches. Modifications have been made to improve sensitivity of the assay for DSA, such as lengthening incubation times and additional wash steps (10). It is possible to augment the sensitivity of the assay by adding antihuman globulin (AHG) antibody specific for kappa light chains. This leads to improved cross-linking of DSA and improved activation of C1q, resulting in complement-mediated cell lysis. The AHG crossmatch can increase the sensitivity of the crossmatch by detecting antibodies that are present in too low a titer to activate complement or are not complement-fixing antibodies (11). The above assays are generally sensitive enough to detect alloantibodies that will produce hyperacute rejection. However, these assays are limited by the fact that they require activation of complement and cell lysis to be detected. Use of flow cytometry for crossmatching allows direct detection of recipient antibody binding to donor lymphocytes. In addition to the above techniques that require the presence of donor lymphocytes, anti-HLA antibodies can be detected by using purified HLA molecules attached to a solid phase with flow cytometry, by ELISA methods, or by Luminex technology. It is important to recognize the significance of the type of testing used to detect the antibody. In general, the more sensitive the test is at detecting HLA antibodies, the less specific the test is at predicting hyperacute rejection. The more sensitive tests may be picking up antibodies present at a very low titer or that bind with less affinity. These antibodies may not lead to immediate graft loss, but only represent a marker of an increased risk of rejection or graft loss over time. For instance, the significance of a positive flow cytometry crossmatch in the setting of a negative traditional or AHG-CDC crossmatch has been a matter of debate. Some earlier studies showed negligible impact on outcome, at least in primary renal transplant recipients, but recent studies suggest that patients with a positive flow crossmatch are at increased risk for early graft loss and acute rejection (12–15). Using historical data from 1992 to 2000, Cho and Cecka showed that flow positive crossmatches in the setting of negative AHG-CDC crossmatch were associated with an increased risk of graft loss at one year (16). Thus, a positive flow cytometric crossmatch in the setting of a negative NIH-CDC or AHG-CDC crossmatch is considered an intermediate risk transplant. Still, improvements in diagnosis and treatment of AMR may allow patients to be transplanted despite a flow cytometric positive crossmatch with reasonable outcomes. Therefore, the results of antidonor antibody testing need to be placed in the appropriate context based on the information that one is trying to obtain. In practice, two different types of testing may need to be done in order to assess appropriately the immunologic risk of the transplant. At our center, we perform both AHG-CDC and flow cytometry crossmatches on potential recipients of living donor kidneys. Additionally, one must also be cognizant of the impact that various immunosuppressive agents have on the reliability of the various assays, particularly if one is trying to determine the presence of alloantibody post-transplantation. For instance, administration of antithymocyte globulin or anti-CD3 monoclonal antibody can result in a false positive T-cell crossmatch, while anti-CD20 monoclonal antibody can cause a false positive B-cell crossmatch. Finally, the relevance of a positive B-cell crossmatch has been questioned. B-cells express the

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Fc-receptor in large amounts, and thus tend to have more nonspecific antibody binding. However, if the antibody in question is a donor-specific anti-HLA antibody, then a positive B-cell crossmatch is an important indicator of immunologic risk. Multiple assays may therefore be necessary to determine the presence, quantity, and specificity of the alloantibody in question. DIAGNOSIS OF ANTIBODY-MEDIATED REJECTION The diagnosis of AMR is central to achieving successful outcomes with incompatible live donor renal transplants. The historically poor results seen with transplantation in sensitized patients have been largely related to the inability to diagnose reliably AMR and the subsequent failure to commence effective therapy. Improvements in establishing the presence of AMR has been another major advance. Previously, the diagnosis of AMR was made based on histologic characteristics. These characteristics include neutrophil margination in the peritubular capillaries, glomerulitis, endovasculitis, and fibrin thrombi in renal arterioles, particularly in the presence of antidonor antibodies detected in the serum. Fibrin thrombi are not limited to cases of AMR. This finding can easily be confused with those seen in thrombotic microangiopathy. In addition, antidonor antibodies are not always detectable in the serum at the time of AMR. When DSAs are present in the recipient, antibody binds to the relevant antigen on the endothelium, leading to complement activation. Activation of the classical complement pathway eventually results in conversion of C4 to C4b. C4b then gets inactivated to C4d, which may become covalently bound to endothelium and basement membranes (17). Initially recognized by Feucht et al. as being associated with worse renal transplant outcomes, it has been tied to the presence of DSAs and other features of AMR (17,18). However, there may be cases of AMR that are C4d-negative. This is particularly true if the patient is undergoing or has undergone PP or treatment with IVIG. PP can deplete complement components and IVIG may inactivate complement. C4d staining has now been codified as a criterion for AMR in an addition to the Banff ’97 Classification of Renal Allograft Rejection (19). The routine staining for C4d allows improved detection of antibodymediated injury to the allograft, allowing earlier therapy. Recognition of the risk factors for AMR, and having a high degree of suspicion about it, has also facilitated its prompt diagnosis. At our center, we consider the following as risk factors for AMR: (i) enrollment in an ABO-incompatible or positive crossmatch protocol; (ii) history of producing anti-HLA antibody; (iii) prior transplantation; and (iv) child donating to mother or husband donating to wife. In a review of 179 renal transplants performed over a one-year period, we found that of the 71 patients who had one or more of the above risk factors, 29.6% developed AMR, compared with 0% of the 108 patients who were free of risk factors (p < 0.001) (unpublished data). Thus, we recommend that when trying to establish the diagnosis of AMR, it is important to take into consideration not only the histopathologic data but also the clinical setting and serologic data as well. TREATMENT OF ANTIBODY-MEDIATED REJECTION Since the 1970s, it has been known that antibodies directed against the renal allograft were associated with a high risk of graft loss. In the 1980s, attempts at using PP to reverse refractory rejection associated with DSAs were either unsuccessful or equivocal. The addition of IVIG combined with PP and more potent maintenance immunosuppression has dramatically improved outcomes. Pascual and colleagues at the Massachusetts General Hospital first reported the successful treatment of five patients with AMR (20). Despite having been refractory to other therapies, all five patients responded to treatment with PP to remove the antibody, followed by infusion of IVIG, with conversion to an immunosuppressive regimen of tacrolimus and mycophenolate mofetil. Follow-up serum creatinines were 0.9 to 1.8mg/dL (21). This was in stark contrast to previously reported outcomes in patients with AMR, where a 75% to 100% incidence of allograft loss was observed. Since then, there have been multiple reports on the treatment of AMR with PP/IVIG (22–27). Overall, the combination of PP/IVIG reverses approximately 90% to 100% of AMRs. In a review of 21 cases of AMR at Columbia University/New York–Presbyterian Hospital, we found that all episodes were successfully reversed with PP/IVIG except for one graft, which was lost to a biopsy complication (4.8%) (unpublished data). Importantly, the

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number of PP/IVIG treatments necessary to reverse an episode of AMR can be quite variable and should not be limited to a finite number of treatments. We have seen patients who required as many as 31 PP/IVIG treatments to reverse an episode of AMR successfully. Other therapies to treat AMR have been tried. These other therapies include high-dose immunoglobulin alone, or PP with IVIG and rituximab (anti-CD20 monoclonal antibody), and plasmapheresis in combination with anti-thymocyte globulin (28–30). IVIG has previously been used to reverse rejections not responsive to standard therapy or in situations where additional immunosuppression with standard agents may not be tolerated (i.e., rejection in the setting of severe infection) (31–33). The use of IVIG alone for the specific purpose of reversing AMR has been limited. Jordan et al. reported that they were able to reverse seven episodes of “humoralvascular” rejection in renal transplant recipients and one of three episodes in heart transplant recipients (28). Subsequently, they were able to reverse 13 of 18 episodes of humoral rejection in patients who had previously received IVIG pretransplant for desensitization (34). EVOLUTION OF A NEW PARADIGM IN RENAL TRANSPLANTATION Many patients have potential living donors who are both willing to donate and are medically suitable for live kidney donation, but are excluded because of immunologic incompatibility either related to a positive crossmatch (DSA against HLA) or to ABO blood group incompatibility (DSA against blood group antigens). In the past, the presence of DSA as evidenced by a positive crossmatch was considered an absolute contraindication to renal transplantation. However, now with a better understanding of humoral immune responses, improved diagnostic capabilities for AMR, and successful treatments for AMR, a new paradigm is evolving in renal transplantation. Successful strategies have now emerged that allow optimal utilization of living kidney donors. We are now able to desensitize a patient and abrogate a positive crossmatch, and achieve successful transplant outcomes. The approach to patients believed to have DSA against a prospective donor requires asking the questions shown in Table 2. These questions define the significance of the antibody present and whether specific therapy is needed. They also determine the extent of the treatment necessary prior to transplantation. Following the titer of the DSA after transplantation helps assess the risk of recurrent rejection, the need for repeat biopsies in the absence of graft dysfunction, and guide both immunosuppressant management and necessity of plasmapheresis. Two successful therapeutic strategies have emerged to abrogate a positive crossmatch and desensitize patients successfully prior to live donor renal transplantation. The first of these protocols employs high-dose IVIG (2 g/kg/dose) and was originally developed by Jordan and Tyan in California and Glotz in Paris. In 1994, Jordan et al. initially reported use of high-dose IVIG to desensitize a 13-year-old patient whose PRA decreased from 95% to 15% in response to TABLE 2

Approach to the Patient Presumed to Have Donor Specific Antibody

Is a relevant donor specific antibody present? IgM, autoantibodies, or antibodies with nonspecific binding are generally not considered relevant. What is the specificity of that antibody? MHC class I versus class II. Knowing the specificity of the DSA will help determine which tests should be used to follow the antibody and which drugs interfere with those assays (e.g., B-cell crossmatching techniques may be required to follow DSA directed against MHC class II, while rituximab (anti-CD 20 monoclonal antibody) may result in a false positive B-cell crossmatch. Is the titer of DSA sufficient to cause hyperacute rejection? Generally, hyperacute rejection is unlikely to occur if DSA is detected only by flow cytometry crossmatch and not by a cytotoxic crossmatch. What will it take to eliminate that antibody? The titer of the DSA will determine how many plasmapheresis treatments are required to sufficiently eliminate that particular antibody. Is that antibody gone after treatment? Can the antibody be detected after transplant? Abbreviations: DSA, donor specific antibodies; MHC, major histocompatibility complex.

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IVIG administration, allowing successful transplantation (35). Subsequently, they reported data on 26 patients with positive crossmatches against potential donors who were treated with highdose IVIG (36). Twenty-four of the 26 patients had a negative crossmatch after a single 2 g/kg dose, allowing transplantation. The rejection rate was 31% (most of which was reversible), with an 89% two-year graft survival. They concluded that “these results are comparable to nonsensitized transplant recipients.” In an NIH-sponsored, prospective randomized, double blind trial of 101 patients comparing high-dose IVIG with an albumin placebo, 31% of patients in the IVIG arm underwent transplantation (both live and deceased donor), compared with 12% in the placebo arm (p = 0.0137) (37). The main difficulty with high-dose IVIG is that not all patients respond and not all anti-HLA antibodies are suppressed equally (35). Thus, Tyan has developed an in vitro assay that is predictive of the efficacy with which high-dose IVIG will successfully desensitize an individual. Therefore, time and expense need not be wasted in a fruitless attempt to utilize this particular desensitization strategy. The alternative strategy is to use a combination of plasmapheresis combined with lowdose IVIG (100 mg/kg). Plasmapheresis followed by low-dose IVIG (100 mg/kg) immediately after each plasmapheresis treatment can very effectively remove antibody in preparation for transplantation. Relative to the use of high-dose IVIG (2 g/kg/dose), PP/IVIG allows for more consistent and universally reliable removal of antidonor antibody prior to transplantation. When planning the transplantation, the DSA (Table 2) must be characterized for specificity and titer. As a rule of thumb, each PP/IVIG treatment reduces the DSA titer by one dilution. Thus, the number of PP/IVIG treatments necessary can be projected (Table 3). This allows planning of the operation. However, the crossmatch must be repeated (often multiple times) to be sure that it is sufficiently negative (i.e., cytotoxic crossmatch negative) at the time of surgery. It should be noted that high-titer alloantibodies (i.e., >1:256 by cytotoxic crossmatching techniques) might be prohibitive because the logarithmic kinetics of antibody removal by plasmapheresis may plateau before the target level of a negative cytotoxic crossmatch is achieved. In addition, patients are started on immunosuppression with tacrolimus and mycophenolate mofetil prior to initiation of PP/IVIG to limit antibody resynthesis. This technique was first reported by Ratner and colleagues, who initially described successful transplantation in four patients with positive crossmatches (24). The same Johns Hopkins University group later described successful transplantation in 31 patients with anti-HLA antibodies to potential donors (38). Using a similar protocol, Schweitzer and colleagues at the University of Maryland reported on 11 patients who received PP/IVIG as desensitization prior to transplantation. All 11 patients were alive with functioning grafts at one year, and their mean serum creatinine was 1.6 mg/dL (39). Gloor et al. described a similar sensitization protocol with the addition of splenectomy and anti-CD20 antibody in 14 patients with HLA class I antibodies (40). Eleven of 14 grafts were still functioning with a mean follow-up of 488 days; mean creatinine was 1.4 ± 0.3 mg/dL. The patients received frequent protocol biopsies whether or not there was graft dysfunction. The incidence of C4d-positive AMR ranged from 30% to 50%; most rejections TABLE 3 Determination of Extent of Plasmapheresis/Intravenous Immunoglobulin (Every Other Day Schedule)

Flow + XM Low risk of hyperacute rejection PreTx: 2 PP/IVIg PostTx: 2 PP/IVIg Cytotoxic + XM Higher risk of hyperacute rejection PreTx: ≥ 3 PP/IVIg PostTx: 2–3 PP/IVIg Each PP/IVIg reduces titer by ~1 dilution Higher risk of AMR

Starting titer Cytotoxic + XM

# PP/IVIg Pre Tx

1:2 1:4 1:8 1:16 1:32 1:64 1:128 1:256 1:512

3 4 5 5 6 7 8 9 10

Abbreviations: AMR, antibody-mediated rejection; IVIG, intravenous immunoglobulin; PP, plasmapheresis.

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occurred early after the transplant (39,40). The majority of these rejections were reversible with the resumption of PP/IVIG. Zachary et al. have observed that the majority of patients continue to have long-term suppression of their DSA after either desensitization or treatment of AMR with PP/IVIG, but other alloantibodies against third parties return (38). This implies that while the response to other antigens is intact, those antibody/antigen interactions in the allograft lead to specific downregulation of antibody production against the kidney. Absorption into the kidney has not been completely excluded, but there does not appear to be ongoing antibody mediated injury. Anecdotally, it appears that this downregulation of alloantibody production is not the result of a deletion of DSA-producing cells. We observed in one patient who had an anti-HLA A1 antibody prior to desensitization that an alloantibody with the same specificity for HLA A1 returned 64 months later, when that patient abruptly became noncompliant with his immunosuppressive medications. Others have attempted to use single doses of rituximab for desensitization. When given to nine dialysis patients with PRA >50%, rituximab resulted in no change in PRA in two patients, decreased antibody diversity in four patients, a decrease in absolute antibody amount (titer decreased from 1:16 to 1:4), and abrogation of a positive crossmatch in one patient with a living donor. Thus, the utilization of rituximab alone for desensitization has not been shown to be efficacious. ABO-INCOMPATIBLE LIVE DONOR RENAL TRANSPLANTATION Incompatibility between donor and recipient ABO blood groups has previously been an absolute contraindication to renal transplantation. However, transplantation across disparate blood types is now possible. It is estimated that in the United States, by virtue of the distribution and frequency of blood types, approximately 35% of living donors would be excluded based on blood group incompatibilities. Hume first reported attempts at transplantation across blood groups in 1955. In his series, eight of 10 grafts were lost within days (41). Since then, transplantation into patients with antibodies against donor blood groups was forbidden. From the late 1970s to the early 1990s, several attempts had been made at placing kidneys from donors with blood group A2 (a subtype of blood group A with both decreased surface expression density and limited carbohydrate chain variability) into blood group O or B recipients with low titers of anti-A isoagglutinins, generally resulting in intermediate success (42). From 1994 to 2000, the Midwest Transplant Network placed 41 A2 kidneys into blood group O or B recipients. Nelson et al. reported this experience in 2002 and showed a death-censored graft-survival rate of 91% at one year and 85% at five years. These rates were comparable to those seen with other blood group B recipients (43). These patients did not receive any specific therapy for their antibodies, but the majority (39/41) of these patients had low antibody titers against blood group A. The importance of the low titer against the donor blood group was likely crucial to their success, since others have reported graft loss/rejection with higher anti-A titers in A2 → O transplantation (44). It should be noted that, although the strategy of using A2 kidneys transplanted into O or B recipients with low anti-A titers was quite successful, its applicability is limited, since < 20% of blood group A individuals are of the subtype A2, and only a small percentage of potential recipients will have low enough titers of the relevant antibody to be candidates. ABO-incompatible transplantation can also be performed using similar DSA removal strategy, as described previously for desensitization with allo-DSA. However, initial reports by Alexandre and colleagues in Belgium emphasized the importance of splenectomy in order to prevent early graft loss (45). More complete data from a larger patient population have been collected in Japan. Because of a lack of deceased donors in Japan for legal and cultural reasons, the Japanese transplant community has been utilizing ABO-incompatible living kidney donors for over 15 years. Using conditioning regimens of either plasmapheresis or immunoadsorption, with splenectomy, the success rates have been comparable to those achieved with traditional live donor transplantation. In 2004, Takahashi et al. reported the combined experience of 55 Japanese transplant centers with follow-up on 441 of the 494 patients who had received ABO-incompatible grafts since 1989 (46). The nine-year graft survival rate was 59% in the ABO-incompatible group compared with 57% in the control

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group of over 1000 ABO-compatible live donor recipients. The early acute rejection rate was high (58%), and the early graft loss was slightly higher in the ABO-incompatible group. However, since the commercial introduction in Japan of mycophenolate mofetil, the early rejection rates and the severity of those rejection episodes observed in ABO-incompatible transplants have profoundly decreased (personal communication, K. Tanabe). The similar long-term success rates despite ABO incompatibility and the presence of antibodies against the donor blood group reflect a process called “accommodation.” The levels of antibodies persist against the donor blood group, albeit generally at lower levels than prior to the initiation of antibody removal, but there is no evidence of antibody-mediated damage in renal biopsies, and excellent renal function is maintained. This is in contradistinction to the situation with anti-HLA alloantibodies, which are generally rendered undetectable following successful desensitization, and whose re-emergence commonly portends both rejection and poorer long-term prognosis. Changes within the endothelium of the ABO-incompatible allograft, such as upregulation of complement inhibitory proteins as well as protective antibodies, have been implicated in this phenomenon (47). The approach to ABO-incompatible live donor and recipient pairs are similar to that outlined in Table 2 for desensitization of anti-HLA antibodies. In short, the titer of the relevant antibody needs to be determined in order to estimate the number of PP/IVIG treatments that are necessary to reach the final target titer. We have titered both the anti-A or B IgG and IgM, since it has not been firmly established that antiblood group IgMs are not pathogenic. However, because IgG is distributed within both the intravascular and the interstitial space, while IgM is primarily found in the intravascular space, it is more difficult to sufficiently remove IgG. We have utilized a target titer of 1:16 to proceed with transplantation. However, it has been hypothesized that higher titers may be permissible. On several occasions, we have successfully performed ABO-incompatible live donor transplantation with a titer that was weakly positive at 1:32 by Coombs testing. Despite this, we would urge caution in this regard, since the only hyperacute rejection that we have observed was in a patient that had an anti-A1 titer of 1:16 at the time of transplantation. Recently, the necessity of splenectomy in ABO-incompatible renal transplantation has been called into question. Transplantation across the blood group barriers without splenectomy is now being performed with increasing frequency. Patients with an antibody titer less than 1:128 may be safely transplanted using rituximab as part of the preconditioning regimen, obviating the need for splenectomy (48,49). In addition, some groups have begun to perform ABO-incompatible transplants successfully without splenectomy or rituximab. In Europe, some centers have begun utilizing an immunoadsorption column consisting of the carbohydrate epitopes that comprise the relevant A or B blood type antigens for isoagglutinin removal. The potential advantage of this device is that plasmapheresis associated hypogammaglobulinemia and coagulopathy is minimized, and that fewer administrations of albumin, IVIG, or other blood products are required (49,50). However, this device has not yet been approved by the U.S. Food and Drug Administration and; therefore, is not commercially available in the United States. In general, it is easier to overcome ABO incompatibility than a positive crossmatch, since the risk of rejection is less. AMR is unlikely to occur after approximately the first month in the ABO-incompatible situation, but can be recurrent and more persistent in those patients previously sensitized to HLA antigens. The immunopathogenetic mechanisms that account for these differences remain unknown. Finally, it has been possible to transplant across both ABO incompatible and positive crossmatch barriers at the same time (51). This requires that the titer of each DSA be determined and followed with therapy being driven by the DSA with the highest titer. PAIRED KIDNEY EXCHANGES An alternative strategy to overcome an ABO blood-group incompatible donor and recipient combination is that of the paired kidney exchange. Paired kidney exchanges require multiple incompatible donor/recipient pairs to exchange donors with one another, so that each recipient receives a compatible live-donor renal transplant. At Columbia University, we view our paired

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kidney exchange program to be complementary to our ABO-Incompatible Renal Transplant Program, and part of our overall comprehensive Incompatible Renal Transplant Program. Paired kidney exchange programs are discussed in detail in Chapter 11. FINANCIAL IMPLICATIONS Renal transplantation offers considerable cost savings relative to dialysis. However, the incompatible transplants are more expensive than conventional live donor transplants because of the incremental costs associated with IVIG, plasmapheresis, assays for determining specificity and titer of DSA, and the increased incidence of rejection. Several investigators have studied the financial implications of incompatible renal transplant protocols. In their prospective randomized NIH sponsored trial of high-dose IVIG versus albumin placebo for desensitization, Jordan and colleagues found that for each patient transplanted as a result of successful desensitization, there was a savings of $300,000 over the course of the study (37). Segev et al. (52) examined the relative costs incompatible transplantation employing plasmapheresis and low-dose IVIG for both ABO incompatible live-donor renal transplantation and live-donor renal transplantation following the abrogation of a positive crossmatch in patients with a PRA ≥ 80%. They estimated that, relative to waiting for a deceased donor transplant, the differential costs for an ABO incompatible transplant were $171,553 versus $240,908, and for the abrogation of a positive crossmatch, $219,483 versus $405,430. Thus, although more expensive than routine live donor transplantation, incompatible transplants utilizing either of the two major antibody removal strategies are both quite cost effective. CONCLUSIONS Great progress has been made in overcoming previously insurmountable humoral immunologic incompatibilities. Therefore, at present virtually any medically suitable, willing potential live donor can be utilized. However, caring for the recipients of these incompatible transplants is more difficult and requires a working knowledge of the various assays employed to define and quantify the relevant DSA. The results so far are promising, but their main limitations are the small numbers of patients and lack of long-term (>10 year) follow-up. Nevertheless, we expect that in the near future, most renal transplant centers will start performing ABO incompatible transplants and/or initiate desensitization protocols. REFERENCES 1. Zachary AA, Ste inberg AG, Bias WB, et al. The frequencies of HLA alleles and haplotypes and their distribution among donors and renal patients in the UNOS registry. Transplantation 1996; 62(2):272–283. 2. Sautner T, Gnant M, Banhegyi C, et al. Risk factors for development of panel reactive antibodies and their impact on kidney transplantation outcome. Transpl Int 1992; 5(suppl 1):S116–S120. 3. Mauiyyedi S, Crespo M, Collins AB, et al. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J Am Soc Nephrol 2002; 13(3):779–787. 4. Danovitch GM, Cohen DJ, Weir MR, et al. Current status of kidney and pancreas transplantation in the United States, 1994–2003. Am J Transplant 2005; 5(4 Pt 2):904–915. 5. 2004 OPTN/SRTR annual report. http://www.ustransplant.org/p/ar?p=501_can-pra-pk_ki.htm&y= 2004. 2005. 6. Meier-Kriesche HU, Port FK, Ojo AO, et al. Effect of waiting time on renal transplant outcome. Kidney Int 2000; 58(3):1311–1317. 7. 2004 OPTN/SRTR annual report. http://www.ustransplant.org/p/ar?p=501_can-pra-pk_ki.htm&y= 2004. 2005. 8. Patel R, Mickey MR, Terasaki PI. Serotyping for homotransplantation. XVI. Analysis of kidney transplants from unrelated donors. N Engl J Med 1968; 279(10):501–506. 9. Terasaki PI, Mickey MR, Singal DP, et al. Serotyping for homotransplantation. XX. Selection of recipients for cadaver donor transplants. N Engl J Med 1968; 279(20):1101–1103. 10. Gebel HM, Bray RA, Nickerson P. Pre-transplant assessment of donor-reactive, HLA-specific antibodies in renal transplantation: contraindication versus risk. Am J Transplant 2003; 3(12):1488–1500. 11. Fuller TC, Fuller AA, Golden M, et al. HLA alloantibodies and the mechanism of the antiglobulinaugmented lymphocytotoxicity procedure. Hum Immunol 1997; 56(1–2):94–105.

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12. Kerman RH, Van Buren CT, Lewis RM, et al. Improved graft survival for flow cytometry and antihuman globulin crossmatch-negative retransplant recipients. Transplantation 1990; 49(1):52–56. 13. Karpinski M, Rush D, Jeffery J, et al. Flow cytometric crossmatching in primary renal transplant recipients with a negative anti-human globulin enhanced cytotoxicity crossmatch. J Am Soc Nephrol 2001; 12(12):2807–2814. 14. Kerman RH, Susskind B, Buyse I, et al. Flow cytometry-detected IgG is not a contraindication to renal transplantation: IgM may be beneficial to outcome. Transplantation 1999; 68(12):1855–1858. 15. Scornik JC, Clapp W, Patton PR, et al. Outcome of kidney transplants in patients known to be flow cytometry crossmatch positive. Transplantation 2001; 71(8):1098–1102. 16. Cho YW, Cecka JM. Crossmatch tests—an analysis of UNOS data from 1991–2000. In: Cecka JM, Terasaki PI, eds. Clinical Transplantation. Los Angeles, CA: UCLA Tissue Typing Laboratory, 2002: 237–246. 17. Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant 2003; 18(11):2232–2239. 18. Feucht HE, Schneeberger H, Hillebrand G, et al. Capillary deposition of C4d complement fragment and early renal graft loss. Kidney Int 1993; 43(6):1333–1338. 19. Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria—an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3(6):708–714. 20. Pascual M, Saidman S, Tolkoff-Rubin N, et al. Plasma exchange and tacrolimus-mycophenolate rescue for acute humoral rejection in kidney transplantation. Transplantation 1998; 66(11): 1460–1464. 21. Lobo PI, Spencer CE, Stevenson WC, et al. Evidence demonstrating poor kidney graft survival when acute rejections are associated with IgG donor-specific lymphocytotoxin. Transplantation 1995; 59(3):357–360. 22. Bohmig GA, Regele H, Exner M, et al. C4d-positive acute humoral renal allograft rejection: effective treatment by immunoadsorption. J Am Soc Nephrol 2001; 12(11):2482–2489. 23. Crespo M, Pascual M, Tolkoff-Rubin N, et al. Acute humoral rejection in renal allograft recipients: I. Incidence, serology and clinical characteristics. Transplantation 2001; 71(5):652–658. 24. Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000; 70(6):887–895. 25. White NB, Greenstein SM, Cantafio AW, et al. Successful rescue therapy with plasmapheresis and intravenous immunoglobulin for acute humoral renal transplant rejection. Transplantation 2004; 78(5):772–774. 26. Lennertz A, Fertmann J, Thomae R, et al. Plasmapheresis in C4d-positive acute humoral rejection following kidney transplantation: a review of 4 cases. Ther Apher Dial 2003; 7(6):529–535. 27. Rocha PN, Butterly DW, Greenberg A, et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation 2003; 75(9):1490–1495. 28. Jordan SC, Quartel AW, Czer LS, et al. Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 1998; 66(6):800–805. 29. Shah A, Nadasdy T, Arend L, et al. Treatment of C4d-positive acute humoral rejection with plasmapheresis and rabbit polyclonal antithymocyte globulin. Transplantation 2004; 77(9):1399–1405. 30. Becker YT, Becker BN, Pirsch JD, et al. Rituximab as treatment for refractory kidney transplant rejection. Am J Transplant 2004; 4(6):996–1001. 31. Luke PP, Scantlebury VP, Jordan ML, et al. IVIG rescue therapy in renal transplantation. Transplant Proc 2001; 33(1–2):1093–1094. 32. Jordan S, Cunningham-Rundles C, McEwan R. Utility of intravenous immune globulin in kidney transplantation: efficacy, safety, and cost implications. Am J Transplant 2003; 3(6):653–664. 33. Casadei DH, del CR, Opelz G, et al. A randomized and prospective study comparing treatment with high-dose intravenous immunoglobulin with monoclonal antibodies for rescue of kidney grafts with steroid-resistant rejection. Transplantation 2001; 71(1):53–58. 34. Jordan SC, Vo AA, Toyoda M, et al. Post-transplant therapy with high-dose intravenous gammaglobulin: applications to treatment of antibody-mediated rejection. Pediatr Transplant 2005; 9(2):155–161. 35. Tyan DB, Li VA, Czer L, et al. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation 1994; 57(4):553–562. 36. Jordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation 2003; 76(4):631–636. 37. Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol 2004; 15(12):3256–3262.

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38. Zachary AA, Montgomery RA, Ratner LE, et al. Specific and durable elimination of antibody to donor HLA antigens in renal-transplant patients. Transplantation 2003; 76(10):1519–1525. 39. Schweitzer EJ, Wilson JS, Fernandez-Vina M, et al. A high panel-reactive antibody rescue protocol for cross-match-positive live-donor kidney transplants. Transplantation 2000; 70(10):1531–1536. 40. Gloor JM, DeGoey SR, Pineda AA, et al. Overcoming a positive crossmatch in living-donor kidney transplantation. Am J Transplant 2003; 3(8):1017–1023. 41. Stegall MD, Dean PG, Gloor JM. ABO-incompatible kidney transplantation. Transplantation 2004; 78(5):635–640. 42. Schnuelle P, van der Woude FJ. Should A2 kidneys be transplanted into B or O recipients? Lancet 1998; 351(9117):1675–1676. 43. Nelson PW, Shield CF, III, Muruve NA, et al. Increased access to transplantation for blood group B cadaveric waiting list candidates by using A2 kidneys: time for a new national system? Am J Transplant 2002; 2(1):94–99. 44. Gloor JM, Lager DJ, Moore SB, et al. ABO-incompatible kidney transplantation using both A2 and non-A2 living donors. Transplantation 2003; 75(7):971–977. 45. Alexandre GP, Squifflet JP, De Bruyere M, et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc 1987; 19(6):4538–4542. 46. Takahashi K, Saito K, Takahara S, et al. Excellent long-term outcome of ABO-incompatible living donor kidney transplantation in Japan. Am J Transplant 2004; 4(7):1089–1096. 47. Galili U. Immune response, accommodation, and tolerance to transplantation carbohydrate antigens. Transplantation 2004; 78(8):1093–1098. 48. Sonnenday CJ, Warren DS, Cooper M, et al. Plasmapheresis, CMV hyperimmune globulin, and antiCD20 allow ABO-incompatible renal transplantation without splenectomy. Am J Transplant 2004; 4(8):1315–1322. 49. Tyden G, Kumlien G, Fehrman I. Successful ABO-incompatible kidney transplantations without splenectomy using antigen-specific immunoadsorption and rituximab. Transplantation 2003; 76(4):730–731. 50. Tyden G, Kumlien G, Genberg H, et al. ABO-incompatible kidney transplantations without splenectomy, using antigen-specific immunoadsorption and rituximab. Am J Transplant 2005; 5(1):145–148. 51. Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous ABO-incompatible and positive crossmatch barriers. Am J Transplant 2004; 4(4):561–568. 52. Segev DL, Gentry SE, Warren DS, et al. Kidney paired donation-optimizing use of live donor organs. JAMA 2005; 293(15):1883–1890.

11

Expanding Live-Donor Renal Transplantation Through Paired and Nondirected Donation Dorry L. Segev Division of Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, Maryland, U.S.A.

Sommer E. Gentry United States Naval Academy and Division of Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, Maryland, U.S.A.

Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Robert A. Montgomery Division of Transplantation, Department of Surgery, Johns Hopkins University, Baltimore, Maryland, U.S.A.

INTRODUCTION In 2004, 27,292 patients were added to the deceased donor renal waiting list, while in the same year only 16,004 transplants were performed (1). This discrepancy in organ availability grows annually and has contributed to a kidney waiting list that currently exceeds 60,000 patients. Despite significant efforts to increase deceased donation, the number of kidney transplants from deceased donors increased by a relatively modest 32% from 7061 in 1988 to 9357 in 2004. During this interval, live donation has more than tripled from 1812 in 1988 to 6648 in 2004 (Fig. 1). Of these live donors, a growing number are not related to their recipient (35% in 2004), and some donors even present without an intended recipient. There were two transplants from living nondirected donors (LNDD, also referred to as altruistic, Good Samaritan, anonymous or benevolent community donations) in 1998; six years later, this number had increased to 86 transplants (Fig. 2). Clearly, expanding live donation is the most promising approach to reducing the disparity between organ supply and demand. In this chapter, we discuss several approaches to expanding live donation. Many willing live donors are excluded from donation to an intended recipient because of blood type or tissue incompatibility. In the United States, based on distribution of blood group antigens, there is a 35% chance that any two individuals will be ABO incompatible (ABOi). In addition, exposure to human leukocyte antigen (HLA) from transfusions, pregnancies, or previous transplants can lead to sensitization and a positive crossmatch (+XM). In both cases, the incompatibility results from circulating preformed antibodies to blood group or HLA antigens that can cause hyperacute rejection and graft destruction (2). Through mathematical simulation, we have predicted that between 2000 and 4000 patients present annually with an ABOi or +XM incompatible donor as the only willing, healthy donor available (3–5). Most of these patients will have to forgo the live donor's offer and instead join the deceased donor waiting list. A number of specialized centers report success in removing or suppressing the blood type or HLA antibodies prior to transplantation, using desensitization strategies like plasmapheresis, intravenous immunoglobulin, pharmacologic B-cell depletion, or splenectomy (6–19). Although the results are encouraging, desensitization has only been performed at a few centers, and long-term patient and allograft outcomes remain unknown.

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Living Donor

10,000 9,000 # Kidney Transplants

8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 1988

1990

1992

1994

1996 Year

1998

2000

2002

2004

FIGURE 1 Comparison of deceased-donor and living-donor growth rates since 1988.

Kidney paired donation (KPD), first suggested by Rapaport in 1986, allows for exchange of donor organs between incompatible donor and recipient pairs, such that the resulting pairs achieve compatibility (20). Both donor operations are performed simultaneously to avoid cancellation by the second donor after the kidney from the first donor has been removed. KPD matches have been achieved using ABOi pairs, recipients with +XM with their donors, or combinations of these between two or even three pairs. We discuss the various types of paired donation currently used, the outcomes from local and regional experiences, and the potential impact of a national program. Like KPD, LNDD allocation has been limited to local or single-[organ procurement organization (OPO)] experiences. Ethical models include one that selects healthier recipients for the sake of optimized outcomes from the LNDD, one that favors the most vulnerable recipient, and one that adheres to the currently established principles of deceased donor allocation. We describe the various allocation models, as well as our single-center experience with a combined LNDD and KPD program [domino paired donation (DPD)], which multiplies the benefits of the LNDD by enabling the use of unmatched incompatible live donors. CONVENTIONAL PAIRED DONATION In its original implementation, KPD represented an exchange between a blood type A/B and B/A donor/recipient pairs (Fig. 3A). Since donors with blood type O could donate to any intended recipient and AB recipients could only receive an AB kidney, these groups were excluded from consideration in the first generation of KPD. It was quickly shown that A/B or

90

# Living Non-Directed Donors

80 70 60 50 40 30 20 10 0 1998

1999

2000

2001 Year

2002

2003

2004

FIGURE 2 Growth of nondirected kidney donation since 1998.

Live-Donor Renal Transplantation Through Paired and Nondirected Donation Donor

(A)

(B)

B

ABO incompatible with intended donor

B

A

ABO incompatible with intended donor

O

ABO incompatible with intended donor

O

A

Positive crossmatch with intended donor

Recipient

A

O

ABO incompatible with intended donor

B

A

ABO incompatible with intended donor

O

B

Positive crossmatch with intended donor

Donor

Recipient

O

A

Crossmatch titer >1024 with intended donor

O

O

Crossmatch titer >1024 with intended donor

O

O

Crossmatch titer >1024 with intended donor

Donor

(D)

Recipient

A

Donor

(C)

Recipient

A

Donor

127

Recipient

O

A

Negative crossmatch with matched donor

O

O

Low titer crossmatch (4) with matched donor

O

O

Negative crossmatch with matched donor

FIGURE 3 (A) Conventional paired donation is restricted to donor/recipient pairs with incompatible blood types. (B) Unconventional paired donation allows participation of patients with a positive crossmatch against intended donors. (C) Three-way matching expands opportunities for donor/recipient pairs in small-paired donation programs. (D) Patients too broadly sensitized to find a negative crossmatch could be matched with a donor against whom they have a low-titer positive crossmatch amenable to desensitization. Source: From Ref. 23.

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B/A blood types were the most rare combinations and only 6% of incompatible pairs could benefit from conventional KPD (21,22). UNCONVENTIONAL PAIRED DONATION Blood type O donors and AB recipients may, however, participate in KPD if a +XM exists between the donor and the recipient. In these cases, a pair with a +XM can offer an O donor or an AB recipient to a blood type incompatible or +XM pair that would not be eligible for conventional KPD (Fig. 3B). Three-Way Matching Three-way KPD (Fig. 3C) can expand the number of solutions for difficult-to-match patients (23). In a single-center KPD program with a high average panel of reactive antibodies (PRA), this situation arises frequently, and we have utilized three-way exchanges for several of our incompatible pairs (24). Disadvantages include the increased logistical complexity of arranging multiple simultaneous operating rooms and the increased risk that one of six patients or donors will become ill on or before the intended transplant day. Matching to Reduce Immunologic Barriers Many patients are referred to our center for incompatible transplantation, but have antibody titers against their donors that are too high for desensitization. These patients are often so broadly sensitized that matching with a XM-negative donor is a very rare event. For these patients, we relax the matching criteria for a paired donation and allow them to match with a donor against whom they have a +XM, but one with a titer amenable to desensitization (Fig. 3D). Local and Regional Experiences In a single-center KPD program, we have transplanted 27 patients since 2001 through six conventional, two unconventional, two three-way unconventional, and two DPDs (discussed later in this chapter). In this cohort, six patients were highly sensitized with PRA > 80%. Sixteen recipients were included to avoid ABOi, four to eliminate a +XM, two to avoid repeat mismatches in sensitized recipients, three to reduce a high titer +XM that would not have been amenable to desensitization, and one pair that remained in the match pool for altruistic reasons (Table 1). Other than one graft that was lost the night of surgery because of technical reasons, all grafts remain functioning with a median six-month creatinine of 1.2 mg/dL. The patient and graft survival rates are 100% and 96.3%, respectively (Table 2). It has been our institutional experience that outcomes following KPD are equivalent to those of directed live donor renal transplants, despite the inclusion of a greater percentage of regrafts and highly sensitized patients. Nationally, KPD is expanding and, to date, 82 transplants from 24 transplant centers have been reported to United Network for Organ Sharing (UNOS). Two regional programs have been formed in the hope of finding more matches from larger pools of patients, namely the Ohio Paired Donation Consortium (25) and the New England Organ Bank paired donation program (26). Park et al. reported outcomes from the national experience in Korea, where 101 patients have been transplanted through KPD with results comparable to direct live donor

TABLE 1

Results from the Johns Hopkins Kidney Paired Donation Program: Patient Demographics

Type of paired donation

No. of recipients

Age (median)

PRA (mean peak)

12 2 4 6 3

55 49 41 33 41

7 0 54 58 48

Conventional, 2-way Conventional, 2-way domino Unconventional, 2-way Unconventional, 3-way Unconventional, 3-way domino Abbreviation: PRA, panel of reactive antibodies.

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TABLE 2

Results from the Johns Hopkins Kidney Paired Donation Program: Outcomes No. of episodes

Type of paired donation

Cellular rejection

Antibody rejection

Graftsa lost

One week median Cr

Three months median Cr

Six months median Cr

Median follow-up (months)

1 0

0 0

1 0

1.2 1.4

1.2 1.2

1.2 1.2

21 7

0 3 1

0 0 0

0 0 0

1.3 1.3 1.2

1.4 1.2 1.2

1.5 1.3 1.5

37 28 9

Conventional, 2-way Conventional, 2-way domino Unconventional, 2-way Unconventional, 3-way Unconventional, 3-way domino a

Graft lost on first postoperative night due to technical reasons.

transplants (27). The Dutch national KPD program is similarly encouraging, having registered 60 pairs and transplanted 26 patients last year (28). Impact of a National Paired Donation Program With the success of the Korean (27) and Dutch (28) efforts, there has been an expanded interest in the concept of creating national programs that would provide large pools of incompatible pairs and generate a higher percentage of matches. In a country as large as the United States, there are significant logistical and geographic barriers that would need to be resolved before a national KPD program can be established. Unfortunately, although a great deal of data are collected regarding renal transplant candidates and their ultimate donors, no information is gathered regarding willing, healthy live donors that are rejected for blood type or XM incompatibilities. As a result, estimates of the potential impact of a national KPD program in the United States are limited to mathematical simulation. To estimate the number of patients each year that will present with an incompatible donor as the only eligible live donor, we developed a model for simulating kidney transplant candidates and their live donors (3–5). In brief, each patient is simulated with the characteristics of patients added to the UNOS deceased donor waiting list. For each patient, a social network is simulated, which includes friends, siblings, spouse, parents, and/or children, depending on the known distribution of live donor relationships in the UNOS database (Fig. 4). Between one and four donors from this social network are simulated to be available to each patient. Each donor undergoes a virtual medical and psychosocial work-up as well as virtual blood type and XM

How many incompatible pairs are out there?

Simulated Patients Mother

Father Friend

Sibling

Patient

Sibling

Child Relationship to Donor

Spouse

Child %

Parent

19.7

Child

16.8

Sibling

42.4

Spouse

10.0

Unrelated

11.2

FIGURE 4 Simulation of patients with end-stage renal disease and their relationship to potential live donors.

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Simulated work-up:

Decision Tree Model Each patient has 1-4 potential donors Medical and Psychosocial Work-up Eligible

Failed

ABO and XM test

Donor Patient Compatible

Direct donation Keep simulating patients until 6468 live directed donors are found

Check other donors For eligibility

Incompatible Check other donors for compatibility If none are compatible, join KPD

FIGURE 5 Monte Carlo Decision Tree Model for simulating renal transplant patients with incompatible donors.

testing. If one donor is incompatible or ineligible, the other donors are tested in a similar manner. If a compatible donor is found, a direct donation is simulated. If the only eligible donor is incompatible, this pair is added to the simulated KPD pool (Fig. 5). We found that, depending on the number of potential live donors available to each kidney transplant candidate, between 2400 and 4400 patients yearly are predicted to present with an incompatible donor as the only eligible live donor (3). Interestingly, the approximate size (relative to the number of live-donor kidney transplants performed) and blood type distribution of the population of patients with incompatible donors identified has been validated by the characteristics of the patients entering the Dutch national program (28). We also discovered that the choice of mathematical algorithm used to match incompatible donor/recipient pairs significantly impacted the number of matches identified from any given pool of incompatible pairs (4). The most appropriate technology for representing incompatible pairs is the field of graph theory, and the most successful method of matching pairs is an optimized algorithm, as illustrated in Figure 6. With optimized matching and a national KPD program of the size simulated by our model, we anticipate that approximately half of the incompatible pairs entering a KPD pool would match on the first match run, with fewer than 3% required to travel outside of their region to find a match (4).

FIGURE 6(A) An example of the importance of an optimized matching algorithm for matching incompatible donor/recipient pairs in a kidney-paired donation (KPD) program. Representing a KPD pool: an example graph shows 20 incompatible donor/recipient pairs, numbered zero through 19. Each node (numbered circle) represents all the necessary information regarding one donor/recipient pair, and each edge (line connecting two nodes) is drawn when a paired donation would be possible between the two connected pairs.

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FIGURE 6(B) Effect of donor blood type: pair 4 (donor blood type O and recipient blood type A) can match with nine other pairs, because the O donor can donate to almost any recipient. However, the recipient in pair 13 (donor blood type B and recipient blood type A) has the same blood type as the recipient in pair 4, but far fewer match opportunities because of a lessuniversal donor.

FIGURE 6(C) Effect of travel preference: pair 11 (donor blood type A and recipient blood type O) can match with three other pairs. However, pair 16 (donor blood type A and recipient blood type O), which has the same donor and recipient blood types but is unwilling to travel outside of the region, sees fewer match opportunities.

LIVING NONDIRECTED DONATION To date, 302 patients have received kidney transplants from LNDD (1). The rise in nondirected donation inspired a number of ethics publications (29,30) and a consensus conference regarding ethical considerations and practical policies (31). Several programs have reported single-center or single-OPO experiences, including the University of Minnesota (32,33) and the Washington, DC. OPO (34). Still, no national allocation policy has been established for LNDDs and the model of allocation has remained within the purview of the center or OPO to which the LNDD presents. We will discuss three allocation models that have been developed de novo among the centers performing LNDD transplants, as delineated by William H. Marks (personal communication): donor-centric, recipient-centric, and socio-centric. Finally, we present our single center allocation system, DPD. DPD represents an integration of nondirected donation and paired donation, whereby an LNDD facilitates more than one transplant by matching with incompatible pairs from our KPD program.

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FIGURE 6(D) Importance of each match decision: to demonstrate that even one match can significantly affect opportunities for everyone else in the pool, we demonstrate what happens when pair 4 matches with pair 17.

Donor-Centric Allocation The goal of this allocation model is to ensure a good recipient outcome from the LNDDs gift. It is felt that since a healthy individual took the risk of undergoing an operation to help someone else and the medical community enabled this act, we have a responsibility to ensure the maximum likelihood that the outcome will be successful. The increased odds of a good result when the kidney is allocated to a recipient predicted to do well make it more likely that the LNDD will feel that the sacrifice was fruitful. The limitation of this model is that the healthiest patients are most likely to tolerate dialysis or have a good outcome from a deceased donor organ. Recipient-Centric Allocation In this model, the argument is advanced that the patients who are in most need of a kidney should receive one that becomes available as a result of an altruistic gesture. In other words,

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since allocation through the deceased donor waiting list will inevitably leave some patients vulnerable and disadvantaged, organs available through new sources should be directed to these populations. Children, highly sensitized patients, and patients who can no longer tolerate dialysis (lack of vascular access or medical illness related to dialysis) have been allocated LNDD organs at institutions using a recipient-centric model. However, since the recipients are drawn from high-risk groups, the outcomes would be predicted to be inferior, and this could be perceived by the LNDD or general public as a wasted donation. Socio-Centric Allocation If the LNDD offer is viewed as a public resource similar to deceased donor organs, a sociocentric model requires that the LNDD be allocated to the patient at the top of the deceased donor waiting list by the same principles that govern deceased donor allocation. This allocation system selects patients who already have the morbidity associated with long periods of dialysis and are likely to receive the next available deceased donor organ. Domino Paired Donation In our center, by combining LNDD with our paired donation program, we have developed an allocation system that we feel achieves the goals of all three ethical models described previously (35). In DPD, a LNDD is matched with an incompatible donor/recipient pair from our KPD pool, initiating a domino effect in which the intended donor of the incompatible pair then donates to the next available patient on the deceased donor waiting list (Fig. 7). We feel that the ethical tenets of all three allocation systems are united in this model: (i) it is donor-centric in that more than one transplant is facilitated by the LNDD, (ii) it is recipient-centric in that patients unmatched in our KPD program tend to be highly sensitized or have hard-to-match blood types, and (iii) it is socio-centric in that, at the end of the domino, the last kidney is allocated to the patient at the top of the deceased donor waiting list. In this way, the LNDDs gift is multiplied. We have performed both two-way as well as three-way DPDs. In each case, the domino begins with a LNDD giving a kidney to a recipient with an incompatible donor, and ends with a donation to the waiting list. As the number of LNDDs continues to increase, the models for allocation will need to be further investigated and debated. CONCLUSIONS The fastest growing source of kidneys in the United States is from live donors. Expanding the utilization of willing, healthy live donors who are incompatible with their intended recipients will require innovative programs such as desensitization and paired donation. Every incompatible donor gained through one of these programs means one less patient added to the growing deceased donor waiting list. Furthermore, the advent of a new category of living donors who are willing to give a kidney to anyone in need is an unanticipated addition to the donor pool that must be managed in a way that optimizes the impact of their altruism. Efficient and fair

Donor

Recipient Nondirected (altruistic) donor

A

O

A

O

Positive crossmatch with intended donor, otherwise unable to match through KPD, negative crossmatch with nondirected donor 1st patient from the UNOS match run for blood type O

FIGURE 7 Domino paired donation utilizes a live nondirected donor (altruistic donor) in a paired donation (with an incompatible pair otherwise unable to match through kidney paired donation) in order to facilitate two transplants.

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utilization of organs from LNDD is critical and will hopefully encourage others to follow in their path. REFERENCES 1. UNOS. Organ Procurement and Transplantation Network data as of May 24, obtained from and available at the United Network for Organ Sharing website, 2005. 2. Hume DM, Merrill JP, Miller BF, et al. Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest 1955; 34(2):327–382. 3. Gentry SE, Segev DL, Montgomery RA. A comparison of populations served by kidney paired donation and list paired donation. Am J Transplant 2005; 5(8):1914–1921. 4. Segev DL, Gentry SE, Warren DS, et al. Kidney paired donation and optimizing the use of live donor organs. JAMA 2005; 293(15):1883–1890. 5. Segev DL, Gentry SE, Melancon JK, et al. Characterization of waiting times in a simulation of kidney paired donation. Am J Transplant 2005; 5(10):2448–2455. 6. Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000; 70(6):887–895. 7. Montgomery RA, Zachary AA. Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr Transplant 2004; 8(6):535–542. 8. Zachary AA, Montgomery RA, Ratner LE, et al. Specific and durable elimination of antibody to donor HLA antigens in renal-transplant patients. Transplantation 2003; 76(10):1519–1525. 9. Takahashi K, Saito K, Takahara S, et al. Excellent long-term outcome of ABO-incompatible living donor kidney transplantation in Japan. Am J Transplant 2004; 4(7):1089–1096. 10. Sonnenday CJ, Warren DS, Cooper M, et al. Plasmapheresis, CMV hyperimmune globulin, and antiCD20 allow ABO-incompatible renal transplantation without splenectomy. Am J Transplant 2004; 4(8):1315–1322. 11. Tyden G, Kumlien G, Fehrman I. Successful ABO-incompatible kidney transplantations without splenectomy using antigen-specific immunoadsorption and rituximab. Transplantation 2003; 76(4):730–731. 12. Jordan SC, Vo AA, Nast CC, et al. Use of high-dose human intravenous immunoglobulin therapy in sensitized patients awaiting transplantation: the Cedars-Sinai experience. Clin Transpl 2003; 193–198. 13. Gloor JM, Lager DJ, Moore SB, et al. ABO-incompatible kidney transplantation using both A2 and non-A2 living donors. Transplantation 2003; 75(7):971–977. 14. Montgomery RA, Cooper M, Kraus E, et al. Renal transplantation at the Johns Hopkins Comprehensive Transplant Center. Clin Transpl 2003; 199–213. 15. Sonnenday CJ, Ratner LE, Zachary AA, et al. Pre-emptive therapy with plasmapheresis/intravenous immunoglobulin allows successful live donor renal transplantation in patients with a positive crossmatch. Transplant Proc 2002; 34(5):1614–1616. 16. Stegall MD, Dean PG, Gloor JM. ABO-incompatible kidney transplantation. Transplantation 2004; 78(5):635–640. 17. Glotz D, Antoine C, Julia P, et al. Desensitization and subsequent kidney transplantation of patients using intravenous immunoglobulins (IVIg). Am J Transplant 2002; 2(8):758–760. 18. Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch barriers. Am J Transplant 2004; 4(4):561–568. 19. Jordan SC, Vo AA, Peng A, et al. Intravenous gammaglobulin (IVIG): a novel approach to improve transplant rates and outcomes in highly HLA-sensitized patients. Am J Transplant 2006; 6(3):459–466. 20. Rapaport FT. The case for a living emotionally-related international kidney-donor exchange registry. Transplant Proc 1986; 18(3 suppl 2):5–9. 21. Terasaki PI, Gjertson DW, Cecka JM. Paired kidney exchange is not a solution to ABO incompatibility. Transplantation 1998; 65(2):291. 22. Woodle ES, Ross LF. Paired exchanges should be part of the solution to ABO incompatibility in living donor kidney transplantation. Transplantation 1998; 66(3):406–407. 23. McLellan F. US surgeons do first “triple-swap” kidney transplantation. Lancet 2003; 362(9382):456. 24. Montgomery RA, Zachary AA, Ratner LE, et al. Clinical results from transplanting incompatible live kidney donor/recipient pairs using kidney paired donation. JAMA 2005; 294(13):1655–1663. 25. Woodle ES. The potential of paired donation programs: modeling and reality. Am J Transplant 2005; 5(8):1787–1788. 26. Delmonico FL, Morrissey PE, Lipkowitz GS, et al. Donor kidney exchanges. Am J Transplant 2004; 4(10):1628–1634. 27. Park K, Lee JH, Huh KH, et al. Exchange living-donor kidney transplantation: diminution of donor organ shortage. Transplant Proc 2004; 36(10):2949–2951.

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28. de Klerk M, Keizer KM, Claas FH, et al. The Dutch national living-donor kidney exchange program. Am J Transplant 2005; 5(9):2302–2305. 29. Henderson AJ, Landolt MA, McDonald MF, et al. The living anonymous kidney donor: lunatic or saint? Am J Transplant 2003; 3(2):203–213. 30. Spital A. Public attitudes toward kidney donation by friends and altruistic strangers in the United States. Transplantation 2001; 71(8):1061–1064. 31. Adams PL, Cohen DJ, Danovitch GM, et al. The nondirected live-kidney donor: ethical considerations and practice guidelines: a National Conference Report. Transplantation 2002; 74(4):582–589. 32. Matas AJ, Garvey CA, Jacobs CL, et al. Nondirected donation of kidneys from living donors. N Engl J Med 2000; 343(6):433–436. 33. Jacobs CL, Roman D, Garvey C, et al. Twenty-two nondirected kidney donors: an update on a single center’s experience. Am J Transplant 2004; 4(7):1110–1116. 34. Gilbert JC, Brigham L, Batty DS, Jr, et al. The nondirected living donor program: a model for cooperative donation, recovery and allocation of living donor kidneys. Am J Transplant 2005; 5(1):167–174. 35. Montgomery RA, Gentry SE, Marks WH, et al. Domino paired kidney donation: a strategy to make best use of live non-directed donation. Lancet 2006; 368(9533):419–421.

12

Living-Donor Renal Transplantation in HIV Positive Recipients Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

David J. Kaczorowski Department of Surgery, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION End-stage renal disease (ESRD) in patients infected with the human immunodeficiency virus (HIV) has become an increasingly common clinical problem. In the past, patients with HIV were generally not considered candidates for renal transplantation. Furthermore, outcomes after renal transplantation in these patients were often poor. However, the introduction and widespread administration of highly active antiretroviral therapy (HAART) for patients with HIV has substantially decreased the incidence of opportunistic infections in these patients and improved their overall survival as well. The decrease in the rate of opportunistic infections and mortality afforded by the use of HAART, in addition to the increasing prevalence of ESRD in this growing population of patients, has led to new trials of renal transplantation in patients with HIV. Despite improvements in the medical management of patients infected with HIV, the supply of deceased donor kidneys is inadequate, and justification of the use of these organs in HIV positive patients remains difficult. The use of living donor kidneys is a reasonable way to provide organs for these patients without utilizing scarce deceased donor kidneys. Recent data support the use of living donor renal transplantation in HIV positive patients and demonstrate the safety and efficacy of this approach. HUMAN IMMUNODEFICIENCY VIRUS Human Immunodeficiency Virus Pandemic In June of 1981, a series of five young homosexual men with Pneumocystis carinii pneumonia and other unusual infections was reported (1). This report was the first description of what is now recognized as the acquired immunodeficiency virus syndrome (AIDS). The following month, several more cases of Pneumocystis pneumonia and Kaposi’s sarcoma were reported in homosexual men in California and New York (2). Approximately one year later, a cluster of Kaposi’s sarcoma and Pneumocystis pneumonia in homosexual men living in Los Angeles and Orange County was reported, and it was hypothesized that a sexually transmitted infectious agent might be responsible (3). In May 1983, a novel retrovirus belonging to the human T-cell leukemia virus (HTLV) family was isolated from a patient with AIDS, and this virus was implicated in the pathogenesis of the disease (4). Later studies found that this virus, which was eventually recognized as HIV, was frequently isolated from the peripheral blood lymphocytes of patients with AIDS (5). Since these initial reports, HIV has spread to all corners of the world. As of 2004, there were an estimated 40 million people living with HIV and an incidence of roughly five million cases per

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year according to the United Nations Joint Program on HIV/AIDS (UNAIDS) (6). Of the 14,000 new HIV infections that occur each day across the world, almost 2000 are in children under the age of 15. Of the remaining 12,000 new HIV infections occurring daily, about 50% are in patients 15 to 24 years of age. There were approximately 3.1 million deaths related to AIDS in 2004. No effective vaccine is available, and there is no sign that a vaccine will be available in the immediate future. Human Immunodeficiency Virus and End-Stage Renal Disease As the prevalence of HIV increases, ESRD in patients with HIV will become an increasingly common clinical scenario. Patients with HIV are susceptible to the many causes of ESRD that affect patients without HIV. Furthermore, infection with hepatitis C is more common in patients with HIV, and glomerulonephritis associated with hepatitis C is also more common. There are also causes of ESRD specific to patients with HIV. HIV-associated nephropathy (HIVAN) has become an important cause of renal failure in patients with HIV. HIVAN has become the third leading cause of renal failure in African Americans between the ages of 20 and 64, and is the most common cause of ESRD in patients with HIV (7). The prevalence of HIVAN is probably underestimated. HIVAN is characterized by a collapsing focal and segmental glomerulosclerosis. Diagnosis is confirmed by renal biopsy. The use of HAART may reduce the risk of HIVAN (8), and angiotensin-converting enzyme(ACE) inhibitors and steroids are currently being investigated for the treatment of HIVAN. Unfortunately, a substantial number of these patients ultimately require dialysis. The survival of patients with HIV on dialysis has been poor. Although there have been improvements in patient survival in recent years, the survival of patients with HIV and ESRD is still very poor compared to matched controls without HIV. One analysis found that the one- and two-year survival for patients for HIV infected dialysis patients was 58% and 41%, respectively, while the survival of controls matched for age, race, and gender was 87% and 79%, respectively (9). Highly Active Anti-retroviral Therapy The development of HAART has had a profound impact on the management of patients with HIV. There are three classes of drugs commonly used to treat HIV infection: nucleoside analog reverse-transcriptase inhibitors (NRTI), non-nucleoside reverse-transcriptase inhibitors (NNRTI), and protease inhibitors (PI). HAART regimens typically incorporate three (or more) drugs from these classes into an antiviral regimen. Regimens may vary, but typically consist of either a PI or an NNRTI with two NRTIs. Although higher rates of virologic failure may occur, regimens utilizing three NRTIs have also been employed. In some instances, another PI such as ritonavir will be added to regimens already containing a PI to increase drug levels by inhibiting the CYP3A4 system. Over 20 different drugs are available for use. Specific regimens are developed to optimize the combination of the agents, pharmacokinetic interactions, pill burden, and side effects. With the implementation of HAART, dramatic reductions in the morbidity and mortality of patients with HIV were observed. Significant reductions in mortality, regardless of age, sex, and race were documented with combination antiretroviral therapy, as illustrated in Figure 1 (10). Similarly, the risk of major opportunistic infections, including Pneumocystis carinii pneumonia, Mycobacterium avium complex, and cytomegalovirus retinitis were substantially reduced, as can be seen in Figure 2 (10,11). With these developments, HIV was transformed into a potentially chronic medical condition. RENAL TRANSPLANTATION IN HIV+ RECIPIENTS Outcomes in the Pre-highly Active Antiretroviral Therapy Era Prior to the advent and widespread use of HAART, there were several small series and case reports of renal transplantation in HIV+ patients. In some instances, the patients were HIV+ prior to transplantation, while others were infected in the perioperative period or after transplantation. There were multiple cases of HIV transmission from organ donors to recipients, including cases of transmission through living donor renal transplantation (12). The clinical

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FIGURE 1 The mortality of patients with HIV has decreased with the increasing use of combination antiretroviral therapy including protease inhibitors. Source: From Ref. 10.

courses and the ultimate outcomes of HIV+ patients that received renal transplants prior to the availability of HAART were variable. In 1990, Tzakis and colleagues reported the results of a retrospective analysis of HIV+ recipients of solid organ transplants at the University of Pittsburgh, with a mean overall followup of 2.75 years (13). Of 3023 recipients of solid organ transplants between January 1981 and September 1988, 25 (0.8%) patients were found to be HIV+. This group included five kidney transplant recipients, 15 liver transplant recipients, and five heart transplant recipients. Four out of the five kidney transplant recipients were alive, with a mean follow-up of 3.4 + 2.2 years for the survivors. One renal transplant recipient, who seroconverted after transplantation, died of generalized tuberculosis five months after transplantation. In this study, there were three renal transplant recipients who were HIV+ at the time of transplant. Two of these patients had survived five or more years after transplantation, and one had lost the allograft to acute rejection eight months after transplantation. Two of the five renal transplant recipients were pediatric patients (ages 13 and 16). When the entire group was considered, the best results were in the pediatric population, with 70% survival at follow-up. Overall, organ transplantation plus immunosuppression appeared to shorten the AIDS-free survival time of the group when compared with a control group of HIV+ hemophiliacs and transfusion recipients, but the difference did not reach statistical significance. In 1991, Erice and colleagues reported on five cases of HIV+ solid organ transplant recipients from the University of Minnesota and performed a comprehensive review of the literature (14). Of the five cases from the University of Minnesota, three of the patients were recipients of deceased-donor renal transplants, and two of these patients received living-related donor kidneys. One of the living donor recipients, whose HIV status at the time of transplantation is unknown, had course notable for multiple infectious complications starting two months after

FIGURE 2 The incidence of opportunistic infections also decreased with increasing use of combination antiretroviral therapy. Source: From Ref. 10.

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transplantation. These included thoracic herpes zoster, cytomegalovirus (CMV) retinitis, candidemia, E. coli bacteremia, respiratory failure related to influenza A, and Pneumocystis carinii pneumonia. He was diagnosed with AIDS four years after transplantation and died five and a half years after transplantation in the setting of multiple infectious complications. The other recipient of a living donor renal allograft was likely infected with HIV after receiving multiple blood transfusions in the postoperative period. This patient was doing well except for chronic diarrhea of unclear etiology at 79 months after transplantation. Her CD4 count had dropped to 200 cells/mm3 at 68 months post-transplant and 120 cells/mm3 at 72 months post transplant. In their review of the literature, Erice and colleagues identified 83 cases of HIV infection in solid organ transplant recipients between 1985 and 1990 (14). Eleven patients who were HIV+ prior to renal transplantation were identified. Out of the eight patients for whom data on allograft function was available, six patients (75%) had functioning grafts. With a mean followup of 30.7 months, three of the 11 patients (27%) had developed AIDS. Four of the 11 patients (36%) died at a mean of 14.7 months after transplantation. Another patient died of sepsis that was thought to be unrelated to HIV disease two months after transplantation. In 1993, a group from Germany reported a series of four cases in which HIV was transmitted from donors to recipients of renal allografts, and also reviewed the literature (15). In their series, one patient died of endocarditis and another from cerebral hemorrhage at 66 and 74 months post transplant. Multiple infectious complications were observed, including several urinary tract infections, shunt infection, bronchitis, herpes stomatitis, herpes zoster, and CMV. There were also eight episodes of rejection reported. Of note, in their review of the literature, they found that the cumulative incidence of AIDS was significantly lower in 40 transplant recipients who received an immunosuppressive regimen that included cyclosporine when compared with 13 transplant recipients who received an immunosuppressive regimen that did not include cyclosporine. A large historical cohort analysis of United States Renal Data System (USRDS) was performed by Swanson and colleagues to determine the impact of HIV infection prior to transplantation on graft and patient survival after deceased donor renal transplantation in the era prior to the availability of HAART (16). The authors analyzed data from 63,210 deceased donor solitary renal transplant recipients with HIV serology entries in the USRDS system between 1987 and 1997. Thirty-two patients (0.05%) were HIV+ at the time of transplant. Details of recipient selection were not available. The HIV+ patients were comparable to the remainder of the USRDS population regarding to gender and ethnicity. However, the HIV+ patients were younger overall and had younger donors and better HLA matching. Despite these differences, both the patient and graft survival were significantly reduced at three years in the HIV+ group (83% patient and 53% graft) when compared to the overall USRDS patient population (88% patient and 73% graft). Furthermore, the authors noted that HIV seropositivity was independently associated with and increase in graft failure and mortality in a multivariate analysis. Transplantation in the Highly Active Antiretroviral Therapy Era Although outcomes of transplantation in HIV+ patients during the pre-HAART era were mixed, there has been renewed interest in renal transplantation in this patient population. This interest has been prompted by both the increasing prevalence of patients with both HIV and ESRD, and also the decrease in morbidity and mortality afforded by HAART. A pilot trial designed to evaluate the safety and efficacy of kidney and liver transplantation was recently performed at the University of California, San Francisco (17). Ten patients with HIV received renal transplants, with a mean follow-up of 480 days. Four of the patients received living related kidney transplants, and the remaining six received either deceased donor or highrisk deceased donor grafts, as defined by the Centers for Disease Control and Prevention. For the 10 recipients of renal transplants, patient and graft survival was 100%, and all patients had good allograft function. There was no evidence of any adverse effect of HIV on graft function. In this study, antibody induction therapy was not used. Maintenance immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF). Mild rejection was treated with a steroid bolus and a switch of maintenance immunosuppression from cyclosporine to tacrolimus. Vascular rejection was treated in the same fashion, with the addition of thymoglobulin. Rejection occurred

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in five of 10 (50%) kidney transplant recipients, and three of the five required Thymoglobulin to treat the rejection. While CD4 counts generally dropped transiently in all patients immediately after transplantation, they soon returned to normal levels. However, in all patients treated with thymoglobulin, CD4 counts dropped below 220 cells/mm3 and were slow to recover. No AIDS-defining infections occurred in this series. However, one patient developed Staphylococcus aureus endocarditis, and another developed Pseudomonas aeruginosa pneumonia and sepsis after treatment with Thymoglobulin. There were also two cases of S. aureus wound infections and one case of influenza B pneumonia. One significant barrier to renal transplantation in individuals with HIV is the utilization of immunosuppressive medications in patients who may become immuncompromised because of their viral disease (18). Because donor organs are scarce and the waiting list for renal transplantation continues to grow, the utilization of donor organs for this patient population has generated controversy, and represents another significant barrier to transplantation in patients with HIV. At the University of Pittsburgh, we have employed strategies to overcome these barriers. Increased use of laparoscopic live donor nephrectomy (LLDN) has been used to increase the supply of donor organs available for transplantation (19). Furthermore, we have successfully employed novel immunosuppressive strategies involving recipient pretreatment with lymphocyte depleting agents followed by the use of steroid-free minimal post-transplant immunosuppression (20). The use of alemtuzumab, a humanized monoclonal anti-CD52 monoclonal antibody, has yielded excellent preliminary results with lower early rejection rates than with Thymoglobulin (21,22). We recently reported on four cases of deceased donor renal transplants in the HAART era at the University of Pittsburgh, and four cases where LLDN was utilized (23,24). In the deceased donor cases, the immunosuppressive regimens utilized a tacrolimus-based regimen without antibody induction. For the living-related cases, alemtuzumab preconditioning followed by post-transplant steroid-free low-dose tacrolimus monotherapy was utilized. Of the recipients of deceased donor organs, only one patient continued to have good graft function at follow-up. Three of the patients experienced decreases in their CD4 counts, and one patient experienced an increase in viral load. One patient had multiple infectious complications, but none of them was AIDS defining illnesses. Three of these patients experienced at least one episode of acute cellular rejection (Table 1). Although the follow-up time was shorter (mean follow-up of 453 + 191 days) in the living donor group, patient and graft survival was 100% (Table 2). Good graft function was observed in all patients, with a mean creatinine of 1.4 + 0.5 mg/dL. HIV viral loads remained undetectable in all patients. CD4 counts dropped as expected with alemtuzumab induction, but began to recover in all patients. There were no opportunistic infections. Importantly, no episodes of rejection occurred. Furthermore, there was no donor morbidity or mortality (Table 3). This study demonstrated that LLDN is an effective method of providing organs for patients with ESRD who are infected with HIV. Long-term data will clearly be required, but the preliminary findings suggest that an immunosuppressive regimen involving recipient preconditioning with alemtuzumab followed by steroid-free low-dose tacrolimus monotherapy is safe and effective for preventing graft rejection in patients with HIV. One of the largest trials of renal transplantation in HIV+ patients was conducted by Kumar and colleagues (25). In this study, 40 patients with ESRD underwent kidney transplantation after induction therapy with basiliximab. Maintenance immunosuppression consisted of cyclosporine, sirolimus, and steroids. Of the 40 patients, four received living donor renal transplants. Of the 36 deceased donor organs, eight had a history of drug abuse, three had a history of alternative lifestyle, and eight were expanded criteria donors. Thirty-nine of the 40 recipients were African American. Patient survival at one and two years was 85% and 82%, and graft survival at one and two years was 75% and 71%. HIV viral loads remained undetectable in all patients and all CD4 counts remained >400 cells/μL. Several infectious complications were observed. These included one death related to an infected lymphocele, another death from sepsis, and one other death from necrotizing fasciitis. No patients developed AIDS-defining infections. The rate of acute rejection in this study was 25% and was thought to be related, in part, to relatively low doses of immunosuppression.

58

45

32

46

1

2

3

4

C

AA

AA

C

Race

5.6

9.2

1.7

1.3

Tacrolimus, prednisone, mycophenolate,

1.5

4.0

1.6

Tacrolimus, mycophenolate, prednisone,

1.3

Cr (most recent)

Cr (lowest)

Maintenance

HTN, Tacrolimus, HIVAN sirolimus, prednisone, PKD Tacrolimus

HTN, DM

PKD

Indication

Lamivudine, zidovudine, efavirenz Nevirapine, lamivudine, stavudine

Lamivudine, zidovudine, abacavir

Lamivudine, stavudine, nevirapine

Anti-retrovirals

CD4 Post Tx 482

172

98

944

CD4 Pre Tx >500

1054

391

411

<50

5774

<50

<50

Viral load copies/mL

Delayed graft function, Periallograft hematoma following biopsy, ACR, plantar fasciitis, cellulitis Delayed graft function, multiple episodes of ACR, chronic allograft nephropathy, dialysis dependent Multiple episodes of ACR, severe chronic rejection, dialysis dependent Basal cell carcinoma, s/p excision

Complications

69

39

51

39

Follow up (mo)

a

The mean follow-up of this group is 49 ± 14 months. Note that only one patient continues to have good graft function. Three patients experienced decreased CD4 counts. One patient experienced an increased viral load. Three patients experienced at least one episode of ACR. Abbreviations: DM, diabetes mellitus; HTN, hypertension; HIVAN, HIV associated nephropathy; PKD, polycystic kidney disease.

Age

Deceased Donor HIV+ Renal Transplant Recipientsa

Recipient

TABLE 1

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44

40

58

37

1

2

3

4

C

C

AA

C

Race

M

M

F

M

Sex

ADPKD

Reflux nephropathy

HTN

DM

Indication

Cr 1.7

0.9

1.8

1.0

7.7

4.0 <1 8.6

FK506 16 mg PO qod

FK506 4 mg PO qod FK506 5 mg PO qod

FK506 0.05 mg PO qod

Maintenance Lamivudine, lopinavir/ ritonavir, abacavir, efavirenz Lamivudine, zidovudine, efavirenz Lamivudine, zidovudine, efavirenz Lamivudine, zidovudine, efavirenz

Anti-retrovirals

110

164

713

155

304

1843

230/44 (PAK 10/23/04)

CD4 Post-Tx

692

CD4 Pre-Tx

Tacrolimus toxicity by bx

Tacrolimus toxicity by bx

Complications

188

447

557

620

Duration of follow-up (days)

A24,31 B8, 65 DR 1,17

A2,3, B8,-, DR1,17

A30,36, B18,35, DR1,11

A2,3, B8,27, DR16,17

HLA

a

The mean follow-up of this group is 453 ± 191 days. Patient and graft survival are 100%. HIV viral loads have remained undetectable. CD4 counts are recovering. No opportunistic infections were noted. No episodes of graft rejection have been observed. Two patients developed tacrolimus toxicity. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; DM, diabetes mellitus; HTN, hypertension; HLA, human leukocyte antigen.

Age

FK506 level (mg/dL)

Living Related Donor HIV+ Renal Transplant Recipientsa

Recipient

TABLE 2

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Characteristics of Donors Undergoing LLDN for Transplantation into HIV+ Recipientsa

Donor

Age

Sex

Race

Kidney donated

Cr prior to LLDN

Cr postLLDN

Days hospitalized

Complications

HLA

1 2 3 4

46 32 56 29

M F F F

C AA C C

Left Left Left Left

1.0 0.7 0.6 0.7

1.4 1.1 0.9 0.9

3 2 3 4

None None None None

A3,24, B8,35, DR16,11 A1,74, B58,72, DR8,11 A2,-, B35,60, DR1,7 A2,31, B14,44, DR1,14

The mean post-op creatinine of this group of patients was 1.1 ± 0.2 mg/dL. The mean length of hospitalization was 3 ± 0.8 days. No donor morbidity or mortality was observed. Abbreviations: ACR, acute cellular rejection; DM, diabetes mellitus; HTN, hypertension; HIVAN, HIV associated nephropathy; LLDN, laparoscopic live donor nephrectomy; PKD, polycystic kidney disease. a

Taken together, these trials demonstrate that renal transplantation is feasible in patients with HIV and that good early outcomes can be achieved. Living donor renal transplantation under alemtuzumab induction followed by steroid-free low-dose tacrolimus monotherapy has provided particularly promising early results. However, it is clear that further studies are required to determine the optimal management of these patients regarding to immunosuppression (including both induction and maintenance therapy), antiviral therapy, and antimicrobial prophylaxis. The paradoxically high rate of rejection in this group of patients in some series also merits further investigation. IMMUNOSUPPRESSION The management of immunosuppression in HIV+ renal transplant recipients represents a unique challenge, as an unexpectedly high rejection rate in patients with HIV has been observed in several series. Pharmacologic interactions between antiviral drugs used to treat HIV and commonly used immunosuppressive agents must also be taken into account. Interestingly, some agents that are commonly used in transplant recipients have been found to have inhibitory effects on HIV propagation. The ideal strategy for immunosuppression in HIV+ recipients of renal transplants has yet to be determined. On a molecular level, interaction between the viral protein Gag and cyclophilin A is thought to be required for HIV-1 replication. Cyclosporine has been shown to inhibit HIV-1 replication by disrupting the interaction between Gag and cyclophilin A (26,27). Accordingly, in one retrospective review performed in the pre-HAART era, cyclosporine appeared to slow the progression to AIDS in transplant recipients who were on immunosuppressive regimens that included cyclosporine when compared with recipients whose regimen did not include cyclosporine (14). In more recent trials, where patients with primary HIV infection were treated with cyclosporine and HAART, the addition of cyclosporine to HAART for an eight-week period had a durable and beneficial effect on CD4 counts and T-cell profiles (28). However, in one placebo-controlled clinical trail designed to assess the use of cyclosporine in HIV infection, no beneficial effects were observed, and patients who received cyclosporine had a small but significant rise in plasma HIV RNA levels, indicating that these findings must be interpreted cautiously (29). Significant drug interactions between cyclosporine and antiretroviral drugs exist. Frasseto and colleagues examined pharmacokinetic parameters in patients on cyclosporine who were receiving HAART (30). Patients who were taking a protease inhibitor had a threefold increase in cyclosporine area under the curve, and thus required an 85% reduction in cyclosporine doses in these patients. In contrast, NNRTI demonstrated only minimal interactions with cyclosporine. Like cyclosporine, tacrolimus undergoes metabolism by the cytochrome P4503A system. PIs have a profound effect on drug metabolism, and up to 50-fold reductions in tacrolimus dosing have been observed (31). NRTI and NNRTI produce less dramatic alterations in tacrolimus metabolism. While it has not been as extensively studied as cyclosporine, there are also some data suggesting that tacrolimus interferes with HIV production and inhibits the growth of HIV-infected cells in a selective manner (32).

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There is mounting evidence that MMF might have inhibitory effects on HIV replication, in addition to its immunosuppressive properties. In vitro studies suggest that mycophenolic acid synergistically enhances the activity of abacavir and didanosine against both wild type HIV-1 and a nucleoside reverse transcriptase resistant isolate of HIV-1 (33). In the same study, mycophenolic acid also enhanced the antiviral activity of tenofovir in an additive manner. In another study, mycophenolic acid was demonstrated to induce apoptosis of activated CD4+ lymphocytes, suggesting that it also inhibited HIV propagation by depleting the pool of activated CD4+ T-lymphocytes (34). When MMF was given to HIV+ patients, the number of dividing CD4+ cells was reduced, and inhibition of virus isolation from CD4+ lymphocyte populations was observed (34). In one small series involving five HIV+ patients failing maximal therapy, MMF was added to the antiviral regimen (35). Some decrease in viral load was observed in four of the five patients. The declines in viral load were lost in two of the patients at six and eight weeks. CD4 counts did not change significantly at 60 weeks follow-up. However, in a recent small randomized trial, the addition of MMF to a HAART regimen failed to increase significantly the plasma HIV-1 RNA decay rate or the decay rate of latent viral infected cells (36). There is also evidence suggesting that sirolimus may antagonize HIV propagation. CD4+ T-lymphocytes and macrophages express a chemokine coreceptor known as CCR5, which is required for propagation of R5 strains of HIV. Sirolimus interferes with CCR5 expression at the transcriptional level and thereby inhibits HIV replication (37). This inhibitory effect occurs at concentrations well below those used for immunosuppression in renal transplantation. Other reports have demonstrated that sirolimus directly inhibits viral replication by preventing HIV-1 gene transcription (38). Case reports have suggested that PIs also increase significantly sirolimus levels, indicating that cautious monitoring must also be employed when this drug is used in patients on a protease inhibitor (39).

SUMMARY There are over 40 million people infected with HIV worldwide, and ESRD in this patient population is becoming an increasingly common clinical problem. The widespread use of HAART has decreased the morbidity and mortality associated with HIV, allowing for new trials of renal transplantation in these patients. However, the use of scarce deceased donor organs for patients with HIV and ESRD remains controversial. Preliminary results from several centers have demonstrated encouraging early outcomes. LLDN has been employed as a safe and effective means of providing organs for patients with HIV without depleting the pool of scarce deceased donor organs. Rejection rates have been unexpectedly high under some immunosuppressive protocols. While long-term follow-up data are needed, the use of preconditioning therapy with alemtuzumab followed by steroid-free low dose tacrolimus monotherapy appears to prevent rejection without causing an increased risk of infectious complications. Future studies will be required to optimize the immunosuppressive and antiviral regimens for these patients and to explore the mechanisms underlying the unexpectedly high rate of rejection in these patients.

REFERENCES 1. Centers for Disease Control and Prevention. Pneumocystis pneumonia—Los Angeles. Morb Mortal Wkly Rep 1981; 30:250. 2. Centers for Disease Control and Prevention. Kaposi’s sarcoma and Pneumocystis Pneumonia among homosexual men—New York City and California. Morb Mortal Wkly Rep 1981; 30:250. 3. Centers for Disease Control and Prevention. A cluster of Kaposi’s sarcoma and Pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange Counties, California. Morb Mortal Wkly Rep 1982; 31:305–307. 4. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983; 220(4599):868–871. 5. Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984; 224(4648):500–503.

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6. http://www.unaids.org/en/resources/epidemiology/epicore.asp, (accessed June, 2005). 7. U.S. Renal Data System. USRDS 2003 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2003. 8. Lucas GM, Eustace JA, Sozio S, et al. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS 2004; 18(3):541–546. 9. Ahuja TS, Grady J, Khan S. Changing trends in the survival of dialysis patients with human immunodeficiency virus in the United States. J Am Soc Nephrol 2002; 13(7):1889–1893. 10. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338(13):853–860. 11. Detels R, Tarwater P, Phair JP, Margolick J, Riddler SA, Munoz A. Multicenter AIDS Cohort Study. Effectiveness of potent antiretroviral therapies on the incidence of opportunistic infections before and after AIDS diagnosis. AIDS 2001; 15:347–355. 12. Quarto M, Germinario C, Fontana A, Barbuti S. HIV transmission through kidney transplantation from a living related donor. N Engl J Med 1989; 320(26):1754. 13. Tzakis AG, Cooper MH, Dummer JS, et al. Transplantation in HIV+ patients. Transplantation 1990; 49:354–358. 14. Erice A, Rhame FS, Heussner RC, et al. Human immunodeficiency virus infection in patients with solid-organ transplants: report of five cases and review. Rev Infect Dis 1991; 13:537–547. 15. Schwarz A, Offermann G, Keller F, et al. The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation—data on four cases and review of the literature. Transplantation 1993; 55:95–103. 16. Swanson SJ, Kirk AD, Ko CW, et al. Impact of HIV seropositivity on graft and patient survival after deceased donor renal transplantation in the United States in the pre-highly active antiretroviral therapy (HAART) era: an historical cohort analysis of the United States Renal Data System. Transpl Infect Dis 2002; 4:144–147. 17. Stock PG, Roland ME, Carlson L, et al. Kidney and liver transplantation in human immunodeficiency virus-infected patients: a pilot safety and efficacy study. Transplantation 2003; 76:370–375. 18. Hirose K, Baxter-Lowe LA, Carlson L, et al. Unexpectedly high rejection rates in HIV-positive recipients of renal transplants. Am J Transplant 2004; 4(8):290. 19. Tan HP, Orloff M, Marcos A, Mieles L, Kavoussi LR, Ratner LE. Laparoscopic live donor nephrectomy. Graft 2002; 5:404–415. 20. Shapiro R, Jordan ML, Basu A, et al. Kidney transplantation under a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning. Ann Surg 2003; 238:520–525. 21. Shapiro R, Basu A, Tan H, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with thymoglobulin or Campath. J Am Coll Surg 2005; 200(4): 505–515. 22. Tan HP, Kaczorowski DJ, Basu A, et al. Steroid-free tacrolimus monotherapy following pretransplant thymoglobulin or campath and laparoscopy in living donor renal transplantation. Transpl Proc 2005; 37:4235–4240. 23. Tan HP, Kaczorowski DJ, Basu, et al. Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience. Transplantation 2004; 78(11):1683–1688. 24. Tan HP, Kaczorowski DJ, Basu, et al. Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience (abstract). Am J Transplant 2005; 5(suppl 11):386. 25. Kumar MS, Sierka DR, Damask AM, et al. Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients. Kidney Int 2005; 67(4):1622–1629. 26. Franke EK, Luban J. Inhibition of HIV-1 replication by cyclosporine A or related compounds correlates with the ability to disrupt the Gag-cyclophilin A interaction. Virology 1996; 222(1):279–282. 27. Bukovsky AA, Weimann A, Accola MA, Gottlinger HG. Transfer of the HIV-1 cyclophilin-binding site to simian immunodeficiency virus from Macaca mulatta can confer both cyclosporin sensitivity and cyclosporin dependence. Proc Natl Acad Sci USA 1997; 94:10943–10948. 28. Rizzardi GP, Harari A, Capiluppi B, et al. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest 2002; 109(5):681–688. 29. Calabrese LH, Lederman MM, Spritzler J, et al. Placebo-controlled trial of cyclosporin-A in HIV-1 disease: implications for solid organ transplantation. J Acquir Immune Defic Syndr 2002; 29(4): 356–362. 30. Frassetto L, Baluom M, Jacobsen W, et al. Cyclosporine pharmacokinetics and dosing modifications in human immunodeficiency virus-infected liver and kidney transplant recipients. Transplantation 2005; 80(1):13–17. 31. Jain AK, Venkataramanan R, Shapiro R, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl 2002; 8(9):841–845.

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32. Karpas A, Lowdell M, Jacobson SK, Hill F. Inhibition of human immunodeficiency virus and growth of infected T-cells by the immunosuppressive drugs cyclosporin A and FK 506. Proc Natl Acad Sci USA 1992; 89(17):8351–8355. 33. Hossain MM, Coull JJ, Drusano GL, Margolis DM. Dose proportional inhibition of HIV-1 replication by mycophenolic acid and synergistic inhibition in combination with abacavir, didanosine, and tenofovir. Antiviral Res 2002; 55(1):41–52. 34. Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2002; 31(1):45–49. 35. Chapuis AG, Paolo Rizzardi G, D’Agostino C, et al. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med 2000; 6(7):762–768. 36. Sankatsing SU, Jurriaans S, van Swieten P, et al. Highly active antiretroviral therapy with or without mycophenolate mofetil in treatment-naive HIV-1 patients. AIDS 2004; 18(14):1925–1931. 37. Heredia A, Amoroso A, Davis C, et al. Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1. Proc Natl Acad Sci USA 2003; 100(18):10411–10416. 38. Roy J, Paquette JS, Fortin JF, Tremblay MJ. The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother 2002; 46(11):3447–3455. 39. Jain AK, Venkataramanan R, Fridell JA, et al. Nelfinavir, a protease inhibitor, increases sirolimus levels in a liver transplantation patient: a case report. Liver Transpl 2002; 8(9):838–840.

13

Pediatric Living-Donor Kidney Transplantation Vivek Sharma and Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Demetrius Ellis Division of Pediatric Nephrology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION The main goals of renal transplantation in children with end-stage renal disease (ESRD) are to improve long-term patient and graft survival, quality of life, and optimize growth and development. Currently 52% of all children in North America undergoing renal transplantation receive a kidney from a live donor [North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)] (1), and children under five years of age are more likely to receive living donor kidneys. The use of live donors can optimize the timing of transplantation and reduce the rate of delayed graft function and acute tubular necrosis. The improvement in allograft survival has been seen especially in children less than five years of age receiving living donor kidneys. Over time, graft and patient survival have improved with the introduction of new immunosuppressive drugs and regimens. Systematic audits, reviews, and large collaborative database efforts, such as the NAPRTCS, launched in 1987, have increased our understanding of the impact of various immunosuppressive strategies and regimens on graft and patient survival. More recent strategies have aimed to reduce complications associated with steroid use and heavier immunosuppression by the use of regimens that avoid or eliminate corticosteroids and minimize the use of calcineurin inhibitors. HISTORICAL BACKGROUND The success of kidney transplantation in pediatric patients has lagged behind that seen in adults. Until recently, renal transplantation in pediatric patients was systematically provided in only a few centers (2–5). In the early days of renal transplantation, several ethical and medical issues troubled transplant surgeons caring for pediatric patients, including the risk to live donors, effects on family dynamics, the health of well siblings, and scepticism about long-term prognosis (6). These issues have been largely addressed over the years with a greater understanding of the immune response in the pediatric population and the evolution of immunosuppressive strategies, along with technical refinements of both the recipient and the donor operations. PRE-EMPTIVE TRANSPLANTATION Transplantation is the preferred choice for long-term therapy in children with ESRD. If it is possible to avoid dialysis by transplanting children pre-emptively, the results are even better (7,8). Pre-emptive transplantation is generally performed when it is likely that dialysis will be required within six months. There are data in both adults and children suggesting improved outcomes after pre-emptive transplantation compared with transplantation after a period of

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dialysis (9). Dialysis is associated with substantial morbidity, including a higher incidence of seizures, interdialytic weight gain contributing to hypertension, and cardiovascular complications—cardiomyopathy, congestive heart failure, and pericarditis. It is also disruptive of the child’s school schedules and social development. Hemodialysis has, in addition, the problem of access surgery and local complications. Although less restrictive, peritoneal dialysis is associated with its own problems, particularly peritonitis. There are certain situations, however, that necessitate a period of dialysis prior to transplantation. Children requiring native nephrectomies for congenital nephritic syndrome, Dennis-Drash syndrome, Wilms’ tumor, polycystic kidney disease, uncontrolled hypertension, and possibly intractable proteinuria with a low glomerular filtration rate may have to undergo dialysis for a period of time. To facilitate living-donor renal transplantation (LDRT), a period of waiting may be unavoidable if the donor needs to be assessed or reduce body weight, and so on, and this may also necessitate interim dialysis. The patient’s initial presentation may be with acute renal failure or previously unsuspected ESRD requiring dialysis, or there may be issues with compliance that need to be targeted, as noncompliance is still a major cause of rejection and graft failure in children and adolescents (10,11). In practice, pre-emptive transplantation is performed in almost 25% of children with primary transplants and should be considered the preferred therapy if dialysis is not otherwise mandated. ADVANTAGES OF LIVING-DONOR RENAL TRANSPLANTATION Reduced Waiting Times A reduced waiting period for a living-donor organ may decrease the risk of decompensation or death before transplantation. Furthermore, every transplantation with a kidney obtained from a living donor potentially frees up a deceased donor kidney for transplantation into another recipient. In addition, the living donor recipient does not have to wait on dialysis and may even circumvent dialysis if the transplant is performed pre-emptively. Delay in transplantation disproportionately impairs growth and development in younger children who typically have the lowest z-scores for growth prior to transplantation. Optimizing Recipient and Donor Conditions With a living donor, the transplant can obviously be planned electively. The recipient’s medical condition can be optimized, with the assurance of adequate dialysis, the absence of anemia or infection, and as good a metabolic profile as can be achieved on dialysis. In addition, the time pressures associated with logistics of deceased donation and prolonged preservation times are eliminated. The pretransplant donor evaluation allows a thorough preoperative work-up to establish the safety of donation and vascular imaging to prevent anatomic surprises. ETHICAL CONSIDERATIONS Donor Risks The Hippocratic principle of primum non-nocere is of primary importance in the evaluation of the potential living donor. As a first step, therefore, the donor must be informed about the risks of donor surgery and the other possible recipient options (i.e., deceased donor transplantation and dialysis). A number of studies have addressed outcomes after living kidney donation, and an operative mortality of 0.03% has been published in multiple analyses (12). Overall complication rates have been 8.2% to 17%, with major complications between 0.2% and 2.5% (13). The average donor quality of life has been better than that of the general U.S. population, and only 4% were dissatisfied and regretted their decision to donate a kidney (13). Long-term follow-up for up to two to three decades has demonstrated the safety of this procedure in the donors, with better donor survival and no increase in the incidence of renal dysfunction compared with the general population. Adoption of laparoscopic donor nephrectomy has reduced the morbidities associated with a large surgical wound and, at the same time, has reduced the time to recovery after donation.

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The success of the LDRT produces a substantive benefit for the recipient, and most religions and many cultures now see kidney donation as an act of genuine altruism and, therefore, intrinsically good, rather than an unwarranted assault on the donor’s bodily integrity. Relative Benefit Given the preceding discussion, it seems clear that the minimal risk to the donor is acceptable if the benefit to the recipient is substantial. It is less clear in the circumstance of the child with a second life-threatening disease (e.g., progressive cardiomyopathy, or the child with multiple anomalies) or organ failure (e.g., ventilator dependence). It is therefore important to consider each case individually. Donor Age Donor age may be a significant factor, in the case of older donors. The older donor (e.g., a grandparent) may present greater risks surgically, and the transplanted kidney may have renal vascular disease superimposed on the aging process. It is the biological age that is the key here, and additional evaluation of the donor may be needed to clarify the renal function. Using the young child as a donor, even if the prospective donor is an identical twin, is never indicated. Teenage donors under the age of 18 are also not generally accepted. In exceptional circumstances, a court order can be obtained to allow donation to go forward, and assistance from a psychologist may be invaluable in assessing the donor’s competence. Donor Autonomy The most difficult situations arise when a donor insists on donation, but the risks to the donor are perceived to be too high. This may arise when donors have other medical conditions that may dramatically increase their surgical risks (i.e., ischemic heart disease and morbid obesity). There are also situations where a healthy donor may insist on donating to a child with multiple comorbidities. In these circumstances, an ethics consultation may be helpful. DONOR EVALUATION AND SURGERY The donor assessment has been described in detail in Chapters 3 and 4 (Mc Cauley et al. and Unruh et al.). In brief, all patients have a thorough medical history and physical examination. All data are evaluated and approved by a multidisciplinary committee consisting of transplant surgeons, nephrologists, psychologists/psychiatrists, social workers, nurse coordinators, fiscal coordinators, and consultants (including urologists, cardiologists, gastroenterologists, pulmonologists, hepatologists, anesthesiologists, transplant infectious disease specialists, nutritionists, and so on). The evaluation by helical/spiral CT-angiography and 3-D reconstruction precedes the final selection of side (right or left) and the decision to proceed. Our policy is to try for left laparoscopic donor nephrectomy as the primary donor option (as the left renal vein is longer than the right). From 2003 to 2005, we have performed 23 living donor transplants for pediatric recipients. TECHNICAL CONSIDERATIONS The technique of transplantation in older children and adolescents is similar to that in adults (14). The main deviation from the common adult technique is that the vascular anastomoses are more cephalad. The comments in this section focus on the surgical techniques in infants and small children. Forty percent (9/23) of our recipients between 2003 and 2005 were less than five years old at the time of transplantation, the youngest being 16 months old. It is our policy to have the same multidisciplinary team of surgeons, nephrologists, anesthesiologists, intensivists, nutritionists, transplant infectious disease specialists, pathologists, and clinical pharmacologists looking after the patient. While a recipient weight of 10 kg or more is preferable, it is not mandatory. Developmental delay frequently occurs with a moderate degree of renal failure. Ideally the transplant is done when dialysis is imminent but before it is instituted. Thus, in younger children, plateauing of

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growth, despite adequate nutrition, is often a better indication for renal transplantation than the absolute serum creatinine level. Native Nephrectomy Uncommonly, there may be an indication for recipient native nephrectomy as part of the preparation for the LDRT. Children with significant nephrotic syndrome or recurrent pyelonephritis may require a nephrectomy at least six weeks prior to transplantation, allowing those with nephrotic syndrome a period to correct the low albumin level and minimize the risk of coagulopathy (this may not always be necessary or may be performed at the time of transplantation). If massive reflux is observed on the voiding cystourethrogram and the kidneys are small, with large native ureters, the ureters may need to be removed with the native kidneys (this may be done at the time of the transplant). Some children have had previous urologic procedures or have significant urological problems impacting on adequate drainage of the transplanted ureter. It is essential to plan an adequate drainage procedure in conjunction with the pediatric urologist. Infants and small children (especially <20 kg) with reflux nephropathy, polycystic kidneys, or dysplasia with hypertension may undergo nephrectomy at the time of transplantation, as these patients will require a midline approach. In the older child, it may (or may not) be advantageous to perform the unilateral native nephrectomy prior to transplantation as the recipient procedure is essentially extraperitoneal. In general, only a small minority of children requires native nephrectomy. Dialysis Access It is easier (more convenient) to insert a central venous catheter or a Tenckhoff at the time of native nephrectomy if this is indicated pretransplantation. This may be used for short-term dialysis. The decision for those undergoing long-term dialysis pretransplantation and the choice between peritoneal and hemodialysis is made by the nephrologists in conjunction with the patient/family’s needs and the local program’s capabilities. Preoperative Considerations A final negative crossmatch with the living donor is confirmed, and dialysis is performed (if indicated) prior to transplantation. The recipient is admitted the day prior to transplantation to ensure that there is no active infection (this is particularly important for patients on peritoneal dialysis), aspects of informed consent are reviewed with the patient and family, the fluid-electrolyte status is checked, and a final plan is prepared with the nephrologist, intensivist, anesthesiologist, surgeon, and urologist (if necessary). Operative Procedure The recipient procedure is carried out in a specialized children’s hospital. The recipient is taken into the operating room soon after the donor is placed under general anesthesia. If not already present, a central venous line is placed along with an arterial line in the recipient. The recipient is placed in the supine position, on a warming blanket. The arms are usually out and the patient is catheterized and the bladder emptied. The bladder is then filled with an antibiotic solution, and the catheter connected to a drainage bag and clamped; the clamp is accessible to the circulating nurse under the sterile drapes. Plastic drapes are placed to exclude the sides and perineum from the field, and bear-hugger air warming blankets are placed to keep the child warm. The operating room temperature is maintained at 32°C and all prep solutions and fluids are warmed. The recipient’s body temperature is monitored to prevent hypothermia. It is important that the central venous pressure (CVP) and blood pressure be adequate (systolic blood pressure of 120–130 mmHg) when the kidney is revascularized. We use a combination of crystalloid, colloid, and blood transfusions (if necessary) to maintain a high CVP, with volume expansion to maintain an optimum blood pressure. Renal dose dopamine may be initiated, but larger doses of dopamine or other pressors are generally avoided. Intravenous heparin may be necessary if there is a predisposing hypercoagulable state or arterial reconstruction with small vessels that may predispose to thrombosis. All patients receive baby aspirin after transplantation.

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In infants and small children weighing <20 kg, the transplant is performed through a midline incision. The cecum and right colon are mobilized along with the peritoneum tethering the terminal ileum. This exposes the lower vena cava, the aorta, and the iliac vessels. If synchronous native nephrectomies are indicated, they are performed first. The aorta (from just below the inferior mesenteric artery) and right common iliac artery are carefully isolated. The lumbar vessels are ligated or clipped, if necessary (usually, this is not necessary). The inferior vena cava is likewise mobilized from above its origin for 2 to 3 cm to the right common iliac vein; sometimes, the left common iliac vein needs to be mobilized also. The lumbar tributaries are carefully divided between ligatures, if necessary (again, this is not usually necessary). The field is filled with warm soaked laparotomy pads, and the donor kidney is prepared. The recipient team takes over the preparation of the donor kidney once it is removed by the donor surgeon, who helps with the identification and confirmation of anatomy on the backtable. The kidney is flushed with cold lactated Ringer’s solution (containing 100 mg procaine and 10,000 units of heparin per liter), and cooled over ice. Back-table preparation of the kidney requires further careful removal of the perinephric fat and preparation of the artery and vein. If necessary, extension grafts from ABO compatible deceased donor iliac grafts are used, and any accessory vessels reconstructed using microvascular techniques. Placement of the anastomoses is determined by the lie of the kidney, and often the venous anastomosis (performed first) will extend from the cava into the upper right common iliac vein, and the arterial anastomosis will start on the aorta below the inferior mesenteric artery take-off. The anastomoses are staggered—the arterial above the venous—to make it technically easier. A standard four-suture vascular technique with 6/0 or 7/0 polypropylene is used to prevent inadvertent suture of the posterior wall. During the vascular anastomoses, the kidney is cooled topically with liberal amounts of cold saline. It is important to flush the inside of the vessels to prevent any debris or clot from embolizing, prior to completing the anastomoses. Intravenous furosemide, 1 mg/kg, and mannitol, 1 g/kg, are administered while the vessels are being anastomosed. Once the anastomoses are completed, the venous clamps followed by the distal and proximal arterial clamps are released. The kidney is warmed with saline. The large adult kidney will require recipient over-hydration prior to unclamping. Constant communication with the anesthesiologist is essential. Hemostasis is ensured as quickly as possible. Attention is then given to ureteral implantation. Retraction is redirected to expose the bladder, and the kidney is placed in a comfortable position. An appropriate length of ureter that is not redundant yet will comfortably reach the bladder without tension is utilized. The distal mesentery of the ureter is ligated with an absorbable ligature and divided at the point of transection. The end is spatulated and heel and toe sutures are placed, to facilitate the feeding of an appropriately sized double J ureteral silastic stent into the renal pelvis. The extraperitoneal fat over the bladder is divided and the bladder mucosa is exposed for 2 to 3 cm on its dome to the right side. The ureteroneocystostomy is performed over a double J ureteral stent with 6/0 PDS or Maxon continuous sutures tying the sutures at the heel and the toe to prevent a purse string effect. This ensures mucosa-to-mucosa approximation in a water-tight fashion. At this point, the urethral catheter is unclamped, and the urine output is recorded. A second layer of interrupted polydioxanone (PDS) sutures may be used to create a tunnel to decrease the incidence of reflux (this depends on surgeon preference). The key is to perform a large ureteral anastomosis with a well-vascurlarized ureter to prevent strictures. A decision to place a drain is then made. The incidence of delayed graft function in our pediatric LDRT is 0%, so that if the kidney allograft is functioning well one usually elects to remove the peritoneal dialysis catheter, if present, before closing the wound in layers. The skin is then closed with an absorbable subcuticular suture. Postoperative Care Immediate postoperative care is usually in the pediatric intensive care or intermediate care unit for the infants and younger child. Strict hourly intake and output are monitored and replacement is tailored to maintain adequate filling pressures monitoring the CVP and arterial blood pressures. The composition and volume of solution is adjusted to results of serum electrolytes and urine output. Generally, a D1W0.45% N.S. with NaHCO3 10 mEq/L is used as mL for mL replacement of urine output. Calcium loss is also replaced intravenously if necessary.

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Oliguria is rare in LDRT, but, if present, should be investigated in a systematic fashion: 1. Exclude catheter blockage. 2. Duplex ultrasound of the transplant with Doppler to confirm vascular patency, hematomas/collections compressing the graft, and pelvic dilatation. If the suspicion for a vascular thrombus or bleeding is high, emergent exploration should be performed without waiting for the ultrasound. 3. A Technetium MAG3 nuclear medicine scan can be used to assess urinary leak (this is uncommonly indicated). Fluid status is continually reassessed and, if necessary, a bolus is given to titrate to an adequate filling pressure without overloading the child. Judicious use of furosemide 1mg/kg IV may also be necessary. In the rare case of fluid overload not responding to diuretics, a period of dialysis may be required. Ileus is commonly seen after intra-abdominal transplantation and may take up to three to five days to recover. Nasogastric tube decompression is often required. A period of tube feeding or total parenteral nutrition (TPN) may be necessary if prolonged ileus is anticipated. Hypertension is another important problem in the postoperative period and will require careful management. Calcium channel blockers, clonidine, intravenous labetalol or hydralazine, and, rarely, intravenous nitroprusside may be required. IMMUNOSUPPRESSION Long-term allograft survival under current immunosuppressive regimens is plagued by the development of chronic allograft nephropathy (CAN). Two major contributors to CAN are acute rejection and chronic nephrotoxicity associated with calcineurin inhibitors. To address some of these important issues, a somewhat different approach to immunosuppression following the principles of recipient preconditioning and minimal post-transplant immunosuppression was started in May 2003, at the Children’s Hospital of Pittsburgh. Results in adult kidney recipients had suggested that excellent outcomes in unselected patients were achievable (15–19). Once it became apparent that this approach had a number of advantages, we began to utilize it in our pediatric kidney recipients. The initial results and the early outcomes observed in this group of patients suggest that it is an excellent and attractive approach to post-transplant immunosuppression. Between May 2003 and July 2004, 17 pediatric kidney alone transplantations utilizing this regimen were performed at the Starzl Transplantation Institute and Children’s Hospital of Pittsburgh (STI CHP) (Table 1). The mean recipient age was 9.5 ± 6.6 years (range 1–18). Fifteen (88%) were undergoing their first transplant, and two (12%) were undergoing their second. The mean donor age was 36.2 ± 9.0 years (range 18–53), 14 (82%) were living donors, and three (18%) were deceased donors. The mean cold ischemia time for the deceased donor cases was 23.4 ± 9.3 hours (range 16.8–34.0). The mean human leukocyte antigen (HLA) mismatch was 2.6 ± 1.2. Preconditioning was with 5 mg/kg Thymoglobulin (rabbit antithymocyte globulin) (n = 8) (15–17,19–21), or 0.4–0.5 mg/kg alemtuzumab (Campath-1H) (n = 9) (17–19,22–27). TABLE 1

Recipient and Donor Demographics

Recipients n Age Range First transplant Second transplant Donors Age Range Living Deceased

17 9.5 ± 6.6 1–18 15 (88%) 2 (12%) 36.2 ± 9.0 18–53 14 (82%) 3 (18%)

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Two doses of intravenous methylprednisolone (10–15 mg/kg) were given: prior to antibody preconditioning and during the arterial anastomosis, to prevent cytokine release. Tacrolimus monotherapy was started on postoperative day 1, with target levels of 10 mg/mL. Approximately four to six months after transplantation, the twice-daily tacrolimus dosage was consolidated to once-daily dosing. About four to six months later, spaced weaning to every other day tacrolimus was instituted on an individualized basis. More recently, class I and II enzyme-linked immunosorbent assay (ELISA) antibody studies have been utilized to permit spaced weaning and have been studied serially to monitor weaning. Routine trimethotrim-sulfamethoxazole, nystatin, and antiviral prophylaxis with oral valganciclovir for at least six months were utilized in all patients. Twelve-month prophylaxis was utilized in cases where the donor was EBV seropositive and the recipient was EBV seronegative; these cases also received one dose of cytomegalovirus (CMV) immune globulin 100 mg/kg on postoperative day 1. Serial monitoring of CMV antigenemia and Epstein-Barr virus (EBV) polymerase chain reaction (PCR) was also performed. The administration of thymoglobulin with tacrolimus monotherapy had been utilized as the standard immunosuppressive regimen for over two years at STI CHP for the pediatric liver and intestinal recipients (28), when it began to be utilized in the pediatric kidney recipients. Alemtuzumab was not on the formulary at the CHP, and its utilization was declared to represent Innovative Clinical Therapy by the CHP Pharmacy and Therapeutic Committee. Thus, parents were asked to sign a separate informed consent prior to the administration of Campath-1H (until early 2006). Data analysis utilized a computerized, anonymized database whose managers fulfilled the institutional requirements of being an “honest broker,” and was covered by an Institutional Review Board (IRB)-approved protocol. The mean follow-up was 22 ± 4.9 months. RESULTS The donor and recipient survival was 100% (Table 2). The graft survival was 94%; one Thymoglobulin preconditioned patient undergoing retransplantation lost her kidney to noncompliance 20.5 months after transplantation. The mean serum creatinine at most recent follow-up was 0.8 ± 0.34 mg/dL, and the calculated creatinine clearance was 96 ± 29 mL/1.73 m2. Two (25%) patients receiving Thymoglobulin preconditioning experienced mild biopsyproven acute rejection, and were treated with steroids. None of the Campath-1H preconditioned patients experienced acute rejection. There were no cases of steroid-resistant rejection. The incidence of delayed graft function was 0%. Neither tissue-invasive CMV disease nor post-transplant lymphoproliferative disorder (PTLD) virus were observed in any of the patients. Nine (53%) of the cases were with CMV TABLE 2 Results of 17 Pediatric Kidney Transplantation from May 2003 to July 2004 at Starzl Transplantation Follow-up Patient survival Graft survival Serum creatinine Calculated creatinine clearance Preweaning acute rejection Thymoglobulin Campath-1H Delayed graft function Cytomegalovirus Post-transplant lymphoproliferative disorder Polyoma (BK) virus Post-transplant diabetes mellitus Autoimmune hemolytic anemia Spaced weaning Thymoglobulin Campath-1H Post weaning acute rejection

15 ± 4.9 months 100% 94% 0.8 ± 0.34 mg/dL 96 ± 29 mL/min/1.73 m2 2 (25%) 0 0 0 0 0 2 2 5/7 (71%) 8/9 (89%) 0

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seropositive donors/CMV seronegative recipients, and 11 (65%) were with EBV seropositive donors/EBV seronegative recipients. Polyoma (BK) virus was also not observed in any of the patients. One patient receiving Campath-1H preconditioning developed post-transplant diabetes mellitus. This improved with spaced weaning to every other day tacrolimus, but had not been completely reversed at most recent follow-up. This patient had developed post-transplant diabetes after his first transplant as well. Another alemtuzumab patient, who is wheel chair-bound, became diabetic after developing morbid obesity. Two patients, one each receiving Thymoglobulin and Campath-1H preconditioning, developed autoimmune hemolytic anemia of uncertain etiology. Both were treated with a course of corticosteroids that was eventually tapered off completely. The Thymoglobulin preconditioned patient was converted first to every other day tacrolimus, then to cyclosporine, and, finally, to sirolimus, and remains on sirolimus monotherapy, with normal renal function. The Campath-1H preconditioned patient was converted to every other day tacrolimus, and remains on every other day tacrolimus monotherapy. The anemia resolved completely in both patients. At most recent follow-up, five (71%) of the seven Thymoglobulin preconditioned patients with functioning kidneys were on spaced-dose tacrolimus monotherapy (four are on every other day, and one is on three times weekly tacrolimus). Spaced weaning was initiated a mean of 12.9 ± 4.5 months after transplantation. Eight (89%) of the nine Campath-1H preconditioned patients were on spaced-dose tacrolimus monotherapy (every other day in all cases); spaced weaning was initiated 9.2 ± 1.2 months after transplantation. No cases of postweaning rejection have been seen thus far. DISCUSSION The pediatric experience described here represents an extension of the much larger adult experience that has been previously described (15–19). While based on the same underlying immunosuppressive principles of recipient preconditioning and post-transplant minimal immunosuppression, it differs slightly. The overwhelming majority of the cases was with living donors, and, in most cases, were primary transplantations. Delayed graft function was not observed. Spaced weaning was initiated somewhat later in the pediatric patients than in the adult cases, and this was related to concerns about the development of postweaning rejection. The delay in weaning may explain the absence (thus far) of postweaning rejection observed in the pediatric patients. The incidence of preweaning acute rejection (25% in the Thymoglobulin preconditioned group and 0% in the alemtuzumab preconditioned group) paralleled the adult experience. At the present time, Campath-1H preconditioning is utilized exclusively in our pediatric kidney recipients. The immunosuppressive regimen was relatively straightforward and was well-tolerated. CMV and PTLD were not observed, in spite of the fact that 53% of the cases were high risk for CMV (seropositive donor/seronegative recipient) and 65% were high risk for EBV (seropositive donor/seronegative recipient). Prolonged antiviral prophylaxis with valganciclovir almost certainly played a helpful role here. There was one case of post-transplant diabetes mellitus (and an additional case most likely related to morbid obesity), and two cases of autoimmune hemolytic anemia of uncertain etiology, both of which resolved after a course of steroids and after conversion to sirolimus or spaced dosing of tacrolimus. While these complications are of obvious concern, the overall outcomes associated with this regimen were relatively favorable. The only other publication regarding the use of Campath-1H in pediatric renal transplantation is a report of four cases from the University of Wisconsin (27). These were high-risk patients; three of the four experienced acute rejection, and one had recurrent focal segmental glomerulosclerosis (FSGS), but all are alive with excellent kidney function. CONCLUSION Obviously, much more follow-up will be required to establish the long-term efficacy of this regimen. Thus far, however, the results to date are encouraging and suggest that this approach

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to immunosuppression in pediatric renal transplant recipients is efficacious, safe, and well-tolerated. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

https://web.emmes.com/study/ped/annlrept/annlrept2005.pdf (p2–3, p2–6), accessed 7/5/2006. Starzl TE. Experience in Renal Transplantation. Philadelphia, PA: WB Saunders Company, 1964. Williams GM, Lee HM, Hume DM. Renal transplants in children. Transplant Proc 1969; 1(1):262–266. Fine RN, Korsch BM, Stiles Q, et al. Renal homotransplantation in children. J Pediatr 1970; 76(3): 347–357. Najarian JS, Simmons RL, Tallent MB, Kiellstrand CM, Buselmeier TJ, Vernier RL, et al. Renal transplantation in infants children. Ann Surg 1971; 174(4):583–601. Riley CM. Thoughts about kidney homotransplantations in children. J Pediatr 1964; 65:797. Migliori RJ, Simmons RL, Payne WD, et al. Renal transplantation done safely without prior chronic dialysis therapy. Transplantation 1987; 43(1):51–55. Flom LS, Reisman EM, Donovan JM, et al. Favorable experience with pre-emptive renal transplantation in children. Pediatr Nephrol 1992; 6(3):258–261. Gill JS, Tonelli M, Johnson N, Pereira BJG. Why do pre-emptive kidney transplant recipients have an allograft survival advantage? Transplantation 2004; 78(6):873–879. Cole BR. The psychosocial implications of pre-emptive transplantation. Pediatr Nephrol 1991; 5(1):158–161. Didlake RH, Dreyfus K, Kerman RH, Buren CTV, Kahan BD. Patient noncompliance: a major cause of late graft failure in cyclosporine-treated renal transplants. Transplant Proc 1988; 20(3 suppl 3):63–69. Najarian JS, Chavers BM, McHugh LE, Matas AJ. 20 years or more of follow-up of living kidney donors. Lancet 1992; 340(8823):807–810. Johnson EM, Najarian JS, Matas AJ. Living kidney donation: donor risks quality of life. Clin Transpl 1997; 231–240. Simmons RL, Najarian JS. Comprehensive Manuals of Surgical Specialities. In: Egdahl RH, ed. Springer-Verlag, 1984. Shapiro R, Jordan ML, Basu A, et al. Kidney transplantation under a tolerogenic regimen of recipient pretreatment low-dose postoperative immunosuppression with subsequent weaning. Ann Surg 2003; 238(4):520–525, discussion 525–527. Starzl TE, Murase N, Elmagd KA, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003; 361(9368):1502–1510. Shapiro R, Basu A, Tan H, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath. J Am Coll Surg 2005; 200(4):505–515. Tan HP, Kaczorowski DJ, Basu A, et al. Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning steroid-free tacrolimus monotherapy: a single center preliminary experience. Transplantation 2004; 78(11):1683–1688. Tan HP, Kaczorowski D, Basu A, et al. Steroid-free tacrolimus monotherapy after pretransplantation Thymoglobulin or Campath and laparoscopy in living donor renal transplantation. Transplant Proc 2005; 37(10):4235–4240. Préville X, Flacher M, LeMauff B, et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation 2001; 71(3):460–468. Mueller TF. Thymoglobulin: an immunologic overview. Curr Opin Organ Transplant 2003; 8(4): 305–312. Hale G, Waldmann H, Dyer M. Specificity of monoclonal antibody Campath-1. Bone Marrow Transplant 1988; 3(3):237–239. Calne R, Friend P, Moffatt S, et al. Prope tolerance, perioperative Campath 1H, low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 1998; 351(9117):1701–1702. Stuart FP, Leventhal JR, Kaufman DB. Alemtuzumab facilitates prednisone free immunosuppression in kidney transplant recipients with no early rejection. Am J Transplant 2002; 2(suppl 3):397. Knechtle SJ, Pirsch JD, Fechner JH, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003; 3(6):722–730. Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (Campath-1H). Transplantation 2003; 76(1):120–129. Bartosh SM, Knechtle SJ, Sollinger HW. Campath-1H use in pediatric renal transplantation. Am J Transplant 2005; 5(6):1569–1573. Bond GJ, Mazariegos GV, Sindhi R, Elmagd KMA, Reyes J. Evolutionary experience with immunosuppression in pediatric intestinal transplantation. J Pediatr Surg 2005; 40(1):274–279, discussion 279–280.

Part III

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LIVING-DONOR LIVER TRANSPLANTATION

Evaluation: Specific Issues Vladimir Bogin Internal Medicine, Longview, Washington, D.C., U.S.A.

Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Thomas Shaw-Stiffel Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Living-donor liver transplantation (LDLT) initially gained favor in the late 1980s in pediatric patients because of the shortage of livers from deceased donors (1,2). Since then, left hepatic lobe LDLT and left lateral segment LDLT have both become safe and effective alternatives to deceased donor liver transplantation (DDLT), with similar recipient morbidity and mortality (3). In fact, LDLT now accounts for about 30% of all liver transplantations performed in children in the United States (4). In adults, the need to find an alternative source for liver grafts was particularly acute in Japan, where cultural acceptance of DDLT has remained limited for years. As a result, the first right hepatic lobe adult-to-adult LDLT was performed in Japan in 1993 (5). By the late 1990s, despite various initiatives in the United States to increase the donation rate for DDLT, the number of adults on the liver-transplant waiting list surpassed the availability of deceased donor livers by almost five to one. Furthermore, at least 10% of patients awaiting a new liver continued to die while on the waiting list (4). Thus, many transplant centers across the United States considered starting their own adult LDLT programs in order to increase the organ pool. At the time, it was thought that within a few years, LDLT would become as common as DDLT (6). In fact, the annual number of LDLT cases in the United States rose rapidly from 86 in 1998 to over 500 in 2001 (almost 10% of all liver transplants performed that year) (4). However, after the widely publicized postoperative death of a liver donor at Mount Sinai Medical Center in New York City in January 2002 (7), the number of LDLT cases performed annually fell by almost 40%. By 2006, however, the numbers were steadily rising again. Nevertheless, only about 5% to 10% of all patients listed for liver transplantation are expected to undergo LDLT (4,6). This chapter focuses on the selection process for adult-to-adult LDLT, first in general, and then specifically for the recipient and the donor separately. For additional information, the reader is directed to Chapter 2 for psychosocial issues, Chapter 3 for other general aspects of the evaluation of living donors, and Chapter 19 for pediatric LDLT. RATIONALE One of the main advantages of LDLT (Table 1) is the reduced amount of time that a recipient needs to wait for a new liver, thereby ensuring a better outcome especially for those at significant risk of dying without a transplant in the short term. In a recent study, the median waiting

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Advantages and Disadvantages of Living-Donor Liver Transplantation

Pros Extensive workup to exclude other diseases in the donor (e.g., acute hepatitis C) Vascular and liver anatomy known well before transplant (e.g., congenital defects) Avoids organ procured from terminally ill patient with possible end-organ damage Reduced waiting time for transplant (e.g., hepatocellular carcinoma) Stabilization of medical condition (e.g., treat hepatitis B or C, clear infection) Reduced cold ischemia time Younger age of donor (in general)

Cons Small-for-size syndrome based on expected liver mass and/ or sicker recipient (see text) Biliary complications in 15–30% (see Chapters 17 and 18) Slightly higher risk of hepatic artery thrombosis (see Chapters 17 and 18) Donor mortality in 1:1000 to 1:2000 (see Chapter 16) Out-of-pocket expense to the donor (estimate at $3600 at one medical center, Trotter)

time for LDLT recipients was one-third of that for DDLT cases. However, there was no significant difference in recipient mortality between the two groups (8,9). The adult-to-adult LDLT (A2ALL) study sponsored by the National Institutes of Health (NIH) is currently addressing this issue, among others. Preliminary results (10) in 385 adult-to-adult LDLT recipients at nine centers across the United States showed that one-year recipient survival was 89%, with 9.6% requiring retransplantation. One-year graft survival was 81%, with 13.2% of grafts failing within the first 90 days. The most common causes of graft failure were vascular thrombosis, primary nonfunction, and sepsis. Biliary complications were common (30% early and 11% late). Older recipient age and cold ischemia time were significant predictors of graft failure. Centers that performed more than 20 LDLT operations per year had fewer graft failures and improved outcomes compared with those that performed less than 20 (10). Another key advantage with LDLT is the opportunity to treat, or at least control, viral hepatitis B or C infection prior to transplantation (in those who can tolerate the medication pretransplant). In a similar manner, bacteremia or sepsis can be cleared with appropriate antibiotic therapy prior to LDLT. The entire surgical team is also more rested since the surgery is planned electively for LDLT. One further potential benefit with LDLT is the short cold ischemia time (about one hour), since the organ is transported between adjacent operating rooms. Despite this, there has as yet been no major improvement in outcomes after LDLT, compared with those following DDLT (10–17). The main drawback with LDLT is the known donor morbidity and mortality (as discussed in Chapter 16) (Table 1). One major problem, the small-for-size syndrome, can usually be prevented by careful size-matching between the donor and the recipient (see later) (18–20). However, biliary complications can occur in up to 30% of living donor recipients because of potential biliary devascularization and the greater amount of liver exposed during transection (10–17,21). The risk of living donor death is obviously of great importance, given the fact that the donor does not need to undergo a major surgery to begin with. Fortunately, the number of reported deaths in living donors has been very low. As of mid-2006, the recorded donor mortality in the United States was two in about 1600, or less than 0.14%. In Japan, one death has been reported in over 2000 living donor operations, for a mortality rate of less than 0.05%. Regarding the long-term health risks to the donor, these are likely to prove insignificant, given that LDLT has been performed in Japan for well over 13 years, and no major health issues have yet been identified. The United Network for Organ Sharing (UNOS) in the United States recently initiated a database for outcomes following LDLT, which should help track donor morbidity and mortality rates more effectively. In terms of donor selection, most transplant centers that offer LDLT have developed their own multidisciplinary guidelines and protocols, which standardize donor selection (6,22). These are based on published practice guidelines including those of the “live organ consensus group” (23), the American Society of Transplant Surgeons (24), and the NIH conference on LDLT (25). Of note, emergency LDLT for acute liver failure is ideally best avoided, as the urgency of the situation can put undue stress on the donor, with more than the usual ethical, medical, logistical, and economic concerns (26).

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TABLE 2 Contraindications for Recipient Listing for Living-Donor Liver Transplantation Absolute Not a candidate for deceased donation Multisytem organ failure/severe and uncontrolled sepsis Irreversible brain damage Extrahepatic malignancy Advance cardiopulmonary disease Active substance abuse Medical noncompliance Relative HIV infection Primary hepatobiliary malignancy Adverse psychosocial factors Age >65 years Morbid obesity (body mass index >40)

RECIPIENT EVALUATION AND SELECTION Given the potential risks to the living donor (as discussed previously, as well as in Chapter 16), only recipients with a reasonably favorable post-transplant outcome should be considered for LDLT (9,27–31). Therefore, all potential LDLT recipients must first be listed for a DDLT according to UNOS criteria (Table 2). This not only ensures that the recipient is an appropriate candidate for liver transplantation, and thereby avoids the potential use of LDLT in patients with a futile outcome [(e.g., inoperable hepatocellular carcinoma (HCC)], but more importantly, should there be any life-threatening post-transplant complication(s), the recipient can be listed as a UNOS status one to obtain a whole liver and undergo a DDLT (see Chapter 17). Thus, before proceeding to work up any potential living donor, the recipient candidate should first be deemed suitable for the LDLT operation both medically as well as surgically (9,27–31). In terms of medical criteria, transplant urgency based on the modified end-stage liver disease (MELD) scores usually takes precedence (30). Most experts suggest that a MELD score of 18 is a reasonably good cut-off level above which LDLT is warranted. This is related to the fact that a patient with a MELD score of 18 or higher has a greater than 10% risk of dying within 90 days without a new liver, which is higher than the risk of dying at one year following LDLT (generally taken to be less than 10%) (31). On the other hand, recent data from the Scientific Registry for Transplant Recipients (SRTR) suggests that for patients with a MELD score below 17, the risk of transplant surgery outweighed the risk of death from liver disease (32). However, some of these patients with low MELD scores (usually those with cholestatic liver diseases such as primary biliary cirrhosis or primary sclerosing cholangitis) already have significant complications from their end-stage liver disease (e.g., severe pruritus, intractable ascites, infection, or hepatic encephalopathy), which prompt the liver transplant team to consider early LDLT transplantation. Furthermore, intervention with LDLT can help prevent life-threatening complications (e.g., cholangiocarcinoma in primary sclerosing cholangitis) that are known to develop in a significant proportion of patients during the natural history of the disease. Nevertheless, recipient welfare and donor safety must be kept carefully in the balance. This is the approach taken by most liver transplant centers in the United States, including our own, and recent UNOS data confirm that recipients of LDLT have a lower MELD score overall than do recipients of DDLT. Freeman and colleagues reported that the mean MELD was 23.5 for DDLT recipients compared with only 14.8 or those undergoing LDLT (33). A greater proportion of recipients with a MELD score less than 20 underwent LDLT (71%) versus DDLT (48%). A similar finding was seen at the University of Colorado Health Sciences Center (UCHSC), where the median MELD score for LDLT recipients was 15 compared with 23 for DDLT recipients. In addition, when the MELD score was less than 20, a greater proportion of recipients underwent LDLT (71%) than DDLT (48%) (8). An additional report by Sugawara and colleagues suggested that left-lobe grafts could be used safely in adult recipients as long as their MELD score was less than 15 (34).

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In contrast, some experts argue that a MELD score greater than 20 to 25 precludes LDLT as a viable option, since a whole allograft, rather than a partial liver, is required to ensure adequate post-transplant recovery and avoid the small-for-size syndrome. In one study that assessed outcomes in LDLT recipients who had more severe hepatic decompensation (former UNOS status 2A), the long-term mortality rate following LDLT was found to be three-fold higher than that after DDLT (57% versus 18%) (35). However, investigators at UCHSC looked at the predictive value of pretransplant MELD score in 62 of their LDLT recipients with more than six months of follow-up and found that there was no significant association between the MELD score and post-transplant survival, even when the MELD score was very elevated (i.e., greater than 30). Nevertheless, recipients with a MELD score greater than 18 spent twice as much time in the hospital during the first three months postoperatively compared with those with a MELD score of 18 or less. A poor outcome after LDLT was also predicted pretransplant by the need for mechanical ventilation or hemodialysis, and by a very low Karnofsky (functional) score, independent of the MELD score (8). As a result, the UCHSC group found that only about 25% of their potential LDLT recipients were medically suitable to undergo LDLT (9). Given these concerns, in its 2002 report, the New York State Health Department recommended that LDLT not be offered to patients with a MELD score greater than 25 (36). At the University of Pittsburgh Medical Center, Starzl Transplantation Institute (UPMC STI), we generally do not recommend LDLT for recipients with MELD scores under 10 (unless there are compelling reasons in patients with cholestatic liver diseases), nor for those with MELD scores above 25. More studies on this issue are clearly needed. Once deemed medically suitable, the recipient must also be deemed to be surgically appropriate to undergo LDLT. Absolute contraindications for LDLT are similar to those for DDLT (Table 2). Common relative contraindications in the recipient include morbid obesity, uncontrolled diabetes, HIV, adverse psychosocial factors, and advanced age. About 40% of recipients will have at least one psychiatric disorder (37). Budd-Chiari syndrome and portal vein thrombosis are not usually deemed to be absolute contraindications at the University of Pittsburgh Medical Center (UPMC). Overall, at some transplant centers, only about 50% of recipients who are found to be suitable medically will also end up being deemed surgically appropriate, so that only 10% to 15% of all recipients undergo LDLT (9). At the UPMC STI, however, this figure approaches 30%, possibly related to the fact that a larger number and wider spectrum of potential LDLT recipients are assessed. It is important to mention at this point that there have been concerns that the risk of recurrent hepatitis C virus (HCV) infection post-transplant might be higher in LDLT recipients than in DDLT recipients (38,39), related possibly to the effects of liver regeneration on viral replication and/or immunosuppressive drug levels (40). More recent studies have shown less concern, although controversy persists (41–43). Clearly more research is also needed in this area. There are two main groups of recipients best suited for LDLT. The first are patients with HCC who may benefit from an expeditious transplant via LDLT (see Chapter 20). However, these patients must first meet the Milan criteria (e.g., a single lesion less than 5 cm in diameter, or no more than three lesions, each of which must be less than 3 cm in maximum diameter). One study from Japan in 316 living donor recipients showed improved outcomes in such cases even when liver function was markedly impaired, or the HCC could not be controlled by conventional anti-tumor techniques. One- and three-year patient survival was 78% and 69%, respectively, and one- and three-year recurrence-free survival was 73% and 65%, respectively (44). The other major group includes patients with a low MELD score that does not truly reflect their illness burden, because of refractory and/or severe symptoms related to hepatic decompensation (e.g., recurrent cholangitis episodes in patients with PSC). Others in this group include patients with symptomatic benign hepatic masses (e.g., hemangioma, hemangioendothelioma, polycystic liver disease), or metabolic disorders (e.g., familial amyloidosis, hyperoxaluria, tyrosinemia, and glycogen storage disease). DONOR EVALUATION AND SELECTION The selection of a proper donor is guided by two key issues: (i) maximizing donor safety by minimizing morbidity, and avoiding mortality and (ii) identifying the optimal partial liver

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Evaluation Protocol for Potential Living Donors

Step 1 Clinical evaluation: history and physical exam. Body mass index. Informed consent (for testing and surgery) Laboratory: blood group, hematology; chem. 12; glucose tolerance testa; coagulation profile; protein C; antithrombin III; factor V, VII, and VIII; C-reactive protein; and thyroid function tests (TSH, T3, T4) Serology: hepatitis A, B (surface antigen, core antibody, surface antibody), and C Imaging studies: chest X-ray (PA and lateral) and abdominal ultrasound Step 2 Clinical evaluation: informed consent, and psychological evaluation Laboratory: HLA typing, cross match, alpha-1-antitrypsin, transferring, ferritin, ceruloplasmin, tumor markers (AFP, CEA), urinalysis, and pregnancy test Serology: CMV IgG and IgM, HSV, EBV IgG and IgM, VDRL, and HIV (PCR) Imaging studies: CT scan with contrast to assess liver volume and vascular anatomy, and MRI (optional) Special studies: pulmonary function tests, ECG, ECHO, and cardiac stress testa Step 3 Histology: liver biopsy Step 4 Clinical evaluation: planning of OR date and availability of ICU facilities Blood bank: autologous blood donation Second informed consent (for blood and surgery) ªOnly performed if indicated. Abbreviations: AFP, alpha fetoprotein; CEA, carcinoembryonic antigen; CMV, cytomegalovirus; EBV, Eptein–Barr virus; ECG, electrocardiogram; ECHO, echocardiogram; HLA, human leucocyte antigen; HSV, herpes simplex virus; ICU, intensive care unit; Ign, immunoglobulin; MRI, magnetic resonance imaging; OR, operating room; PA, posterior-anterior; PCR, polymerase chain reaction; TSH, thyroid stimulating hormone; VDRL, venereal disease research laboratory.

allograft so that both recipient and graft survival rates are at least equivalent to those with DDLT (29,45–47). Since the potential LDLT donor is asked to consider a major surgery of a type that would rarely, if ever, be needed for his or her own good, the dictum of “safety first” clearly applies throughout the evaluation and selection process, during the surgery itself and in the recovery period. As a result, prospective donors should have a complete understanding of the risks involved, not only for themselves but also for the recipients. All the information provided must also be tailored to the educational background of the donor, and the consent form(s) should be translated into the language of the donor, if at all possible (Table 3). In general, only one living donor candidate should be evaluated at a given time in order to minimize a sense of “competition” among multiple potential donors and also to reduce the costs and risks during the work-up. Most experts agree that the best donors tend to be identified early in the evaluation process, with the “law of diminishing returns” when evaluating a progressively larger number of potential donors (9,29). Donors should be related in some way to the recipients, at least emotionally. Of interest, in the United States, Hispanics are more likely to undergo LDLT than other ethnic groups, possibly related to their having more extensive family networks from which a potential donor can arise (48). Occasionally, an unrelated (so-called “altruistic”) donor may volunteer to be assessed for adult-to-adult LDLT, but such a practice is best avoided if possible, in contrast to the situation with adult-to-pediatric LDLT. The intrinsic reasons for such unreserved altruism, especially in the adult-to-adult LDLT setting, are usually ill-defined prior to the surgery, and may only surface afterward, leading to serious unforeseen problems (49). The minimum age for a LDLT donor is usually 21, although younger individuals have donated without any adverse outcomes. On the other hand, the upper age limit is set at 55 by most transplant centers (6,9,29,45–47), since the rapidity and degree of liver regeneration is thought to be less robust beyond that age, possibly compromising donor as well as recipient outcomes (39). Absolute exclusion criteria for LDLT include the following: any significant underlying medical condition (e.g., diabetes mellitus, severe or uncontrolled hypertension, cardiovascular disease, and chronic renal insufficiency), ABO incompatibility, work-up suggestive of chronic liver disease, greater than 20% steatosis at liver biopsy, active infections, inadequate graft size, and pregnancy. Positive hepatitis B, C, or HIV serologies are absolute contraindications for living donation, even when considered for recipients with positive serologies. The only exception is a live donor who is positive for hepatitis B core antibody, but negative for

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hepatitis B surface antigen, when donating to a hepatitis B positive recipient, as long as the donor has nondetectable serum hepatitis B quantitative viral DNA, normal liver enzymes, and normal histology at liver biopsy. Hypercoagulable conditions such as factor V Leiden, prothrombin mutation (G20210A), antithrombin III, protein C and S deficiencies, as well as elevated factor VIII, antiphospholipid or cardiolipin antibodies, are all relative contraindications to LDLT because of the potential increased risk for pulmonary embolus postoperatively. Smokers are strongly encouraged to quit, and oral contraceptive use is discontinued four weeks prior to surgery (9,29). Ultimately, only about one-third of donors are able to proceed to LDLT. The most common exclusions involve the recipient (e.g., worsening clinical status), donor technical issues (e.g., abnormal hepatic vasculature), or donor liver biopsy findings (more than 20% steatosis). Donors with more than this amount of steatosis on liver biopsy may occasionally improve after dieting and weight loss, so that they may proceed safely with living donation as long as they fulfill other inclusion criteria, and a repeat liver biopsy shows less than 20% steatosis (9,29). The evaluation of a LDLT donor candidate is usually divided into four steps (Table 3). The first step consists of the prospective donor contacting the liver transplant center to volunteer for consideration. It is important that there be no apparent or perceived “solicitation” of donors by the transplant center, although general brochures or similar materials discussing LDLT can be used for educational purposes. Once the donor has made contact either by telephone or via electronic mail, the transplant coordinator will ask the prospective donor to complete a brief questionnaire to uncover any medical or psychosocial contraindications. Routine blood work is then scheduled to screen for abnormal liver function tests and any possible underlying liver disease or other condition that might preclude donation. This prevents any further unnecessary testing in the subsequent steps. Blood typing of the donor is also done at this stage to ensure compatibility with the recipient. Once these tests are completed and there are no concerns, the potential donor can proceed to step 2. Step 2 involves a thorough history and physical to determine eligibility for the operation. An extensive psychosocial and psychiatric assessment is also performed (see Chapter 2). Some transplant centers use personnel from outside the center itself to conduct these assessments in order to distance the donor from the transplant surgeons, so that any sense of “coercion” is further minimized. Other centers feel instead that the best assessment of the potential donor and provision of any information during the evaluation process is performed by personnel with the most understanding of the operation and its inherent risks and benefits. Additional screening tests are also performed at this stage (Table 3). At this point, informed consent to proceed with the necessary tests as well as the LDLT surgery itself is also discussed in detail with the prospective donor. After all the donor candidate’s questions are answered to his or her satisfaction, written consent is obtained, and a copy of the consent form is given to the candidate to keep. This is separate from a second written informed consent, which is obtained after all the steps in the evaluation are completed and the donor has been deemed appropriate by the medical-surgical team, but prior to the LDLT surgery itself. Upon completion of step 2, a decision regarding donor acceptability needs to be made by a multidisciplinary committee, which takes into consideration both the medical and ethical aspects of each case. As part of the donor evaluation process, it is prudent to ensure early on that the amount of donor liver mass to be used will match that required by the recipient. In most instances, a helical/spiral computerized tomography angiogram (CTA) with 3-D reconstruction provides the key volumetric parameters for the surgeons to decide on this. Essential to fine-tuning this assessment is the amount of hepatic steatosis in the donor, which according to most experts is best determined by a liver biopsy, not simply by imaging tests (see later). The main concern here is that without enough liver mass, the recipient of a living donor graft may develop the “small-for-size” syndrome (18–20,44–47), with poor graft function manifested by severe cholestasis and sluggish bile flow. The exact mechanism remains uncertain, but it appears related to excess portal blood flow through the hepatic sinusoids leading to “shear” damage and an inflammatory cytokine response. A second (usually deceased donor) graft is then required on an urgent basis. Recently, a distal portacaval shunt performed at the time of LDLT to minimize

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this effect in adult recipients of the smaller left-hepatic lobe grafts has led to encouraging results in Europe (50,51) and Asia (52–56), but this practice has not yet been adopted elsewhere. There are two ways to determine a proper donor-recipient size match in terms of liver mass: (i) the percentage of liver mass and (ii) the graft volume-to-recipient weight ratio (GRWR) (10,13,29). Most transplant centers in the United States use the GRWR. The consensus is that the GRWR should be greater than 0.8 % (equivalent to about 40 % of the standard liver volume). For example, an 80-kg recipient would require a new liver mass of at least 800 g (GRWR = 1%) especially if a liver biopsy during the work-up showed that about 20% (0.2) of the hepatocytes had a significant degree of steatosis (but were otherwise of good quality), to give a final GRWR of 0.8% (1 − 0.2%). However, in sicker recipients, a higher threshold GRWR is needed. In fact, one study showed that in recipients with a Child-Pugh-Turcotte score of B or C, a GRWR of greater than 0.85% is best. Recipients with a GRWR below this level had a graft survival of only 33%, compared with 85% in those with a GRWR above this level (57). Some transplant centers reserve liver biopsies only for selected donors, mostly those with concerns about imaging or blood work, or those with a body mass index (BMI) greater than 25 kg/m2. However, significant hepatic steatosis or other pathology can be missed when using this approach. In fact, one study from our patients showed that in 100 consecutive ultrasoundguided liver biopsies, a surprising 33% of candidates had some degree of steatosis, even though the prior work-up had been negative (58). In addition, there was a poor correlation between BMI and steatosis. Although 73% of candidates with a BMI greater than 25 kg/m2 had little or no steatosis, 9% of those with a BMI less than 25 kg/m2 had at least 10% steatosis, enough in some cases to have altered the GRWR significantly (as discussed earlier). Helical contrast CT scanning and ultrasound had an increased sensitivity for more severe steatosis (but above a cutoff value of 20%). However, imaging was only 12% sensitive in detecting a small amount of fat (5–10%), and in two cases imaging failed to detect any fat, although the degree of steatosis was 30% on biopsy. Furthermore, three of the 100 living donor candidates had to be excluded because of occult liver disease. In another study from Cedars Sinai, 70 consecutive candidates for adult-to-adult or adultto-child LDLT were assessed, and 67% of the donors had an unexpected abnormality, hepatic steatosis being the most common (27/70 or 38.5%) (59). The majority (70%) had grade 1 steatosis (up to 33% of liver cells, Brunt criteria), whereas 18% had grade 2 and 11% had grade 3. Most (22/27 or 81%) of the candidates with steatosis had no other findings, but five donors had steatohepatitis (1), hepatitis (1), granuloma (2), or nonspecific inflammation (1). The average BMI of living donors with steatosis was 28.6 kg/m2. The investigators found that BMI was not directly predictive of steatosis, as 7/27 (26%) of those with steatosis had a BMI less than 25 kg/ m2, although most of those with a BMI greater than 30 kg/m2 had significant steatosis. A magnetic resonance image (MRI) was done in 62 candidates, but this detected steatosis in only 16/25 (64%) of those with biopsy-proven steatosis. Nine (36%) cases with no detectable steatosis on MRI had only grade 1 on biopsy, but one had greater than 30% steatosis (grade 2). Besides steatosis, several other histopathological abnormalities were noted, including granuloma of uncertain cause (7%), chronic hepatitis (6%), and a variety of others issues (23%), such as a microabscess. Of note, none of these problems had been suspected during the extensive prior work-up. The final step in the selection process is the donor’s informed choice. This has to be made voluntarily; and whenever possible, it is best done after an appropriate “cooling off period” after all tests have been completed (32). The amount of time for this still remains uncertain, but a few weeks seems appropriate. Recently, a separate team to evaluate the donor has been proposed (per the New York State guidelines) (36). However, this must be balanced by the degree to which this team would have sufficient knowledge about the work-up and the surgery involved. A designated “advocate” to act on behalf of the donor has also been proposed, someone who could help the donor through the entire process (but not pre-empt the donor’s decision, since the donor continues to possess the ethical and legal right to decide to proceed with LDLT or not). If a donor elects to bow out of the LDLT surgery for personal or other reasons, transplant centers usually provide a medical excuse for the donor to avoid any guilt feelings for not having helped their loved one.

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CONCLUSIONS In conclusion, the main goal in the donor evaluation is to assure the safety of the donor with the least possible morbidity and no mortality, and provide the optimal donor liver graft for the recipient (60–64). Thorough medical and psychological assessments are essential components of the initial evaluation to ensure appropriate selection. Extensive serologic testing, imaging studies, and a liver biopsy are also essential. We have routinely performed liver biopsies on all live liver donors. An ideal GRBW of 0.8% (corrected for any steatosis seen on liver biopsy) is a safe lower limit for adult recipients, with a maximum of a 60% liver resection. The new UNOSbased registry for donors and recipients should help to monitor outcomes, and identify and evaluate any potential long-term issues after donation. REFERENCES 1. Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet 1989; 2:497. 2. Strong RW, Lynch SV, Ong TH, et al. Successful liver transplantation from a living donor to her son. N Engl J Med 1990; 332:1505–1507. 3. de Ville de Goyet J, Hausleithner V, Reding R, et al. Impact of innovative techniques on the waiting list and results in pediatric liver transplantation. Transplantation 1993; 56:1130–1136. 4. OPTN. www.optn.org/latestData/rptData.asp 5. Hashikura Y, Makuuchi M, Kawasaki S, et al. Successful living-related partial liver transplantation to an adult patient. Lancet 1994; 343:1233–1234. 6. Brown RS Jr, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med 2003; 348:818–825. 7. Miller C, Florman S, Kim-Schluger L, et al. Fulminant and fatal gas gangrene of the stomach in a healthy live liver donor. Liver Transpl 2004; 10:1315–1319. 8. Hayashi PH, Forman L, Steinberg T, et al. Model for end-stage liver disease (MELD) does not predict patient or graft survival in living donor liver transplant recipients. Liver Transpl 2003; 9:737–740. 9. Trotter JF, Hayashi PH, Kam I. Donor and recipient evaluation and selection for adult-to-adult right hepatic lobe liver transplant. In: Transplantation of the Liver. 2nd ed. Philadelphia: Elsevier Saunders, 2005:655–674. 10. Olthoff KM, Merion RM, Ghobrial RM, et al. Outcomes of 385 adult-to-adult living-donor liver transplant recipients: a report from the A2ALL consortium. Ann Surg 2005; 242:314–325. 11. Valentin-Gamazo C, Malago M, Karliova M, et al. Experience after the evaluation of 700 potential donors for living-donor liver transplantation at a single center. Liver Transpl 2004; 10:1087–1096. 12. Pascher A, Sauer IM, Walter M, et al. Donor evaluation, donor risks, donor outcome, and donor quality of life in adult-to-adult living-donor liver transplantation. Liver Transpl 2002; 8:829–837. 13. Marcos A. Right-lobe living donor transplantation. Liver Transpl 2000; 2(suppl):S59–S63. 14. Fan ST, Lo CM, Liu CL, et al. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000; 135:336–340. 15. Broelsch CE, Malago M, Testa G, et al. Living-donor liver transplantation in adults: outcome in Europe. Liver Transpl 2000; 6(suppl):S64–S72. 16. Broering DC, Wilms C, Bok P, et al. Evolution of donor morbidity in living-related liver transplantation: a single-center analysis of 165 cases. Ann Surg 2004; 240:1013–1026. 17. Umeshita K, Fujiwara K, Kiyosawa K, et al. Operative morbidity of living donors in Japan. Lancet 2003; 362:687–690. 18. Dahm F, Georgiev P, Clavien P-A. Small-for-size syndrome after partial liver transplantation: definition, mechanisms of disease and clinical implications. Am J Transpl 2005; 5:2605–2610. 19. Lo CM, Fan ST, Chan JK, et al. Minimum graft volume for successful adult-to-adult living-donor liver transplantation for fulminant hepatic failure. Transplantation. Transplantation 1996; 62:696–698. 20. Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 1999; 67:321–327. 21. Lo CM, Fan ST, Liu CL, et al. Adult-to-adult living-donor liver transplantation using extended right lobe grafts. Ann Surg 1997; 226:261–269, discussion 269–270. 22. Wright L, Faith K; Richardson R, et al. Ethical guidelines for the evaluation of living organ donors. Can J Surg 2004; 47(6):408–413. 23. Authors for the live organ donor consensus group. Consensus statement on the live organ donor. JAMA 2000; 284:2919–2926. 24. American Society of Transplant Surgeons: Ethics committee. American Society of Transplant Surgeons’ position paper on adult-to-adult living-donor liver transplantation. Liver Transpl 2000; 6: 815–817. 25. Shiffman ML, Brown RS, Olthoff KM, et al. Living-donor liver transplantation: summary of a conference at the National Institutes of Health. Liver Transpl 2002; 8:174–188.

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26. Reding R. Is it right to promote living-donor liver transplantation for fulminant hepatic failure in pediatric recipients? Am J Transplant 2005; 5:1587–1591. 27. Trotter JF, Wachs M, Everson GT, et al. Adult-to adult transplantation of the right hepatic lobe from a living donor. N Engl J Med 2002; 346:1074–1082. 28. Trotter JF, Talamantes M, McClure M, et al. Right-hepatic lobe donation for living-donor transplantation: impact on donor quality of life. Liver Transpl 2001; 7:485–493. 29. Tan HP, Patel-Tom K, Marcos A. Adult living donor liver transplantation: who is the ideal donor and recipient? J Hepatol 2005; 43:13–17. 30. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of liver donors. Gastroenterology 2003; 124:91–96. 31. Freeman RB, Harper A, Edwards EB. Liver transplantation outcomes under the model for end-stage liver disease and pediatric end-stage liver disease. Curr Opin Organ Transpl 2005; 10:90–94. 32. Merion RM, Schaubel DE, Dykstra DM, et al. The survival benefit of liver transplantation. Am J Transplant 2005; 5:307–313. 33. Freeman RB. The impact of the model for end-stage liver disease on recipient selection for adult living liver donation. Liver Transpl 2003; 9(suppl 2):S54–S59. 34. Sugarawa Y, Makuuchi M, Kaneko J, et al. MELD score for selection of patients to receive left livergraft. Transplantation 2003; 75:573–574. 35. Testa G, Malago M, Nadalin S, et al. Right-liver living donor transplantation for decompensated end-stage liver disease. Liver Transpl 2002; 8:340–346. 36. New York State Health Department. New York State Committee on quality improvement in living liver donation, 2002. 37. Fink S, Brown RS. Current indications, contraindications, delisting criteria, and timing for liver transplantation. In: Busttil RW, Klintbalm GB, eds. Transplantation of the Liver. Philadelphia: Elsevier Saunders, 2005:95–114. 38. Russo MW, Shrestha R. Is severe recurrent hepatitis C more common after live-donor liver transplantation? Hepatology 2004; 40:524–526. 39. Sugawara Y, Makuuchi M. Should living donor liver transplantation be offered to patients with hepatitis C virus cirrhosis? J Hepatol 2005; 42:472–475. 40. Humar A, Horn K, Kalis A, et al. Living donor and split-liver transplants in hepatitis C recipients: does liver regeneration increase the risk for recurrence? Am J Transpl 2005; 5:399–403. 41. Borzorgzadeh A, Jain A, Ryan C, et al. Impact of hepatitis C viral infection in primary cadaveric liver allograft versus primary living-donor allograft in 100 consecutive liver transplant recipients receiving tacrolimus. Transplantation 2004; 77:1066–1070. 42. Garcia-Retortillo M, Forns X, Llovet JM, et al. Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation. Hepatology 2004; 40:699–707. 43. Shiffman ML, Stravitz RT, Cantos MJ, et al. Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation. Liver Transpl 2004; 10:1248–1255. 44. Todo S, Furukawa H. Japanese study group on organ transplantation. Living-donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004; 240:451–459. 45. Schiano TD, Kim-Schluger L, Gondolesi G, et al. Adult living-donor liver transplantation: the hepatologist perspective. Hepatology 2001; 33:3–9. 46. Russo MW, Brown RS Jr. Adult living-donor liver transplantation. Am J Transplant 2004; 4:458–465. 47. Trotter JF. Living donor liver transplantation: is the hype over? J Hepatol 2005; 42:20–25. 48. Rudow DL, Russo MW, Haflinger S, et al. Clinical and ethnic differences in candidates listed for liver transplantation with and without potential living donors. Liver Transpl 2003; 9:254–259. 49. Truong RD. The ethics of organ donation by living donors (editorial). N Engl J Med 2005; 353:444–446. 50. Masetti M, Siniscalchi A, De Pietri L, et al. Living-donor liver transplantation with left liver graft. Am J Transplant 2004; 4:1713–1716. 51. Troisi R, Ricciardi S, Smeets P, et al. Effects of hemi-portocaval shunts for inflow modulation on the outcome of small-for-size grafts in living-donor liver transplantation. Am J Transplant 2005; 5: 1397–1404. 52. Soejima Y, Taketomi A, Yoshizumi T, et al. Feasibility of left-lobe living-donor liver transplantation between adults: an eight-year, single-center experience of 107 cases. Am J Transplant 2006; 6:1004–1011. 53. Lo CM. Complications and long-term outcome of living liver donors: a survey of 1, 508 cases in five Asian centers. Transplantation 2003; 75(suppl 3):S12–S5. 54. Takada Y, Ueda M, Ishikawa Y, et al. End-to-side portocaval shunting for a small-for-size graft in living-donor liver transplantation. Liver Transpl 2004; 10:807. 55. Shimada M, Ijichi H, Yonemura Y, et al. The impact of splenectomy or splenic artery ligation on the outcome of a living-donor adult liver transplantation using a left lobe graft. Hepatogastroenterology 2004; 51:625–629. 56. Lo CM, Fan St, Liu CT, et al. Lessons learned from one hundred right-lobe living-donor liver transplants. Ann Surg 2004; 240:151–158.

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57. Ben-Haim M, Emre S, Fishbein TM, et al. Critical graft size in adult-to-adult living-donor liver transplantation: impact of the recipient’s disease. Liver Transpl 2001; 7:948–953. 58. Ryan KR, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the work-up of living donors for right lobe liver transplantation. Liver Transpl 2002; 8:1114–1122. 59. Tran TM, Changsri C, Shackleton CR, et al. Living donor liver transplantation: histological abnormalities found on liver biopsies of apparently healthy potential donors. J Gastro Hepatol 2005; 11: 1440–1476. 60. Liu CL, Lam B, Lo CM. Impact of right-lobe live donor liver transplantation on patients waiting for liver transplantation. Liver Transpl 2003; 9:863–869. 61. Russo MW, LaPointe-Rudow D, Kinkhabwala M, et al. Impact of adult living donor liver transplantation on waiting time survival in candidates listed for liver transplantation. Am J Transplant 2004; 4:427–431. 62. Miller CM, Gondolesi GE, Florman S, et al. One hundred nine living donor liver transplants in adults and children: a single center experience. Ann Surg 2001; 234:301–311. 63. Trotter JF, Wachs M, Trouillot T, et al. Evaluation of 100 patients for living donor liver transplantation. Liver Transpl 2000; 6:290–295. 64. Annual report of the Scientific Registry of Transplant Recipients and the Organ Procurement and Transplantation Network: Transplant data, 2003, Richmond, VA, United Network for Organ Sharing (accessed at http://www.ustransplant.org).

15

Technical Aspects of Live-Donor Hepatectomy Vivek Sharma and Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

J. Wallis Marsh and Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION In 1967, Dr. Thomas E. Starzl et al. performed the first successful deceased donor liver transplantation (DDLT) (1). For the next 15 years, poor outcomes, related to inadequate immunosuppression and technical issues, limited the application of the procedure to a very small number of centers. As results began to improve in the early 1980s, there was an exponential rise and then a plateau in the number of liver transplantations being performed. The rise was related to significant advances in immunosuppression, organ preservation, surgical techniques, and intensive care; the plateau was a natural consequence of the limited availability of appropriate donors. For most of the history of transplantation, the demand for organs has far exceeded the supply, and this has stimulated the search for innovative strategies to expand the donor pool. The significant regenerative capacity of the liver has led to the development of reducedsize and split-liver transplantation (2,3); however, the gap between the availability and the need for organs has only widened. This has led surgeons to turn to extended criteria donors and living donor liver transplantation (LDLT). The early pioneering work was done by Broelsch et al. who also established its ethical basis (4–6). The early driving force for LDLT was the high mortality on the pediatric waiting list (7–9). The Japanese enthusiastically pursued adult LDLT (including left lobe grafts) because cultural beliefs hindered widespread adoption of DDLT (10–14). The development of adult LDLT in the United States was stimulated by the >10% mortality on the adult waiting list (15). Initially, only left lobectomies were done, but soon it was realized that some of the recipients, particularly those with advanced portal hypertension, seemed to need more liver mass than that provided by the left lobe and developed a degree of liver insufficiency, or “small-for-size syndrome” (16). This led many centers, including ours, to start using right lobes to increase the actual mass of the graft, and allow wider use of these life-saving procedures (15,17–19). This chapter outlines the technical aspects of the donor procedures (right and left lobectomies and left lateral segmentectomy), with emphasis on right lobe donor hepatectomy (RLDH), as currently practiced in our institute. This is an evolving innovative field with the demands of the waiting list constantly driving technical innovation, and technical advances pushing the boundaries. However, as always, the central premise for this procedure has and will remain the primacy of donor safety. PREOPERATIVE DONOR EVALUATION The preoperative donor evaluation is covered in detail in Chapter 14. Careful documentation of the anatomic roadmap is essential. This is particularly important as anatomic variations in the liver are quite common. Anatomic evaluation of liver mass, right and left lobe volume estimation, and vascular and parenchymal anatomy are currently obtained in our institute by a triphasic contrast enhanced

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FIGURE 1 (See color insert.) CT-angiogram with 3D-reconstruction of arterial anatomy.

spiral/helical CT with software 3D-reconstruction of the arterial anatomy and liver volume determination (Figs. 1–3). Magnetic resonance imaging (MRI) is an alternative for people with contrast allergy. We and others do not believe that magnetic resonance cholangiogram is necessary for preop evaluation (20,21). A few relevant points about anatomy need to be emphasized. Portal Vein The extrahepatic portal vein is the most dorsal of the hilar structures. The bifurcation is to the right, and the left portal branch is long, running transversely up to the ligamentum venosum, whereas the umbilical portion runs up into the umbilical fissure (22). Of particular relevance is the origin of the anterior segment branch of the right portal vein (Fig. 2). The common variations, where the right portal vein bifurcates soon after its origin and where there is a trifurcation, do not require back-table reconstruction. In less than 10%, however, the right anterior segment vein comes from the left portal vein and may require more advanced reconstruction techniques (23–25) to deal with the so-called double portal vein for right lobe LDLT. Multiple intraparenchymal branches to the right anterior segment from the left portal vein, and livers where the remaining

FIGURE 2 (See color insert.) CT showing two right portal veins.

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FIGURE 3 CT images, post-processing showing liver volumes.

segment IV or left lobe blood supply arises from the right portal vein, are reasons to contraindicate right lobe donor hepatectomy. Intrahepatic left portal anomalies rarely preclude donation. Hepatic Artery The arterial anatomy is standard in only 50% of cases (i.e., single right and left arteries from common hepatic artery arising from the celiac trunk from the aorta, see Fig. 1). The most common variations are an accessory or replaced left hepatic artery from the left gastric artery (~25%) and an accessory or replaced right hepatic artery from the superior mesenteric artery (~17%) (23,26,27). About 95% of RLDH, result in only one orifice for the arterial anastomosis (25,28). In our own experience, in order to preserve the donor arterial supply to the bile ducts in cases of low or early bifurcation, we have ended up with two arterial orifices in 11.6% of cases (26) as the arteries are dissected and divided to the right of the bile duct (29). An important consideration is the availability of appropriate deceased donor arterial grafts when planning surgery, where such anatomy is anticipated. Also, in about 10% of cases the right hepatic artery courses anterior to the bile duct. We propose a simple classification of donor right hepatic artery based on the need for one or more arterial anastomosis (Table 1). Type I is the commonest situation (~90% of LDLT) requiring a single recipient arterial anastomosis. Type II (~5%) refers to all variations of the right arterial system requiring two recipient arterial anastomoses. Type III situation is rare and maybe seen sometimes with accessory segmental branches from the LHA, or a replaced/accessory LHA to Couinaud segment V or VIII. Sometimes, the position of the right hepatic duct may necessitate transection of the RHA distal to its natural division, necessitating two or more anastomoses. Hepatic Venous Anatomy Hepatic venous anatomy guides intraparenchymal transection in the donor and dictates the need for graft outflow reconstruction in the recipient. The intrahepatic venous anatomy can be highly variable (30). Usually, the right hepatic vein enters the vena cava separately from the middle and left hepatic veins, but all three may enter collectively together as a single trunk. Segmental venous drainage is redundant with considerable overlap; this allows single small tributaries to be divided without significant compromise of the venous outflow. In up to a quarter of the cases, there is a significant accessory venous tributary, usually from the anterior segments to the middle hepatic vein, that requires careful preservation and reconstruction (24,31). TABLE 1 Proposed Classification for Donor Right Lobectomy Arterial Anatomy Single right hepatic artery requiring single recipient arterial anastomosis All variations of dual right arterial systems requiring two recipient arterial anastomoses Aberrant segmental branches (usually Couinaud V or VIII) from left arterial system requiring two or more recipient arterial anastomoses

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Some surgeons have taken approaches that are variants of the extended right lobectomy to include portions of the middle hepatic vein with the graft to obviate venous tributary reconstruction. Inclusion of the distal middle hepatic vein improves segment V drainage but not that of segment VIII. We take the approach of reconstructing the venous drainage with recipient portal vein, if a significant segment VIII vein is encountered. We believe that inclusion of the entire middle hepatic vein may unnecessarily compromise donor safety, and prefer instead to attempt to preserve any significant segment VIII branch for implantation, if necessary, with back-table reconstruction with extension grafts, as described elsewhere (24). Ensuring adequate venous drainage from the anterior segment also maximizes functional graft mass. Biliary Anatomy Variability in biliary anatomy is the norm rather than the exception in the living donor hepatectomy (32). MRI and all encompassing combined (biliary and angiographic) contrast highresolution CT afford excellent preoperative visualization of the biliary tree for living donors (33,34). However, we maintain that intraoperative cholangiography remains the gold standard. One cannot overemphasize the importance of getting an excellent intraoperative cholangiogram to obtain a definitive roadmap for determining the exact site of bile duct division and planning reconstruction in the recipient. Approximately, one-third of donors will have a variation from the “standard” pattern of confluence—right anterior and posterior ducts join to form the right hepatic duct, which joins with the left hepatic to form the common hepatic duct (23,25). In this instance, when there is a confluence of all three ducts, it may be possible to transect the ducts resulting in one orifice for implantation. In variant cases where the right posterior duct or the right anterior duct joins the left duct, the variant duct may have to be transected intraparenchymally, and require a double duct-to-duct reconstruction or a Roux-en-Y drainage. Another point to emphasize is that the blood supply to the duct comes from the right hepatic artery and the hepatic hilum. We, therefore, try not to skeletonize the duct during the dissection of the right hepatic artery and the hilum. There is a lymphatic plexus around the hilar structures from which the right hepatic artery and the duct have to be dissected, and this is done with careful division of the lymphatics between 4-0 silk ties with great care to avoid any intimal dissection. GRAFT ADEQUACY As discussed in Chapters 14 and 16, preoperative evaluation will have looked at adequacy of the actual liver volume (Fig. 3). At the University of Pittsburgh Medical Center, Starzl Transplantation Institute (UPMC STI), a liver biopsy is always performed and is used to quantify macro- and microsteatosis. Donor safety is of primary concern, and the smallest resection that provides adequate actual and functional mass for the recipient is selected. We have had numerous occasions where the degree of macrosteatosis necessitated a period of diet, exercise, and weight loss prior to donation. In these cases, repeat liver biopsy is performed to confirm response to therapy. We aim for a graft-recipient weight ratio (GRWR) higher than 0.8, corrected for the degree of macrosteatosis, and generally do not accept donors with macrosteatosis over 20%. To prevent the development of “small-for-size syndrome,” one needs to have an understanding of the concept of adequate functional graft size, which is dependent on the degree of portal hypertension and cardiac index of the recipient. As mentioned before, the importance of preserving adequate venous return from the anterior segments cannot be overemphasized. Suboptimal venous outflow, despite adequate GRWR, may cause a Budd-Chiari syndrome of the anterior segment with overflow to the posterior segment, and unrelieved excessive portal venous flow can result in secondary arterial thrombosis, and lead to biliary complications. PERIOPERATIVE CONSIDERATIONS The day before the operation, the donor is instructed to abstain from eating solids after lunch (2 pm). The donor is allowed to have liquids ad lib until midnight, and nothing by mouth after

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Donor Bowel Preparation

Magnesium citrate 10 oz. PO at 4 PM Erythromycin base (EC delayed release) 500 mg PO at 8 PM, 9 PM, and 11 PM Neomycin 1g PO at 8 PM, 9 PM, and 11 PM Fluconazole 400 mg PO at 11 PM

that. The donor is given a bowel preparation as shown in Table 2. Some centers have used other bowel preparations, but we have found this to be adequate, and it has excellent patient tolerability. The donor is admitted to the hospital after midnight on the day of the operation. The family reports to a designated waiting room, where they can receive updates from the transplant coordinator at the time of surgery. A repeat history and physical is done to ensure no acute illness or problems have developed since the last examination. An informed consent is signed and witnessed. Laboratory blood examination (complete blood count, platelets, electrolytes, BUN, creatinine, prothrombin time, and partial thromboplastin time) and urinalysis are repeated. We type and crossmatch five units of packed red blood cells. Dextrose 5% in 0.45% normal saline is started at 100 mL/hr to prevent dehydration. The anesthesiology team reviews the chart and examines the patient again. An epidural catheter for postoperative patient-controlled analgesia is placed. Bilateral sequential compression devices are placed on the lower extremities prior to anesthesia induction, to prevent deep venous thrombosis. Methylprednisolone 250 mg is given intravenously at the time of induction; this appears to help with pain relief and reduces inflammation postoperatively. We infuse antibiotics (piperacillin/tazobactam or vancomycin–ciprofloxacin combination, if allergic to penicillin) prior to the incision, and continue for 48 hours postoperatively. Intravenous antibiotics are discontinued when the patient starts oral intake, and the donor is given a short period of prophylaxis with ciprofloxacin 500 mg PO daily, as some donors will develop transient ascites in the early postoperative period. After induction of general endotracheal anesthesia, an arterial line, a central venous line in the internal jugular vein, a Foley catheter, and a nasogastric tube are inserted. An autologous blood transfusion system, Cell Saver®, is used in every case. The patient is positioned supine with arms outstretched on armrests to allow optimal placement of the retractor system (The Iron Intern®, Automated Medical Products Corp., Edison, New Jersey, U.S.A.) without over extension or ulnar compression. Foam booties are placed on the feet and a pillow placed behind the knees. The lower limbs are brought into gentle pronation with a cotton wool bandage around both feet to prevent peroneal compression. A footboard supports the feet and prevents the patient from sliding down in the reverse Trendelenberg position. Bair Hugger® blankets are positioned to cover the lower extremities up to the mid thighs and above the nipple line to cover the chest and the upper extremities. INITIAL EXPLORATION After sterile prepping and draping, the upper two vertical poles for the Iron Intern are placed superior to the arm rests and fixed to a height that would allow adequate chest wall retraction using the Stieber Rib Grip. The draping is then completed on the sides, and the Stieber Rib Grip assembly is then placed, ensuring that the horizontal bar is positioned to allow easy application of the rib grips and positioning the Lees center platform to attach the Hydra Yoke—the two-arm retractor holder for retracting the liver using malleable paw retractors. The position of the Lees center platform is adjusted later during the operation to place it in the sagittal plane of Cantlie’s line to allow symmetrical liver retraction on either side of the gall bladder fossa during the dissection at the hilum using the paw retractors. A bilateral subcostal incision is made, the abdomen is entered, and the ligamentum teres is divided between ligatures and deliberately left long to allow using it as an anchor to the anterior abdominal wall at the end of the procedure to prevent torsion of the remnant left liver lobe after RLDH. The assistant holds up the rib cage as the falciform ligament is divided to prevent

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any traction on the liver when the Rib Grip retractors are applied. This also affords an excellent view to place the vertical midline incision to the xiphoid process. The two skin flaps are gently sutured back loosely to open up the upper abdomen; this allows unfettered access, good lighting, and an unobstructed view. The falciform is further divided, and the suprahepatic cava is exposed. The right hepatic vein is exposed as it enters the vena cava, and the triangular space between the right hepatic vein, the middle hepatic vein, and the superior surface of the liver is developed to the vena cava at this stage (or after the cholangiogram). As a rule, we avoid dissecting the structures of the remnant side so as not to violate virgin tissue planes on that side (this also prevents potential torsion of the remnant liver). A brief but thorough laparotomy evaluating the liver for size, anatomy, and abnormalities (steatosis, lesions, and congestion) should then be undertaken. We continue to maintain the central venous pressure (CVP) at < 5 mmHg until completion of parenchymal transection. The position of the nasogastric tube is confirmed and, if needed, guided to allow decompression of the stomach. The intestines are briefly inspected and the pelvis examined for masses/tumors, particularly in females. The right coronary ligament may be divided, and warm laparotomy sponges are placed behind and above the liver, in preparation for cholecystectomy and cholangiography. CHOLECYSTECTOMY AND CHOLANGIOGRAPHY The Calot’s triangle is defined, dissected, and the cystic duct is cannulated. We use the Mixter® endoscopic cholangiography set (Cook Surgical, Bloomington, Indiana, U.S.A.). This is a 4 or 5 French (depending on the cystic duct size) 50 cm polyethylene catheter with a three-way clear stopcock to flush heparinized-saline or contrast as desired. This is fixed to the cystic duct with a 2-0 silk tie. Cholangiography is then performed, and while waiting for the films, the cholecystectomy is performed. The cholangiogram catheter is left in situ tied to the cystic duct for several reasons: gentle traction on the catheter helps keep the bile duct taut, facilitating dissection of the hilum; flushing heparinized saline through the catheter helps to identify the biliary tree through saline distention; testing the closure of the biliary stump at the end of the procedure helps to confirm the absence of a bile leak; and, if necessary, it can be used to obtain a closing/completion cholangiogram. We give morphine 2 mg intravenously before the cholangiogram to cause spasm of the sphincter of Oddi. Fluoroscopy with a C-arm may also be beneficial. Once again, we cannot overemphasize the importance of obtaining excellent intraoperative cholangiography. INTRA-OPERATIVE ULTRASOUND The next step is to perform a systematic ultrasound examination of the liver with a linear probe duplex scan using a 5 to 7 MHz probe. The hepatic venous anatomy as surmised from the preoperative computerized tomography is confirmed tracing each hepatic vein to its insertion into the vena cava. The line of parenchymal transection is verified and scored with the electrocautery (electrocautery burns on the surface are easily visualized by ultrasound), identifying the line to the right of the middle hepatic vein. At this stage, the significant anterior segment veins draining into the middle hepatic vein are also assessed, their sites marked, and their depths from the surface noted to facilitate their identification for preservation or transection. (If < 4 mm, the right hepatic vein is large and they are not perceived to compromise the functional outflow of the graft, they are not preserved). Significant accessory veins draining segments VI and VII directly into the vena cava are also identified. Last but not least, the portal vein confluence is dissected and identified, and the segmental branches visualized, especially the branches to segment IV. This can forewarn the surgeon about the need to ligate and divide them, or to plan the parenchymal transection to avoid compromising the blood supply to the remaining liver. MOBILIZATION The cholangiogram films are reviewed and a decision to proceed with right lobectomy is confirmed. The right lobe is now mobilized from its attachments to the diaphragm by dividing

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the coronary and right triangular ligaments, which allows the liver to be lifted anteriorly and to the left. The gastrohepatic and left triangular ligaments are left intact so that the remaining left lobe is not excessively mobile. Division of the inferior, lateral, and superior peritoneal attachments allows the exposure of the retrohepatic cava. The inferior right hepatic veins (accessory veins from segments VI or VII) that need to be preserved are identified and dissected free. Smaller short hepatic veins draining directly into the cava are divided between ligatures or clips to expose the retrohepatic cava. The division of posterior caval ligament sometimes requires application of an angled Potts vascular clamp to allow suture ligation, as there is often a small vessel in it. The aim is to complete the retrohepatic dissection to define the plane around the right hepatic vein. Anteriorly, the plane between the right hepatic and middle hepatic veins is developed to allow full exposure and vascular control of the right hepatic vein. HILAR DISSECTION Attention is then directed to the hilum of the liver. The hilar plate is lowered and the right hepatic artery is dissected just to the left of the common hepatic duct (Figs. 4–6). Manipulation of the artery is minimized to avoid intimal damage, and any segment IV branches are carefully preserved. The right portal vein is then dissected laterally. The portal vein is defined posterior to the right hepatic artery, and fully dissected circumferentially. Small caudate branches from the portal vein are divided between ligatures, exposing the origin of the right and left portal veins. Once again, it is important to emphasize the extreme care needed during the dissection around the common bile duct to avoid devascularization. We do not divide the bile duct at this point (35), although some surgeons do so to facilitate placement of an umbilical tape during parenchymal transection. INTRAPARENCHYMAL TRANSECTION Establishing the proper plane for parenchymal transection is crucial. There has been considerable debate over the exact plane of transection whether to include the entire middle hepatic vein with the graft (see Chapter 16). We do not include the middle hepatic vein in the graft, and our plane of transection is just to the right of the vein. At this stage, we ensure that the CVP is low to

FIGURE 4 (See color insert.) Post-cholangiogram, right hepatic artery dissection.

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FIGURE 5

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(See color insert.) Dissection of two right portal veins.

facilitate transection and try to maintain it < 5 mmHg until completion of transection. This is achieved by titrating intravenous fluids from the beginning of the case. The goal is to avoid significant blood loss as we consider a nonautologous blood transfusion a donor complication. However, given a smaller reserve in the capacitance vessels in case of bleeding, it is imperative to follow a meticulous hemostatic routine at all stages of this operation. We use a combination of devices during this stage of the operation (Table 3) (36). The parenchymal transection is started with the electrocautery (settings of 70, monopolar on spray) for the superficial liver parenchyma. Further dissection in the deeper planes is performed using a combination of electrocautery and the cone-tipped TissueLink device. The TissueLink also allows definition of smaller vessels that are cauterized, ligated with surgical clips, or sutured with 4-0 prolene. The larger crossing hepatic

FIGURE 6

(See color insert.) Dissection of two right portal veins and right hepatic artery.

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TABLE 3

Special Instrumentation

Electrocautery Argon TissueLink Helix CUSA

Valleylab Force FX-C™ a CONMED System 7500® b TissueLink DS 3.5-C™ dissecting sealer c ERBE Helix Hydro-Jet® d CUSA EXcel™ Ultrasonic Surgical Aspirator

a

From Ref. 48. From Ref. 49. c From Ref. 50. d From Ref. 51. Abbreviation: CUSA, cavitron ultrasonic surgical aspirator. b

venous branches that do not require back-table reconstruction can be stapled with the EndoGIA™ 30-2.0 staples. The large accessory vein(s) from segment VIII are carefully preserved with the ERBE® Helix Hydro-Jet. Closer to the hilum, during dissection of the bile ducts, we do not use electrocautery or TissueLink, but use the Cavitron Ultrasonic Surgical Aspirator (CUSA) to avoid potential injury to the bile duct or its blood supply. Some surgeons pass an umbilical tape between the right and middle hepatic veins in the precaval retrohepatic space to emerge behind the hilar plate between the right and left hepatic veins. We do not find this useful and rely on accurate gentle symmetric retraction by the surgeon and first assistant to bring the liver “down and out” as the transection proceeds to cut the liver as described before. Careful observation for the transmitted pulsations in the middle hepatic vein allows the surgeon to maintain a safe distance of a few millimeters to its right and in the correct plane of transection (Fig. 7). We do not temporarily occlude any inflow (e.g., Pringle’s maneuver) during intraparenchymal transection in the belief that warm ischemia may be detrimental, and by avoiding this we avoid any chance of intimal vessel injury. Some reports have used successful inflow occlusion in living donors without adverse outcomes (37–40). It can reduce blood loss and intermittent occlusion may have a preconditioning effect on the liver.

FIGURE 7 (See color insert.) The liver after parenchymal transection.

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Note Regarding Ensuring Adequacy of Graft Venous Drainage Some surgeons temporarily occlude the right hepatic artery to evaluate segmental portal blood flow. Occlusion of significant accessory venous branches from segments V and VIII can demonstrate grafts with obvious impairment as demarcated congested areas. After intraparenchymal transection, persistent hepatopedal flow on temporary arterial occlusion suggests the presence of adequate intrahepatic venous collaterals for drainage without reconstruction. BILE DUCT TRANSECTION Once again, while the recipient operation is proceeding simultaneously, one can time the transection appropriately. At this stage, attention is turned back to the hilum and correlating the cholangiogram with direct visualization, the surgeon can clearly define the biliary anatomy and select a point of transection. It is important to remember that the blood supply to the cut edge of the bile duct is entirely dependent on the right hepatic artery via the periductal plexus. Sharp dissection, strict avoidance of electrocautery, and not stripping the plane between the artery and right duct are critically important details. The transection proceeds with partial division followed by confirming with biliary probes the precise location of the hepatic duct confluence. It is possible by this technique to fashion the transection in a curve to allow at least a 2 mm margin of the left duct for closure, particularly with shorter right hepatic ducts, to prevent common hepatic duct stricture. Flushing heparinized-saline through the cholangiogram cannula at this stage helps define the biliary anatomy. Sometimes, a branch of the right hepatic artery traverses the back of the duct and one must be mindful of this if it is cut inadvertently. After complete transection, the individual ducts are probed again to confirm that the donor’s remnant left hepatic and common hepatic ducts are not compromised. One should search carefully for small missed transected ducts along the hilar plate (Figs. 8 and 11). GRAFT REMOVAL The remaining parenchyma is now transected that entails dividing part of the caudate lobe, so that the right lobe is completely free of the cava and is attached only by its vascular pedicles. The back table is prepared with ice-slush and cold (~5°C) University of Wiscosin (UW) solution. Complete hemostasis is assured and communication with the recipient team ensures an appropriate time for cross clamping. At the appropriate time, the right hepatic artery is clamped and

FIGURE 8

(See color insert.) Transection of right hepatic duct.

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divided. A vascular clamp is applied on the right portal vein vertically to allow closure without compromising the inflow to the remnant liver. If there are two right portal veins, the right anterior and posterior veins are clamped separately to allow closure without compromising the left portal vein from which they arise. Next, a vascular clamp is applied on the accessory hepatic vein (if present), and it is divided. A vascular clamp is then placed on the right hepatic vein, which is divided sharply with consecutive placement of 4-0 prolene sutures at ~3mm intervals (as division progresses) and held as stays for right hepatic vein stump control in case of retraction or vascular clamp failure (Fig. 9). Once the liver is free, heparinized saline is flushed into the right portal vein prior to taking the liver to the back table to be flushed with cold UW solution (Fig. 10). The right hepatic vein stump is sutured using 3-0 prolene in two layers, and the stay sutures of 4-0 prolene placed earlier are tied for reinforcement. The right portal vein stump is then sutured with 5-0 prolene with a small growth factor to avoid portal vein stenosis. The right hepatic artery stump is sutured closed with a 4-0 prolene and reinforced with a 2-0 silk tie. The opening in the right hepatic duct is closed using a 6-0 PDS suture using two retention sutures in a fashion to avoid common hepatic duct stricture. The liver cut surface and hilum are once again inspected carefully for bile or blood, and heparinized saline is flushed through the cholangiogram cannula to confirm that there is no bile leak. The Mixter cannula is then removed, and the cystic duct stump is doubly ligated. We do not routinely do a closing ultrasound or cholangiogram. Some surgeons give systemic heparin prior to vascular clamping. We do not find this necessary. The donor cut surface is again inspected for hemostasis and bile leaks. This is generally done by placing fresh, dry gauze, swabbing gently against the cut surface and looking for bile stains. Any leak from biliary radicles is controlled with by suture ligation (Fig. 11). The cut surface of the liver is sprayed with fibrin glue. The falciform ligament is reattached to the anterior abdominal wall to prevent torsion of the left lobe remnant (41). Cell Saver blood is returned and, if necessary, fluids are replaced intravenously to ensure euvolemia, good urine output, and a falling lactate level. We have rarely needed to use banked blood (< 0.5%), but a 0.5% to 5% exogenous blood transfusion incidence is reported in the literature (42,43). BACK-TABLE PROCEDURE Once the graft is removed, it is brought back to the back table, and flushed with cold UW solution. The flushing is continued through the portal vein until the effluent from the hepatic vein is completely clear. This usually requires 3 mL/g of liver weight. We do not flush the artery. After the flush, the liver is weighed.

FIGURE 9

(See color insert.) Transection of right hepatic vein.

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FIGURE 10

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(See color insert.) Right hepatic lobe allograft, immediately after resection.

The liver is transported to the recipient operating room and any vascular reconstruction is performed. Our first choice is to use the recipient’s portal vein for the venous reconstructions. These are described in Chapter 17 and elsewhere (24,26,44). CLOSURE Two Jackson-Pratt suction drains are placed, one facing the cut surface and the other at the hilum. The transverse incision is closed in two layers and the vertical part of the “Mercedes incision” is closed in one layer using continuous #1 PDS. We use staples or subcuticular sutures

FIGURE 11

(See color insert.) The cut surface of the left lobe and the liver bed after removal of the graft.

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for the skin, and the drains are sutured to the skin. Closing films are taken to confirm the absence of lap pads or foreign objects. POSTOPERATIVE CARE Donors are generally extubated in the operating or recovery rooms. They go to the transplant intensive care unit in the early postoperative period. The CVP is monitored continuously. The nasogastric tube is kept on low intermittent wall suction, usually until the morning after surgery. The Foley catheter is kept in place until the epidural is removed. Sequential compression devices are kept on the lower extremities until the donor is ambulatory. All donors are started on pantoprazole 40 mg intravenously once daily and metoclopramide 10 mg intravenously twice daily until they start oral intake, at which time the pantoprazole and metoclopramide are given orally. It is important to be vigilant regarding the reduced hepatic mass, as the donors are particularly susceptible to narcotic overdose. Preoperative discussion regarding pain management helps in the post-operative period. We use patient-controlled analgesia via an epidural catheter—a combination of hydromorphone and ropivacaine. When the donor is taking medications orally, we switch to hydromorphone 1 mg every six hours as needed. It is important to emphasize that these patients often have a low-pain threshold and are healthy individuals. Antibiotic prophylaxis with intravenous piperacillin/tazobactam is continued for 48 hours; thereafter, donors receive ciprofloxacin 500 mg orally once a day until the drains are removed. The donors are monitored closely for signs of hepatic insufficiency in the immediate postoperative period, checking a complete blood count, electrolytes, BUN, creatinine, liver function tests, prothrombin time, partial thromboplastin time, calcium, magnesium, and phosphorus. As the liver regenerates, patients may develop hypophosphatemia and require replacement (45). The donors are encouraged to ambulate early. There are fiscal pressures to discharge patients early, but these are a special group of patients whose safety is paramount. We discharge them at an average of seven days when they are ambulatory, tolerating a regular diet, and when they feel confident that they will be able to manage themselves outside the hospital. CONSIDERATIONS FOR LEFT LOBECTOMY/LATERAL SEGMENTECTOMY It is important to stress that with left lobectomy or with left lateral segmentectomy, the same principles described above apply. Operative cholangiography and cholecystectomy are performed. Any accessory or replaced left hepatic artery from the left gastric artery is carefully preserved as the gastrohepatic ligament is divided. The left lobe is mobilized by dividing the left triangular ligament, to define the drainage of the left hepatic vein into the suprahepatic vena cava. The hilar dissection is approached from the left to isolate the left hepatic artery, carefully identifying and preserving the arterial branches (if any) to segment IV. The left portal vein is usually longer than the right, and a reasonable segment is isolated and looped. Some surgeons advocate preserving the caudate lobe and its dominant vein draining into the vena cava (46). The retrohepatic cava is defined after incising the overlying peritoneum along its lateral aspect, exposing the cava up to the left hepatic vein junction. Smaller draining veins are ligated or clipped as the entire left lobe and caudate lobe are retracted to the right, and the left and middle hepatic veins are isolated as they drain into the cava. It is important to recognize and avoid transecting the right posterior hepatic duct that sometimes drains into the left hepatic duct. Once again, it is important to stress the importance of preserving any medial left lobe arteries for reconstruction to ensure the segment IV biliary arterial supply (47). The parenchymal transection line is to the right of the middle hepatic vein and marked as described earlier using introperative ultrasound. For a lateral segmentectomy graft, the parenchymal transection is just to the right of the falciform ligament; the caudate lobe is left with the donor.

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CONCLUSION LDLT will remain an important source of providing life-saving liver transplants for the foreseeable future. This is possible only through a generous gift by our unselfish living donors. It is thus imperative to ensure their safety perioperatively and intraoperatively, to allow for an uncomplicated postoperative and long-term course. Painstaking adherence to detail, a thorough understanding of anatomy, a firm grasp of hepatic physiology, and meticulous operative technique form the basis for making this operation as safe as possible. REFERENCES 1. Starzl TE, Groth CG, Brettschneider L, et al. Orthotopic homotransplantation of the human liver. Ann Surg 1968; 168(3):392–415. 2. Bismuth H, Morino M, Castaing D, et al. Emergency orthotopic liver transplantation in two patients using one donor liver. Br J Surg 1989; 76(7):722–724. 3. Pichlmayr R, Ringe B, Gubernatis G, et al. Transplantation of a donor liver to two recipients (splitting transplantation)—a new method in the further development of segmental liver transplantation. Langenbecks Arch Chir 1988; 373(2):127–130. 4. Broelsch CE, Emond JC, Whitington PF, et al. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg 1990; 212(3):368–375; discussion 75–77. 5. Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg 1991; 214(4):428–437; discussion 37–39. 6. Singer PA, Siegler M, Whitington PF, et al. Ethics of liver transplantation with living donors. N Engl J Med 1989; 321(9):620–622. 7. Otte JB. The availability of all technical modalities for pediatric liver transplant programs. Pediatr Transplant 2001; 5(1):1–4. 8. Otte JB. History of pediatric liver transplantation. Where are we coming from? Where do we stand? Pediatr Transplant 2002; 6(5):378–387. 9. Testa G, Malagó M, Broelsch CE. From living related to in-situ split liver transplantation: how to reduce waiting-list mortality. Pediatr Transplant 2001; 5(1):16–20. 10. Hashikura Y, Kawasaki S, Miyagawa S, et al. Recent advance in living donor liver transplantation. World J Surg 2002; 26(2):243–246. 11. Hashikura Y, Makuuchi M, Kawasaki S, et al. Successful living-related partial liver transplantation to an adult patient. Lancet 1994; 343(8907):1233–1234. 12. Kawasaki S, Hashikura Y, Ikegami T, et al. First case of cadaveric liver transplantation in Japan. J Hepatobiliary Pancreat Surg 1999; 6(4):387–390. 13. Lo CM, Fan ST, Liu CL, et al. Extending the limit on the size of adult recipient in living donor liver transplantation using extended right lobe graft. Transplantation 1997; 63(10):1524–1528. 14. Yamaoka Y, Washida M, Honda K, et al. Liver transplantation using a right lobe graft from a living related donor. Transplantation 1994; 57(7):1127–1130. 15. Malagó M, Testa G, Marcos A, et al. Ethical considerations and rationale of adult-to-adult living donor liver transplantation. Liver Transpl 2001; 7(10):921–927. 16. Emond JC, Renz JF, Ferrell LD, et al. Functional analysis of grafts from living donors. Implications for the treatment of older recipients. Ann Surg 1996; 224(4):544–52; discussion 52–54. 17. Marcos A. Right-lobe living donor liver transplantation: a review. Liver Transpl 2000; 6(1):3–20. 18. Miller CM, Gondolesi GE, Florman S, et al. One hundred nine living donor liver transplants in adults and children: a single-center experience. Ann Surg 2001; 234(3):301–311; discussion 11–12. 19. Wachs ME, Bak TE, Karrer FM, et al. Adult living-donor liver transplantation using a right hepatic lobe. Transplantation 1998; 66(10):1313–1316. 20. Bassignani MJ, Fulcher AS, Szucs RA, et al. Use of imaging for living donor liver transplantation. Radiographics 2001; 21(1):39–52. 21. Fulcher AS, Szucs RA, Bassignani MJ, et al. Right-lobe living donor liver transplantation: preoperative evaluation of the donor with MR imaging. AJR Am J Roentgenol 2001; 176(6):1483–1491. 22. Imamura H, Makuuchi M, Sakamoto Y, et al. Anatomical keys and pitfalls in living-donor liver transplantation. J Hepatobiliary Pancreat Surg 2000; 7(4):380–394. 23. Kawarada Y, Das BC, Taoka H. Anatomy of the hepatic hilar area: the plate system. J Hepatobiliary Pancreat Surg 2000; 7(6):580–586. 24. Marcos A, Orloff M, Mieles L, et al. Functional venous anatomy for right-lobe grafting and techniques to optimize outflow. Liver Transpl 2001; 7(10):845–852. 25. Varotti G, Gondolesi GE, Goldman J, et al. Anatomic variations in right-liver living donors. J Am Coll Surg 2004; 198(4):577–582.

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26. Marcos A, Killackey M, Orloff MS, et al. Hepatic arterial reconstruction in 95 adult right-lobe living donor liver transplants: evolution of anastomotic technique. Liver Transpl 2003; 9(6):570–574. 27. Soin AS, Friend PJ, Rasmussen A, et al. Donor arterial variations in liver transplantation: management and outcome of 527 consecutive grafts. Br J Surg 1996; 83(5):637–641. 28. Kishi Y, Sugawara Y, Kaneko J, et al. Classification of portal vein anatomy for partial liver transplantation. Transplant Proc 2004; 36(10):3075–3076. 29. Tan HP, Marcos A. Hepatic arterial anatomy for right liver procurement from living donors. Liver Transpl 2004; 10(1):134–135. 30. Nakamura S, Tsuzuki T. Surgical anatomy of the hepatic veins and the inferior vena cava. Surg Gynecol Obstet 1981; 152(1):43–50. 31. Nakamura T, Tanaka K, Kiuchi T, et al. Anatomical variations and surgical strategies in right lobe living donor liver transplantation: lessons from 120 cases. Transplantation 2002; 73(12):1896–1903. 32. Huang TL, Cheng YF, Chen CL, et al. Variants of the bile ducts: clinical application in the potential donor of living-related hepatic transplantation. Transplant Proc 1996; 28(3):1669–1670. 33. Lim JS, Kim MJ, Kim JH, et al. Preoperative MRI of potential living-donor related liver transplantation using a single dose of gadobenate dimeglumine. AJR Am J Roentgenol 2005; 185(2):424–431. 34. Schroeder T, Malago M, Debatin JF, et al. “All-in-one” imaging protocols for the evaluation of potential living liver donors: comparison of magnetic resonance imaging and multidetector computed tomography. Liver Transpl 2005; 11(7):776–787. 35. Marcos A, Fisher RA, Ham JM, et al. Right-lobe living donor liver transplantation. Transplantation 1999; 68(6):798–803. 36. Tan HP, Marsh W, Marcos A. Liver resection using a saline-linked radiofrequency dissecting sealer for transection of the liver. J Am Coll Surg 2005; 201(1):152; author reply 3–4. 37. Miller CM, Masetti M, Cautero N, et al. Intermittent inflow occlusion in living liver donors: impact on safety and remnant function. Liver Transpl 2004; 10(2):244–247. 38. Makuuchi M, Kawasaki S, Noguchi T, et al. Donor hepatectomy for living related partial liver transplantation. Surgery 1993; 113(4):395–402. 39. Imamura H, Takayama T, Sugawara Y, et al. Pringle’s manoeuvre in living donors. Lancet 2002; 21–28; 360(9350):2049–2050. 40. Clavien PA, Yadav S, Sindram D, et al. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg 2000; 232(2):155–162. 41. Pitre J, Panis Y, Belghiti J. Left hepatic vein kinking after right hepatectomy: a rare cause of acute Budd-Chiari syndrome. Br J Surg 1992; 79(8):798–799. 42. Brown RS, Jr., Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med 2003; 348(9):818–825. 43. Lo CM. Complications and long-term outcome of living liver donors: a survey of 1,508 cases in five Asian centers. Transplantation 2003; 75(3 Suppl):S12–S15. 44. Marcos A, Orloff M, Mieles L, et al. Reconstruction of double hepatic arterial and portal venous branches for right-lobe living donor liver transplantation. Liver Transpl 2001; 7(8):673–679. 45. Tan HP, Madeb R, Kovach SJ, et al. Hypophosphatemia after 95 right-lobe livingdonor hepatectomies for liver transplantation is not a significant source of morbidity. Transplantation 2003; 76(7):1085–1088. 46. Sugawara Y, Makuuchi M, Kaneko J, et al. New venoplasty technique for the left liver plus caudate lobe in living donor liver transplantation. Liver Transpl 2002; 8(1):76–77. 47. Suehiro T, Ninomiya M, Shiotani S, et al. Hepatic artery reconstruction and biliary stricture formation after living donor adult liver transplantation using the left lobe. Liver Transpl 2002; 8(5):495–499. 48. http://www.valleylab.com/ 49. http://www.conmed.com/ 50. http://www.tissuelink.com/ 51. http://www.erbe-usa.com/

16

Donor Outcomes Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Abigail E. Martin and Arman Kilac Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Roberto Lopez and Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION According to the Organ Procurement and Transplantation Network (OPTN), 77,775 liver transplantations (74,682 deceased donors and 3093 living donors) were performed between January 1, 1988 and May 31, 2006 (1). Prior to 1999, less than 2% of these transplantations were performed utilizing living donors. By 2005, this percentage had more than doubled (4.6% or 323 of 7013) and living donor liver transplantation (LDLT) has been established as a viable alternative to deceased donor liver transplantation (DDLT). One-year and five-year unadjusted patient and graft survivals of DDLT are 86.8%, and 73.1%, and 82.2% and 66.9%, respectively (1). One-year and five-year unadjusted patient and graft survivals of LDLT are slightly higher at 87.7% and 77.4%, and 81.7% and 69.9%, respectively. One explanation for the rise in the proportion of live donor hepatectomies (LDHs) is that the procedure was extended to adult recipients in the mid-1990s, about six years after the first pediatric case was successfully done (2). As with all operations, but especially one that puts an otherwise healthy individual at risk, patient safety is of the utmost importance. A number of studies have been published regarding donor outcomes, and the reported mortality has been extremely low. The worldwide mortality for pediatric and adult LDHs has been estimated to be 0.13% and 0.2%, respectively (3). There are currently 19 documented donor deaths and one donor in a chronic vegetative state following LDLTs worldwide (4). The estimated total number of LDLTs performed worldwide is 7087. The estimated rate of donor death “definitely” related to donor surgery is (13/7087) or 0.18%, and the rate of donor death that is “definitely” (n = 13) or “possibly” (n = 2) related to the donor surgery is 15/7087 or 0.21% (Table 1). Reports on morbidities vary, especially for adult LDHs, but generally establish LDH as a safe procedure. The focus of this chapter is on donor outcomes, with an emphasis on publications reporting on larger patient populations. Donor morbidity and mortality are discussed, as well as specific contributing factors, such as surgeon experience and right versus left LDHs. CATEGORIZING COMPLICATIONS IN LIVE DONOR HEPATECTOMIES An universally accepted classification system for LDH complications would be ideal. This would allow accurate comparisons between studies and help establish trends in the assessment of morbidity. In 1994, Clavien and colleagues introduced a four-tiered classification system to describe complications observed in liver transplant recipients (5). Broering and colleagues recently modified the Clavien classification system to make it more suitable to describe complications in LDHs (2). This modified system consists of four grades of severity and is described in Table 2. Grade I consists of complications that are not life threatening and do not result in any significant morbidity, such as superficial wound infections or transient bile leaks. Grade II includes

186 TABLE 1

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Donor Mortality Worldwide Definitely, Possibly, or Unlikely Attributed to Donor Surgery

Country

Time post-op

Asia, #1, #2 Brazil, #3 Egypt, #4 Europe, #5 France, #6 Germany, #7, #8 India, #9 Japan, #10 U.S.A., #11 to #13 U.S.A., #14, #15 Germany, #16 Japan, #17, #18 U.S.A., #19

4 days, 70 days 7 days 30 days 21 days 14 days 2 days, 32 days 10 days 270 days 3 days, 3 days, 30 days 22 mo, 23 mo 11 yrs 3 yrs, 10 yrs 2 yrs

Cause MI, peptic ulcer CVA Sepsis Sepsis Sepsis PE, liver failure Unknown Liver failure Sepsis, unknown, sepsis Suicide, drug OD ALS Unknown, unknown MVA

Attributed to surgery D, D D D D D D, D D D D, D, D P, P U U, U U

Abbreviations: CVA, cerebral vascular accident; D, definite; MI, myocardial infection; MVA, motor vehicle accident; OD, overdose; P, possible; PE, pulmonary emboli; U, unlikely. Source: From Ref. 4.

complications that have the potential to be life threatening or those requiring drug therapy, but not requiring invasive corrective procedures and not resulting in significant disability. A typical example of a Grade II complication would be any infectious sequelae requiring antimicrobial treatment. Grade III complications are potentially life threatening, and also require some type of invasive intervention. For example, postoperative bleeding requiring relaparotomy would be categorized as Grade III, whereas bleeding that does not require a relaporotomy would be classified as Grade II. Grade IV injuries result in either lasting disability or death, such as a LDLT donor who subsequently develops liver failure and requires a liver transplantation. Most complications will be Grade I or II, as evidenced by Broering’s study, where approximately one-third of complications were Grade I, one-third were Grade II, and one-third were Grade III or IV (2). PEDIATRIC LIVING DONOR LIVER TRANSPLANTATION Historically, living donors were utilized for pediatric LDLT several years before living donation was available to adult recipients (2). The procedure was developed as a way to address the shortage of appropriate size matched deceased donors available to children on the liver transplant waiting list. Whereas donors typically undergo a left lobectomy (LL, segments II to IV) or a left lateral segmentectomy (LLS, segments II and III) for a pediatric recipient, donating for an adult recipient often requires a donor to undergo a right lobectomy (RL, segments V to VIII) to ensure adequate liver mass for the recipient. Over the past 15 years, a number of studies have been published describing the outcomes in donors following either LL or LLS. The data are summarized in Table 3. The University of Chicago published their first series on pediatric LDLT in 1991, following the world’s first successful LDLT in 1989 (6). The donor group in this initial study consisted TABLE 2 Modification of Clavien Classification for Donor Hepatectomies Complications Following Living Donor Liver Transplantation Grade I II III IV

Definition of complication Non-life-threatening, does not result in residual disability, does not require therapeutic intervention or drugs. Potentially life threatening, requires use of drug therapy or >1 foreign blood unit, but does not require therapeutic invasive therapy and does not result in residual disability. Potentially life threatening, requires therapeutic invasive intervention, use of drugs, foreign blood, and/or leads to readmission into the ICU, but does not lead to residual disability. Leads to residual disability and/or death.

Source: From Ref. 2.

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TABLE 3 Morbidities in Left Lobectomy and Left Lateral Segmentectomy in Pediatric Living Donor Liver Transplantation Authors Grewal (1998) (7)

Lo (2003) (9)

Wiederkehr (2004) (8)

n

Major morbidities (%)

Minor morbidities (%)

Total morbidities (%)

Hospital stay (days)

100 9 LL 91 LLS 939 334 LL 605 LLS 60

14 — — — — — —

20 — — — — — —

34 — —

6.8 7.6 6 — — — 9.5

7.5 9.3 11.7

Abbreviations: LL, left lobectomy; LLS, left lateral segmentectomy.

of 12 mothers, seven fathers, and one grandmother, and the results were excellent. Minimal complications were present in the first three cases where LLs were performed. When the procedure was changed to LLSs in the final 17 cases, no complications were encountered. Donor mortality within 18 months was 0%, and the median hospital stay was six days (6). Since that time, a handful of studies with relatively large numbers of patients have been published. Grewal and colleagues expanded the series at the University of Chicago and reported their experience in 100 living-related donors between November 1989 and November 1996 (7). Of these 100 LDHs, 91 were LLSs and nine were LLs. The mean hospital stay for the entire group was 6.8 days (4 to 20 days); however, there was a marked reduction from 7.6 to 6 days (p < 0.001) between the first 50 donors and the second 50 donors. There were 14 major and 20 minor complications reported in this series, accounting for an overall complication rate of 34%. The major complications included seven biliary complications, one hepatic artery thrombosis, one intra-abdominal abscess, one splenectomy, one perforated duodenal ulcer, one gastric outlet obstruction, and two wound dehiscences. Five patients required reoperation. Donor hospital mortality was 0% (7). Wiederkehr and colleagues published 60 consecutive pediatric LDLT cases performed in Brazil (8). Four donors (6.7%) developed temporary biliary fistulas, and one of these patients required endoscopic papillotomy and surgical drainage. Other complications included one incisional hernia (1.7%), one pneumonia (1.7%), and one deep venous thrombosis (1.7%). The mean hospital stay was 9.5 days, and all donors survived (8). Lo reported on the LDLT experience of five major transplant centers in Asia (9). This survey included donors for pediatric and adult recipients, but categorized the donors into groups based on the type of resection rather than the age of the recipient. In this series, 334 LLs and 605 LLSs were performed, with a 7.5% and 9.3% overall complication rate, respectively. Biliary leakage or stricture and wound infections were the most common complications. Biliary complications were present in 2.4% and 5.6% of patients, respectively, and wound infections in 3.0% and 1.5% of patients, respectively. Other complications included gastric outlet obstruction, small bowel obstruction, pneumonia, hyperbilirubinemia, pancreatitis, bleeding duodenal ulcer, and gastric perforation. There were no reported mortalities (9). These studies demonstrated that LDHs for pediatric recipients (LLSs for younger and LLs for older pediatric recipients) are relatively safe, but have significant complications occurring in over 7% of donors. Renz and colleagues reported in their review that donor hospital stays were routinely less than 10 days with overall complication rates between 15% and 20% (3). Biliary complications were most frequent, occurring in 5% to 10% of patients. Overall, donor morbidity and mortality in pediatric cases is minimal, suggesting that LDLT is a viable alternative when suitable organs are not available. ADULT LIVING DONOR LIVER TRANSPLANTATION Following the establishment of pediatric LDLT as a safe procedure for donors, the operation was expanded to include adult recipients several years later. Initially, transplant surgeons performed LLS and LL on the donors, offering the same donor surgery as for pediatric LDLT (2).

188 TABLE 4

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Morbidities and Mortalities in Three Large Multicenter Studies of Donor Right Lobectomy

Authors

n

Major morbidities (%)

Minor morbidities (%)

Overall morbidity (%)

Mortality (%)

Broelsch (2000) (12) Lo (2003) (9) Brown (2003) (13)

123 561 449

17.8 — —

14 — —

31.8 28 14.5

0.8 0 0.2

When this practice was extended to adults in the 1990s, the result was recognition of smallfor-size syndrome, a syndrome in recipients in which the transplanted liver tissue does not provide enough mass for sufficient metabolic function, leaving the recipient with residual liver failure (10). As early as 1994, some centers reported performing RLs in the donors to prevent this syndrome from developing in recipients (11). Currently, donors in adult-to-adult LDLT typically undergo a RL, and substantial research has been conducted to investigate the outcomes in these donors following RL. Three multicenter studies are discussed in this section, and the results are summarized in Table 4. The Asian LDLT experience was reviewed by Lo and included 561 donors who underwent a RL (9). The overall complication rates were 28%, and the most frequent complications were hyperbilirubinemia (7.3%), biliary leakage (6.1%), and wound infection (4.6%). There was no donor mortality (9). Broelsch et al. and Brown et al. reported the European and American RL experiences, respectively (12,13). The European survey consisted of 11 transplant centers operating on a total of 123 donors. Minor and major complications were present in 14% and 17.8% of patients, respectively, resulting in an overall complication rate of 31.8%. There was one donor death, resulting in a mortality rate of 0.8% (12). The American survey consisted of 42 centers with a total of 449 RL donors, accounting for nearly all adult-to-adult LDLTs in the United States in the period between 1997 and 2000. The overall complication rate was 14.5%, with the most common being biliary leakage (6.0%). There was one donor death (mortality rate of 0.2%), and 4.5% of donors required reoperation. The median length of stay was only six days (13). These large series multicenter studies suggest that donor outcomes vary for RL, but there is a higher morbidity rate than with LL and LLS. Beavers and colleagues found in their review that donor morbidity after RL ranged from 0% and 67%, and concluded that published data vary widely in this particular operation (14). Lo and colleagues, in the largest direct comparison available, reported an almost three-fold increase in complications when comparing RL donation (28%) with LL donation (9.3%) or LLS donation (7.5%) (9). Similarly, Dondero and associates compared LL with RL donors and found overall complication rates of 32% and 66%, respectively (15). In light of the documented increased risk for donors undergoing RL, several authors have encouraged either more stringent criterion for accepting potential donors undergoing RL (3) or a re-evaluation of the use of LL and LLS for potential donors (15). In a three-year period from March 2003 to February 2006, a total of 114 LDHs were performed at the University of Pittsburgh, resulting in 98 adult LDLT and 16 pediatric LDLT (16). No mortality was reported, and donor morbidities were 8.8 % (n = 10). Grade I complications were present in 4.4% (n = 5), including three bile leaks (all managed conservatively), one case with prolonged elevated liver function tests (LFTs), and one narcotic psychosis. Grade II complications occurred in 4.4% (n = 5), including two cases of transfusion (one unit of packed red blood cells each), one pneumonia, one deep venous thrombosis, and one incisional hernia. There were no Grade III or IV complications. The mean donor hospital stay was seven days. Similar morbidities were reported with an earlier group of 95 RL LDHs performed between July 2000 and May 2002 (17). MIDDLE VEIN RECOVERY The venous drainage of a RL graft depends upon the right hepatic vein and the veins of segments V and VIII, which are drained by the middle hepatic vein (MHV). There is a current controversy regarding the recovery of the MHV, as it is technically challenging and may lead to impaired function in the remaining portion of donor liver because of partial venous congestion. At least two studies have examined the effect of MHV recovery on donor outcomes.

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FIGURE 1 Preoperative and postoperative (A) bilirubin levels, (B) prothrombin time ratio, (C) alanine aminotransferase levels and kinetics, and (D) aspartate aminotransferase levels and kinetics according to whether the middle hepatic vein was harvested (◆) or not (●). Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; BILI, bilirubin; PT, prothrombin time. Source: From Ref. 18.

Scatton and colleagues compared the outcomes of 21 donors undergoing MHV recovery with 20 donors who underwent RL donation without MVH recovery (18). The authors stated that there were no significant differences between the groups with regard to complications or mean hospital stay. Also, no differences existed when LFTs and early regeneration index (ERI) were compared. The LFTs from this study are shown in Figure 1 (18). Cattral and colleagues reported similar results in their study of 28 donors with MHV recovery versus 28 donors without (19). Morbidities did not differ significantly between the groups, and data from both studies are summarized in Table 5. The peak prothrombin time (PT) [international normalized ratio (INR)] was significantly higher in the group with MVH recovery; however, time to normalization was similar in both groups. No differences existed between the groups in other LFTs and mean hospital stays (19). ROLE OF SURGEON EXPERIENCE The outcomes of most, if not all, operations are better as more experience is gained with the technical aspects of the operation, as well as management of the postoperative patients. LDH is TABLE 5

Morbidities with or Without Middle Hepatic Vein Harvesting

Authors

n

Pulmonary morbidities (%)

Biliary morbidities (%)

Overall morbidities (%)

Scatton (2004) (18) With MHV Without MHV Cattral (2004) (19) With MHV Without MHV

41 21 20 56 28 28

— 28.5 35 — 7.1 10.7

— 4.7 20 — 0 10.7

— 36 55 — 32.1 46.4

Abbreviation: MHV, middle hepatic vein.

190 TABLE 6

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Role of Surgeon/Transplant Center Experiences in Morbidities of Live Donor Hepatectomies

Author Grewal (1998) (7) First 50 donors Second 50 donors Broering (2003) (2) 1991–1995 1996–2000 2000–2003

n

Major morbidities (%)

Minor morbidities (%)

Total morbidities (%)

Hospital stay (days)

100 50 50 165 52 47 66

14 — — — — — —

20 — — — — — —

34 48 20 27.3 53.8 23.4 9.2

— 7.6 6.0 — 11.4 7.3 5.9

no exception. Two important studies reporting on the effect of experience on complication rates are discussed in this section, and the results of these studies are summarized in Table 6. Grewal and colleagues reported on the results of 100 donors undergoing LL or LLS between November 1989 and November 1996 at the University of Chicago (7). The overall complication rate was 34%; however, the complication rate dropped significantly between the first 50 donors (48%) and the last 50 donors (20%). Other significant reductions between the two groups were noted in mean surgical time (312 minutes to 234 minutes) and mean hospital stay (7.6 days to 6 days) (7). Broering and colleagues conducted an analysis of 165 cases from January 1991 to August 2003 at the University of Hamburg-Eppendorf (2). The study was divided into three periods: 1991–1995 (period 1), 1996–2000 (period 2), and 2001–2003 (period 3). Donor morbidity was classified according to the modified Clavien classifications as in Table 2. The overall morbidity rate for the 165 donors was 27.3%. This rate decreased significantly from period 1 (53.8%) to period 2 (23.4%), and was the lowest in period 3 (9.2%). The mean hospital stay also declined from 11.4 days (period 1) to 7.3 days (period 2) to 5.9 days (period 3) (2). These two studies suggest, as would be expected, that surgeon and transplant center experience play an extremely significant role in complication rates and morbidity. Therefore, measures aimed at optimizing donor outcomes would need to be rooted in the training and practice of the specific surgical procedure. POSTOPERATIVE LIVER FUNCTION TESTS AND REGENERATION IN DONORS Kokudo et al. recently published a consecutive 200 patient series from the University of Tokyo (20). The outcomes that were measured included LFTs. It was found that the postoperative serum total bilirubin (TB) was significantly elevated in RL grafts versus non-RL grafts (20). PT was also significantly higher in RL grafts. Aspartate aminotransferase (AST) was significantly reduced in the RL graft group, and there was a trend toward a lower alanine aminotransferase (ALT) level in the RL group (p = 0.059). The results are shown in Table 7. Choi and colleagues found levels of AST, ALT, PT, and TB peak one to two days postoperatively (21). Serum AST and ALT levels were similar between RL and non-RL groups, whereas PT and TB were significantly higher in the RL group one week following surgery. All levels normalized and were similar between groups one month postoperatively (21).

TABLE 7 Comparison of Donor Liver Function Tests Between Right Lobectomy and Non-Right Lobectomy Groups Donor parameters Maximal postoperative levels Total bilirubin (mg/dL) Prothrombin time (INR) Alanine aminotransferase (U/L) Aspartate aminotransferase (U/L) Abbreviation: INR, international normalized ratio.

Right lobectomy grafts (n = 114)

Non-right lobectomy grafts (n = 86)

p-Value

2.21 ± 0.09 1.77 ± 0.03 203 ± 7 212 ± 9

1.79 ± 0.10 1.47 ± 0.02 246 ± 15 298 ± 19

<0.0001 <0.0001 0.059 <0.0001

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FIGURE 2 Overall donor remnant liver regeneration. Forty-three donors with complete data were included in the statistical evaluation. All time points are statistically different when compared with previous visit (P < 0.01). Source: From Ref. 22.

Pomfret and colleagues performed a study on the liver regeneration of 43 donors of RL grafts (22). Donor residual volume was 49.4 ± 5.7% and the liver regenerated to 83.4 ± 9.0% of the original volume by one year. Gender was the only factor shown to have an impact on liver regeneration, with female donors having significantly slower regeneration (p < 0.01). The volume regeneration curve from this study is shown in Figure 2 (22). MORTALITY When considering LDHs, the potential morbidity and mortality is of the utmost importance since these patients are otherwise healthy individuals. In January 2002, the unexpected death of a living-related liver donor at Mt. Sinai hospital in New York prompted a temporary suspension of their LDLT program as well as a public debate about the ethical dilemma of subjecting potential donors to this risk. One paper estimates that there have been about seven donor deaths in the United States related to living liver donation (23). Middleton and colleagues performed a review of 214 studies involving more than 6000 procedures, and they found an overall donor mortality rate of 0.2% (24). When looking specifically at RL donors, however, the mortality was slightly higher, and was estimated to be 0.23% to 0.5% (24). QUALITY OF LIFE AFTER DONATION No discussion of donor outcomes would be complete without discussing the impact on their long-term quality of life. Most studies that address this question measure quality of life using the Medical Outcomes Study Short-Form Health Survey (SF-36), a 36 question self-administered survey that assesses quality of life in eight domains that encompass both physical and psychological impact on the patient (3,25–28). The eight domains include mental health, emotional limits, social function, vitality, physical function, physical limits, pain, and general health. With liver donors, most of these surveys are limited by the low number of respondents, usually numbering less than 50 (25–28). Most donors express satisfaction with their overall experience, as evidenced by the fact that their responses on the SF-36 indicated scores that were similar to control group responses (25–28). Most donors report full recovery approximately three months after surgery (27), and by one year, 100% report full recovery (3). The only survey that directly compared donors undergoing RL with LLS donors found that recovery times to predonation activity levels for donors undergoing RL were longer (66 days versus 55 days), as was time off work (61 days versus 32 days). However, all other measurements of quality of life were similar (28). In the specific areas of mental and general health, donors whose recipients had no significant complications scored better than the general population; whereas donors whose recipients did suffer major complications scored lower (26). When asked if they would donate again, more than 90% responded that they would do so (27,28).

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FINANCIAL ASPECT Each donor will have a different financial situation. Despite this, it is important to comment on potential costs the donor may incur. The United Network for Organ Sharing (UNOS) Web site provides comprehensive insight into this particular aspect of LDLT, and the information contained herein is a summary of that insight. According to UNOS, the donor should not incur any costs regarding the initial evaluation. Either the recipient’s insurance or the transplant centers organ acquisition fund (OAF) covers the screening. However, if any health concerns arise during the evaluation, these will not be covered and are the responsibility of the donor. Both the donor surgery and postoperative care are routinely covered by an inclusive fee that the transplant center charges to the recipient’s insurance. There may be lost wages related to an inability to work during the postoperative recovery period. In some instances, employers provide donors with disability or paid leave, but this is not always the case. Other potential costs that the donor may incur include travel to the transplant center, accommodations during travel, and other nonmedical costs. Twelve states have passed legislation and another 20 states are considering legislation that allows for compensation of donors who are required to leave work. These either provide a paid leave of absence for state employees or a $10,000 state tax deduction for those who donate (Tables 8 and 9). At the federal level, the Organ Donation and Recovery Improvement Act (H.R. 3926) was signed into law April 5, 2004, although the funds have not yet been appropriated. This law provides federal financial aid to donors to help with nonmedical costs such as travel and lodging. As for post-donation insurability, most living donors are not restricted by insurance companies. However, there have been instances where higher premiums or waiting periods have made changing insurance carriers difficult for donors. Donors are urged to discuss these matters with financial advisors at the transplant center as each situation is unique. DISCUSSION Because of the tremendous obstacles faced by the pediatric population to find a suitable size allograft and the increasing scarcity of deceased donor livers for adults, living related donation TABLE 8

States Considering Legislation

State California Connecticut Florida Hawaii Illinois Indiana Louisiana Maryland Michigan Missouri New Jersey New York North Carolina Ohio Oregon Pennsylvania South Carolina Texas Vermont Washington Source: From Ref. 1.

Legislation $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction (HB 5808, authored by Rep. Carson) $10,000 Organ Donation Tax Deduction Leave of absence for organ and bone marrow donors Organ Donor Leave (HB 324) and $10,000 Organ Donation Tax Deduction (HB 262) $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction(SB 26, authored by Sen. McPherson) $10,000 Organ Donation Tax Deduction, (SB 443, authored by Sen. Hollinger) $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction (SB 44, authored by Sen. Wheeler) $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction (A01612) and leave of absence for organ or bone marrow donation granted to state employees (A03934) $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction (HB 156, authored by Rep. Wagner) $10,000 Organ Donation Tax Deduction, (HB 2692, authored by Rep. Marsh) Leave of absence for organ and bone marrow donors (HB 153) and deduction for contributions for organ and tissue donation awareness (SB 231) $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction $10,000 Organ Donation Tax Deduction

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TABLE 9

States with Legislation Already Passed

State Arkansas Georgia Iowa Minnesota Missouri New Mexico North Dakota Ohio Oklahoma

Utah Virginia

Wisconsin

Law $10,000 Organ Donation Tax Deductiona $10,000 Organ Donation Tax Deductiona $10,000 Organ Donation Tax Deductiona $10,000 Organ Donation Tax Deductiona $10,000 Organ Donation Tax Deductiona $10,000 Organ Donation Tax Deductiona $10,000 Organ Donation Tax Deductiona Liver, kidney, or bone marrow donor leave Organ Donor Education and Awareness Program (ODEAP)

$10,000 Organ Donation Tax Deductiona Paid Leave of Absence

Comments Signed into law on March 9, 2005. Signed into law on April 29, 2004. Signed into law on May 12, 2005. Signed into law on July 14, 2005. Effective January 1, 2006. Signed into law on April 5, 2005. Signed into law on March 14, 2005. Signed into law in 2002. Signed into law in May 2002. Provides for 30 days of paid leave for state employees who provide verification that they will become organ donors. It also provides that a state agency shall not penalize an employee who asks for leave under the provisions of the law. And, that seniority, pay or pay advancement, performance awards and employment benefits will not be affected by the paid leave, if taken. Signed into law on March 21, 2005. State employees are allowed up to thirty days of paid leave in any calendar year, in addition to other paid leave, to serve as bone marrow or organ donors.

$10,000 Organ Donation Tax Deduction and Paid Leave of Absence

aLaw

allows living-organ donors to deduct as much as $10,000 on their state income taxes for travel, lodging, and lost wages related to the donation. The law applies to donations of a liver, pancreas, kidney, intestine, or bone marrow from living donors only. Source: From Ref. 1.

has increased substantially over the last decade. The pediatric population has benefited the most, as living related donation is a well-established option to DDLT, yielding excellent results in both donor and recipient. Living donation offers a suitable alternative to those adults who are not favored by the current allocation system; they can simultaneously benefit more as a function of their overall health condition. Patients with few and mild manifestations of portal hypertension fall into this population. On the other hand, the patients with severe hepatic decompensation will present with grimmer outcomes. However, a surgical procedure (LDH) of this magnitude in a healthy population comes with a considerable price in the form of significant morbidities and as with any major surgery, the ever-present but low risk of death. Thus, it cannot be stressed enough that every possible precaution must be taken to reduce morbidity and mortality. Unfavorable results are often related to the surgical procedure itself and not to any previous medical conditions; consequently, this risk can be minimized with improvements in surgical and anesthetic techniques. However, the risk of complications will never be completely eliminated. Once the results prove to be consistently positive for both the donor and the recipient, the risk and the benefits will be balanced. An effort to establish donor selection and evaluation guidelines has been made by the Live Organ Donor Consensus Group (29), The National Institute of Health (30), The American Society of Transplant Surgeons (31), and by the Thomas E. Starzl Transplantation Institute (32), echoing the demands of society and the medical community. However, an improved collecting and reporting data system is clearly needed on a national and international basis. A standardized live donor hepatectomy complication classification scheme is urgently needed

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for standardize reporting. Living donation reached its highest level in the beginning of this millennium and has since declined for unknown reasons. There have been seven reported liver donor deaths in the United States, and this probably contributed to its decline (23). So far, living liver donation has proved to be a significant achievement by the transplant community, offering excellent results to a select group of patients. However, only a precise analysis of consistently collected data will provide the information that will lead to the broader recognition and acceptance of this modality. REFERENCES 1. http://www.optn.org (assessed August 9th, 2006). 2. Broering DC, Wilms C, Bok P, et al. Evolution of donor morbidity in living related liver transplantation: a single-center analysis of 165 cases. Ann Surg 2004; 240:1013–1024. 3. Renz JF, Roberts JP. Long-term complications of living donor liver transplantation. Liver Transpl 2000; 6(6 suppl 2):S73–S76. 4. Kenison JR, Adam R, Lo CM, et al. Nineteen donor deaths following living donor liver transplantation: review of the worldwide literature. World transplant Congress, Boston, 2006; 116. 5. Clavien PA, Camargo CA Jr, Croxford R, et al. Definition and classification of negative outcomes in solid organ transplantation: application in liver transplantation. Ann Surg 1994; 220:109–120. 6. Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living related donors: surgical techniques and results. Ann Surg 1991; 214:428–437. 7. Grewal HP, Thistlewaite JR Jr, Loss GE, et al. Complications in 100 living-liver donors. Ann Surg 1998; 228:214–219. 8. Wiederkehr JC, Schuller S, Camargo CA, et al. Results of 60 consecutive hepatectomies for pediatric living donor liver transplantation. Transplant Proc 2004; 36:918–919. 9. Lo CM. Complications and long-term outcome of living liver donors: a survey of 1,508 cases in five Asian centers. Transplantation 2003; 75(3 Suppl):S12–S15. 10. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic observations and histopathologic recognition of the portal hyper-perfusion or small-for-size syndrome. Am J Surg Pathol 2006; 30:986–993. 11. Yamaoka Y, Washida M, Honda K, et al. Liver transplantation using a right lobe graft from a living related donor. Transplantation 1994; 57:1127–1130. 12. Broelsch CE, Malago M, Testa G, et al. Living donor liver transplantation in adults: outcome in Europe. Liver Transpl 2000; 6(6 suppl 2):S64–S65. 13. Brown RS Jr, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med 2003; 348:818–825. 14. Beavers KL, Sandler RS, Shrestha R. Donor morbidity associated with right lobectomy for living donor liver transplantation to adult recipients: a systematic review. Liver Transpl 2002; 8:110–117. 15. Dondero F, Farges O, Belghiti J, et al. A prospective analysis of living-liver donation shows a high rate of adverse events. J Hepatobiliary Pancreat Surg 2006; 13:117–122. 16. Tan HP, Marsh JW, Tom K, et al. Living donor hepatectomies: program experience and lessons learned. World Transplant Congress 2006, Boston, 707. 17. Tan HP, Madeb R, Kovach SJ, et al. Hypophosphatemia after 95 right-lobe living-donor hepatectomies for liver transplantation is not a significant source of morbidity. Transplantation 2003; 76:1085–1088. 18. Scatton O, Belghiti J, Dondero F, et al. Harvesting the middle hepatic vein with a right hepatectomy does not increase the risk for the donor. Liver Transpl 2004; 10:71–76. 19. Cattral MS, Molinari M, Vollmer CM, et al. Living-donor right hepatectomy with or without inclusion of middle hepatic vein: comparison of morbidity and outcome in 56 patients. Am J Transplant 2004; 4:751–757. 20. Kokudo N, Sugawara Y, Imamura H, et al. Tailoring the type of donor hepatectomy for adult living donor liver transplantation. Am J Transplant 2005; 5:1694–1703. 21. Choi SJ, Gwak MS, Kim MH, et al. Differences of perioperative liver function, transfusion, and complications according to the type of hepatectomy in living donors. Transpl Int 2005; 18:548–555. 22. Pomfret EA, Pomposelli JJ, Gordon FD, et al. Liver regeneration and surgical outcome in donors of right-lobe liver grafts. Transplantation 2003, 76:5–10. 23. Surman OS. The ethics of partial-liver donation. NEJM 2002; 346:1038. 24. Middleton PF, Duffield M, Lynch SV, et al. Living donor liver transplantation—adult donor outcomes: a systematic review. Liver Transpl 2006; 12:24–30. 25. Basaran O, Karakayali H, Emiroglu R, et al. Donor safety and quality of life after left hepatic lobe donation in living-donor liver transplantation. Transplant Proc 2003; 35:2768–2769. 26. Kim-Schluger L, Florman SS, Schiano T, et al. Quality of life after lobectomy for adult liver transplantation. Transplantation 2002; 73:1593–1597. 27. Karliova M, Malago M, Valentin-Gamazo C, et al. Living-related liver transplantation from the view of the donor: a 1-year follow-up survey. Transplantation 2002; 73:1799–1804.

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28. Humar A, Carolan E, Ibrahim H, et al. A comparison of surgical outcomes and quality of life surveys in right lobe versus left lateral segment liver donors. Am J Transplant 2005; 5:805–809. 29. Authors for the live organ donor consensus group. Consensus statement on the live organ donor. J Am Med Assoc 2000; 284:2919–2926. 30. Shiffman ML, Brown RS, Olthoff KM, et al. Living donor liver transplantation: summary of a conference at the National Institute of Health. Liver Transpl 2002; 8:174–188. 31. American society of transplant surgeons: ethics committee. American Society of Transplant Surgeons’ position paper on adult to adult living donor liver transplantation. Liver Transpl 2000; 6:815–817. 32. Tan HP, Tom K, Marcos A. Adult living donor liver transplantation: who is the ideal donor and recipient? J Hepatol 2005; 43:13–17.

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Recipient Outcomes After Living-Donor Liver Transplantation James J. Pomposelli, Elizabeth A. Pomfret, and Roger L. Jenkins Division of Hepatobiliary Surgery and Liver Transplantation, Lahey Clinic Medical Center, Burlington, Massachusetts, U.S.A.

INTRODUCTION Historical Perspective Living-donor liver transplantation (LDLT) has evolved as a surgical innovation to address the issue of organ shortages. After the first published report of a live-donor liver transplant by Raia et al. in 1989 (1), Broelsch et al. soon followed with publication of the first series of 20 successful cases of LDLT in children at the University of Chicago (2). Anticipating the ethical debate that would follow with any new surgical innovation (3), the University of Chicago group performed a “research ethics consultation” to determine if such procedures were ethically appropriate (4). Since that time, LDLT has matured significantly, especially in countries where deceased donors are extremely rare or absent because of societal, religious, or moral issues. Improvements in pre-operative donor assessment, imaging technology, surgeon experience, and postoperative care have steadily improved outcome. Transplant recipients of live-donor liver grafts now enjoy patient and graft survival that equal or exceed those observed with deceased donors (5). The major disadvantage of live donation is the risk of donor morbidity and mortality (6–9). This chapter reviews the outcome of LDLT stratified by the graft type. We discuss the importance of program experience and maturation through the development of “field strength,” which ultimately improves donor safety and recipient outcome. A comprehensive multidisciplinary team approach to donor and recipient pre-operative evaluation with accurate liver volumetric measurement, standardized graft procurement procedures, and subsequent postoperative care have led to the best opportunity for favorable outcomes. LEFT LATERAL SEGMENT GRAFT The major impetus to perform LDLT has always been the organ shortage. The initial attempts at splitting a liver into smaller usable parts began with “reduced-sized” grafts of the left lateral segment and the left hepatic lobe from deceased donors (10–13). Since organ availability for the pediatric patient was even more restricted than for adults, the concept of “reduced-sized” liver transplantation evolved, and favorable results made it a viable option when whole organs of appropriate size were not available (12). The reduced size graft, however, disadvantaged the adult waiting list since the remnant liver was often destroyed and not useable. The first demonstration of a true left-right split graft for transplanting two adult recipients was introduced by Bismuth et al. to salvage two patients with fulminant hepatic failure (14). Despite the fact that the patients survived only 20 and 45 days, respectively, the era of “split-liver” transplantation was underway, and helped set the stage for LDLT as we know it today. The first “live donor” series of 20 liver transplant procedures was published by Broelsch et al. from the University of Chicago using three left lobes and 17 left-lateral segment grafts in children (2). Initial results were excellent, with a recipient operative mortality of approximately 15% and overall graft survival of 75%. Hepatic artery thrombosis (HAT) was problematic and occurred in 20% of patients, and resulted in retransplantation in patients experiencing this complication. In the Broelsch et al. series, donor morbidity was low in left-lateral segment donors, with nearly all the complications occurring in the three left lobe donors. After modifying the

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procedure of the left-lateral segment-graft procurement, donor morbidity was minimal, yet liver function and recovery in the recipient remained acceptable. The Chicago group continued to refine its technique, and was able to reduce the incidence of HAT to 10% with actuarial twoyear patient and graft survival rates of 89% and 76%, respectively (15). Despite these excellent results, the obvious disadvantage of LDLT was the risk to the donor. Otte et al. initiated a LDLT program for children when their program noted that the waiting list mortality was increasing despite innovations such as reduced sized and split liver transplantation (16). Over a four-year period, 53 live donor transplants using left-lateral segment grafts were performed in children, with 90% survival. Subsequently, Rogiers et al. demonstrated that two functional grafts could be obtained from a deceased donor through in situ splitting that would safely serve the needs of a small pediatric patient using the left-lateral segment graft and an adult using the extended right lobe graft (17). The excellent patient and graft survival of 92.8% and 85.7% at six months observed by Rogiers et al. convinced many that LDLT for children was no longer necessary, except in countries where societal and religious beliefs prevented the use of deceased donors. In these latter countries, the application of LDLT grew rapidly (18). Current results with in situ split grafts suggest that there is no penalty to either the recipient of the left lateral segment (19) or the extended right lobe graft in terms of patient and graft survival (93% at one and three years) (20). These results support the conclusion of Rogiers et al. that LDLT in infants should be minimized by more aggressive splitting programs utilizing deceased donors (17), which also has had the additional benefit of significantly reducing the pediatric waiting list time and mortality (21,22).

LEFT LOBE GRAFT The first report of left-lobe liver transplantation was anecdotal (23,24). The experience necessary for developing surgical techniques for successful LDLT utilizing left lobe grafts was achieved with a combination of experimental anatomic studies (25), transplantation in dogs (26,27) and using reduced-sized deceased-donor grafts in humans (28). The initial clinical report of a successful LDLT using a left lobe graft was in an adolescent with fulminant hepatic failure, who received a graft from his father (29). Both the donor and recipient did well, and the authors concluded that LDLT should be expanded to include adults (29). Shortly thereafter, the first miniseries of left lobe grafts transplanted into three children between the ages of 11 and 13 with fulminant hepatic failure was reported (30). As LDLT was gradually applied to adults (31), “small for size” syndrome began to surface (32,33). In addition, the problem of graft loss associated with the sacrifice of the segment IV arterial and portal venous supply in many donors resulted in further appreciation of the essential vascular anatomy necessary for the success of the partial liver graft (34,35). Despite these problems, results with left lobe grafts remained acceptable and ushered in the era of LDLT in adults utilizing both right and left lobe grafts (31,36–41). The importance of graft size as it relates to recipient outcome was reported by Kyoto University (42). In this study, grafts that were less than 0.8% graft weight to body weight ratio (GW/BW) had significantly worse graft survival (42% actuarial one-year survival) compared with larger grafts (1–3% GW/BW, 92% survival) (42). Ben-Heim et al. took the observation one step further, and noted that healthy recipients can tolerate smaller grafts, whereas critically ill patients need more liver tissue (43). For this reason, there was a gradual evolution toward the utilization of right lobe grafts since they provide the recipient with more liver volume. The disadvantage of right lobe grafting was associated with the risk of complications in the donor (44–46). Since deceased donation is limited or absent for religious and/or societal reasons in much of Asia, it is not surprising that the largest series of LDLT in adults has been performed in Asia (40,47–49). At this time, the University of Kyoto has performed well over a 1000 LDLTs to date. Therefore, it is not surprising that the Kyoto group was the first to report a comparison of various segmental grafts used in 470 cases performed between 1990 and 1999 stratified by graft type (18). Of these, 45 were extended left-lateral segment grafts not including the middle hepatic vein (MHV), 99 grafts were formal left-lobe grafts that included the MHV, and 43 were right

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lobe grafts (18). In this series, patient and graft survival were similar in all groups; however, there was a tendency for donors of right lobe grafts to have a longer length of stay and more biliary leaks compared with left lobe grafts (18). As experience increased with LDLT, the influence of various parameters on outcome began to be appreciated. The relationship of graft size to standard liver volume (SLV) in terms of outcome was reported by Lo et al., and determined that a graft size less than 40% of the SLV was associated with significantly worse recipient outcomes (50). In addition, the issue of donor age after left lobe donation suggested that donors older than 50 years had worse liver regeneration and function initially (51). However, Pomfret et al. found no association of age with liver regeneration in right lobe donors (52). In an attempt to increase graft size, the addition of the caudate lobe with the left lobe graft increased graft size by approximately 2% and reduced blood loss in the donor (53). Interestingly, regeneration in the caudate lobe occurred, despite the fact that venous drainage was not restored (54). Since each graft type has advantages and disadvantages in terms of the relative impact on the donor and recipient, the concept has been advanced that graft size can be tailored to the recipient’s need to help avoid unnecessary harm to the donor (55). Another strategy for increasing graft volume is the use of “dual grafts” consisting of two left lobes from separate donors (56,57). Technically, this is a challenging operation, since one of the grafts is implanted upside-down. Obviously, much of the difficulty associated with inadequate liver volume utilizing the left lobe graft have been solved by use of right lobe grafts. In Asia and Japan, where adult recipients are generally smaller than their Western counterparts, the left lobe graft has remained popular and has provided excellent results. Many authors have moved to use right-lobe liver grafts in order to increase volume (57–59) despite the risk of increased donor morbidity compared with left sided grafts (60). As experience with both left and right lobe grafts increases, multivariate analysis identified several features related to outcome that suggest that a GW/BW ratio of less than 0.8, an intraoperative blood loss greater than six units, left lobe grafts, and an increased donor age are all significant independent risk factors for worse outcomes (61). Of all these parameters, graft size has proven to be the most important, especially in critically ill recipients, and has resulted in the steady evolution of utilizing right lobe grafts for adult-to-adult LDLT. RIGHT LOBE GRAFT The first published report of a LDLT utilizing a right lobe was in 1992, in a child receiving the right lobe donated from his parent (62). This was a single case in a report of a larger 20-case series utilizing 11 left lobes and eight left lateral segment grafts. An additional single case was reported from Japan a year later as part of a larger series (63,64). As of 1995, approximately 100 cases of LDLT, primarily in children, had been performed (65), with only a few cases reporting the use of right lobe grafts. Lo et al. published the first series of LDLT using extended right lobe grafts that included the MHV (66). In this series, seven critically ill, ICU-bound patients were transplanted with an operative morbidity of 86% but with a mortality of only 14%. While the left lobe and left-lateral segment grafts had been favored for the majority of patients in Japan prior to this series, the superb outcome achieved by Lo et al. in this small but important series opened the door for the right lobe graft to become the favored graft for the majority of adults undergoing LDLT around the world today (9,41,67). The first reported LDLT using a right-lobe graft performed in the United States was in 1997 (41). Shortly thereafter, a number of groups in the United States initiated adult-to-adult LDLT programs using either right- or left-lobe grafts (7,36,38,68–71). Surgeons in the United States have been the benefactors of the pioneering work of the surgeons in Asia and Europe who perfected many of the technical and management issues related to live liver donation (9,48,72–75). As more experience has been gained, the live donor procedure continues to be refined in both donors and recipients. Controversy exists regarding technical issues, such as the best way to reconstruct the biliary system or maximize venous drainage (76–79). What has emerged is the realization that surgeon and program experience are major factors in ensuring favorable outcomes (5,36,80).

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RIGHT LOBE OUTCOME Despite the organ shortages observed in the United States, the need for LDLT must always be tempered by the morbidity to the donor and the fact that deceased-donor liver transplantation (DDLT) is a viable option. In addition, most authors agree that live-donor liver grafts are associated with increased technical complications (biliary and hepatic artery), causing some to consider these to be “marginal” grafts. Although reported outcomes after LDLT have been similar to those observed in deceased donors in several reports (5,80–82), in most cases, live donor grafts are placed in healthier recipients compared with deceased donor recipients. The adult-to-adult live-donor liver transplant (A2ALL) consortium was a National Institutes of Health (NIH)-sponsored study with nine centers. In a recent report, 385 recipients of live-donor liver grafts (80) demonstrated a one-year graft survival of 81%, with 13.2% of the grafts failing within the first 90 days. Surprisingly, neither recipients’ modified end-stage liver disease (MELD) score nor graft size were predictors of graft loss. Center experience (<20 LDLT procedures), however, was associated with an 83% higher risk of graft failure (P < 0.0045) (80). Biliary complications were common and occurred in 30% of recipients. In an attempt to identify donor and recipient characteristics of LDLT that affect allograft survival, Abt et al. used the United Network for Organ Sharing (UNOS) database to analyze 731 patients who underwent LDLT compared with 14,359 recipients of DDLT (83). LDLT recipients had a higher rate of retransplantation but not death when compared with DDLT (Fig. 1). Thulivath et al. compared the outcome of 764 patients who underwent LDLT with 1470 matched recipients of DDLT (81). Recipients were well-matched for age, sex, race, diagnosis, and weight, but differed significantly in renal function, cold ischemic time, UNOS listing (1/2A), and need for life support, all of which favored live donor recipients. The donor demographics were also matched, except in age (35.8 versus 38.9 years, P < 0.001), race, and ABO matching (P < 0.001 for both) (81). The results suggested that primary graft nonfunction was similar between the LDLT and DDLT groups (3.5% versus 3.3%), as was the acute cellular rejection rate, but limited data were presented. Two-year patient survival was similar (79% versus 80%) but graft survival was significantly worse after LDLT compared with deceased donors (64.4% versus 73.3%) (Fig. 2). Our group initiated a live-donor liver transplant program in 1998 since waiting list mortality in our region of the country exceeded 20% (5,7). Like others, we were able to improve our outcomes with program experience and modifications. Analyzing our program’s first 100 live-donor transplant using right lobe grafts, overall patient and graft survival have been 85% and 83%, respectively. After a learning curve of approximately 25 cases (5), overall patient and graft survival in the subsequent 75 cases improved to 93.4% and 92.9%, respectively. Others have suggested that their learning curve experience was approximately 20 cases (36). In our series, the first 25 cases were performed during the initial two-year period of the

1.0

Allograft Suvival (%)

.9 .8 .7

DDLT

.6

LDLT

.5 .4 .3 .2 .1 0.0

0

200

400

600 800 Time (days)

1000

1200

FIGURE 1 United Network for Organ Sharing database showing live-donor liver transplantation versus deceased-donor liver transplantation. Source: From Ref. 83.

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FIGURE 2 Comparison of live-donor liver transplantation with deceased-donor liver transplantation. Source: From Ref. 81.

live-donor liver transplant program at the Lahey Clinic. During that time period, several modifications in the program were carried out, and improved technologies became available. The surgical techniques in both donors and recipients were modified and improved. After that initial two-year period, we felt that the program had matured and that the team had achieved an adequate level of “field strength,” as eloquently described by the late Dr. Francis D. Moore in discussing the ethics of medical and surgical innovation (3). First, recipient selection was refined when it was realized that patients who were more debilitated, who suffered significant malnutrition, and who had significant portal hypertension were more likely to experience “small-for-size” syndrome than those with well-compensated liver failure (43). In this respect, the MELD score alone does not take into consideration other comorbidities that may also predict poor outcome (84). While we have successfully performed LDLT in patients with very high MELD scores in the setting of fulminant hepatic failure, the absence of significant portal hypertension along with relatively low blood loss (<10 units) during those procedures contributed to favorable outcomes. Our current practice is to consider LDLT in patients with MELD scores that are likely to benefit from transplantation (i.e., >15) (85), while being more cautious when the unadjusted MELD scores are above 30 (86). There are no absolute contraindications to LDLT, based on MELD score, since some patients with lower MELD scores may have had life-threatening events (variceal bleeding), or suffer from inadequate quality-of-life that increases the desire to proceed with transplantation. Obviously, the decision to proceed with LDLT is complicated and is dependent on many interrelated variables between the donor and the recipient, and is impacted by the availability of deceased donor organs and waiting list mortality (87). Second, a competent, comprehensive and independent medical evaluation of each donor has had the positive effect of improving donor safety, while providing the best possible graft for the recipient. Undiagnosed medical illnesses such as renal cell cancer, liver disease, diabetes, hypertension, and coagulopathy were just a few of the problems identified in so-called “healthy” donors. The medical evaluation of donors has been expanded to screen routinely for hypercoaguable states after a recipient with homozygous Factor V Leiden, who received a graft obtained from a heterozygous Factor V Leiden donor, developed complete graft thrombosis while on therapeutic heparin and warfarin. Factor V Leiden in the donor and recipient is now an absolute contraindication for LDLT in our practice. Major advances in imaging technology with segmental volume assessment have resulted in better identification of suitable donors in terms of graft size and have aided in the development of the concept of “graft at risk” from segment V and VIII hepatic vein branches. Recently, the addition of a biliary contrast agent to the volumetric CT scan has allowed for simultaneous noninvasive assessment of the donor biliary anatomy and has avoided the need for preoperative or invasive biliary imaging in the donor. Figure 3 shows a three-dimensional rendering of a donor’s liver graft with segmental anatomy. The software allows for precise calculation of graft volume and contribution of each segment to the total graft volume.

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FIGURE 3 Hepatic vein territories of a live donor liver using three-dimensional CT renderings. Each color depicts segmental drainage, and demonstrates two large inferior hepatic veins draining directly into the vena cava and another draining segment VIII into the MHV. Volume for each segment can be calculated individually to estimate “graft at risk” if not reconstructed. Total estimated graft volumes utilizing virtual resection planes were 90% to 95% accurate in predicting actual graft volumes. Images were provided by post-imaging software (Hepavision™, MeVis, Bremen, Germany) after “rapid slice” CT scanning.

The addition of more precise post-imaging software technology has also allowed for adequate surgical planning when considering donors with more complicated anatomy. Initially, higher risk donors with complicated portal vein anatomy and marginal liver size were avoided to maximize donor safety and to simplify the recipient procedure. With more experience, more complicated donor anatomy was considered acceptable, such as those with trifurcated portal veins (i.e., the right posterior portal vein originates from the left portal vein). While many operations are technically feasible, it may not be reasonable to attempt these more difficult situations until the team has achieved adequate “field strength.” Another technical modification in the donor operation that has improved recipient outcome was achieved by standardizing the liver parenchymal transection. After a trial of various surgical techniques and instruments used for dividing the liver, we have found that the water hydro-jet dissection technique superior and more rapid in most cases. The hydro-jet device has helped to minimize graft injury and the zone of necrosis along the transection line compared with other techniques. Donor operative times have steadily and significantly decreased as well (5.4 hours “early” versus 3.9 hours “later,” P < 0.001). Other techniques using bipolar electrocautery alone can result in a larger zone of necrosis. In one case, where a “floating ball” electrocautery device was used, a 2 cm3 area on the cut surface of the right-lobe liver graft was lost, contributing to the development of “small for size” syndrome. Not surprisingly, it has become clear that the success of the recipient procedure was not only dependent on the quality of the recipient operation, but also on the quality of the donor evaluation and graft procurement. As results steadily improved, it was felt that consistency of the surgical team was a positive influence and should not be changed to avoid secondary learning curves. Biliary problems continue to be the most common complication after LDLT and were not influenced by program experience or method of reconstruction. Investigation of the literature suggests that the rate of biliary complications ranges widely, but has persisted despite various reconstructive techniques with or without the use of stents. Biliary complications are related to multiple factors and not surgical technique alone. Therefore, attempts to identify donor features (number of bile ducts, arterial blood supply to the right hepatic duct, etc.) may provide clues as to how to reduce biliary complications after LDLT. Ultimately, better donor selection with favorable anatomic features may be the best strategy for avoiding biliary complications. Another area of concern and surgical debate is the issue of maximal venous outflow and the best method for surgical reconstruction to avoid graft congestion. Three surgical techniques for maximizing venous outflow have evolved. These comprise: (i) including the MHV with the

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donor graft in all cases, (ii) selectively reconstructing larger segment V and VIII venous tributaries draining to the MHV, or (iii) performing remedial backbench procedures to create “cloacae maximum” to augment drainage (79,88). Since donor safety was paramount, our program made a decision not to include the MHV with the donor graft. This decision has not compromised surgical outcome, nor increased the incidence of “outflow block.” Patients with more severe illness and a higher MELD score may benefit from routine inclusion of the MHV to increase graft size since this technique can also be performed safely (79). One clear advantage of LDLT is the quality of the graft, which should be ensured with adequate donor work-up. While graft quality is an important feature during LDLT, the contribution of an experienced hepatobiliary surgeon in preserving graft integrity during live-donor liver procurement is unquantifiable but undoubtedly of paramount importance to achieve favorable outcomes. In regions of the country where the waiting list mortality can exceed 20%, LDLT provides a suitable alternative for patients with end-stage liver disease. Excellent results can be achieved with LDLT despite high recipient morbidity rates. In our experience, simplifying the surgical technique as much as possible has proven to be advantageous for both the patient and the operative team. Comprehensive medical and anatomic evaluation of the donor avoids “surprises” and provides the recipient with the best possible graft. Continuing efforts to identify donor features that contribute to the pathogenesis of recipient complications will continue to improve safety and surgical outcome. REFERENCES 1. Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet 1989; 2(8661):497. 2. Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg 1991; 214(4):428. 3. Moore FD. Therapeutic innovation: ethical boundaries in the initial clinical trials of new drugs and surgical procedures. CA Cancer J Clin 1970; 20(4):212. 4. Singer PA, Siegler M, Lantos JD, et al. The ethical assessment of innovative therapies: liver transplantation using living donors. Theor Med 1990; 11(2):87. 5. Pomposelli JJ, Verbessey J, Simpson MA, et al. Improved survival after live-donor adult liver transplantation (LDALT) using right lobe grafts: program experience and lessons learned. Am J Transplant 2006; 6:589–598. 6. Malago M, Testa G, Frilling A, et al. Right-living donor liver transplantation: an option for adult patients: single institution experience with 74 patients. Ann Surg 2003; 238(6):853. 7. Pomfret EA, Pomposelli JJ, Lewis WD, et al. Live-donor adult liver transplantation using right lobe grafts: donor evaluation and surgical outcome. Arch Surg 2001; 136(4):425. 8. Miller C, Florman S, Kim-Schluger L, et al. Fulminant and fatal gas gangrene of the stomach in a healthy live liver donor. Liver Transpl 2004; 10(10):1315. 9. Broelsch CE, Malago M, Testa G, Valentin Gamazo C. Living-donor liver transplantation in adults: outcome in Europe. Liver Transpl 2000; 6(6 suppl 2):S64. 10. Silvestri E. The left hepatic lobe as an anatomical unit for heterotopic transplant. Boll Soc Ital Biol Sper 1967; 43(13):810. 11. Shumakov VI, Galperin EI. Transplantation of the left liver lobe. Transplant Proc 1979; 11(2):1489. 12. Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in children. Surgery 1984; 95(3):367. 13. Otte JB, de Hemptine B, Moulin D, et al. Liver transplantation in children. Chir Pediatr 1985; 26(5):261. 14. Bismuth H, Morino M, Castaing D, et al. Emergency orthotopic liver transplantation in two patients using one donor liver. Br J Surg 1989; 76(7):722. 15. Piper JB, Whitington PF, Woodle ES, Newell KA, Alonso EM, Thistlethwaite JR. Living-related liver transplantation in children: a report of the first 58 recipients at the University of Chicago. Transpl Int 1994; 7(suppl 1):S111. 16. Otte JB, de Ville de Goyet J, Reding R, et al. Pediatric liver transplantation: from the full-size liver graft to reduced, split, and living related liver transplantation. Pediatr Surg Int 1998; 13(5–6):308. 17. Rogiers X, Malago M, Gawad K, et al. In situ splitting of cadaveric livers. The ultimate expansion of a limited donor pool. Ann Surg 1996; 224(3):331. 18. Fujita S, Kim ID, Uryuhara K, et al. Hepatic grafts from live donors: donor morbidity for 470 cases of live donation. Transpl Int 2000; 13(5):333.

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19. Baccarani U, Adani GL, Risaliti A, et al. Long-term results of in situ split-liver transplantation. Transplant Proc 2005; 37(6):2592. 20. Spada M, Cescon M, Aluffi A, et al. Use of extended right grafts from in situ split livers in adult liver transplantation: a comparison with whole-liver transplants. Transplant Proc 2005; 37(2):1164. 21. Porta E, Cardillo M, Pizzi C, Poli F, Scalamogna M, Sirchia G. Split liver is an effective tool to transplant paediatric patients. Transpl Int 2000; 13(suppl 1):S144. 22. Broering DC, Mueller L, Ganschow R, et al. Is there still a need for living-related liver transplantation in children? Ann Surg 2001; 234(6):713. 23. Shumakov VI, Gal’perin EI, Zhuravlev VA, Nekliudova EA, Korolev VI. Transplantation of the left lobe of the liver (anatomical study). Khirurgiia (Mosk) 1977; 3:43. 24. Shumakov VI, Gal’perin EI, Nekliudova EA, Mikhailov AT, Korolev VI. Experimental and clinical transplantation of the left lobe of the liver. Khirurgiia (Mosk) 1978; 6:22. 25. Czerniak A, Lotan G, Hiss Y, Shemesh E, Avigad I, Wolfstein I. The feasibility of in vivo resection of the left lobe of the liver and its use for transplantation. Transplantation 1989; 48(1):26. 26. Cherqui D, Emond JC, Pietrabissa A, Michel M, Roncella M, Broelsch CE. Orthotopic liver transplantation and living donors. An experimental study in the dog. Chirurgie 1990; 116(8–9):711. 27. Cherqui D, Emond JC, Pietrabissa A, et al. Segmental liver transplantation from living donors. Report of the technique and preliminary results in dogs. HPB Surg 1990; 2(3):189. 28. Emond JC, Heffron TG, Whitington PF, Broelsch CE. Reconstruction of the hepatic vein in reduced size hepatic transplantation. Surg Gynecol Obstet 1993; 176(1):11. 29. Emond JC, Heffron TG, Kortz EO, et al. Improved results of living-related liver transplantation with routine application in a pediatric program. Transplantation 1993; 55(4):835. 30. Tanaka K, Uemoto S, Inomata Y, et al. Living-related liver transplantation for fulminant hepatic failure in children. Transpl Int 1994; 7(suppl 1):S108. 31. Fan ST, Lo CM, Chan KL, et al. Liver transplantation—perspective from Hong Kong. Hepatogastroenterology 1996; 43(10):893. 32. Emond JC, Renz JF, Ferrell LD, et al. Functional analysis of grafts from living donors. Implications for the treatment of older recipients. Ann Surg 1996; 224(4):544. 33. Tucker ON, Heaton N. The ‘small-for-size’ liver syndrome. Curr Opin Crit Care 2005; 11(2):150. 34. Shinohara H, Tanaka A, Hatano E, et al. Anatomical and physiological problems of Segment IV: liver transplants using left lobes from living related donors. Clin Transplant 1996; 10(4):341. 35. Cheng YF, Chen CL, Haung TL, et al. Post-transplant changes of segment 4 after living-related liver transplantation. Clin Transplant 1998; 12(5):476. 36. Marcos A, Ham JM, Fisher RA, Olzinski AT, Posner MP. Single-center analysis of the first 40 adult-to-adult living donor liver transplants using the right lobe. Liver Transpl 2000; 6(3):296. 37. Rosenthal P. Living-related liver transplants for adults? The time has come! J Pediatr Gastroenterol Nutr 1996; 23(3):335. 38. Miller CM, Gondolesi GE, Florman S, et al. One hundred nine living-donor liver transplants in adults and children: a single-center experience. Ann Surg 2001; 234(3):301. 39. Ikai I, Morimoto T, Yamamoto Y, et al. Left lobectomy of the donor: operation for larger recipients in living-related liver transplantation. Transplant Proc 1996; 28(1):56. 40. Kiuchi T, Inomata Y, Uemoto S, et al. Living-donor liver transplantation in Kyoto, 1997. Clin Transpl 1997;191. 41. Wachs ME, Bak TE, Karrer FM, et al. Adult living-donor liver transplantation using a right hepatic lobe. Transplantation 1998; 66(10):1313. 42. Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 1999; 67(2):321. 43. Ben-Haim M, Emre S, Fishbein TM, et al. Critical graft size in adult-to-adult living-donor liver transplantation: impact of the recipient‘s disease. Liver Transpl 2001; 7(11):948. 44. Neuhaus P. Live donor/split liver grafts for adult recipients: when should we use them? Liver Transpl 2005; 11(11 suppl 2):S6. 45. Renz JF, Emond JC, Yersiz H, Ascher NL, Busuttil RW. Split-liver transplantation in the United States: outcomes of a national survey. Ann Surg 2004; 239(2):172. 46. Verbesey JE, Simpson MA, Pomposelli JJ, et al. Living-donor adult liver transplantation: a longitudinal study of the donor’s quality of life. Am J Transplant 2005; 5(11):2770. 47. Lo CM, Fan ST, Liu CL, et al. Extending the limit on the size of adult recipient in living-donor liver transplantation using extended right lobe graft. Transplantation 1997; 63(10):1524. 48. Kawasaki S, Makuuchi M, Matsunami H, et al. Living-related liver transplantation in adults. Ann Surg 1998; 227(2):269. 49. Tanaka K, Yamada T. Living-donor liver transplantation in Japan and Kyoto University: what can we learn? J Hepatol 2005; 42(1):25. 50. Lo CM, Fan ST, Liu CL, et al. Minimum graft size for successful living-donor liver transplantation. Transplantation 1999; 68(8):1112. 51. Ikegami T, Nishizaki T, Yanaga K, et al. The impact of donor age on living-donor liver transplantation. Transplantation 2000; 70(12):1703.

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52. Pomfret EA, Pomposelli JJ, Gordon FD, et al. Liver regeneration and surgical outcome in donors of right-lobe liver grafts. Transplantation 2003; 76(1):5. 53. Nomoto K, Nishizaki T, Shimada M, Okano S, Minagawa R, Sugimachi K. Extended lobectomy for procurement of the left lobe with caudate lobe for living-related liver transplantation. Hepatogastroenterology 2005; 52(64):1216. 54. Ikegami T, Nishizaki T, Yanaga K, et al. Changes in the caudate lobe that is transplanted with extended left lobe liver graft from living donors. Surgery 2001; 129(1):86. 55. Kokudo N, Sugawara Y, Imamura H, Sano K, Makuuchi M. Tailoring the type of donor hepatectomy for adult living-donor liver transplantation. Am J Transplant 2005; 5(7):1694. 56. Lee S, Hwang S, Park K, et al. An adult-to-adult living-donor liver transplant using dual left lobe grafts. Surgery 2001; 129(5):647. 57. Lee SG, Park KM, Hwang S, et al. Adult-to-adult living-donor liver transplantation at the Asan Medical Center, Korea. Asian J Surg 2002; 25(4):277. 58. Hirata M, Sugawara Y, Makuuchi M. Living-donor liver transplantation at Tokyo University. Clin Transpl 2002; 215. 59. Fan ST, Lo CM, Liu CL, Yong BH, Chan JK, Ng IO. Safety of donors in live-donor liver transplantation using right lobe grafts. Arch Surg 2000; 135(3):336. 60. Lo CM. Complications and long-term outcome of living liver donors: a survey of 1,508 cases in five Asian centers. Transplantation 2003; 75(suppl 3):S12. 61. Lee DS, Gil WH, Lee HH, et al. Factors affecting graft survival after living-donor liver transplantation. Transplant Proc 2004; 36(8):2255. 62. Ozawa K, Uemoto S, Tanaka K, et al. An appraisal of pediatric liver transplantation from living relatives. Initial clinical experiences in 20 pediatric liver transplantations from living relatives as donors. Ann Surg 1992; 216(5):547. 63. Tanaka K, Uemoto S, Tokunaga Y, et al. Surgical techniques and innovations in living-related liver transplantation. Ann Surg 1993; 217(1):82. 64. Yamaoka Y, Tanaka K, Ozawa K. Liver transplantation from living-related donors. Clin Transpl 1993: 179. 65. Pappas SC, Rouch DA, Stevens LH. New techniques for liver transplantation: reduced-size, splitliver, living-related and auxiliary liver transplantation. Scand J Gastroenterol Suppl 1995; 208:97. 66. Lo CM, Fan ST, Liu CL, et al. Adult-to-adult living-donor liver transplantation using extended right lobe grafts. Ann Surg 1997; 226(3):261. 67. Fan ST, Lo CM, Liu CL. Donor hepatectomy for living-donor liver transplantation. Hepatogastroenterology 1998; 45(19):34. 68. Marcos A, Fisher RA, Ham JM, et al. Right lobe living-donor liver transplantation. Transplantation 1999;68(6):798. 69. Kim-Schluger L, Florman SS, Gondolesi G, et al. Liver transplantation at Mount Sinai. Clin Transpl 2000; 247. 70. Emond JC, Rosenthal P, Roberts JP, et al. Living-related donor liver transplantation: the UCSF experience. Transplant Proc 1996; 28(4):2375. 71. Pomposelli JJ, Verbesey J, Simpson MA, et al. Improved survival after live-donor adult liver transplantation (LDALT) using right lobe grafts: program experience and lessons learned. A J Transplant 2006. 72. Rogiers X, Malago M, Nollkemper D, Sterneck M, Burdelski M, Broelsch CE. The Hamburg liver transplant program. Clin Transpl 1997: 183. 73. Fan ST, Lo CM, Liu CL. Technical refinement in adult-to-adult living-donor liver transplantation using right lobe graft. Ann Surg 2000; 231(1):126. 74. Tanaka K, Ogura Y. “Small-for-size graft” and “small-for-size syndrome” in living-donor liver transplantation. Yonsei Med J 2004; 45(6):1089. 75. Inomata Y, Tanaka K, Uemoto S, et al. Living-donor liver transplantation: an 8-year experience with 379 consecutive cases. Transplant Proc 1999; 31(1–2):381. 76. Yi NJ, Suh KS, Cho JY, Kwon CH, Lee KU. In adult-to-adult living-donor liver transplantation hepaticojejunostomy shows a better long-term outcome than duct-to-duct anastomosis. Transpl Int 2005; 18(11):1240. 77. Settmacher U, Steinmuller TH, Schmidt SC, et al. Technique of bile duct reconstruction and management of biliary complications in right-lobe living-donor liver transplantation. Clin Transplant 2003; 17(1):37. 78. Malago M, Molmenti EP, Paul A, et al. Hepatic venous outflow reconstruction in right live-donor liver transplantation. Liver Transpl 2005; 11(3):364. 79. Fan ST, Lo CM, Liu CL, Wang WX, Wong J. Safety and necessity of including the middle hepatic vein in the right lobe graft in adult-to-adult live-donor liver transplantation. Ann Surg 2003; 238(1):137. 80. Olthoff KM, Merion RM, Ghobrial RM, et al. Outcomes of 385 adult-to-adult living-donor liver transplant recipients: a report from the A2ALL Consortium. Ann Surg 2005; 242(3):314. 81. Thuluvath PJ, Yoo HY. Graft and patient survival after adult live-donor liver transplantation compared to a matched cohort who received a deceased donor transplantation. Liver Transpl 2004; 10(10):1263. 82. Russo MW, Galanko J, Beavers K, Fried MW, Shrestha R. Patient and graft survival in hepatitis C recipients after adult living-donor liver transplantation in the United States. Liver Transpl 2004; 10(3):340.

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83. Abt PL, Mange KC, Olthoff KM, Markmann JF, Reddy KR, Shaked A. Allograft survival following adult-to-adult living-donor liver transplantation. Am J Transplant 2004; 4(8):1302. 84. Cabre E, Gassull MA. Nutrition in chronic liver disease and liver transplantation. Curr Opin Clin Nutr Metab Care 1998; 1(5):423. 85. Merion RM. When is a patient too well and when is a patient too sick for a liver transplant? Liver Transpl 2004; 10(10 suppl 2):S69. 86. Yoo HY, Thuluvath PJ. Short-term post-liver transplant survival after the introduction of MELD scores for organ allocation in the United States. Liver Int 2005; 25(3):536. 87. Russo MW, LaPointe-Rudow D, Kinkhabwala M, Emond J, Brown RS, Jr. Impact of adult living-donor liver transplantation on waiting time survival in candidates listed for liver transplantation. Am J Transplant 2004; 4(3):427. 88. Kornberg A, Heyne J, Schotte U, Hommann M, Scheele J. Hepatic venous outflow reconstruction in right-lobe living-donor liver graft using recipient‘s superficial femoral vein. Am J Transplant 2003; 3(11):1444.

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Adult Recipient Outcomes: The Pittsburgh Experience with Alemtuzumab Preconditioning and Tacrolimus Monotherapy—Two-Year Outcomes Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Kusum Tom, Ngoc L. Thai, Paulo Fontes, and Michael DeVera Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Joseph Donaldson Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Igor Dvorchik Departments of Surgery and Biostatistics, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION We congratulate the team at the Lahey Clinic for their excellent results (see Chapter 17). Here, we report our Pittsburgh results because they represent the outcomes with a fundamentally different strategy of immunosuppression. The Pittsburgh strategy evolved as follows: A pivotal step in 1992 by Starzl et al. unified organ and bone marrow transplantation when sparse numbers of donor cells (collectively termed microchimerism) were found at one or more sites in all 30 examined, long-surviving human kidney and liver recipients (1,2). From these findings, it was concluded that alloengraftment involved a double immune reaction in which “… responses of coexisting donor and recipient cells, each to the other, resulted in reciprocal clonal exhaustion, followed by peripheral clonal deletion” (Figs 1 and 2). In essence, organ engraftment and successful bone marrow transplantation differed fundamentally only in the proportions of donor and recipient cells. Efforts to exploit this insight over the next decade (e.g., by infusing adjunct donor bone marrow cells at the time of organ transplantation) were disappointing. In a review of transplantation tolerance published in 2001, Starzl and Zinkernagel (3) suggested that the worldwide practice of heavy multiple drug immunosuppression from the time of organ transplantation (with or without adjunct bone marrow cells) reduced the window of opportunity for the seminal mechanism of organ-induced tolerance: that is, the clonal exhaustion–deletion that coincides with acute passenger leukocyte migration (Fig. 2B). With later reduction of the strong immunosuppression, recovery of the inefficiently deleted clone would leave the patient prone to chronic rejection and dependent on lifetime drug treatment (Fig. 2B). Yet, failure to give enough early immunosuppression would lead to irreversible damage to the transplanted organ (Fig. 2B, dashed arrow). It was proposed by Starzl and Zinkernagel (3) that the dilemma of over- versus underimmunosuppression could be addressed in the organ recipient by applying the two therapeutic

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Immunosuppression

Failure

HVG Recipient

Immune Reaction

Success

GVH Donor

Failure

Time after Organ Transplantation FIGURE 1 Contemporaneous HVG (upright curves) and GVH (inverted curves) responses following organ transplantation. In contrast to the usually dominant HVG reaction of organ transplantation, the GVH reaction usually is dominant after bone marrow cell transplantation to the irradiated or otherwise immunodepressed recipient. Therapeutic failure with either type of transplantation implies the inability to control one, the other, or both of the contemporaneous responses with a protective umbrella of immunosuppression. Abbreviations: GVH, graft versus-host; HVG, host-versus graft. Source: From Ref. 30.

principles depicted in Figure 2A, singly or together: first, recipient pretreatment, and second, minimal post-transplant immunosuppression. With recipient pretreatment, global immune responsiveness is reduced, making it easier to delete the anticipated donor-specific response. Antilymphocyte globulin (ALG) and other lymphoid-depleting antibody preparations could be used for pretreatment with a relatively low risk of graft versus host diseases (GVHD). Beginning five years ago, the policy in Pittsburgh has been to infuse a single large dose of Thymoglobulin (4), or more recently alemtuzumab (Campath-1H®) (5–13), for pretreatment. After transplantation, minimal immunosuppression was with daily tacrolimus monotherapy unless rejection mandated additional agents. After several months, the tacrolimus doses were space weaned to every other day, or longer intervals when possible. In essence, this strategy (which is neither drug- nor organ-specific) “permits” normal tolerogenic interactions between donor and recipient leukocytes. However, alemtuzumab has provided more efficient and trouble-free lymphoid depletion than antithymocyte globulin

Over Immunosuppression

Tolerogenic Immunosuppression Other agent Tacrolimus Rejection

(A)

Clonal recovery with weaning

Tx Time

(B)

Lymphoid Depletion

Loss of donor specific activation exhaustion deletion

Immune Response HVG GVH

Immune Response GVH HVG

Rejection

With pretreatment With both principles

Tx Time

FIGURE 2 Mechanisms of immunosuppression. (A) If the clonal response is eliminated by excessive post-transplant immunosuppression, exhaustion–deletion shown on the left is precluded and subsequent graft survival is permanently dependent on immunosuppression. (B) Conversion of rejection (thick dashed arrow) to an immune response that can be exhausted and deleted by combination of pretreatment and minimalistic post-transplant immunosuppression. Abbreviations: GVH, graft-versus-host; HVG, host-versus-graft; Tx, transplantation. Source: From Ref. 4.

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(ATG, Thymoglobulin®) at our center for liver (5), kidney (6–10), lung (11), small bowel (12), and pancreas (13) transplantation. It has been possible in many of these patients to increase the interval between doses of maintenance tacrolimus monotherapy by weaning to every two days or even to as long as one dose per week (5–13). This immunosuppressive combination was evaluated in 47 right-lobe adult living donor liver transplantation (RLALDLT). One dose of alemtuzumab (30 mg) was used for preconditioning, and tacrolimus monotherapy weaned when possible. The mean model for end-stage liver disease (MELD) score was 12.4 (6 to 25), and the mean follow-up was 24.3 + 10.9 months. Actuarial one-, two-, and three-year recipient and graft survivals were 93.6% and 91.4%, 88.2% and 86.0%, and 88.2% and 86.0%, respectively. The cumulative acute cellular rejection (ACR) incidence was 0%, 4.3%, 8.5%, 8.5%, 10.6%, and 12.8% at 1, 2, 3, 4, 12, and 24 months, respectively. Preweaning ACR was 10.6% and only one patient (2.1%) had postweaning ACR. Weaning was attempted in 31.9% of recipients. At mean two-year follow-up, the mean total bilirubin was 0.83 + 0.54. There were minimal recipients’ infectious complications, no post-transplant lymphoproliferative disease, and no post-transplant insulin dependent diabetes. There were no live donor mortality and minimal donor morbidities (6.7%). This study represents the largest series to date of RLALDLT recipients undergoing alemtuzumab preconditioning and tacrolimus monotherapy, and confirms the short-term safety and efficacy of this approach. However, the optimal use of this immunosuppressive combination is not yet apparent. PATIENTS AND METHODS Between June 10, 2003 and June, 13, 2006, 47 consecutive RLALDLT with alemtuzumab conditioning and tacrolimus monotherapy from 47 right lobe donor hepatectomies (RLDH) at University of Pittsburgh Medical Center (UPMC) Starzl Transplantation Institute (STI) were prospectively analyzed. Nine RLALDLT recipients who received donor stem cells pretransplantation were excluded. The immunosuppressive regimen was based upon pretreatment with a single 30 mg dose of intravenous alemtuzumab (Campath-1H®, Berlex, Montville, New Jersey, U.S.A.). Premedication was with 1 g of methylprednisolone, which was repeated prior to reperfusion to avoid intraoperative hypotension from cytokine release syndrome. Post-transplantation low-dose tacrolimus monotherapy (target trough of 10 ng/mL) for the first three to six months post-transplantation was given, starting on postoperative day 1. At approximately three to six months post-transplantation, the twice-daily dose of tacrolimus was consolidated to once a day in recipients with no clinical evidence of ACR [i.e., increase in liver function tests (LFTs) confirmed by biopsy]. Protocol biopsies were not performed. If the patient continued to do well, the dose was weaned to once every other day after another three months. Further weaning was continued to three times a week, twice a week, or once a week at two-to-six month intervals if the patient continued to do well in the absence of a rising LFTs or clinical ACR. Episodes of biopsy-proven ACR were treated with steroid boluses. Institutional Review Process The primary purpose was to improve the quality-of-life and patient and graft survival. Modification in the timing and dosage of conventional immunosuppression in this context was submitted to the University of Pittsburgh Institutional Review Board (IRB), which judged the changes to be within the boundaries of historically based standard treatment. The treatment protocols were reviewed by the UPMC Committee on Innovative Practices and the Pharmacy and Therapeutics Practices Committee, with approval by both, as previously described (5–13). All patients provided informed consent. In addition, separate informed consent was obtained with IRB approval for studies of immune variables not routinely assayed in our conventional practice. Safety and efficacy monitoring were assured by formal weekly reviews of all patients. Statistical Analysis Baseline demographic and laboratory factors were described as means (+ standard deviation) for continuous variables. Actuarial recipient and graft survivals were calculated beginning at

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the time of transplantation. Liver graft failure was defined as death of recipient or relisting requiring a liver transplant. Actuarial Kaplan-Meier survivals were calculated using the Statistical Package for the Social Science (SPSS) software and the series was followed until September 14, 2006. We present cumulative recipient and graft survival curves using KaplanMeier methods. RESULTS Donor Characteristics and Outcomes The mean donor age was 35.3 + 11.7. There was no donor mortality. There was one (2.1%) major complication wherein the donor developed an empyema and required video-assisted thorascopic decortication. The donor is currently doing well. Two (4.3%) minor complications (incisional hernias) were observed. There was no donor biliary complication. There was no surgical exploration, no blood transfusion, and the mean donor hospital stay was seven days. The mean estimated blood loss was 250 mL. In RLDH, transfusion of heterologous blood can be avoided with routine use of intraoperative cell-saver salvaged, maintenance of low central venous pressure, and meticulous parenchymal transection using a combination technique that includes the cone-tipped TissueLink®, Erbe Helix Hydro-Jet®, and Cavitron® Ultrasonic Surgical Aspirator (CUSA) (14). Recipient and Graft Characteristics and Survival The mean follow-up was 24.3 + 10.9 months. The mean recipient waiting list MELD score was 12.4 (6 to 25). Table 1 explains detailed patient characteristics. At follow-up, the mean total bilirubin and creatinine were 0.83 + 0.54 mg/dL, and 1.39 + 0.81 mg/dL, respectively. The causes of end-stage liver disease in the recipients were alcoholic (9), primary sclerosing cholangitis (9), cryptogenic (5), autoimmune (4), hepatitis C (HCV+) (3), Budd-Chiari (3), nonalcoholic steatohepatitis (3), primary biliary cirrhosis (2), oxalosis (2), multiple diagnoses (2), alpha-1 antitrypsin deficiency (1), focal nodular hyperplasia (1), hemochromatosis (1), hepatocellular carcinoma (HCC)(1), and polycystic liver disease (1). Since our experience with poorer outcomes with HCV+ recipients using alemtuzumab lymphoid depletion and minimalistic maintenance immunosuppression (8), we currently have not included any potential HCV+ recipients in this immunosuppressive combination regimen.

TABLE 1 Characteristics of 47 Adult Right Lobe Living Donor Liver Transplantations at 24.3 Months Follow-Up

Number Mean age A, B, DR mismatch Preoperative model for end stage liver disease Actuarial 1-yr patient survival Actuarial 1-yr graft survival Actuarial 2-yr patient survival Actuarial 2-yr graft survival Actuarial 3-yr patient survival Actuarial 3-yr graft survival Morbidities Major Minor Biliary Surgical interventions Nonsurgical interventions Hepatic arterial complications Hepatic or portal vein complications Mean total bilirubin at 2-yr Mean creatinine at 2-yr

Donor

Recipients

47 35.3 + 11.7 — 12.4 (6 to 25) 100% — 100% — 100% — 6.7% 2.1% 4.3% 0% 0% 0% 0% 0%

47 49.2 + 14.5 3.3 + 1.4 93.6% 91.4% 88.2% 86.0% 88.2% 86.0%

29.8% 6.4% 23.4% 4.3% 0% 0.83 + 0.54 1.39 + 0.81

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At 24.3 months follow-up, six liver allograft losses were from an acute hepatic artery thrombosis on post-transplant day 2, and five deaths. The five patient deaths were from bacterial septic shock (2) on post-transplant days 34 and 115, hepatic artery “blow-out” (1) on post-transplant day 11, myocardial infarction (1) on post-transplant day 411, and recurrent HCC (1) on post-transplant day 667. Unadjusted actuarial one-year recipient and graft survivals were 93.6% and 91.4%, respectively, and compare well to data from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) (15). The 2005 OPTN/SRTR annual report unadjusted one-year recipient and graft survivals of all living donor liver transplants (including the better pediatric recipient results) in 2003 were 90.3% (15) and 84.0% (15), respectively. The OPTN/SRTR unadjusted one-year recipient and graft survivals with waiting list MELD status of 11 to 20 from 2002 to 2003 were 87.6% (15), and 82.5% (15), respectively. The OPTN/SRTR unadjusted three-year recipient and graft survivals for 2001 transplants, were 80.5% (15), and 73.8% (15), respectively. Figure 3 is an actuarial (A) recipient, and (B) graft Kaplan-Meier survival curve of our 47 RLALDLT patients. Our unadjusted actuarial two- and three-year recipient and graft survival were the same at 88.2% and 86.0%, respectively. Our adult right-lobe living donor liver

FIGURE 3 Actuarial recipient (A) and graft (B) survivals of 47 adult right lobe living donor liver transplantations at 24.3 months follow-up.

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transplantations (ARLLDLT) recipients at three-years fare at least as well as OPTN/SRTR living donor liver recipients (which include pediatric patients) at one year. Clearly, long-term follow-up is required to demonstrate this. Incidence and Severity of Acute Cellular Rejection The mean human leukocyte antigen (HLA) A, B, DR mismatch was 3.3 + 1.4. The cumulative ACR over the entire two-year follow-up was 12.8% (n = 6). All ACR episodes were biopsy proven. The cumulative ACR incidence was 0%, 4.3%, 8.5%, 8.5%, 10.6%, and 12.8% at 1, 2, 3, 4, 12, and 24 months, respectively. The severity of ACR is depicted in Table 2 as rejection activity index (RAI) (mean RAI = 4.5). The actual post-transplant days when ACR occurred were 55, 57, 69, 74, 224, and 491 days (Table 2). Preweaning ACR was 10.6% (n = 5) and only one patient (2.1%) had post-weaning ACR; all patients had steroid sensitive rejections. There was no graft loss from ACR. Weaning was attempted in 31.9% (15 of 47) of recipients. At two-year mean follow-up, the mean total bilirubin was 0.83 (+0.54). Of importance in this protocol, at 24.3-months follow-up, at least 75.6% (31 of 41) were still completely steroid-free since the time of transplantation. Immunosuppression Status and Frequency of Dosing At mean 24.3-months follow-up, of the 41 recipients with functioning liver allografts, 17 (41.5%) are on daily tacrolimus monotherapy (11 b.i.d. and 6 q.d.), and 14 (34.1%) recipients had been weaned to spaced-dose monotherapy (five on q.o.d. and nine on 3x/wk). Ten (24.4%) recipients are on multi-immunosuppressive drug therapy [a combination of mycophenolate mofetil (MMF); prednisone or rapamune were added to tacrolimus monotherapy because of ACR (n = 6), or had underlying autoimmune disease requiring prednisone or MMF pre- and posttransplantation (n = 4)]. We anticipate that the number of recipients on spaced-dose monotherapy will continue to increase over time. Recipient Complications Ten (21.3%) ARLLDLT recipients had two bile duct reconstructions. There were 31 (66.0%) duct-to-duct anastomoses and 16 (34.0%) Roux-en-Y anastomoses. Six of the 31 (19.4%) ductto-duct anastomoses involved two bile ducts and four of the 16 (25%) Roux-en-Y anastomoses involved two bile ducts. There were 14 (29.8%) biliary complications. Two of the 14 (14.3%) with biliary complications had two bile duct anastomoses (one each with duct-to-duct and Roux-en-Y). Three (6.4%) biliary leaks required duct-to-duct anastomoses (one had two ducts) to biliary Roux-en-Y reconstructions. Eleven (23.4%) biliary strictures required a nonsurgical interventional approach with endoscopic retrograde cholangiographic (n = 9) or percutaenous transhepatic cholangiographic (n = 2) stent placement. This incidence of recipient biliary strictures is higher than previously, and we speculate that this may be partially related to the current steroid-free protocol. There were two hepatic arterial complications: thrombosis (1) requiring urgent retransplantation, and hepatic arterial “blow-out” (1) resulting in the demise of the patient. There were no hepatic vein or portal vein complications. There was no incidence of fungemia, tissue invasive CMV disease, post-transplant lymphoproliferative disease (PTLD), or post-transplant insulin dependent diabetes. All recipients received nystatin prophylaxis for three to six months, valganciclovir prophylaxis for at least six months, and trimethoprim-sulfamethoxazole for life. DISCUSSION This report represents the largest series to date of ARLLDLT recipients receiving alemtuzumab induction and tacrolimus monotherapy at mean two-year follow-up, and confirms the short-term safety and efficacy of this drug as preconditioning agent. The results were consistent with the studies of alemtuzumab reported by us (5–13) and other centers (16–27) in which alemtuzumab was combined with various maintenance immunosuppressants for different solid organ transplantations. Despite the complexity of ARLLDT, the actuarial one-, two-, and

1190 793 791 639 184 93

2460 5136 5808 6797 2252 470

491 69 57 224 74 55

Time to ACR(d)

1.4 0.7 1.1 1.7 1.4 0.7

Creat@FU 6.7 3.3 3.5 2.3 0.3 3.8

TbilPreOp 0.3 1.7 2.7 2 0.7 NA

Tbil@FU 29 27 31 81 23 NA

AST@FU 34 33 27 97 17 NA

ALT@FU 25 68 36 479 51 NA

GGT@FU 17 14 18 13 6 16

MELDPreOp

0 2 1 1 1 1

A MM

1 2 1 1 1 1

B MM

1 2 1 1 1 1

DR MM

2.5/9 3.5/9 4/9 4/9 7/9 2/3

RAI

Abbreviations: ACR, acute cellular rejections; ALT, alanne transaminase; A MM, human leukocyte antigen a locus mismatch; AST, aspartate transaminase; Creat@FU, creatinine at follow-up; d, days; FU, follow-up; GGT, gamma glutamyl transaminase; RAI, rejection activity index; TbilPreOp, total billirubin pre-operatively.

FU (d)

Six Patients with ACR

Pt

TABLE 2

Adult Recipient Outcomes

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three-year recipient and graft survivals were 93.6% and 91.4%, 88.2% and 86.0%, and 88.2% and 86.0%, respectively, and this compares well with OPTN/SRTR data (15). The OPTN/ SRTR unadjusted three-year recipient and graft survival of all living-donor liver transplants (including pediatric recipients) for 2001 were 80.5% and 73.8%, respectively. Furthermore, good graft function was observed, with a mean total bilirubin of 0.83 + 0.54 at two-year follow-up. The cumulative ACR incidence was 0%, 4.3%, 8.5%, 8.5%, 10.6%, and 12.8% at 1, 2, 3, 4, 12, and 24 months, respectively. Preweaning ACR was 10.6% and only one patient (2.1%) had postweaning ACR. Weaning was attempted in 31.9% of recipients. The mean RAI for all six patients with ACR was 4.5, and all episodes of ACR were successfully treated with steroid boluses. Most importantly, at mean 24.3-months follow-up, at least 75.6% (31 of 41) were still completely steroid-free since the time of transplantation. There were minimal recipient infectious complications and no systemic fungemia, tissue invasive CMV disease, PTLD, or posttransplant insulin dependent diabetes mellitus. There was no live donor mortality and minimal donor morbidity. This experience demonstrates that a single dose of alemtuzumab, followed by tacrolimus monotherapy, weaned when possible, provides effective immunosuppression for ARLLDLT. While alemtuzumab depletes both T- and B-lymphocytes from the peripheral circulation, its effects on monocytes are less pronounced, and plasma cells are not effectively depleted from the circulation. Accordingly, recent reports have described monocyte-predominant ACR (24) as well as severe, early acute humoral rejection (25) in renal transplant recipients. We did not see any early severe acute humoral rejection in our liver transplant recipients with tacrolimus monotherapy. The importance of the calcineurin inhibitor (CNI) requirement in the early posttransplant period with alemtuzumab induction was demonstrated in the pilot studies by Knechtle, Flechner, and colleagues (17,19,26). Longer follow-up is clearly needed before we can reach definitive conclusions. The mean follow-up of our 47 recipients is only 24.3 + 10.9 months, and the sample patient population small. The delayed incidence of ACR that occurs as lymphocytes return to baseline will need to be monitored closely. Repopulation of the profound depletion of peripheral blood lymphocytes, monocytes, and NK cells by alemtuzumab can take up to one year. Knechtle (27) found lymphocytes reach at least 80% of baseline values 18 to 24 months post-alemtuzumab induction. The long-term benefits of this strategy clearly warrant further investigation. The seminal immunologic mechanism that permits the ability to wean immunosuppression in these patients is thought to be clonal exhaustion–deletion (1–4,28,29). Additional studies directed at elucidating this and accessory mechanisms are currently underway. REFERENCES 1. Starzl TE, Demetris AJ, Murase N, et al. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339:1579–1582. 2. Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993; 17:1127–1152. 3. Starzl TE, Zinkernagel R. Transplantation tolerance from a historical perspective. Nat Rev Immunol 2001; 1:233–239. 4. Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003; 361:1502–1510. 5. Marcos A, Eghtesad B, Fung JJ, et al. Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: with particular reference to hepatitis C virus. Transplantation 2004; 78:966–971. 6. Tan HP, Kaczorowski DJ, Basu A, et al. Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience. Transplantation 2004; 78:1683–1688. 7. Tan HP, Kaczorowski DJ, Basu A, et al. Steroid-free tacrolimus monotherapy following pretransplant Thymoglobulin or Campath and laparoscopy in living donor renal transplantation. Transpl Proc 2005; 37:4235–4240. 8. Shapiro R, Basu A, Tan H, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with thymoglobulin or Campath. J Am Coll Surg 2005; 200: 505–515. 9. Shapiro R, Ellis D, Tan HP, et al. Antilymphoid antibody preconditioning with tacrolimus monotherapy for pediatric renal transplantation. J Pediatr 2006; 148:813–818. 10. Tan HP, Kaczorowski DJ, Basu A, et al. Living donor renal transplantation using alemtuzumab induction and tacrolimus monotherapy. Am J Transplant 2006; 6:2409–2417.

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11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

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McCurry K, Iacano A, Zeevi A, et al. Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by post-transplant tacrolimus near-monotherapy. J Thorac Cardiovasc Surg 2005; 130:528–537. Abu-Elmagd K. Intestinal transplantation for short gut syndrome and gut failure: Rewarding outcomes and current consensus. Gastroenterology, 2006; 130(2):132–137. Thai NL, Khan A, Tom K, et al. Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: one and two-year outcomes. Transplantation 2006; 82(12):1621–1624. Tan HP, Marsh W, Marcos A. Liver resection using a saline-linked radiofrequency dissecting sealer for transection of the liver. J Am Coll Surg 2005; 201:152 (editorial). http://www.unos.org. OPTN/SRTR 2005 Annual Report. Tzakis A, Kato T, Nishida S, et al. Preliminary experience with Campath 1H (C1H) in intestinal and liver transplantation. Transplantation 2003; 75:1227. Knechtle SJ, Fernandez LA, Pirsch JD, et al. Campath-1H in renal transplantation: The University of Wisconsin experience. Surgery 2004; 136(4):754. Ciano G, Burke GW, Gaynor JJ, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immunemonitoring. Transplantation 2005; 80(4):457. Flechner SM, Friend PJ, Brockmann J, et al. Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI and steroid-free kidney transplant immunosuppression. Am J Transplant 2005; 5:3009. Gruessner RWG, Kandaswamy R, Humar A, et al. Calcineurin inhibitor- and steroid-free immunosuppression in pancreas-kidney and solitary pancreas transplantation. Transplantation 2005; 79(9):1184. Kaufmann DB, Leventhal JR, Axelrod D, et al. Alemtuzumab induction and prednisone free maintenance immunotherapy in kidney transplantation: comparison with basiliximab induction—long-term results. Am J Transplant 2005; 5:2539. Tryphonopoulos P, Madariaga JR, Kato T, et al. The impact of Campath 1H induction in adult liver allotransplantation. Transplant Proc 2005; 37:1203. Watson C, Bradley JA, Friend P, et al. Alemtuzumab (Campath 1H) induction therapy in cadaveric kidney transplantation—efficacy and safety at five years. Am J Transplant 2005; 5:1347. Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (Campath-1H). Transplantation 2003; 6(1):120–129. Hill P, Gagliardini E, Ruggenenti P, et al. Severe early acute humoral rejection resulting in allograft loss in a renal transplant recipient with Campath-1H induction therapy. Nephrol Dial Transplant 2005; 20: 1741–1744. Knechtle SJ, Pirsch JD, H Fechner J Jr, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003; 3:722–730. Knechtle SJ. Present experience with Campath-1H in organ transplantation and its potential use in pediatric recipients. Pediatr Transplant 2004; 8:106–112. Marcos A, Lakkis F, Starzl TE. Tolerance for organ recipients: a clash of paradigms. Liver Transplant 2006; 12:1448–1451 (editorial). Starzl TE. Acquired immunologic tolerance: with particular reference to transplantation. Immunologic Research 2007; in press. Starzl TE. Antigen localization and migration in immunity and tolerance. New Engl J Med 1998; 339:1905–1913.

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Pediatric Living-Donor Liver Transplantation Kyle Soltys, Geoffrey Bond, Rakesh Sindhi, and Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

George V. Mazariegos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

BACKGROUND AND HISTORY Living-donor liver transplantation (LDLT) was first reported in 1989 by Raia et al. (1) and in 1990 by Strong et al. (2). As size constraints limit the overall deceased donor population for small children, LDLT quickly developed in order to reduce the morbidity and mortality of an extended waiting time in this patient population; successful centers were established in the United States (3), Europe (4), and Japan (5). TECHNIQUE AND RESULTS Outcomes After an initial period of learning and modification, LDLT has developed as a safe alternative to deceased donation for pediatric living-donor liver recipients. Patient and graft survival have continued to improve for both deceased-donor liver transplantation (DDLT) as well as LDLT (6). Of note, infants appear to have a distinct survival advantage with LDLT compared with DDLT (either whole organ or split) (6,7). The advantages of LDLT may include the improved morbidity and mortality associated with less waiting time for an appropriate allograft, a possible immunologic advantage (8,9), and improved immediate graft function. Preliminary data suggest that up to 10% of LDLT may be able to be withdrawn completely from immunosuppression (10). Donor Technique Donor selection criteria for LDLT were first established for pediatric recipients (11), and the techniques have been described by Broelsch et al. (12). Donor mortality risk is exceedingly low (<1/1000) (13), but perioperative morbidities such as post-operative pain and wound complications are common (14). The maximum length of the portal vein and hepatic artery are obtained by dividing distal to the bifurcation. Intraoperative cholangiography is used to define the biliary anatomy and plan the transection of the liver parenchyma to allow for one biliary anastomosis when possible (3). Recipient Technique Recipient hepatectomy proceeds in a similar fashion as with whole organ transplantation, with the important caveat of maximizing portal vein length and dividing the hepatic artery at the level of the lobar branches. This length is important in order to allow tension-free anastomoses

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and allow for appropriate fashioning of the vascular cuffs to match the donor vascular supply. Figure 1 illustrates the hepatic venous, portal, arterial, and biliary anastomoses. The left hepatic vein of the donor liver is anastomosed to the confluence of all hepatic veins, if possible. Alternatively, the triangulation technique may be used to assure a proper hepatic outflow or the cava opened beside the confluence of the middle and left hepatic veins if the right hepatic vein is small or too lateral (inset, Fig. 1). The hepatic artery is anastomosed using high magnification loupes with interrupted monofilament suture or with microsurgical assistance (15). Finally, the biliary anastomosis is completed as a Roux-en-Y hepatico-jejunostomy. Care is taken to avoid tension or excessive intra-abdominal pressure during closure and may require the temporary use of silastic mesh or skin closure only. DIAGNOSIS AND MANAGEMENT OF COMPLICATIONS Allograft-Specific Complications Hepatic Artery Complications Hepatic Arterial Thrombosis

Hepatic arterial complications occur frequently after pediatric liver transplantation (PLT) and may negatively impact graft survival. The reported incidence of hepatic arterial thrombosis (HAT) after PLT has decreased over time from 4% to 26% (16) to more contemporary rates of 5% or less (17,18). Risk Factors for Hepatic Arterial Thrombosis. Several risk factors have been suggested to increase the risk of HAT after PLT. Early studies demonstrated an increased risk in recipients less than 10 kg or three years of age and in arteries with diameters less than 3 mm (19). ABO incompatible transplantation and the use of excessive intraoperative plasma and elevated hematocrit levels have also been postulated to increase the risk of HAT (17,19). The prophylactic use of antiplatelet therapy (aspirin, dipyridamole, and heparin) is recommended after LDLT.

FIGURE 1 Technique of triangulation utilized in creation of the hepatic vein cuff in LDLT. The left hepatic vein (LHV) of the donor segment is anastomosed to the recipient caval cuff, which consists of all three hepatic veins. Alternatively, the right hepatic vein (RHV) orifice can be oversewn and a cavotomy created lateral to the middle hepatic vein. This technique is useful if the right hepatic orifice is too lateral or too large to be incorporated into the anastomosis.

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Diagnosis. The detection of perioperative HAT is expedited by the routine use of surveillance duplex ultrasound (20,21). Several studies have demonstrated the ability of ultrasound to diagnose HAT or hepatic arterial stenosis (HAS) rapidly and noninvasively in the pediatric recipient; however, false negative studies have been reported in pediatric recipients because of collateralization of the liver (22). In the perioperative period, diminished resistive indices or diminished flow velocities mandates further investigation. Hepatic angiography offers a nonoperative method to diagnose and potentially treat HAS with balloon angioplasty. If there is suspicion for ongoing HAT or stenosis, one can choose to delineate further the anatomy with angiography or to proceed immediately with urgent re-exploration. Clinical Management of Hepatic Arterial Thrombosis. Once detected, the clinical management of HAT depends largely on the timing after LDLT and the clinical condition of the patient. Studies have demonstrated that a proportion of grafts with HAT can be salvaged by operative thrombectomy, thrombolysis, and anastomotic revision if the diagnosis is made early (23,24). Once early HAT is diagnosed by ultrasound, the patient is immediately taken to the operating room for exploration. If there is a delay, or if the ultrasound diagnosis is questionable, selective arteriography may be employed to diagnose the site of thrombosis and to begin therapeutic thrombolysis. Once in the operating room, the liver may demonstrate areas of heterogeneous discoloration. If the primary anastomosis was to the recipient hepatic artery, the anastomosis should be inspected and taken down. Low-pressure irrigation of the donor artery is performed and backflow is assessed. After manually removing clot from the orifice, the artery is further flushed and cleared with an embolectomy catheter until backflow is obtained. At this point, 2 mg of dilute tissue plasminogen activator (tPA) is infused into the donor artery and the artery occluded with an atraumatic clamp. Attention is then turned to the proximal (inflow) artery. The vessel is similarly cleared of all clot, inspected for intimal injury, and assessed for adequate inflow. If good inflow is present, a primary anastomosis is again attempted. If adequate inflow is not provided by the recipient hepatic artery, dissection to the celiac axis is performed or an arterial conduit is anastomosed to the aorta. Postoperatively, the patient is closely watched in the ICU with frequent doppler interrogation of the liver. Systemic heparinization is used according to coagulation parameters. Decisions on retransplantation are made based on the patient’s clinical condition, patency of the graft vessels, and appearance of late post-thrombotic complications such as biliary strictures. Late HAT is often asymptomatic because of the development of a rich collateral network. Attempts at operative revision in these patients should not be undertaken, as a large majority of these patients survive with normal allograft function, and any operative procedure carries the risk of destroying the graft-sustaining collaterals. The survival after late HAT has been recently supported by Stringer et al. (24), who described an 83% survival after HAT, with 40% surviving without the need for retransplantation. Patients who experience significant late allograft dysfunction related to HAT should be carefully monitored for septic complications of biloma formation and cholangitis. Most of these complications can be percutaneously managed during evaluation for retransplantation. Attempts at graft salvage in this population are almost universally unsuccessful, often leading to significant delays in retransplantation and associated increases in morbidity and mortality. Hepatic Artery Stenosis

HAS may also be detected on surveillance ultrasonography of hepatic allografts. Dampened waveforms with decreased resistive indices and slow peak velocities suggest HAS on Doppler interrogation of the liver. The diagnosis of HAS in the LDLT population should be confirmed by selective angiography. If diagnosed in the immediate postoperative period, planned exploration and revision of the arterial anastomosis should be undertaken. The patient should remain therapeutically anticoagulated, while awaiting operative revision of the artery. Successful percutaneous angioplasty has also been performed in an infant with HAS after LDLT (25). Biliary Complications The biliary anastomosis has often been referred to as the “Achilles’ heel” (26) of LDLT, with reported complication rates of 15% to 38% (27,28). Biliary complications result in longer

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postoperative stays, increased readmissions, and significant associated morbidity (29,30). Isolated anastomotic strictures and leaks, however, rarely cause graft loss or mortality if recognized and treated expeditiously. Nonanastomotic and diffuse stricturing after transplantation is usually secondary to ischemic biliary injury, either from prolonged ischemia times or from arterial complications. Diffuse strictures are not well-tolerated and often eventually require retransplantation. Several studies have documented an increase in biliary complications in LDLT. Multiple factors contribute to this finding: (i) the relative size of the bile duct anastomosis is smaller in many cases of pediatric LDLT, (ii) delayed arterial revascularization and the lack of arterial perfusion with preservation solution may lead to microvascular injury, (iii) extensive periductal dissection may devascularize the anastomotic site, and (iv) there is an increased risk of biliary leaks from the cut-surface of liver tissue, which of course is not present in deceased donor transplantation. Biliary complications are generally divided into leaks and strictures. The clinical presentation of these two complications is different, and they occur classically at different time points in the post-transplant course. Biliary Leaks

In LDLT, biliary leaks can occur at three potential sites: (i) at the site of the biliary anastomosis (either duct–duct or biliary–enteric), (ii) at the cut surface of the liver, or (iii) at the site of the intestinal anastomosis. Leaks from the biliary anastomosis or from the cut surface of the liver are generally purely bilious in nature and present with increasing right upper quadrant pain and signs of systemic sepsis. Although all of these processes result in peritoneal contamination, leaks from the cut surface and the biliary anastomosis are generally confined to the right upper quadrant, with contamination limited by the transverse mesocolon and omentum. It is imperative to rule out enteric leakage in these cases, with measurement of the amylase in the drainage fluid, along with measurement of the bilirubin. In cases of drainage with significant levels of amylase (greater than serum), urgent exploration and examination of any enteric anastomosis should be performed. Cut-surface leaks often manifest as bile stained fluid in the strategically placed operative drains and can be managed expectantly as long as the biloma is adequately drained. Biliary leaks may also present later in the postoperative course with right upper quadrant pain and fever after the operative drains have been removed. In these cases, percutaneous drainage of the biloma should be performed with a large caliber drain. Adequate drainage of a potentially infected biloma is imperative and operative drainage may be required. Most of these leaks are from small biliary radicals that have necrosed along the cut surface. Leaks from the anastomosis are generally diagnosed early in the postoperative period, with bilious drainage from abdominal drains. If the leak is diagnosed in the immediate postoperative period, operative exploration, drainage, and revision of the anastomosis is warranted. However, if the patient has recovered from the transplant, imaging studies to delineate the anatomy are again indicated. If an anastomotic leak is diagnosed, initial treatment consists of adequate drainage of the surrounding biloma as outlined previously. Once this is achieved and the patient is stabilized with broad-spectrum antibiotics, percutaneous transhepatic cholangiography (PTC) is performed, and an external stent is placed to bypass the flow of bile through the leak. This is followed by a later procedure with careful placement of a small stent across the disrupted anastomosis. Percutaneous management of biliary leaks is successful in the majority of cases; however, it usually requires multiple procedures and close follow-up. Biliary Strictures

Anastomotic stenosis frequently complicates pediatric LDLT. Most large series report an overall stenosis rate of around 15%. Risk factors include cytomegalovirus (CMV) infection, hepatic arterial complications, ABO incompatible transplantation, and prior anastomotic leaks (31,32). The presentation of stricture includes fever, cholangitis, and asymptomatic elevation of liver function tests (LFTs), and strictures usually present at least one month after LDLT. Ultrasound is the initial diagnostic modality of choice; however, ductal dilatation is often a late manifestation of stricture. Despite the advances in magnetic resonance cholangiography, direct cholangiogram remains the gold standard for diagnosis and should be pursued in suspected cases of stenosis. As most, pediatric LDLT are done with hepaticojejunostomies. PTC is the only method

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available for accessing the bile ducts. PTC also offers the potential for treatment of anastomotic and isolated intrahepatic strictures. Isolated biliary strictures are successfully treated by percutaneous techniques in 85% of cases. In most contemporary series, 90% to 100% of cases are treated in this manner with operative treatment reserved for patients with intractable strictures and complications of percutaneous therapies. Strictures frequently require long-term catheter placement and multiple procedures, with catheters left in situ for a median of 8.5 months in one series (28). It is important to note that any patient with biliary stenosis, especially those with multiple strictures or those recalcitrant to percutaneous treatment, should undergo evaluation for HAT, as biliary complications are a frequent manifestation of HAT. Angiography may be necessary to diagnose late HAT, as collateralization can cause false negative doppler exams. Patients with strictures associated with HAT should continue to undergo percutaneous treatment; however, operative exploration should be avoided, as it disrupts the complex arterial collateral network supplying the graft with blood. Evaluation for retransplantation should occur if strictures continue to affect graft function, especially if associated with bilomas and frequent bouts of cholangitis. Portal Venous Complications Portal Vein Thrombosis

Portal vein thrombosis (PVT) occurs in 1% to 5% of all pediatric liver transplants with a similar incidence in most contemporary series of LDLT (23,33–35). PVT occurs more frequently in cases requiring interposition grafts, especially in cases of portal venous hypoplasia and in cases using cryopreserved venous conduits. Diminished flow in the portal vein is also a risk factor, such as in cases with proximal native PVT and extensive collateralization, or in cases of portosystemic shunts (operative or spontaneous). Patients who have undergone splenectomy are also at an increased risk. Portal venous thrombosis is usually heralded by recurrent ascites, elevated LFTs, thrombocytopenia, and splenomegaly. Gastrointestinal hemorrhage from varices and from mesenteric venous congestion at the jejunojejunostomy may also occur. Any of these symptoms should prompt emergent doppler evaluation of the transplant. Early PVT in the initial perioperative period should be treated with surgical thrombectomy and revision, especially in cases of significant allograft dysfunction. In cases of recurrent PVT, allograft venous conduits should be employed from the superior mesenteric vein. Late PVT may require surgical shunting to decompress the portal system as treatment of the complications of the resulting portal hypertension. Portal Vein Stenosis

Portal vein stenosis (PVS) may also be seen in segmental and living related grafts utilizing venous conduits. PVS usually presents late, at a median of about 50 months after transplant with ascites, variceal bleeding, splenomegaly, and thrombocytopenia. Diagnosis is initially made with ultrasound and confirmed by venography. Because of the relative insensitivity of ultrasound, venography should be used in any cases of clinically suspected PVS, even with normal doppler findings. As in the case of hepatic outflow obstruction, pressure measurements are often obtained to measure a gradient across the anastomosis; however, clinical manifestations of venous stenosis and angiographic evidence of collateralization should prompt intervention rather than relying on absolute pressure gradient findings. Initial treatment of PVS consists of percutaneous balloon venoplasty, which is successful in 77% of cases. A quarter of those managed percutaneously required repeat venoplasty and stenting. Recurrent stenosis occurred in 36% of those initially managed percutaneously; all were in living related allografts. All recurrences were amenable to repeat venoplasty and stenting. PVS not responsive to percutaneous methods can be medically managed or undergo surgical decompressive shunts if clinically warranted. Not surprisingly, patients who were successfully treated percutaneously had a better survival rate than those who failed. Hepatic Venous Complications In large series of PLT, hepatic venous complications have occurred in approximately 2% of cases (16,23,36). Living-related and technical variant grafts are more likely to experience complications involving the hepatic venous anastomosis depending on the series, with rates ranging

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from 2% (36) to 27% (37). In addition to the common technical causes of hepatic venous stenosis (HVS), in living-related and segmental liver transplantation, rotation of the allograft with subsequent kinking of the anastomosis is also a possibility. Allograft regeneration with subsequent rotation may also account for some cases. Diagnosis of HVS occurs at a mean of 37 months (range 2–120 months), and clinical manifestations include ascites, peripheral edema, fluid retention, hyponatremia, hepatomegaly, and elevated LFTs. Ultrasound is used as the initial diagnostic modality; however, if clinically indicated, venography and allograft biopsy should be performed in spite of normal doppler findings. Biopsy findings suggestive of outflow obstruction include sinusoidal dilatation as well as zone 3 congestion and fibrosis. Similar to PVS, percutaneous treatment of HVS is successful in most cases. Balloon venoplasty alone is successful in over 50% of cases; however, multiple procedures are often required. Stent placement is used for cases that do not respond to simple dilatation and is usually needed in cases caused by anastomotic rotation (38). Overall, percutaneous methods are successful in 75% of cases. Anticoagulation is an important adjunct therapy in this group of patients, and failure is often successfully managed medically, with good long-term results. Retransplantation is reserved only for failure of medical management and is rarely needed in this setting. General Operative Complications Abdominal Compartment Syndrome In adult to pediatric LDLT, the size of the segmental graft may be several times larger than the native liver. Intestinal edema and distention after portal vein clamping also contributes to this problem. Although resectional techniques do exist to decrease the size of the allograft, the abdominal cavity often remains too small to accommodate the allograft and allow closure. If closed with considerable intra-abdominal tension, recipients may exhibit symptoms of a classic abdominal compartment syndrome with respiratory compromise, renal insufficiency, and hemodynamic instability. The placement of the oversized allograft on the vena cava of the recipient may also exacerbate this. Allograft thrombosis may also occur in this situation because of excessive pressure and positional kinking of the graft. To avoid the development of this syndrome, several groups have published experiences with delayed closure in situations where oversized grafts are used. The most common device used is the silastic mesh (39), with gradual reduction in the size of the mesh over time, after decompression of the abdominal viscera and successful diuresis of the patient. This process often takes one to two weeks and several laparotomies for gradual closure. This technique facilitated abdominal closure in cases with donor-to-recipient weight ratios of up to 9.1 in one series (40). Tissue expanders have also been used by some centers in an effort to prevent rotational complications, with good results (41). At the Children’s Hospital of Pittsburgh, we use a modification of the Lonestar retractor to place continuous tension on fascial edges to facilitate gradual closure of full-thickness tissue edges. Pulmonary Complications Respiratory complications following pediatric LDLT have been shown to be a significant source of morbidity and mortality. Risk factors for the development of pulmonary complications include a history of respiratory complications, United Network for Organ Sharing (UNOS) status at the time of LDLT, and patients who are short for their age. Intraoperative blood loss of more than 20% of body weight is also associated with more pulmonary complications (42). Pulmonary complications include severe atelectasis, pneumonia, and volume overload. Aggressive pulmonary toilet has been associated with decreased complications (43). Small, malnourished children that receive large-for-size grafts are more likely to be unable to ventilate adequately against the increased intra-abdominal pressure associated with the allograft. Delayed closure and the liberal use of prosthetic mesh improve the pressure issues; however, this necessitates prolonged intubation, another risk factor for the development of pulmonary complications. Intestinal Complications Intestinal complications after pediatric LDLT are fortunately relatively rare; however, they have a substantial impact on morbidity and mortality. Bowel perforation remains a feared

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complication after transplantation, and breakdown of enteroenteric anastomosis may lead to overwhelming sepsis. Technical aspects of enteric anastomosis, such as two-layer technique and avoiding tension on the suture line, should be stressed. Careful closure of mesenteric defects should also be employed to avoid internal herniation and volvulus. Children with a history of multiple abdominal procedures, especially portoenterostomy, are at increased risk for post-transplant gut perforation (44). Severe malnutrition and excessive intraoperative transfusion requirements are also associated with perforation. There is also a risk for postoperative bowel obstruction after LDLT, both adhesive and anastomotic in nature. Obstruction should be managed aggressively with prompt decompression and fluid resuscitation. Investigation of obstructive symptoms should be undertaken with abdominal CT to rule out other potential causes of obstruction, such as post-transplant lymphoproliferative disorder (PTLD). If there is no evidence of PTLD and the patient remains clinically stable, short periods of nonoperative treatment are allowed with careful monitoring for signs of intestinal compromise or perforation. Infectious Complications Perioperative Infections Early infections after pediatric LDLT transplantation can be divided into those related to the procedure, such as biliary leaks and bowel perforations, and those not directly related to the operation, such as pneumonia and catheter-related sepsis (45). A detailed review of infections and complications is found elsewhere in this text; however, some pertinent points are presented here. In the early postoperative period, nontechnical infectious complications contribute substantially to morbidity. Analysis of the Studies of Pediatric Liver Transplantation (SPLIT) database revealed respiratory complications and pneumonias in 18% of patients with 39% experiencing culture-positive bacterial infections (46). Intra-abdominal sepsis and catheterrelated bloodstream infections were the most common sources of bacterial infections. Overall, surgical complications, including enteric and biliary leaks and vascular thromboses, dramatically increase the risk of bacterial and fungal sepsis. Fungal infections can be particularly devastating in the post-transplant patient, with a peak incidence in the first two months (47). The SPLIT database described a 9.8% fungal infection rate (46). Risk factors included transplantation for fulminant hepatic failure, retransplantation, prolonged operative times, malnutrition, and the use of high dose steroids and broad-spectrum antibiotics. Aggressive drainage of fluid collections, debridement of devitalized tissue, maintenance of nutrition, and the use of potent antifungal therapy can reduce the morbidity and mortality of invasive fungal infections. Prophylaxis in high-risk patients should also be considered, although the use of perioperative fluconazole can interfere with tacrolimus metabolism. Although over 80% of fungal infections are related to candida species, an increasing awareness of Aspergillus species is required, as antemortem diagnosis is achieved in only 50% of patients. The availability of voriconazole and high-dose liposomal amphotericin has afforded viable treatment options for patients infected with Aspergillus. Surgical site infections following pediatric LDLT are increased by prolonged operative and cold ischemia times, large volumes of intraoperative transfusions, pre-operative ascites, and hypoalbuminemia (48). The use of antilymphocyte antibodies and the occurrence of rejection have also been associated with increased surgical site infections. Viral infections can have a devastating effect on the immunosuppressed child in the early postoperative period. Common pathogens include CMV, Epstein-Barr virus (EBV), herpes simplex virus (HSV), adenovirus, and influenza viruses. In the pediatric age group, many patients have no prior protective exposure to these viruses, and primary infection can occur (49,50). Recent advances in prophylaxis and pre-emptive therapy have been successful in decreasing the early morbidity associated with EBV, CMV, and HSV to an incidence of <5% (49–51). Because of the lack of effective treatments, disseminated viremia, necrotizing pneumonitis, and bacterial superinfection can result from common respiratory viruses, such as influenza and adenovirus in the early postoperative period. Post-transplant Lymphoproliferative Disorder PTLD remains a significant cause of late mortality in pediatric LDLT (52–54). Post-transplant infection with EBV results in a spectrum of diseases from mononucleosis syndromes and plasma cell hyperplasia (reactive hyperplasia) to neoplastic PTLD. Although a small subpopulation of

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PTLD (5% to 10%) is not associated with EBV, in situ hybridization reveals the presence of EBV-encoded RNA in most cases. Early studies found that primary tacrolimus use in pediatric patients was associated with a 15% long-term risk of PTLD, with almost 80% of these cases occurring in the first two years after transplant (55,56). Infants and toddlers comprise a majority of transplant waiting lists and are usually EBV-seronegative, with an increased risk of developing a primary infection under immunosuppression and an increased risk of developing clinical disease (57–59). In contrast, clinical disease rarely occurs in children who are seropositive prior to transplantation. The diagnosis of EBV disease in children after LDLT hinges on the history and physical examination coupled with confirmatory laboratory and radiologic studies. A high index of suspicion in these high-risk patients is warranted, and leads to early diagnosis and institution of therapy. Patients often complain of sporadic fever, lethargy, and malaise. Weight loss, diarrhea, and gastrointestinal complaints are often common, as are symptoms of allograft dysfunction. Persistent sore throat, adenopathy, headaches, seizures, and cutaneous lesions may also been seen. Physical examination may reveal adenopathy, tonsillar changes, and hepatosplenomegaly. Standard laboratory evaluation may show leukopenia and atypical lymphocytosis, anemia, and thrombocytopenia. Hemoccult-positive stool specimens suggest gastrointestinal involvement, and LFTs may also be elevated. The current availability of well-validated tests to measure EBV viral load in the peripheral blood allows clinicians to monitor the replication of EBV in the recipient and follow the response to treatment. Further evaluation of PTLD is guided by initial findings, and contrast-enhanced CT scanning of the head, neck, chest, abdomen, and pelvis, and endoscopy should be performed if indicated by initial studies. Histologic examination of tissue is optimal, and surgical/ endoscopic specimens should be promptly submitted fresh for in situ hybridization using antiEBV antibodies. An evaluation for CD20 staining should also be performed (58). Reliable polymerase chain reaction (PCR) monitoring of EBV viral loads in the peripheral blood has led to the era of pre-emptive therapy of EBV viremia prior to its evolution to PTLD. For prospective monitoring to be efficient, the frequency of monitoring needs to be sufficient to catch relevant rises in EBV viral loads. As the highest risk for EBV infection in seronegative patients after LDLT is in the first three months, we monitor EBV PCR more frequently during this time period, with a gradual decrease over the first year. Response to an elevated EBV PCR is graded according to the degree of elevation. Mild increases prompt a reduction in immunosuppression to tacrolimus levels of 3–5 ng/mL until EBV PCR levels are normal, or biopsyproven rejection occurs. With more significant PCR elevations, immunosuppression is similarly decreased, and investigation for clinical disease begins with an enhanced screening CT scan of the head, neck, chest, abdomen, and pelvis. The presence of any suspicious nodes or masses prompts biopsy and treatment with ganciclovir and cytogam as a bi-weekly dosage until levels have normalized (58). In children with documented PTLD, immunosuppression should be stopped completely, and successful reduction or disappearance of lesions is usually seen (58,60). A prompt fall in EBV PCR levels predicts a good clinical response in this situation, often before lesions shrink. PTLD that is unresponsive to this treatment plan should be treated with the anti-CD20 chimeric monoclonal antibody, rituximab, if the PTLD is CD20+. Complete remission rates of 60% to 70% have been documented in children. The drug is well-tolerated, and although up to 20% can recur, most can be cured with retreatment. B-cell depletion persists for up to nine months after rituximab, and children should thus be carefully monitored for infectious complications and treated with intravenous immunoglobulin (IVIG) in cases of documented hypogammaglobulinemia. For PTLD refractory to rituximab, low-dose cytotoxic chemotherapy and prednisone has been effective. Cytotoxic chemotherapy is also immunosuppressive and allows complete elimination of calcineurin inhibitors while it is being administered (60).

REFERENCES 1. Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet 1989; 2(8670):1042–1043. 2. Strong RW, Lynch SV, Ong TH, et al. Successful liver transplantation from a living donor to her son. N Engl J Med 1990; 322(21):1505–1507.

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3. Millis JM, Cronis DC, Brady LM, et al. Primary living-donor liver transplantation at the University of Chicago: technical aspects of the first 104 recipients. Annals of Surg 2000; 232(1):104–111. 4. Otte JB. Paediatric liver transplantation—a review based on 20 years of personal experience. Transpl Int 2004; 17:562–573. 5. Tanaka K, Uemoto S, Tokunaga Y, et al. Living-related liver transplantation in children. Am J Surg 1994; 168(1):41–48. 6. Magee JC, Bucuvalas JC, Farmer DG, et al. Pediatric transplantation. Am J Transplant 2004; 4(9):54–71. 7. Roberts JP, Hulbert-Shearon TE, Merion RM, et al. Influence of graft type on outcomes after pediatric liver transplantation. Am J Transplant 2004; 4:373–377. 8. Justin MT, Feurer ID, Chari RS, et al. Survival after pediatric liver transplantation: why does living donation offer an advantage? Arch Surg 2005; 140(5):465–470, discussion 470–471. 9. Li Y, Koshiba T, Yoshizawa A, et al. Analysis of peripheral blood mononuclear cells in operational tolerance after pediatric living-donor liver transplantation. Am J Transplant 2004; 4(12):2118–2125. 10. Takatsuki M, Uemoto S, Inomata Y, et al. Weaning of immunosuppression in living-donor liver transplant recipients. Transplantation 2001; 72(3):449–454. 11. Morimoto T, Ichimiya M, Tanaka A, et al. Guidelines for donor selection and an overview of the donor operation in living-related liver transplantation. Transpl Int 1996; 9(3):208–213. 12. Broelsch CE, Whitington PF, Emond JC, et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg 1991; 214:428–439. 13. Otte JB. History of pediatric liver transplantation. Where are we coming from? Where do we stand? Pediatr Transplant 2002; 6:378–387. 14. Renz JF, Roberts JP. Long-term complications of living-donor liver transplantation. Liver Transpl 2002; 6(suppl 2):S73–S76. 15. Guarrera JV, Sinha P, Lobritto SJ, et al. Microvascular hepatic artery anastomosis in pediatric segmental liver transplantation: microscope versus loupe. Transpl Int 2004; 17:585–588. 16. Sieders E, Peeters PMJG, TenVergert EM, et al. Early vascular complications after pediatric liver transplantation. Liver Transpl 2000; 6:326–332. 17. Hatano E, Terajima H, Yabe S, et al. Hepatic artery thrombosis in living-related liver transplantation. Transplantation 1997; 64:1443–1446. 18. Rela M, Muiesan P, Bhatnagar V, et al. Hepatic artery thrombosis after liver transplantation in children under five years of age. Transplantation 1996; 61:1355–1357. 19. Mazzaferro V, Esquivel CO, Makowka L, et al. Hepatic artery thrombosis after pediatric liver transplantation—a medical or surgical event? Transplantation 1989; 47:971–977. 20. Fujimoto M, Moriyasu F, Nada T, et al. Hepatic arterial complications in pediatric segmental liver transplantations from living donors: assessment with color Doppler ultrasonography. Clin Transplant 1997; 11:380–386. 21. Nishida S, Kato T, Levi D, et al. Effect of protocol doppler ultrasonography and urgent revascularization on early hepatic artery thrombosis after pediatric liver transplantation. Arch Surg 2002; 137:1279–1283. 22. McDiarmid SV, Hall TR, Grant EG, et al. Failure of duplex sonography to diagnose hepatic artery thrombosis in a high-risk group of pediatric liver transplant recipients. J Pediatr Surg 1991; 26:710–713. 23. Someda H, Moriyasu F, Fujimoto M, et al. Vascular complications in living-related liver transplantation detected with intaoperative and postoperative Doppler ultrasound. J Hepatol 1995; 22:623–632. 24. Stringer MD, Marshall MM, Muiesan P, et al. Survival and outcome after hepatic artery thrombosis complicating pediatric liver transplantation. J Pediatr Surg 2001; 36:888–891. 25. Hasegawa T, Sasaki T, Kimura T, et al. Successful percutaneous transluminal angioplasty for hepatic artery stenosis in an infant undergoing living-related liver transplantation. Pediatr Transplant 2002; 6:244–248. 26. Egawa H, Inomata Y, Uemoto S, et al. Biliary anastomotic complications in 400 living-related liver transplants. World J Surg 2001; 25(1):1300–1307. 27. Egawa H, Uemoto S, Inomata Y, et al. Biliary complications in pediatric living-related liver transplantation. Surgery 1998; 124:901–910. 28 Kling K, Lau H, Colombani P. Biliary complications of living-related pediatric liver transplant patients. Pediatr Transplant 2004; 8:178–184. 29. Orri T, Ohkohchi N, Satomi S. Rehospitalization after pediatric living-donor liver transplantation. Transplantation 2004; 77(6):880–885. 30. Goldstein MJ, Salame E, Kapur S, et al. Analysis of failure in living-donor liver transplantation: differential outcomes in children and adults. World J Surg 2003; 27:356–364. 31. Schindel D, Dunn S, Casas A, et al. Characterization and treatment of biliary anastomotic stricture after segmental liver transplantation. J Pediatr Surg 2000; 35:940–942. 32. Egawa H, Inomata Y, Uemoto S, et al. Biliary anastomotic complications in 400 living-related liver transplantations. World J Surg 2001; 25:1300–1307. 33. Reding R, de Goyet JDE, Delbeke I, et al. Pediatric liver transplantation with cadaveric or living related donors: comparative results in 90 elective recipients of primary grafts. J Pediatr 1999; 134:280–286.

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34. Farmer DG, Yersiz H, Ghobrial RM, et al. Early graft function after pediatric liver transplantation. Transplantation 2001; 72:1795–1802. 35. Kuang AA, Rosenthal P, Roberts JP, et al. Decreased mortality from technical failure improves results in pediatric liver transplantation. Arch Surg 1996; 131:887–893. 36. Buell JF, Funaki B, Cronin DC, et al. Long-term venous complications after full-size and segmental pediatric liver transplantation. Ann Surg 2002; 236:658–666. 37. Tannuri U, Mello ES, Carnevale FC, et al. Hepatic venous reconstruction in pediatric living-related donor liver transplantation—experience of a single center. Pediatr Transplant 2005; 9:293–298. 38. Mazariegos GV, Garrido V, Jkowski-Phillips S, et al. Management of hepatic venous obstruction after split-liver transplantation. Pediatr Transplant 2000; 4:322–327. 39. Seaman DS, Newwll KA, Piper JB, et al. Use of polytetraflouroethylene patch for temporary wound closure after pediatric liver transplantation. Transplantation 1996; 62:1034–1036. 40. De Ville de Goyet J, Struye de Swielande Y, Reding R, et al. Delayed primary closure of the abdominal wall after cadaveric and living-related donor liver graft transplantation in children: a safe and useful technique. Transpl Int 1996; 11:117–122. 41. Inomata Y, Tanaka K, Egawa H, et al. Application of a tissue expander for stabilizing graft position in living-related liver transplantation. Clin Transplant 1997; 11:56–59. 42. Hasegawa S, Mori K, Inomata Y, et al. Factors associated with postoperative respiratory complications in pediatric liver transplantation from living-related donors. Transplantation 1996; 62:943–947. 43. Sato T, Okamoto K, Sadanaga M, et al. High incidence of postoperative pulmonary complications after orthotopic liver transplantation in children. J Anesth 1994; 8:274. 44. Soubrane O, el Meteini M, Devictor D, et al. Risk and prognostic factors of gut perforation after orthotopic liver transplantation for biliary atresia. Liver Transpl Surg 1995; 1:2–9. 45. Bouchut JC, Stamm D, Boillot O, et al. Post-operative infectious complications in pediatric liver transplantation: a study of 48 transplants. Paediatr Anaesth 2001; 11:93–98. 46. The SPLIT Research Group. Studies of Pediatric Liver Transplantation (SPLIT): year 2000 outcomes. Transplantation 2001; 72(3):463–476. 47. Suzuki T, Hashimoto T, Nakamura T, et al. Fungal infection in living-related liver transplantation patients. Transplant Proc 2000; 32:2231–2232. 48. Hollenbeak CS, Alfrey EJ, Sheridan K, et al. Surgical site infections following pediatric liver transplantation: risks and costs. Transpl Infect Dis 2003; 5(2):72–78. 49. Green M. Viral infections and pediatric liver transplantation. Pediatr Transplant 2002; 6:20–24. 50. Keough WL, Michaels M. Infectious complications in pediatric solid-organ transplantation. Pediatr Clin N Am 2003; 50:1451–1469. 51. Slifkin M, Doron S, Snydman DR. Viral prophylaxis in organ transplant patients. Drugs 2004; 64:2763–2792. 52. Martin SR, Atkison P, Anand R, et al. and the SPLIT Research Group. Studies of Pediatric Liver Transplantation 2002: patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada. Pediatr Transplant 2004; 8:273–283. 53. Fridell JA, Jain A, Reyes J, et al. Causes of mortality beyond one year after primary pediatric liver transplant under tacrolimus. Transplantation 2002; 74(12):1721–1724. 54. Sudan DL, Shaw BW, Langnas AN. Causes of late mortality in pediatric liver transplant recipients. Ann Surg 1998; 227(2):289–295. 55. Jain A, Mazariegos G, Kashyap R, et al. Pediatric liver transplantation. A single center experience spanning 20 years. Transplantation 2002; 73(6):941–947. 56. Cacciarelli TV, Reyes J, Jaffe R, et al. Primary tacrolimus (FK506) therapy and the long-term risk of post-transplant lymphoproliferative disease in pediatric liver transplant recipients. Pediatr Transplant 2001; 5:359–364. 57. Green M, Webber S. Post-transplantation lymphoproliferative disorders. Pediatr Clin N Am 2003; 50:1471–1491. 58. Green M. Management of Epstein-Barr Virus induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation. Am J Transplant 2001; 1:103–108. 59. Smets F, Sokal EM. Lymphoproliferation in children after liver transplantation. J Pediatr Gastroenterol Nutr 2002; 34(5):499–505. 60. Soltys K, Green M. Posttransplant lymphoproliferative disease. J Pediatr Infect Dis 2005; 24(12): 1107–1108.

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Living-Donor Liver Transplantation for Hepatocellular Carcinoma J. Wallis Marsh Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Matthew P. Holtzman Department of Surgical Oncology, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Igor Dvorchik Departments of Surgery and Biostatistics, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION The unequivocal indication for the operation of liver replacement was originally considered to be primary hepatic malignancy, which could not be treated with conventional techniques of subtotal liver resection. It remains to be determined whether orthotopic liver transplantation will be an effective method for treating primary carcinoma of either the liver cells or intrahepatic bile ducts” (1). Although written by Dr. Thomas E. Starzl in 1969, the issue of organ allocation and transplantation for hepatocellular carcinoma (HCC) is as controversial now as it was then. In the intervening years since this was written, deceased-donor liver replacement for “early-stage” HCC has become an accepted indication worldwide. However, the applicability of living donors for this disease is much less clear. The decision to procure live donors for patients with HCC is predicated upon three issues, the first two of which equally apply to any indication for living donor transplantation: 1. Can the donor operation be performed safely? 2. Is there a need (i.e., is there a shortage of deceased donor organs)? 3. What is the fate of candidates who drop out of the waiting lists or those outside the current United Network for Organ Sharing (UNOS) criteria? CAN THE DONOR OPERATION BE PERFORMED SAFELY? Donor safety, above all considerations, is of paramount importance as living donation is the only operation performed for which there is no indication. This is a sobering thought, for the loss of a life, which was not ill and for whom there was no indication to perform surgery, except for the willingness of one human being to sacrifice his or her life for another, must always remain the overriding concern. Because there is no worldwide registry, the morbidity and mortality for living liver donation is impossible to ascertain, but the mortality risk is estimated to be 0.1%, which should continue to decrease as experienced is gained. However, no matter the improvements, the risk of death for the donor will never be zero. IS THERE A NEED? ”Will there be enough donor organs to meet recipient need? The answer to this question is already in: no! The increasing number of patients with chronic hepatitis C has already expanded waiting lists beyond their capacity to provide adequate numbers of donor organs in a timely fashion. Within this subgroup of patients, another phenomenon is occurring: an increasing

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number of patients developing HCC either before listing or after they have been listed. Once HCC develops in those patients with cirrhosis, the clock is ticking. The limited deceased donor supply cannot meet this need” (2). This statement addressing the profound shortage of deceased donor organs was made by Dr. Gregory T. Everson at a conference in 2000 addressing advances and controversies in liver transplantation (HCC, viral hepatitis, and living donor liver transplantation in adults), and more than adequately describes the severe shortage of organs faced by all recipients, not only those with HCC. WHAT IS THE FATE OF CANDIDATES WHO DROP OUT OF THE WAITING LIST OR THOSE OUTSIDE THE CURRENT UNOS CRITERIA? There are two groups of patients who must be considered: 1. Patients who initially meet UNOS listing criteria, but experience dropout because of tumor progression while on the waiting list. 2. Patients outside listing criteria at the time of presentation. UNOS does not dictate to any transplant program which patient with HCC can be transplanted; however, this is the net effect of its policy since practically speaking only patients with a high model for end-stage liver disease (MELD) score have any realistic chance of receiving a deceased donor organ in a timely fashion (which is critical for patients with cancer). MODEL FOR END-STAGE LIVER DISEASE SCORE Patients accepted for liver transplantation are placed on the UNOS waiting list and are ranked according to their MELD score. The MELD score is a numerical scale, ranging from six (less ill) to 40 (gravely ill), which is used for adult liver transplant candidates and gives each individual a “score” (number) based on how urgently the transplant is needed within the next three-month period. (MELD scores are regularly updated to reflect the changing status of the potential recipient.) The MELD score is calculated by a complex formula using three routine lab test results: bilirubin, international normalized ratio (INR), and creatinine (3). Initially, the MELD score for patients with HCC is calculated as with any patient, but may then be increased according to the estimated stage of the patient’s HCC. At the current time, only patients with Stage II HCC in accordance with the modified tumor-node-metastasis (TNM) staging classification (Table 1) may receive extra priority points (i.e., an upgrade) on the UNOS waiting list. The patient must have undergone a thorough assessment to evaluate the number and size of the tumor(s), and to rule out any extrahepatic spread and/or macrovascular

TABLE 1

American Liver Tumor Study Group Modified Tumor-Node-Metastasis Staging Classification

Classification TX, NX, MX TO, NO, MO T1 T2 T3 T4a T4b N1 M1 Stage 1 Stage II Stage III Stage IVA1 Stage IVA2 Stage IVB

Definition Not assessed Not found 1 nodule ≤1.9 cm 1 nodule 2.0–5.0 cm; 2 or 3 nodules, all <3.0 cm 1 nodule >5.0 cm; two or three nodules, at least one >3.0 cm 4 or more nodules, any size T2, T3, or T4a plus gross intrahepatic portal or hepatic vein involvement as indicated by CT, MRI, or ultrasound Regional (portal hepatis) nodes, involved Metastatic disease, including extrahepatic portal or hepatic vein involvement T1 T2 T3 T4a T4b Any N1, any M1

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involvement. Strangely enough, a prelisting biopsy is not mandatory, but the lesion must meet defined imaging criteria. The assessment of the patient should include ultrasound of the patient’s liver, a computerized tomography (CT), or magnetic resonance imaging (MRI) scan of the abdomen that documents the tumors and a CT of the chest that rules out metastatic disease. In addition, the patient must have at least one of the following: a vascular blush corresponding to the area of suspicion, an alpha-fetoprotein level of >200 ng/mL, an arteriogram confirming a tumor, a biopsy confirming HCC, or cytoreductive or cytoablative treatment (e.g., chemoembolization of the lesion, radiofrequency ablation, cryoablation, or chemical ablation), which can be performed without biopsy proof of any malignancy. A patient not meeting the above criteria may continue to be considered a liver transplant candidate, but must be listed at the calculated MELD score with no additional priority given because of the HCC diagnosis. All other patients with HCC, including those with downsized tumors (i.e., having undergone ablative therapy and whose original/presenting tumor was greater than a Stage T2), must be referred to the applicable regional review board for prospective review (4). Based on the above criteria, a patient with presumed Stage II HCC may be upgraded on the UNOS waiting list equivalent to a MELD score of 22 (a 15% probability of candidate death within three months). Patients with HCC on the waiting list must be re-examined for tumor progression every three months. Should the tumor progress to more than Stage II, the patient may remain on the transplant center’s waiting list (according to each program’s individual policy), but loses the additional waiting points previously awarded. Obviously for those with advancing tumor stage, this severely limits their only potentially curative option. If the tumor can be downstaged through methods such as chemoembolization, liver resection, or radiofrequency ablation, application for the additional waiting points can again be sought for through the regional review board. While no statistics are available, it is reasonable to assume that nearly all of these patients progress to death from their malignancy without the potential benefit of transplantation unless rescued with living donation.

PATIENTS OUTSIDE CURRENT UNOS CRITERIA For patients outside the current listing criteria (more than Stage II ), the same nontransplant options are available; that is, medical or surgical therapies that attempt to downgrade the tumor after which time the application of the additional MELD points might apply. However, is this algorithm reasonable? First, how accurate is the pre-operative staging for patients with HCC? A recent review of the UNOS database described 400 cases with complete information for patients listed and subsequently transplanted with suspected HCC. Of these, 235 did not have a pre-operative ablative procedure, meaning the explant specimen could be fully evaluated for confirmation of HCC. Surprisingly, 59 (25%) had no evidence of HCC on the explant pathology report. Of the 165 cases who did undergo a preoperative ablative procedure, only 66 (40%) had a pre-operative biopsy reported in the UNOS database. The explant pathology showed that 104/165 (63%) had HCC detected. Thirty-seven cases (22%) had only necrosis or infarct on histology, but six (16%) of these had had a positive biopsy prior to the ablation. (The remaining 24 cases had nonmalignant diagnoses.) Therefore, only 110/165 (66%) of the ablated cases had documented proof of HCC (5). Second, given that the staging system is so imprecise, what would be the effect of loosening the staging requirements for upgrading patients on the waiting list? There are many publications that show that survival after transplant for HCC under the current UNOS criteria is excellent; some, in fact, report survival equal to that in patients without malignancy (6–13). However, these criteria ignore the approximately 35% to 40% of patients outside the current UNOS criteria who will not suffer HCC recurrence after liver transplantation (LT) (14); this fact calls out for the revision of the current staging systems (15–17). These patients are the ones who could benefit most from living donation.

LIVING DONATION Currently, there is controversy about how best to serve this patient population (those outside the current listing criteria, but who have at least a 50% chance of five-year tumor-free survival). One thought is that these patients should be the recipients of living donor organs, as it does not

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diminish the deceased donor pool of available organs (18). However, this ignores the issue of the higher relative risk of recurrence for the recipient (since the cancer stage is more advanced) and the impact this might have on the living donor. On the other hand, given the lack of study in this area, it is entirely possible that the donor would feel that the organ donation was the only possible chance to help or rescue the recipient. The opposing view is that until the limits of HCC tumor progression that can reasonably be cured by liver transplantation (50% five-year tumor-free survival) have been widely established and agreed upon, a modest extension of the criteria should be performed in those receiving deceased donor organs (14). This approach could potentially diminish the number of organs available if one could prove that the number of living donors willing to donate would decrease if the life of the potential recipient were not in imminent danger (i.e., the impetus to donate might be far greater when the intended recipient has malignancy). In any of these circumstances, the potential for HCC recurrence and death of the recipient must be stressed with the living donor, particularly if the indication is advanced HCC. Given this scenario and the probability that, at least for the moment, potential recipients with more advanced HCC will be shunted into the living donor pool, is there a way to maximize the foreknowledge of the risk of recurrence and therefore the impact on the live donor?

PRE-TRANSPLANT BIOPSY AND FRACTIONAL ALLELIC LOSS Though uncommonly performed pre-operatively (because proof of diagnosis is not required either for listing patients with HCC or for the application of the additional MELD points), a biopsy of the tumor can yield a wealth of predictive molecular information (in addition to the actual diagnosis), such as the fractional allelic loss (FAL) rate of a panel of nine microsatellites (Table 2) (19,20). (The FAL is calculated by dividing the number of mutated microsatellites by the total number of microsatellites for which the patient was found to be informative.) The predictive power of FAL surpasses even that of vascular invasion. We recently reviewed 183 patients transplanted in the presence of HCC; all patients had at least five years of follow-up. Seventeen patients had macrovascular invasion, positive lymph nodes, positive margins or metastatic disease, and were therefore excluded from review because of uniform disease recurrence. Of the remaining 166, 11 had no FAL data (secondary to complete tumor necrosis from pretreatment). Of the remaining 155 cases, 75 were inside the UNOS criteria while 80 were outside. For patients inside the UNOS criteria, the mean tumor-free survival was 15.1 years; for those outside, the mean tumor-free survival was 9.7 years (Fig. 1). Four patients (5.3%) inside the UNOS criteria suffered tumor recurrence, and while 44/80 (55%) of the patients outside the UNOS criteria suffered cancer recurrence, 36/80 (45%) did not. While a 94.7% nonrecurrence rate (those inside the UNOS criteria) is excellent, it is perhaps too excellent as it denies consideration for liver transplantation to the 45% of patients outside the criteria who also would not suffer tumor recurrence. In an effort to gain insight into the potential usefulness of the molecular information that can be provided by biopsy, we stratified all 155 patients only by the FAL, ignoring all other

TABLE 2 Microsatellites and Their Associated Genes Used to Calculate the Fractional Allelic Loss Rate Microsatellite 17p13 D17S 974 17p13 D17S 1289 18q21 D18S 814 1p34 D1S 407 3p26 D3S 1539 5q21 D5S 615 9p21 D9S 251 1p34 MYCL 5NT 17p13 TP53 I1

Associated gene TP53 TP53 DCC p34 OGG1 APC CDKN2A MYC1 TP53

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Tumor-Free Survival Stratified by Milan Criteria No Macrovascular Invasion 1.0

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components of the current listing criteria. The patients were divided into three groups: Group 1—those 80 patients with an FAL ≤ 20%; Group 2 — those 28 patients with an FAL between 21% and 40%; and Group 3 — those 47 patients with an FAL > 40%. The means of tumor-free survival were 15.2 years, 8.5 years, and 3.7 years for Groups 1, 2, and 3, respectively (Fig. 2). The overall rates of nonrecurrence were 93.59% (73/78), 70.83% (17/24), and 43.48% (10/23) for Groups 1, 2, and 3, respectively (P < 0.0001). Therefore, the measurement of FAL alone would allow 27 (21.6%) additional patients to receive liver transplantation, assuming of course that the mean tumor-free survival rate of 8.5 years and a recurrence rate of 29.2% (those in Group 2) would be acceptable to the transplant community. This survival rate is well within the suggested 50% five-year survival rate suggested in a recent review by Llovet et al. (21) The same analysis was performed on those 75 patients inside the UNOS/Milan criteria. There were 60 patients in Group 1, 11 patients in Group 2, and four patients in Group 3. The means of tumor-free survival were 15.5 years, 8.1 years, and 4.4 years for Groups 1, 2, and

Tumor-Free Survival Stratified by FAL No Macrovascular Invasion FAL =< 20% 21% - 40% > 40%

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FIGURE 2 Tumor-free survival stratified by fractional allelic loss (no macrovascular invasion). Abbreviation: FAL, fractional allelic loss.

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3, respectively (P < 0.03). The rates of nonrecurrence were 96.67% (58/60), 90.91% (10/11), and 75% (3/4) for Groups 1, 2, and 3, respectively (Fig. 3). The use of FAL could have excluded at least three patients inside the UNOS criteria (Group 3) who would have suffered recurrence. While one patient in Group 3 who did not suffer recurrence would have been excluded from LT, this is considerably less than the 29 patients outside the current criteria who would not suffer the recurrence. Finally, the analysis was also performed on those 80 patients outside the UNOS/Milan criteria. There were 20 patients in Group 1, 17 patients in Group 2, and 43 patients in Group 3. The mean tumor-free survival rates were 13.8 years, 7.4 years, and 3.5 years for Groups 1, 2, and 3, respectively (P < 0.0001). The rates of nonrecurrence were 83.33% (15/18), 53.85% (7/13), and 36.84% (7/19) for Groups 1, 2, and 3, respectively (Fig. 4). Once again, depending upon the philosophy of the transplant community for an acceptable recurrence rate, 31 patients (Groups 1 and 2) who are currently being excluded from receiving additional listing could have been offered liver transplantation if molecular tools currently available were incorporated into listing criteria (22).

Tumor-Free Survival Stratified by FAL Patients Outside UNOS Criteria FAL =<20% 21% - 40% > 40%

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FIGURE 4 Tumor-free survival stratified by fractional allelic loss (patients outside UNOS criteria). Abbreviation: FAL, fractional allelic loss.

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SUMMARY Living donation for patients with HCC is an issue not likely to be resolved in the near future. However, it often represents the only avenue open to patients with “advanced” HCC but still with an acceptable five-year survival rate. With newer technologies now available, the method of distributing organs to this group of patient should be revised accordingly. REFERENCES 1. Starzl, TE. Candidacy. In: Starzl TE, Putnam CW, eds. Experience in Hepatic Transplantation. Philadelphia: WB Saunders, 1969. 2. Everson GT. Increasing incidence and pretransplantation screening of hepatocellular carcinoma. Liver Transpl 2000; 6(6 suppl 2):S2–S10. 3. http://www.unos.org/resources/MeldPeldCalculator.asp?index = 98 4. Policy 3.6.4.4 on organ allocation from the UNOS website (www.unos.org). 5. Freeman, RB personal communication. Abstract in press. 6. Gonzalez-Uriarte J, Valdivieso A, Gastaca M, et al. Liver transplantation for hepatocellular carcinoma in cirrhotic patients. Transplant Proc 2003; 35:1827–1829. 7. Khakhar A, Solano E, Stell D, et al. Survival after liver transplantation for hepatocellular carcinoma. Transplant Proc 2003; 35:2438–2441. 8. Regalia E, Coppa J, Pulvirenti A, et al. Liver transplantation for small hepatocellular carcinoma in cirrhosis: analysis of our experience. Transplant Proc 2001; 33:1442–1444. 9. Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 2003; 238:508–518. 10. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 1999; 19:311–322. 11. Jonas S, Bechstein WO, Steinmuller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001; 33:1080–1086. 12. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30:1434–1440. 13. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334:693–699. 14. Marsh JW, Dvorchik I. Liver organ allocation for hepatocellular carcinoma: are we sure? Liver Transpl 2003; 9:693–696. 15. Marsh JW, Dvorchik I, Bonham CA, Iwatsuki S. Is the pathologic TNM staging system for patients with hepatoma predictive of outcome? Cancer 2000; 88:538–543. 16. Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 2002; 8:765–774. 17. Llovet JM, Bruix J, Fuster J, et al. Liver transplantation for small hepatocellular carcinoma: the tumornode-metastasis classification does not have prognostic power. Hepatology 1998; 27:1572–1577. 18. Bruix J, Fuster J, Llovet JM. Liver transplantation for hepatocellular carcinoma: Foucault pendulum versus evidence-based decision. Liver Transpl 2003; 9(7):700–702. 19. Marsh JW, Finkelstein SD, Demetris AJ, et al. Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival. Liver Transpl 2003; 9:664–671. 20. Finkelstein SD, Marsh W, Demetris AJ, et al. Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma. Hepatology 2003; 37:871–879. 21. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362:1907–1917. 22. Marsh JW, Dvorchik I. Should we biopsy each liver mass suspicious for hepatocellular carcinoma before liver transplantation?—Yes. J Hepatol 2005; 43(4):558–562.

Part IV

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LIVING-DONOR PANCREAS TRANSPLANTATION

Living-Donor Pancreas Transplantation Miguel Tan, Raja Kandaswamy, David E. R. Sutherland, and Rainer W. G. Gruessner Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A.

INTRODUCTION Although the pancreas was the first extrarenal organ to be used from living donors (LDs) (1), of the more than 18,000 pancreas transplants performed since the 1960s, fewer than 1% have come from LDs (2,3). Reasons for the underuse of this resource include the potential morbidity of an open distal pancreatectomy in an otherwise healthy donor and the higher technical failure rate as compared with deceased donor transplants. In selected cases, however, LD pancreas transplantation may be an appropriate option for high panel-reactive antibody (PRA) recipients who are unlikely to receive a deceased donor organ or for uremic diabetics on the simultaneouspancreas-kidney (SPK) waiting list. Before 1994, our institution only offered LD pancreas transplants as either a solitary pancreas transplants alone (PTA) or a pancreas-after-kidney (PAK) transplant because of the fear that multi-organ retrieval from LDs entailed too much morbidity (4). With this approach, however, diabetic uremic recipients would have to endure two separate procedures, which many patients are reluctant to undergo. Patients will often pass up a single organ in order to undergo an SPK transplant with its attendant prolonged waiting time. Furthermore, although 43% of patients with end-stage renal disease (ESRD) are diabetic, only 28% undergo a kidney transplant (5). Some data suggest that diabetic patients on dialysis have increased morbidity and mortality rates as compared with nondiabetics on dialysis. The twoand three-year mortality rates of diabetics on dialysis are 17% and 27%, respectively, as compared with 8% and 14% for nondiabetics over the same period (5). Consequently, we now perform LD SPK transplants to decrease morbidity and mortality for patients waiting for an SPK deceased donor. The donor operation is a major consideration in performing LD pancreas transplants. The pancreas procurement can be performed using open or laparoscopic techniques. Although open donor distal pancreatectomy can be done safely and is the more established procedure, it is associated with potentially significant postoperative morbidity due to the bilateral subcostal incision. With the advent of laparoscopic technology, there are alternatives. This has been demonstrated most clearly with laparoscopic donor nephrectomy, which has rapidly become the procedure of choice for kidney donation because of reduced hospital stay and more rapid convalescence (6,7). Cosmetically, it is more appealing to potential donors than the traditional flank incision required for open nephrectomy. It is equivalent to the open procedure in terms of donor safety and quality of allograft (7). Consequently, laparoscopic techniques have rapidly been applied to other organ systems, including the pancreas. Laparoscopic distal pancreatectomies have been described for the treatment of a variety of pathologic states, and appear to be safe with the additional benefits of reduced hospital costs, decreased pain, and accelerated postoperative recovery (8,9). In this chapter, we describe both the open technique of retrieval from a LDs, our initial experience with laparoscopic LD pancreatectomy, the recipient operation, and donor and recipient outcomes. PRE-OPERATIVE DONOR EVALUATION Metabolic Work-up Because of the potential harm to an otherwise healthy donor, an extensive pre-operative work-up is essential. The goal is to ensure that the donor can safely undergo donation, and that the pancreatic remnant is sufficient to maintain normal metabolic function. All donors undergo an

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extensive multidisciplinary evaluation, which includes input from experts in endocrinology, nephrology, cardiology, social services, psychiatry, and transplant surgery. Standard pre-operative testing is performed to ensure the medical fitness of the potential donor. This includes electrocardiography (ECG), chest radiography (CXR), biochemical profiles (hemogram, electrolytes, renal function, liver function tests, coagulation profile, and lipid profile), viral serologies [hepatitis B and C, human immunodeficiency virus (HIV), and cytomegalovirus (CMV)]. Panel-reactive antibody testing and ABO typing are also performed. In addition, potential pancreas donors are considered only if they fit the following biochemical criteria: body mass index (BMI) <27 kg/m2; insulin response to glucose or arginine >300% of basal insulin; HgbA1c <6%; basal insulin fasting levels <20 umol/L; plasma glucose <150 mg/L during a 75-g oral glucose tolerance test; and a glucose disposal rate >1% during an intravenous glucose tolerance test (10). In related donors, no other family members other than the recipient can be diabetic. A genetically related donor should be at least 10 years older than the recipient was at the onset of diabetes. A history of pancreatic surgery and other pancreatic disorders are also contraindicated. Furthermore, a history of gestational diabetes and high BMI are considered contraindications to donation. Radiologic Evaluation The evaluation of the donor’s vascular anatomy is undertaken to determine the suitability for donation. At our institution, magnetic resonance angiography (MRA) is the modality of choice, although computed tomography angiogrphy (CTA) is also acceptable. MRA appears to be as sensitive as CTA in detecting vascular abnormalities (11). It is noninvasive, parenchymal details can be visualized, and details of venous anatomy can be seen (11) (Figs 1 and 2). Although CTA may be better at detecting small luminal abnormalities, such as fibromuscular dysplasia, it is associated with complications, such as dye allergy, false aneurysms, hematomas at the puncture site, and femoral artery thrombosis (12). Although the anatomy of the splenic vessels is less variable than the renal vessels, one should try to visualize the takeoff of the splenic artery and the location of the confluence of the splenic vein, inferior mesenteric vein (IMV), and superior mesenteric vein (SMV): as the IMV can sometimes join the splenic vein very close to the portal vein (PV). MRA also allows evaluation of the location and the number of renal vessels in case a simultaneous nephrectomy is to be done. The decision to procure the left or right kidney is made on a case-by-case basis and determined by the number and

FIGURE 1 Magnetic resonance angiogram showing the anatomy of the splenic and renal arteries.

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FIGURE 2 Magnetic resonance angiogram showing the anatomy of the splenic vein and portal confluence.

location of accessory renal arteries. Our preference is to procure the left kidney when possible because of the longer renal vein and subsequent ease of dissection of the inferior margin of the pancreas once the upper pole of the left kidney is dissected. OPERATIVE TECHNIQUE The Donor Operation Open-Donor Distal Pancreatectomy The pancreas may be procured using a bilateral subcostal or midline abdominal incision. If a simultaneous nephrectomy is to be performed, the nephrectomy is done first. The technique for procuring the kidney is described in detail elsewhere (13). Briefly, the colon is mobilized medially. On the left side, the lienocolic ligament is preserved, if possible, as it may carry collateral vessels to the spleen. Once the kidney is ready to be procured, heparin (70 U/kg) is given before the renal artery and vein are ligated. After the vessels are ligated, protamine (10 mg/100 U heparin) is given. The distal pancreas is mobilized by dividing the gastrocolic ligament lateral to the inferior margin of the spleen. The right gastroepiploic and short gastric vessels are preserved to avoid devascularizing the spleen. The inferior margin of the pancreas is mobilized and a peritoneal incision is made over the tail of the pancreas where it joins the hilum of the spleen. The pancreas is dissected from the splenic surface. The splenic vessels are identified, and the main trunks of the splenic artery and vein are divided proximal to the splenic branches in order to preserve the collateral vessels to the spleen. The superior margin of the pancreas is then mobilized. As the pancreas is dissected from its retroperitoneal attachments, it is mobilized medially. The junction of the IMV with the splenic vein is visualized. The location of the junction can vary and may be close to the SMV. The IMV should be divided to allow further mobilization to the pancreatic neck. The portal vein is identified at the confluence of the SMV and splenic vein. The splenic artery is circumferentially mobilized as it takes off from the celiac axis. The pancreatic neck is divided using multiple 4-0 silk ligatures or a 45-mm ETS-Flex Linear Articulating Stapler (Ethicon Endosurgery, Cincinnati, Ohio, U.S.A.). The cut edge of the pancreatic remnant can be oversewn with interrupted sutures in a U-type fashion to fishmouth the edge in order to reduce the incidence of pancreatic leak. The patient is heparinized (70 U/kg), and the splenic artery and vein are divided. The patient is then given protamine sulfate. The distal pancreatic segment is passed off to the

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recipient surgical team to be flushed with cold (4°C) University of Wisconsin solution before implantation (14). Laparoscopic (Hand-Assisted) Distal Pancreatectomy The patient is placed in a modified right-lateral decubitus position. This allows the patient to be rotated from a left-side-up position (for a nephrectomy) to a supine position (for the distal pancreatectomy) if a nephrectomy is to be done simultaneously. The operative table is then flexed to 45° to open up the left subcostal space to facilitate the dissection of the kidney. A 6-cm midline incision is then made either supra- or periumbilically, depending on the patient’s body habitus. A Gelport (Applied Medical, Rancho Santa Margarita, California, U.S.A.) or HandPort (Smith and Nephew Inc., Andover, Massachusetts, U.S.A.) device is placed in the midline incision to allow hand assistance. With standard laparoscopic equipment, a 12-mm port is placed at the level of the umbilicus along the lateral edge of the left rectus for the insertion of a 30° or 45° camera. A second 12-mm port is inserted in the left midabdomen in the plane of the anterior axillary line. This allows the insertion of ultrasonic shears, laparoscopic scissors, and other instruments. Procurement of the kidney is done as per standard procedures (13). Before the ligation of the renal vessels, the patient is given 70 U/kg of intravenous heparin, which is reversed with protamine sulfate after the vessels are ligated. After the removal of the kidney, the partially dissected inferior margin of the pancreas is mobilized using ultrasonic shears and electrocautery. The IMV is identified, ligated with staples, and divided near its insertion into the splenic vein. The posterior surface of the pancreas is then freed from its retroperitoneal attachments using electrocautery. The splenic artery and vein are identified in the hilum of the spleen, and individually ligated and divided using a 35-mm vascular stapler. Care should be taken not to disturb the short gastric vessels and right gastroepiploic artery: they constitute the main remaining blood supply to the spleen. With the pancreas retracted medially, the splenic vein is mobilized circumferentially near its junction with the SMV. The splenic artery is mobilized just as it bifurcates off the celiac axis (Fig. 3). Heparin (30 U/kg) is administered intravenously and the vessels are ligated. Clips are applied to the splenic artery just distal to the celiac axis, and then divided with laparoscopic scissors. Two staples are applied to the splenic vein at the level of its junction; SMV subsequently divided. Protamine sulfate is given as previously described. A 45-mm ETS-Flex Linear Articulating Stapler is used to transect the pancreatic neck (Fig. 4). The distal pancreatic segment is then extracted by hand through the midline incision and passed off to the recipient team to be flushed immediately with cold University of Wisconsin solution. The staple line of the pancreatic remnant is oversewn with 4-0 polypropylene sutures to achieve hemostasis and prevent leakage of the pancreatic duct. A drain is placed near the pancreatic remnant.

FIGURE 3 Pancreas mobilized medially to expose the posterior surface of the pancreas and splenic vessels: (A) pancreas; (B) splenic vein; and (C) splenic artery.

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FIGURE 4 Pancreatic remnant after retrieval of distal pancreas: (A) stapled pancreatic neck; (B) superior mesenteric vein; (C) ligated splenic arterial stump; and (D) ligated splenic vein at portal confluence.

Technical Points In general, we try to preserve the spleen in order to prevent the potential immunologic sequelae associated with splenectomy, such as overwhelming post-splenectomy sepsis (OPSS). In our five laparoscopic donors so far, one splenectomy was performed because of a nonviable spleen that was recognized at the time of surgery. Based on the open donor pancreatectomy data, there is an 8.5% to 25% rate of splenectomy (15,16). At the current stage of evolution of this technique, we prefer the hand-assisted approach because having tactile feedback greatly facilitates safe dissection and partially overcomes the lack of three-dimensional visualization inherent in laparoscopy. Postoperative Care of the Donor The postoperative care of the donor is similar to that of any patient undergoing major abdominal surgery. A nasogastric tube is left in place until the return of bowel function. Hemoglobin, serum amylase, lipase, and glucose levels are followed serially. Persistently elevated amylase and lipase levels suggest pancreatitis, a leak, or pseudocyst formation. Persistent or severe left upper quadrant or left shoulder pain should be evaluated with CT and 99mTc-sulfur-colloid scans of the spleen to assess splenic viability. If the spleen appears infarcted, a splenectomy should be performed. The Recipient Operation Segmental Pancreas Grafts Segmental pancreas grafts taken from LDs may be implanted using either systemic vein and exocrine bladder drainage or systemic vein and enteric exocrine drainage. With an intraabdominal approach, the recipient’s right side is the preferred implantation site. The cecum and ascending colon are mobilized sufficiently to provide exposure of the external and common iliac vessels on the right side. In order to achieve a tension-free venous anastomosis, the right internal iliac vein must often be ligated and divided. The donor splenic vein is anastomosed in an end-to-side fashion to the recipient external iliac vein using running 6-0 or 7-0 polypropylene sutures. The donor splenic artery is then positioned lateral and slightly cephalad to the venous anastomosis. It is anastomosed in an end-to-side fashion to the recipient external iliac artery using 6-0 or 7-0 polypropylene sutures. Less frequently, it may be anastomosed end to end to the hypogastric artery (17). Bladder Exocrine Drainage Pancreatic exocrine drainage into the bladder may be accomplished in two ways. Ductocystostomy involves a direct anastomosis between the pancreatic duct and the urothelium of the bladder. The seromuscular layer of the bladder is first incised to expose 2 to 3 cm of urothelium.

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FIGURE 5 Completed posterior wall of pancreatico-cystostomy using segmental pancreatic graft: (A) cannulated pancreatic duct; (B) pancreas; and (C) bladder.

A posterior row of interrupted 4-0 nonabsorbable sutures is placed from the seromuscular layer of the bladder to the posterior surface of the pancreas. The urothelium is incised and an interrupted posterior row of 7-0 polydiaxanone sutures is made between the urothelium and pancreatic duct. A stent is passed through the pancreatic duct and into the bladder before the anterior closure is complete. The stent is secured to the duct using a single 5-0 absorbable suture. The stent would either be excreted spontaneously or have to be removed cytoscopically after four weeks. After the ductal anastomosis is completed, the anterior seromuscular layer is completed with interrupted 4-0 nonabsorbable sutures. Alternatively, exocrine bladder drainage can be accomplished using an invaginated pancreaticocystostomy. An outer posterior anastomosis is fashioned between the seromuscular layer of the bladder and the posterior surface of the pancreas. A 3- to 4-cm transverse incision is made in the bladder wall and running 4-0 polydiaxanone sutures are placed around the circumference of the cut end of the pancreas and the cystostomy. Finally, the anterior outer layer is completed with 4-0 nonabsorbable sutures. A stent is placed in the pancreatic duct in the same manner as described for ductocystostomy (Fig. 5). Enteric Drainage The vascular anastomosis is constructed, as described earlier. A Roux-en-Y loop of small bowel is used for exocrine drainage. An appropriate length of jejunum is selected and divided with a gastrointestinal anastomosis (GIA) stapler. The stapled distal end is oversewn with 4-0 polypropylene sutures. The posterior wall of the ductojejunostomy is created using 4-0 polypropylene sutures between the posterior surface of the pancreas and jejunal wall. A small incision is made on the antimesenteric side of the jejunum, and a posterior row of 6-0 absorbable sutures is made between the pancreatic duct and full-thickness jejunum. Before the anterior inner row is completed, a stent is placed in the duct, as previously described. Once the inner layer is finished, the anterior outer layer is completed with interrupted 4-0 polypropylene sutures. DONOR OUTCOMES Open Donor Pancreatectomy From January 1978 through July 2000, 115 open LD pancreas transplants were performed at our institution: 51 PTA, 32 PAK, and 32 SPK (16). There were no donor deaths. Donor complications included hemorrhage, splenic infarct, abscess, pancreatitis, and pseudocyst formation. Splenectomy was required in 8% of donors. Pseudocysts occurred in 10%. Percutaneous drainage was necessary in 60% of those with pseudocyst. Within the subset of SPK donors, 20% required perioperative blood transfusions. Two donors required percutaneous drainage of a noninfected peripancreatic fluid collection (14). The median donor age was 44 years (range

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26–49). The median operative time was 6.9 hours, with a median length of stay of eight days (range 6–24) (16). Long-term follow-up was possible in 67 donors. The remaining 48 could not be located, refused to participate, lived outside of the United States, or were deceased. Ten donors had abnormal HgbA1c levels. Three of them required insulin for more than six years postoperatively. One of these donors had a history of gestational diabetes. The other two had predonation BMI >27 kg/m2. One of these donors had a significant alcoholic history, which he had not disclosed. Gestational diabetes and elevated BMI are now contraindications to donation. Since 1996, all donors have maintained normal HgbA1c levels (4.9–6.2%) per these guidelines (16). Laparoscopic (Hand-Assisted) Donor Pancreatectomy From March 1999 through July 2003, five hand-assisted laparoscopic pancreatectomies were performed at our center (18). The mean donor age was 48.4 + 8.7 years with a BMI of 23.7 + 3.0 kg/m2. The mean length of surgery for PTA donors was 4.5 + 0.13; and for SPK donors, 7.9 + 0.38 hours. Mean blood loss was 330 + 228 mL. Once the learning curve has been overcome; however, the hand-assisted laparoscopic approach may actually have shorter operative times, as less dissection is required than with the open technique. In two of the SPK cases, the donor surgical team had to wait 1.5 to 2 hours for the recipient team to receive the organs, thus prolonging the operative time. One splenectomy had to be performed at the time of the donor surgery for a nonviable spleen. No pancreatic leak or pancreatitis was observed. The mean serum glucose was 112 + 11.7 mg/dL upon discharge. The amylase and lipase values on discharge were 72.2 + 26.3 U/L and 67.2 + 34.0 U/L, respectively. None of the donors required oral antidiabetic medications or insulin. At three years follow-up, the mean postoperative HgbA1c was 5.7 + 0.2%. One donor refused biochemical follow-up. Mean postoperative stay of the laparoscopic donors was 8 + 2 days. No obvious statistical advantage was observed in terms of decreased hospital stay. However, considering, the first handful of laparoscopic cases performed, this may be a function of overvigilance on the part of the treating team, as is the case with new procedures. Certainly, in laparoscopic nephrectomy, the advantage of reduced hospital stay and earlier postoperative recovery has been demonstrated (19,20). All our donors reported that they are back to their pre-operative state of health and working. Satisfaction was high in terms of cosmetic result because the donor operation can be performed through a relatively small midline incision and only two trocar sites (Fig. 6). RECIPIENT OUTCOMES Open Donor Pancreatectomy The recipient survival rates were 93% and 90% at one and five years, respectively, in those patients receiving LD segmental pancreases procured using the open technique. In the pretacrolimus epoch, technically successful PTA and PAK recipients had a graft survival rate of 68% and 50%, respectively. The immunologic advantage of LD pancreas transplants, at that

FIGURE 6 Surgical incisions three weeks postlaparoscopic distal pancreatectomy and left nephrectomy: (A) Gelport site; (B) 12-mm camera port site; and (C) 12-mm instrument port site.

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time, was clear. Only 13% of LD pancreas recipients lost their graft to rejection, as compared with 41% of deceased donor organ recipients (16). In the current immunosuppressive era, this difference hardly exists with modern drug regimens (tacrolimus, mycophenolate mofetil etc.), improved operative technique, and aggressive postoperative anticoagulation. Consequently, although solitary LD pancreas transplants are still performed, the focus is primarily on SPK donors in order to address the shortage of deceased donor organs in this subset of pancreas transplant recipients. Thirty-two open LD SPK transplants were done at the University of Minnesota from 1994 to 2000 (16). Patient and kidney graft survival was 100% at one year. Pancreas allograft survival was 87%. This compares favorably with the current deceased donor SPK transplant data that demonstrate 84% one-year survival for pancreas grafts and 90% for kidney grafts (21). This marked improvement in patient and graft survival as compared with our series of LD PTA and PAK transplants before 1994 may be attributed to improved immunosuppression, routine postoperative anticoagulation (perioperative low-dose heparin and long-term aspirin), and better infection prophylaxis (e.g., ganciclovir) (16). Recipient Outcomes with Laparoscopic (Hand-Assisted) Donor Pancreatectomy With hand-assisted laparoscopically procured pancreases, patient and kidney graft survival is 100%, with 100% pancreas graft survival at three-year follow-up (18). One patient required intermittent subcutaneous insulin postoperatively because of steroids. Once the steroids were weaned, the insulin requirement ceased. One of the five recipients had three episodes of acute rejection that were reversed with steroids and antibody therapy. Four recipients had exocrine bladder drainage, and one had enteric drainage. Two recipients had a leak at the duodenocystostomy, and three of the five recipients had an intra-abdominal infection. SUMMARY Although the number of available deceased donor pancreases currently exceeds the number of pancreas transplants performed each year (22), the limiting factor tends to be the quality of the available pancreases, with only a disproportionately small number suitable for implantation. Consequently, the waiting list for diabetics awaiting transplantation is growing by more than 15% annually (16). In the subset of patients awaiting both a pancreas and a kidney transplant, the waiting time continues to be lengthy. About 6% of these patients die annually awaiting an SPK transplant (23). As compared with patients with nondiabetes-related ESRD, fewer diabetics receive kidney transplants; the two- and three-year mortality rate for it is dialyzed diabetics at 17% and 27%, respectively (5). The rationale, therefore, of LD pancreas transplants, especially LD SPK transplants, is to allow the timely transplantation of high-PRA recipients who are and to decrease the morbidity and mortality of diabetics on the waiting list. Although the morbidity and prolonged postoperative recovery on the part of a potential pancreas donor has been a hindrance toward wider acceptance of LD pancreas transplants, the use of laparoscopic techniques may make this procedure more appealing. Hand-assisted laparoscopic pancreatectomy appears to be safe with minimal morbidity; recipient outcomes are equivalent or better, as compared with open techniques of distal donor pancreatectomy. Donor satisfaction is also high in terms of postoperative cosmetic results. FUTURE TRENDS Currently, more institutions are performing robot-assisted laparoscopic donor nephrectomy. The viability and safety of this modality have been demonstrated in this context (24,25). In the future, robot-assisted technique may represent the next step in the evolution of laparoscopic donor pancreatectomy because of its advantages over traditional laparoscopic equipment, including better control of fine movements afforded by articulating instruments; elimination of tremor, and three-dimensional visualization, which overcomes the lack of depth perception inherent in standard laparoscopic monitors.

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REFERENCES 1. Sharara AI, Dandan IS, Khalifeh M. Living-related donor transplantation other than kidney. Transplant Proc 2001; 33:2745. 2. Gruessner AC, Sutherland DER. Pancreas transplant outcomes for United States (U.S.) and non-U.S. cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of October 2002. Clin Transplants 2002:41. 3. Gruessner RWG, Leone JP, Sutherland DER. Combined kidney and pancreas transplants from living donors. Transplant Proc 1998; 30:282. 4. Gruessner RWG, Sutherland DER. Simultaneous kidney and segmental pancreas transplants from living related donors––the first two successful cases. Transplantation 1996; 61:1265. 5. Gruessner RWG. Should priority on the waiting list be given to patients with diabetes: pro. Transplant Proc 2002; 34:1575. 6. Schweitzer EJ, Wilson J, Jacobs S, et al. Increased rates of donation with laparoscopic donor nephrectomy. Ann Surg 2000; 232(3):392. 7. Leventhal JR, Deeik RK, Joehl RJ, et al. Laparoscopic live donor nephrectomy––is it safe? Transplantation 2000; 70(4):602. 8. Ueno T, Oka M, Nishihara K, et al. Laparoscopic distal pancreatectomy with preservation of the spleen. Surg Laparosc Endosc Percutan Tech 1999; 9(4):290. 9. Vezakis A, Davides D, Larvin M, McMahon MJ. Laparoscopic surgery combined with preservation of the spleen for distal pancreatic tumors. Surg Endosc 1999; 13(1):26. 10. Kendall DM, Sutherland DER, Najarian JS, Goetz FC, Robertson RP. Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med 1990; 322:898. 11. Kandaswamy R, Stillman AE, Granger DK, Sutherland DER, Gruessner RWG. MRI is superior to angiography for evaluation of living-related simultaneous pancreas and kidney donors. Transplant Proc 1999; 31:604. 12. Guressner RWG. Living donor pancreas transplantation. In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. Berlin: Springer-Verlag, 2004:423. 13. Gruessner RWG, Kandaswamy R, Denny R. Laparoscopic simultaneous nephrectomy and distal pancreatectomy from a live donor. J Am Coll Surg 2001; 193(3):333. 14. Humar A, Gruessner RWG, Sutherland DER. Living-related donor pancreas and pancreas-kidney transplantation. Br Med Bull 1997; 53(4):879. 15. Troppmann C, Grussner AC, Sutherland DE, Gruessner RW. Organ donation by living donors in isolated pancreas and simultaneous pancreas-kidney transplantation. Zentralbl Chir 1999; 124(8):734. 16. Gruessner R, Sutherland D, Drangstveit M, Bland B, Gruessner A. Pancreas transplants from living donors: short- and long-term outcome. Transplant Proc 2001; 33:819. 17. Gruessner RWG. Surgical aspects of pancreas transplantation. In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas, New York Inc.,: Springer-Verlag, 2004:159. 18. Tan M, Kandaswamy R, Gruessner RWG. Laparoscopic donor distal pancreatectomy for living-donor pancreas transplantation. Am J Transplant 2005; 5:1966. 19. Kercher KW, Heniford BT, Matthews BD, et al. Laparoscopic versus open nephrectomy in 210 consecutive patients: outcomes, cost, and changes in practice patterns. Surg Endosc 2003; 17(12):1889. 20. Jacobs SC, Cho E, Foster C, Liao P, Bartlett ST. Laparoscopic donor nephrectomy: the University of Maryland six-year experience. J Urol 2004; 171(1):47. 21. Gruessner AC, Sutherland, DER. International Pancreas Transplant Registry Annual Report. Clin Transplant 2005; 19:433. 22. Sutherland DER, Najarian JS, Gruessner RWG. Living versus cadaver pancreas transplants. Transplant Proc 1998; 30:2264. 23. Gruessner R, Kendall D, Drangstveit M, Gruessner A, Sutherland D. Simultaneous pancreas-kidney transplantation from live donors. Ann Surg 1997; 226(4):471. 24. Horgan S, Vanuno D, Benedetti E. Early experience with robotically-assisted laparoscopic donor nephrectomy. Surg LaparoscEndosc Percutan Tech 2002; 12(1):64. 25. Horgan S, Vanuno D, Sileri P, Cicalese L, Benedetti E. Robotic-assisted laparoscopic donor nephrectomy for kidney transplantation. Transplantation 2002; 73(9):1474.

Part V

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LIVING-DONOR ISLET-CELL TRANSPLANTATION

Islet-Cell Transplant: Evaluation, Technical Aspects, and Donor and Recipient Outcomes Juliet A. Emamaullee and A. M. James Shapiro Department of Surgery, University of Alberta, Edmonton, Alberta, Canada

INTRODUCTION Therapeutic Options for Patients with Type 1 Diabetes Diabetes is a disease that results from impaired glucose metabolism, either due to a complete loss of the insulin-producing β-cells within the islets of Langerhans of the pancreas [type 1 diabetes mellitus (T1DM)], or to a defect in insulin production and/or utilization [type 2 diabetes mellitus; (T2DM)]. Currently, there are more than 200 million patients with diabetes worldwide, and it is projected that more than 5% of the world’s adult population will be afflicted with diabetes by the year 2025 (1). The increase will occur mainly in T2DM, which can unfortunately no longer be regarded as “adult onset,” as there are over five million children with this diagnosis in North America at present (2). T1DM is often referred to as juvenile-onset diabetes, as approximately 13,000 children are diagnosed with T1DM each year in the United States, making T1DM the most prevalent chronic childhood disease (3). Although careful blood glucose monitoring and insulin administration can provide patients with T1DM with a relatively good quality of life, the long-term impact of this disease remains significant. For patients diagnosed with T1DM as children, it has been estimated that approximately 15% would die before their 40th birthday––a mortality rate that exceeds 20 times that of the general population (3). Causes of death related to T1DM include acute complications, such as hypoglycemic coma and chronic secondary conditions, such as nephropathy or cardiovascular disease (3). Patients with T1DM also face many chronic complications, including nephropathy, retinopathy, peripheral neuropathy, coronary ischemia, stroke, amputation, erectile dysfunction, and gastroparesis (3). It has been determined that patients with diabetes represent 8% of those who are legally blind, 30% of all patients on dialysis because of end-stage renal disease, and 20% of all patients receiving kidney transplants in the United States (3). In an effort to prevent these long-term complications in patients with diabetes, the Diabetes Control and Complications Trial (DCCT) was conducted to examine the benefit of intensive blood glucose regulation by frequent insulin injection or an insulin pump (4–6). Results from the DCCT clearly demonstrated that this approach improved glycosylated hemoglobin levels and significantly protected against nephropathy, neuropathy, and retinopathy (5,6). However, the penalty for improved glycemic control was a threefold increased risk of serious hypoglycemic events, including recurrent seizures and coma (5,7). The miniaturization of insulin pumps has increased their practicality, but the creation of implantable devices has been more challenging. The development of closedloop systems has, until recently, been limited by a failure of chronic glucose sensor technology. Subcutaneous monitoring via needle electrodes suffers from a lag in physiologic response, thus limiting the feedback in a closed-loop system (8). For these reasons, it has become clear that the restoration of an adequate islet mass would provide the best glucose regulation and long-term health outcome for patients with T1DM. The first efforts directed at addressing this issue have involved whole pancreas transplantation. Currently, more than 25,000 pancreas transplants have been performed worldwide for end-stage renal disease (simultaneous kidney pancreas or pancreas after kidney transplantation), or occasionally for severe hypoglycemic unawareness (pancreas transplant alone). Recent improvements

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in surgical techniques (portal venous and enteric exocrine drainage) and maintenance of immunosuppression have substantially improved the risk profile and enhanced long-term outcomes with this approach (9,10). However, only 50% of the patients who have undergone pancreasalone transplantation still maintain evidence of graft function (insulin independence) at five years, according to the International Pancreas Transplant Registry (11). Also, recent data from the United Network for Organ Sharing have shown that only 28% of the approximately 6000 deceased donor pancreata donated each year are transplanted because the organ must conform to strict donor criteria and requirements for a short cold ischemic time to be considered suitable for transplantation (11,12). Despite strong evidence that the procedure can prolong life, reverse established nephropathy, and improve the quality of life, pancreas transplantation is not felt to be suitable for diabetic patients that are early in the evolution of their disease. Compared with vascularized pancreas transplantation, β-cell replacement via transplantation of isolated pancreatic islets offers a simpler procedure that avoids the risks associated with major surgery (11). BACKGROUND An International Registry held in Giessen, Germany, has maintained a comprehensive record of previous clinical attempts at islet transplantation globally (13). A more recent Collaborative Islet Transplant Registry, sponsored by the National Institutes of Health (NIDDK), set out to provide an expedited collection, analysis, and communication of comprehensive islet transplant data performed in North America (14). The experimental islet transplantation first made its mark when Paul Lacy successfully reversed chemical diabetes in rodents in 1972 (15). Attempts to translate these findings to the clinic initially met with failure and occasionally with serious complications, including portal vein thrombosis, portal hypertension, and disseminated intravascular coagulation when impure islets were infused into the portal vein (16). The first subject to achieve insulin independence for one month was reported by Lacy’s group in 1989 (17). Camillo Ricordi developed a method for high-yield isolation of human islets using the so-called “Ricordi Chamber,” and subsequently reported 50% insulin independence rates at one year in subjects who underwent cluster islet–liver transplants for abdominal malignancies in the setting of surgically induced (nonautoimmune) diabetes (18). Groups in Giessen, Germany, and in Milan, Italy, achieved insulin independence in approximately half of their treated subjects in the late 1990s. However, of the total world experience of over 450 attempts at clinical islet transplantation at this time, fewer than 8% of subjects achieved insulin independence. After three decades of research, the one-year insulin independence rates in clinical islet transplantation were still too low to justify the risks associated with portal infusion and life-long immunosuppression in most patients with T1DM (13,19–22). The Edmonton Protocol A new protocol developed by Shapiro et al. in 1999 was designed for patients with “brittle diabetes,” who experienced extreme difficulty in managing their blood glucose levels (“glucose lability”) and/or severe hypoglycemic unawareness (23). Compared with previous clinical islet transplantation studies, the Edmonton Protocol emphasized the avoidance of corticosteroids; the use of potent immunosuppression with combined sirolimus, tacrolimus, and anti-CD25 antibody to protect against rejection and recurrent autoimmunity; and the use of two (or occasionally more) fresh islet preparations to provide a mean islet implant mass of approximately 13,000 islet equivalents (IE)/kg recipient body weight (23). For the first time, dramatic improvements in islet allograft survival were observed, and all of the first seven patients achieved sustained independence from insulin (23). Since 2000, more than 85 consecutive patients have received islet transplants at the University of Alberta, and the one-year insulin independence rate remains steady at approximately 80% after completed transplants. An international multicenter trial [Immune Tolerance Network (ITN)] has replicated the results obtained at the University of Alberta, but has shown a broad spectrum of success based on the center’s previous experience and skill in islet isolation and immunosuppressive management (24). The Miami group has demonstrated that islets can be cultured for up to three days prior to being transplanted, with similar success when transplanted using Edmonton-like immunosuppression (25). The Miami

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group also showed that islets could be successfully shipped and transplanted at a remote facility (Houston) (25,26). A Swiss-French consortium (the GRAGIL Network) also demonstrated the benefits of centralized islet processing facilities servicing a broader network of centers throughout Europe. Islet transplantation has been funded in Alberta, Canada, as accepted clinical standard of care since 2001. In the United States, large registration trials are currently moving forward to secure a Biological License and therefore reimbursement, which will make a significant difference to the availability of islets for transplantation in that country. The breakthrough data obtained in Edmonton has encouraged many centers around the world to implement clinical islet transplantation; and since 2000, more than 550 patients have been transplanted using recent variants of the Edmonton Protocol in almost 50 centers worldwide. Despite this success, islet-alone transplantation remains restricted to patients with severe hypoglycemic unawaremess or glycemic lability, and is presently unsuitable for the majority of patients with T1DM. It has also not been explored yet in patients with T2DM. Most patients require two or occasionally three islet implant procedures in order to achieve insulin independence, although insulin independence following single-donor infusion has been reported in a cohort of patients at the University of Minnesota (27,28). While C-peptide secretion (>0.5 ng/ mL) has been maintained in 88% of islet-graft recipients beyond three years in Edmonton, emerging data on the long-term insulin-independence rates have shown that after three years, only 50% of the recipients remain off insulin, and at five years posttransplant, this number falls to approximately 10% (29). Although the exact cause of the disconnection between the loss of insulin independence and the maintenance of C-peptide status has not been fully elucidated to date, it is likely that multifactorial events are contributing to this observation. Although rejection (acute or chronic) and recurrent autoimmunity may be responsible for graft loss, it is also likely that other, nonimmune events contribute, including chronic toxicity from sirolimus/ tacrolimus, and the failure of islet regeneration or transdifferentiation (again due to antiproliferative effects of sirolimus). Perhaps, even more importantly, islet “burn-out” from constant metabolic stimulation could result in decayed function, as only a marginal mass of islets actually engraft in most subjects. Although the risks of malignancy, post-transplant lymphoma, and life-threatening sepsis have been very low in patients treated to date, fears of these complications limit a broader application in patients with less severe forms of diabetes, including children. Moreover, a number of immunosuppression-related side effects have been encountered, which can be dose or drug limiting in some patients (30). It is clear, therefore, that although the outcomes have improved substantially after islet transplantation, extensive refinements in clinical protocols are needed both to improve safety and to enhance success with single-donor islet infusions. Living Donor Islet Transplantation: The Next Step Living-donor islet transplantation, which is currently an experimental procedure, provides a unique opportunity to treat many more patients with unstable forms of T1DM. In an attempt to meet the demand for donor organs and to improve clinical outcomes, living donor programs have moved forward successfully in kidney, liver, and lung transplantation at most leading transplant centers worldwide. Given the rapid and global implementation of deceaseddonor islet transplantation over the past five years, it seems inevitable that living-donor islet transplantation would become routine eventually. Despite remarkable success in clinical islet transplantation since 1999, islet supply and functional viability remain significant challenges when islets are isolated from deceased organ donors (31). Living-donor islet transplantation represents a unique opportunity to overcome donor organ shortage and procure the islet tissue under perfect conditions, with closer human leukocyte antigen (HLA) matching between the donor and the recipient. Furthermore, opportunities for pretransplant recipient conditioning for specific donor-tolerance induction protocols could be developed in the living donor islet transplant setting. There has been precious little previous clinical experience with living-donor islet allotransplantation, with only three reported cases in the literature (Fig. 1) (32,33). Two clinical attempts at living-donor islet allotransplantation were carried out more than 25 years ago by Sutherland et al. at the University of Minnesota in 1978 (32). Although neither recipient achieved sustained islet function, these pioneering efforts were truly remarkable given the early stage of

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FIGURE 1 Historical context of clinical attempts at living-donor islet transplantation (black shaded), compared with cadaveric islet transplantation. The poor clinical results observed in cadaveric islet transplantation prior to the introduction of the Edmonton Protocol in 2000 discouraged extensive investigation into living donor islet transplantation, which was attempted (unsuccessfully) twice in the late 1970s. However, the first living-donor islet transplant attempted in early 2005 has proven to be successful.

clinical islet transplant development at the time. The immunosuppression available was primitive by current standards (azathioprine and high-dose steroids), and the islets were isolated using suboptimal conditions. The first successful living-donor islet transplantation case was carried out at the University of Kyoto in early 2005, in a collaboration between the Japanese and Edmonton programs (33). The recipient, a 27-year-old female, developed C-peptide-negative, unstable diabetes following chronic pancreatitis as a child. The donor, her 56-year-old mother underwent open surgical resection of the distal half pancreas [47% as measured preoperatively by computed tomography (CT) volumetry]. There were no surgical complications in either the donor or the recipient. The islet mass was 408,114 IE (8200 IE/kg) in a volume of 9.5 mL after tissue digestion, and was transplanted unpurified into the portal vein using the percutaneous approach under full systemic heparin. Immunosuppression was started pretransplantation with the Edmonton Protocol style using sirolimus and low-dose tacrolimus (started seven days pretransplant), combined with anti-IL2R antibody (given four days pretransplant and on the day of transplant) and anti-tumor necrosis factor-α blockade induction (infliximab; given one day pretransplant). The recipient was successfully weaned off insulin at 22 days

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post-transplant, and continues to be insulin independent with excellent glycemic control and a normal HbA1C as of late 2005. The donor has continued to have normal HbA1c values and no evidence of glucose intolerance since the procedure. Although it is difficult to make any substantial conclusions from this single successful case of living-donor alloislet transplantation, results from living-donor islet autotransplantation suggest that the insulin independence may be achieved routinely with a far lower islet transplant mass that has been required for deceased donor allografts to date. Typically in an islet autotransplant, over 70% of patients will remain insulin-free if an islet mass exceeding 300,000 IE (≥2500 IE/kg) is returned (34). A major caveat of the islet autograft data is that robust long-term follow-up is lacking. Living-donor islet autotransplantation is an established and accepted surgical procedure for selected patients with severe pain from chronic pancreatitis, and active living-donor islet autotransplant programs exist at several institutions. The islet yield obtained from the autografted pancreas is inversely related to the degree of pre-existing fibrosis from chronic pancreatitis. The success of islet autotransplantation may be related in part to the use of nonpurified islet preparations, resulting in less islet loss, and the absence of diabetogenic antirejection medications and lack of underlying autoimmunity. The controlled nature of the living donor setting would be of particular benefit in islet transplantation, especially in opening up the limited donor supply. Waiting times for clinical islet transplantation have increased substantially in the Edmonton program since 1999, and this would become more acute as other islet programs move forward, and as whole pancreas transplant programs seek access to the more stable donors. Presently, clinical islet programs rely entirely on a scarce supply of pancreas organs derived from heart-beating, brain-dead deceased donors. Organs obtained for islet transplantation tend to be more “marginal” and come from older, less stable donors. Furthermore, the pancreas is particularly susceptible to toxicity from the circulating products of severe brain injury, hemodynamic instability, and inotropic support in a brain-dead organ donor, and this is compounded by cold ischemic injury during transportation, which inevitably results in islet damage and loss. Contreras et al. demonstrated a marked reduction in islet recovery and islet viability in experimental islet transplantation using tissue derived following brain death compared with healthy rodent donors, highlighting this issue, and recently his group has confirmed these findings using human islets (31). Similarly, Lakey et al. demonstrated a strong relationship between islet recovery and donor stability (35). The extensive processing and purification steps during isolation cause further islet destruction and loss, often resulting in at best 60% recovery of the estimated 107 IE per pancreas (36). For this reason, nearly all islet recipients require islets prepared from two deceased donors, which, combined with reduced tissue viability, may result in alloantigenic priming of the recipient’s immune system. In the living donor setting, the distal half pancreas is procured under “ideal” circumstances, without the exposure of the pancreas to hemodynamic instability or inotropic drugs, and the pancreas is processed immediately without prolonged cold ischemia. Thus, the potency of islets derived from a living donor source is assumed to be far superior to that from deceased donor tissue. DONOR CONSIDERATIONS Assessment and Selection Based on the Minnesota experience in living-donor pancreas transplantation, an extensive set of donor selection criteria has been established that should apply equally to living-donor islet transplantation (37). Donor safety must be paramount throughout the selection process and subsequent surgical intervention. As with all living donor organ transplant procedures, the potential donor should understand the associated risks, must not be coerced, and must be of legal age and competence to provide voluntary consent. A complete history and physical examination should be taken by the surgical team, screening in particular for comorbidities that would exclude a potential donor from surgery (e.g., history of pancreatic disorders or insulin resistance, active infections, or drug or alcohol dependence). The physical examination should include standard biochemical and coagulation profiles, cardiac profiling with electrocardiogram, and virology screening [hepatitis B virus (HBV), hepatitis C virus (HCV),

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cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV)]. Immunological compatibility between a potential donor and the recipient should be assessed with ABO blood grouping, crossmatching, and panel-reactive antibody (PRA) testing. In the case of living pancreas donation for islet transplantation, potential ABO-compatible donors should be selected based on standard criteria used to minimize the risk of postsurgical metabolic dysfunction, summarized in Table 1. Donor safety and avoidance of diabetes induction in a healthy donor as a result of distal pancreatectomy is paramount. Overweight or obese donors [body mass index (BMI) <27 kg/m2] should be avoided, as they have increased risk of developing T2DM. Potential donors should be evaluated with oral glucose tolerance tests (OGTTs) to assess the maximum insulin secretion and functional insulin secretory reserve of the pancreas, to be sure that distal pancreatectomy does not disrupt metabolic function. Acceptable values include fasting blood glucose <110 mg/dL, two-hour postingestion values <140 mg/dL, and no other glucose value >200 mg/dL during the two-hour testing period (37). Further assessment of the potential donor’s β-cell reserve function should be evaluated using either the acute response to insulin (AIR) or the insulinogenic index. The AIR is calculated as the mean of the serum insulin concentrations at times one, three, four, six, eight, and

TABLE 1

Summary of Donor and Recipient Evaluation Criteria Specific to Living-Donor Islet Transplantation

Test Donor selection BMI Oral glucose tolerance test

AIR or insulinogenic index HbA1C Autoantibody screen for GAD, ICA512, and mIAA antibodies Recipient selection BMI HYPO score and LI

HbA1C

Cardiac function assessment

Kidney function assessment

PRA

Acceptable range

Purpose

<27 kg/m2

Avoidance of donors with a propensity for T2DM

Fasting blood glucose <110 mg/dL, 2-hour postingestion values <140 mg/dL, and no other glucose value >200 mg/dL during the 2-hour testing period AIR: >300% of basal insulin values Insulinogenic index: >0.5

Confirmation of a completely normal baseline insulin secretory reserve, ruling out undiagnosed T2DM or underlying glucose intolerance Further assessment of β-cell reserve function

<6% No evidence of elevated serum titers

Indicator of chronic hyperglycemia Rule out donors with a potential to develop T1DM

BMI <30 kg/m2 or weight <90 kg HYPO score: >1047 (90th percentile) LI: >433 mmol/L2/h/wk (90th percentile) Composite: HYPO score >423 (75th percentile) and LI >329 (75th percentile) <10%

Donor: recipient metabolic imbalance Selection of recipients whose risk for adverse hypoglycemic events outweighs the risks of islet transplantation and life-long immunosuppression Elimination of recipients with either poor compliance or inadequate insulin therapeutic regimen Avoidance of cardiac death in the recipient within five to 10 years of transplant

Blood pressure <160/100 mmHg; No myocardial infarction six months prior to assessment; no angiographic evidence of noncorrectable coronary artery disease; Left ventricular ejection fraction >30% as measured by echocardiogram No proteinuria (<1 g/24 hr); glomerular filtration rate >80 (male), >70 (female) mL/min/1.73 m2; Serum creatinine <115 μM (male), <125 μM (female) <20% by flow cytometry

Eliminate recipients who are better candidates for simultaneous kidney–pancreas transplantation and/or those who may experience adverse renal function as a result of calcineurin inhibitor or sirolimus therapy Reduce incidence of antibody-mediated graft rejection

Abbreviations: AIR, acute response to insulin; BMI, body mass index; LI, lability index; HYPO, hypoglycemic; HbA1C, hemoglobin A1C; PRA, panel reactive antibody; T1DM, type 1 diabetes millitus; T2DM, type 2 diabetes mellitus.

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10 minutes during an intravenous glucose tolerance test (IVGTT). For prospective donors, AIR values should be more than 300% of the basal insulin secretion in the fasting state. An alternative to AIR is the insulinogenic index, an index of first-phase insulin secretion, which is calculated as the ratio between the changes in plasma insulin concentrations during the first 30 minutes following an oral glucose load and changes in plasma glucose concentrations over the same period (38). As the insulinogenic index can be calculated using data collected during standard OGTTs (versus the IVGTT required to calculate AIR), and as it has been determined to correlate highly with AIR values, this index may be more readily implemented in donor assessment protocols (38). Plasma HbA1C should be measured in all potential donors as a measure of chronic hyperglycemia, and values of less than 6% are considered to be compatible with donation. Finally, autoantibody titers should be determined for GAD, ICA512, and mIAA antibodies, which are associated with increased susceptibility to T1DM (39). In the case where the potential pancreas donor is a sibling of the recipient with T1DM, the Minnesota group has implemented the requirement that the potential donor must be more than 10 years older than the recipient was at diabetes onset and that no other first-degree relatives have T1DM, in order to reduce the possibility of late-onset T1DM in the donor postdonation (39). After a potential donor has been evaluated by the surgical team, an independent complete assessment of the donor should be obtained using a staff internal medicine consultant who is not connected with the islet program (i.e., following the same procedure used in most liver transplant programs). Using these criteria, the Minnesota living-donor pancreas program has reported that 15% to 20% of the candidates qualify to donate (37). Once a suitable potential donor has been identified, imaging with ultrasound followed by CT volumetry may be carried out to determine the anatomical suitability of the pancreas for donation. Although anatomical variation in vascular supply to the recipient is not a concern for islet transplantation, this is still necessary to further reduce the risk of surgical diabetes by ensuring that the pancreas remnant volume will be at least 50%, and to evaluate the pancreas for evidence of any underlying disease. As the possibility exists that vascular supply to the donor spleen may be compromised resulting in splenectomy, the living donor should receive standard pre-splenectomy immunizations at least two weeks prior to surgery to protect against encapsulated organisms and to reduce the risk of post-splenectomy sepsis. Living Pancreas Donation Procedure Two options exist for the procurement of the distal pancreas––an open laparotomy with a bilateral subcostal incision, or a hand-assisted laparoscopic approach. The open approach is more established, but surgical experience with laparoscopic distal pancreatectomy is now considerable, and may be more appealing from a donor’s standpoint. Once the pancreas has been dissected from the retroperitoneal bed and the splenic hilum, the distal splenic artery and vein are divided and ligated at the level of their respective origins. The distal pancreatic parenchyma should be divided to resect less than 50% of the pancreatic volume, which generally can be achieved by dividing the pancreas to the left side of the superior mesenteric vein. As the preservation of the pancreatic duct for anastomoses is not an issue in islet transplantation, the pancreas can be divided using a vascular stapler, and the staple line in the proximal pancreas should be oversewn (and also possibly infiltrated with tissue fibrin glue) to prevent the development of fistula or leakage postoperatively in the donor. Furthermore, prophylactic octreotide may be given preoperatively in an attempt to further diminish this risk. It is possible to preserve the spleen on its smaller vascular supply via the short gastric vessels; but on occasion, the spleen may become markedly congested, infarct, or tort when preserved in this way. Therefore, if a splenic-preserving approach is chosen, careful further visualization of the spleen should occur once the distal pancreas has been removed to be sure it is still viable. To prepare the distal pancreas specimen for islet isolation, the splenic arterial and venous stumps are reopened (if stapled during retrieval), and the splenic artery is cannulated and flushed with chilled UW solution. The pancreatic duct is then cannulated and flushed with approximately 60 mL of ductal preservative solution (in the Kyoto case, University of Kyoto solution was infused) (33). The pancreas is then transported on a two-layer oxygenated

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perfluorochemical-UW (preferably) to a cyclic guanine monophosphate (cGMP) islet isolation facility, where processing is initiated as soon as possible. The pancreas should be digested using an optimal blend of liberase/collagenase enzyme that has been validated in previously successful clinical islet isolations (40). The tissue digest should be washed extensively. At this juncture, a decision is made regarding the purification––generally, if the islet digest sediment is less than 10 cc in packed tissue volume, then no purification is required. The infusion of unpurified pancreatic digest exceeding 10 cc may increase the risk of portal thrombosis and; therefore, appropriate judgment is needed together with full systemic anticoagulation and continuous monitoring of portal pressure. The recipient should be concurrently prepared for islet transplantation to minimize cold ischemic time, and the islets may be infused either using the percutaneous approach to the portal vein in interventional radiology, or transplanted using surgical access via a minilaparotomy, if indicated. If a large volume of pancreatic digest is to be infused in an unpurified state, it may be safer to administer therapeutic anticoagulation in the more controlled open, operating room environment rather than using a percutaneous approach. The donor should be monitored postoperatively for evidence of bleeding (decreased serum hemoglobin values), and serum lipase and amylase should be monitored to rule out pancreatitis or pancreatic fistula. A Doppler ultrasound examination of the donor should be performed before being discharged home (or at seven to 14 days postsurgery, if discharged earlier) to rule out a possible pancreatic fistula and to confirm the potency of the portal vein. Risks to the Donor Surgical Complications The surgical procedure for distal pancreatectomy is relatively straightforward, is considered a substantially less risky procedure than living-donor right-lobe liver transplantation, and is perhaps comparable in risk to a living-donor kidney procedure in terms of risk. Surgical resection of the distal half of the pancreas is a standard procedure in patients with a variety of conditions, including a variety of benign or malignant pancreatic neoplasms and chronic pancreatitis. The potential risks associated with the surgery have been clearly defined previously. Complications include the general risks of anesthesia and surgery (chest infection, wound infection, deep-vein thrombosis, pulmonary embolism), and the specific risks of the pancreatic resection, including pancreatic fistula, impaired glucose tolerance, or rarely, diabetes, splenic and/or portal vein thrombosis, and the potential risks associated with the asplenic state if the spleen is removed concurrently. A review of more than 200 patients undergoing distal pancreatectomy at Johns Hopkins, which represents the largest single-center experience with this procedure, suggests that the outcome and complication rates clearly vary with the nature of the underlying pancreatic disease (41). In this series, the perioperative mortality rate was 0.9%, and 69% of the patients had no postoperative complications. The overall complication rate was 31%, which included new-onset diabetes (8%), pancreatic fistula (5%), intra-abdominal abscess (4%), small bowel obstruction (4%), and postoperative hemorrhage (4%) (41). These incidences of surgical complications are consistent with those observed in the Minnesota living-pancreas donor program, which has had a 0% mortality rate to date (37). Metabolic Complications The incidence of new-onset diabetes after distal pancreatectomy reflects the loss of islet cell mass associated with the resection. An extensive review of the literature on the effects of pancreatic resection on glucose metabolism suggests that little change in the metabolic status of the surgical patient occurred postoperatively unless more than 80% of the pancreas parenchyma was excised, or if more than 50% was excised in patients with underlying diffuse pancreatic disease (42). The series of living donor segmental pancreas transplants at the University of Minnesota suggests that living pancreas donation for islet transplantation may pose a minimal risk to the donor (39,43). Initial experience suggested a modestly increased donor risk of procedural complications, impaired glucose tolerance, or more seriously, new diabetes induction in healthy donors followed-up long-term (up to 5%) (44). More recently, careful avoidance of obese donors, those with a preresectional impairment of glucose tolerance or those at increased risk of diabetes as a result of positive serological autoimmune

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antibody markers has largely eliminated this risk, with no new cases of postsurgical diabetes since 1996 (37). RECIPIENT CONSIDERATIONS Assessment and Selection Clinical islet transplantation is associated with a number of risks, including bleeding or portal vein thrombosis in the short term and life-long immunosuppression in the longer term. Consequently, much effort is made in assessing potential islet transplant recipients. In particular, individuals at high short-term risk from their diabetes, often because of frequent, severe, and recurrent hypoglycemia, are considered to be suitable candidates for islet transplantation. Unstable blood glucose control, despite an optimized insulin regimen or progressive secondary complications of diabetes have also been identified as potential indications for islet transplantation. When potential recipients are considered for islet transplantation, their metabolic status and diabetes-related secondary complications should be carefully evaluated to select for those patients who would receive the greatest benefit despite the requirement for life-long immunosuppression (Table 1). Currently, islet transplantation is reserved for patients with C-peptide negative (<0.3 ng/mL) T1DM. Recipients with elevated BMI (>30 kg/m2) or those >90 kg are generally avoided, as their metabolic demand may not be met by the transplanted islet mass. The current indications for islet-alone transplantation include severe hypoglycemic unawareness and/or glycemic lability. To assess these symptoms, Ryan et al. developed an objective scoring system to measure the severity of both hypoglycemia (the HYPO score), and the Lability Index (LI), which is based on the changes in blood glucose over time (45). The current selection criteria for islet-alone transplantation include a HYPO score >1047 (90th percentile), LI >433 mmol/L2/hr/week (90th percentile), or a composite with the HYPO score >423 (75th percentile) and LI >329 (75th percentile) (29). Plasma HbA1C should be <10% in all potential recipients to exclude those with poor diabetes compliance or an inadequate baseline insulin regimen. Clearly, if diabetes control can be improved by a more optimized insulin and monitoring regimen, then this negates the need for islet transplantation. In terms of secondary diabetes complications, the patient’s cardiac and renal function should be assessed. Selected recipients should have adequate cardiac function, including blood pressure <160/100 mmHg; no evidence of myocardial infarction in the six months prior to assessment; no angiographic evidence of noncorrectable coronary artery disease; and left ventricular ejection fraction (LVEF) >30% as measured by echocardiogram. To eliminate patients who are better candidates for simultaneous kidney–pancreas transplantation or those who may experience adverse renal function as a result of tacrolimus or sirolimus therapy, selected recipients should have no evidence of macroscopic proteinuria (<300 mg per 24 hours), and should have a calculated glomerular filtration rate (GFR) >80 (>70 in females) mL/min/1.73 m2. It is important to ensure that the subjects do not have unstable proliferative retinopathy at the time of transplant, as acute correction of glycemic control may lead to accelerated retinopathy. Potential recipients should be screened for PRA assays and determined to be <20% to reduce the incidence of antibody-mediated graft rejection. Islet Transplantation Procedure Purified islets can be implanted into the liver by way of the portal vein using two accepted approaches. In deceased-donor islet transplantation, the percutaneous transhepatic approach is most often utilized to implant donor islets (29). This procedure is performed using local anesthesia, combined with opiate analgesia and hypnotics given as premedication. Although intravenous heparin administration is not routinely used for deceased-donor islet transplantation, therapeutic heparinization may be required for living-donor islet transplants, as large volumes of unpurified islet tissue will be infused, increasing the risk for portal vein thrombosis. Access to the portal vein is achieved by a percutaneous transhepatic approach using a combination of ultrasound and fluoroscopy to guide the radiologist. A branch of the right portal vein is cannulated, and a catheter is positioned proximal to the confluence of the portal vein. A portal

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venogram is performed routinely to confirm the position of the catheter. Unfractionated heparin (70 U/kg) is mixed with the islet preparation immediately prior to infusion, to reduce the risk of portal vein thrombosis. Islets are then infused, aseptically, into the main portal vein under gravity, with regular monitoring of portal venous pressure (by an indirect pressure transducer) before, during, and after the infusion. Islet infusion should not proceed if the initial pressure is more than 20 mmHg. Higher peak postinfusion portal pressures may be more acceptable in the living-donor islet transplant setting, where there is much greater concern for the nonuse of retrieved tissue. This may only be accomplished safely when full therapeutic heparinization is initiated, and continued throughout the early postoperative period. The following day, an ultrasound examination is performed to rule out intraperitoneal hemorrhage, and to confirm that the portal vein is patent and has normal flow. The ultrasound should be repeated at one week to exclude any late portal vein thrombosis. An alternative approach involves surgical laparotomy and cannulation of a mesenteric venous tributary of the portal system. This approach should be considered if a patient is anticoagulated prior to transplantation, or if a hemangioma is present on the right side of the liver that may be at risk of puncture and bleeding if the percutaneous approach were to be used. The main advantage of this approach is that it can be carried out with complete surgical control in order to prevent uncontrolled bleeding. Another advantage includes the potential for the use of a dual-lumen catheter for the cannulation of a mesenteric vein (i.e., dual lumen 9Fr Broviac line), which allows continuous monitoring of portal pressure during islet infusion. This surgical approach does present several disadvantages, such as the requirement for a surgical incision, adhesion formation, and the risk of wound infection and wound herniation, which may be exacerbated when the drug sirolimus is used post-transplantation, as this drug interferes with wound healing. Risks to the Recipient Surgical Complications There are two potentially serious surgical complications in islet transplantation: bleeding from the catheter tract created by the percutaneous transhepatic approach, and portal vein thrombosis, particularly when large volumes of tissue are infused. In the Edmonton program, adverse bleeding events occurred early in the development of the program, but have been completely avoided in the past 40 consecutive procedures with the routine use of effective methods to seal and ablate the transhepatic portal catheter tract on egress when the catheter is withdrawn. The combination of coils and tissue fibrin glue (Tisseel®) was used previously; but more recently, we have preferred Avitene® paste (1-g Avitene powder mixed with 3 cc of radiologic contrast media and 3 cc of saline—approximately 0.5 to 1.0 cc of this paste is injected into the liver tract) (46). The main portal-vein thrombosis has not been encountered in Edmonton with the use of purified islet allograft preparations, but thrombosis of a right or left branch, or a peripheral segmental vein has been encountered in approximately 5% of the patients. Other rarely observed procedural side effects include fine-needle gallbladder puncture, arteriovenous fistulae (which may require selective embolization), or steatosis in the hepatic parenchyma, which generally does not present any clinical complications, or require intervention. Immunosuppressive Therapy and Complications Successful islet transplantation for T1DM requires immunosuppression, which can effectively control both alloimmunity and autoimmunity, which lead to diabetes in the first place. A further challenge is the avoidance of agents known to be toxic to islets, particularly corticosteroids, which have been the mainstay of immunosuppression from the time when successful allotransplantation was first developed. In the current version of the Edmonton Protocol, the induction agent daclizumab [anti-CD25 (IL-2 receptor) antibody] is administered intravenously immediately prior to transplantation (1 mg/kg), with a second dose given at two weeks post-transplant. Maintenance of immunosuppression is achieved using sirolimus and a low dose of tacrolimus. Sirolimus appears to be associated with less nephrotoxicity and diabetogenicity than calcineurin inhibitors (i.e., cyclosporine and tacrolimus). A loading dose of sirolimus (0.2 mg/kg) is given prior to transplant, followed by 0.15 mg/kg, and then adjusted subsequently to achieve trough levels between 10 and 12 ng/mL for the first three months and 7 to 10 ng/mL subsequently.

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A low dose of tacrolimus can be used and adjusted to maintain trough levels between 3 and 6 ng/mL. The success of this regimen, described initially at the University of Alberta, has been replicated at other centers as part of a multicenter ITN trial (24,47). Other successful regimens have been reported by Hering et al. from the Minnesota group, including antithymocyte globulin and etanercept (anti-tumor necrosis factor alpha antibody) induction with a combination of sirolimus and mycophenolate mofetil ± low-dose tacrolimus for maintenance, or hOKT3γ1 (Ala–Ala) (humanized anti-CD3 antibody) and sirolimus induction with sirolimus and reduced-dose tacrolimus for maintenance (27,28). Other immunosuppressive agents have been used in some cases because of drug intolerance or other side effects. The risk of renal dysfunction resulting from calcineurin inhibitor therapy has been reduced using low-dose tacrolimus-based regimens, but renal function in islet recipients receiving any tacrolimus should be carefully monitored, as these patients often possess mild pre-existing renal impairment. It has also recently become apparent that the drug sirolimus might also have nephrotoxic side effects, and that this may be compounded when used in combination with a calcineurin inhibitor (48,49). The gastrointestinal side effects of tacrolimus are not infrequent and may lead to episodic diarrhea. Neurotoxicity may be seen with tacrolimus, but is less frequent with low-dose regimens (50). Neutropenia from sirolimus and the risk of mouth ulceration may be reduced by using a lower target trough level and a tablet rather than a liquid formulation. Sirolimus has also been associated with a number of side effects in islet recipients, including peripheral edema, development of ovarian cysts in female recipients, menstrual cycle irregularities, small bowel ulceration, and dyslipidemia (29,51). The risk of all types of malignancy are increased in chronically immunosuppressed individuals, but skin cancers are the most common and most readily treatable. The lifetime risk of lymphoma is estimated to be 1% to 2% in transplant recipients, but this risk may be an overestimate for islet recipients, in whom glucocorticoids and OKT3 are avoided. FUTURE DIRECTIONS Tolerance Induction in Islet Transplantation Exciting progress in the development of a variety of costimulatory blocking antibodies that prevent “Signal 2” activation even as leaving “Signal 1” T-cell receptor antigen engagement unaltered have shown initial promise in primate models, but further testing of a potent anti-CD40 ligand blocking antibody (Hu5C8) has been hampered because of unexpected thromboembolic complications in early clinical trials (52–54). If techniques to induce tolerance to alloantigens fail completely to protect against autoimmune activation, a reasonable compromise may be to use a costimulatory blocking or bone marrow conditioning adjuvant strategy in concert with very low-dose immunosuppression to diminish the risk of malignancy and infection to near zero. Low-dose sirolimus monotherapy would be one obvious choice in this setting, as the priming of activation-induced cell death remains unimpaired in activated T-lymphocytes, and is therefore “tolerance compatible” (55,56). Glucocorticoid treatment may also interfere with active tolerance pathways (57,58). Controversy persists over how essential it would be to eliminate calcineurin inhibitor therapy in tolerance regimens, as a small number of patients have achieved tolerance to kidney allografts following donor bone marrow transplantation from living donors under the temporary cover of cyclosporin therapy (59). It remains to be seen whether strategies that provide robust tolerance to alloantigens would also effectively control the recurrence of autoimmunity in patients with diabetes. Experimentally, techniques to induce either central or peripheral tolerance have shown benefit, but the most promising approaches have used a combined approach to achieve mixed chimerism. The combination of total body irradiation with bone marrow transplantation and two doses of anti-CD40L antibody was able to induce donor-specific allotolerance without the recurrence of autoimmunity with prolonged islet graft survival in overtly diabetic nonobese diabetic (NOD) mice (60). Graft function was maintained beyond 100 days with robust tolerance to donor-strain skin grafts in this model (61). Peripheral tolerance induced by a diphtheria-conjugated T-cell immunotoxin, combined with an inductive course of deoxyspergualin, was able to render streptozotocin-diabetic and spontaneously diabetic primates operationally tolerant to islet allografts, and insulin independence was maintained beyond

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one year (62,63). Although still under investigation, the development of tolerance-inducing strategies holds great promise for expanding the availability of islet transplantation to a broad population of patients with T1DM. CONCLUSION Living-donor islet transplantation offers the potential for a far less limited donor pool to serve patients with T1DM. There are potential and real risks for a living donor in terms of surgically induced diabetes and potential for surgical complications, but with stringent selection criteria and careful surgical technique and postoperative monitoring, these risks may be minimized. Islet transplantation is still in its relative infancy compared with solid organ transplantation, and concerns relating to the long-term durability of an islet graft still need to be addressed. It is likely that an islet transplant derived from a living donor source will be far more potent (and less injured) than islets isolated from deceased donor pancreata. If tolerance induction is to be applied in clinical islet transplantation, the avoidance of islet injury and enhanced donor antigen exposure may be particularly important. REFERENCES 1. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diab Care 1998; 21(9):1414. 2. Fagot-Campagna A, Narayan KM, Imperatore G. Type 2 diabetes in children. BMJ 2001; 322(7283):377. 3. National Diabetes Data Group (U.S.), National Institute of Diabetes and Digestive and Kidney Diseases (U.S.), National Institutes of Health (U.S.). Diabetes in America. 2nd ed. Bethesda, MD.: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1995. 4. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14):977. 5. Keen H. The Diabetes Control and Complications Trial (DCCT). Health Trends 1994; 26(2):41. 6. Diabetes Control and Complications Trial (DCCT). Update. DCCT Research Group. Diab Care 1990; 13(4):427. 7. Adverse events and their association with treatment regimens in the diabetes control and complications trial. Diab Care 1995; 18(11):1415. 8. Sternberg F, Meyerhoff C, Mennel FJ, Bischof F, Pfeiffer EF. Subcutaneous glucose concentration in humans. Real estimation and continuous monitoring. Diab Care 1995; 18(9):1266. 9. Kendall DM, Rooney DP, Smets YF, Salazar Bolding L, Robertson RP. Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Diabetes 1997; 46(2):249. 10. Newell KA, Bruce DS, Cronin DC, et al. Comparison of pancreas transplantation with portal venous and enteric exocrine drainage to the standard technique utilizing bladder drainage of exocrine secretions. Transplantation 1996; 62(9):1353. 11. Larsen JL. Pancreas transplantation: indications and consequences. Endocr Rev 2004; 25(6):919. 12. Statistical Data Reported by the U.S. Scientific Registry of Transplant Recipients and the Organ Procurement and Transplantation Network, vol. 2005, 2005. 13. Brendel MHB, Schulz A, Bretzel R. International Islet Transplant Registry Report. Germany: University of Giessen, 2001. 14. Close NC, Hering BJ, Eggerman TL. Results from the inaugural year of the Collaborative Islet Transplant Registry. Transplant Proc 2005; 37(2):1305. 15. Ballinger WF, Lacy PE. Transplantation of intact pancreatic islets in rats. Surgery 1972; 72(2):175. 16. Walsh TJ, Eggleston JC, Cameron JL. Portal hypertension, hepatic infarction, and liver failure complicating pancreatic islet autotransplantation. Surgery 1982; 91(4):485. 17. Scharp DW, Lacy PE, Santiago JV, et al. Insulin independence after islet transplantation into type I diabetic patient. Diabetes 1990; 39(4):515. 18. Ricordi C, Tzakis AG, Carroll PB, et al. Human islet isolation and allotransplantation in 22 consecutive cases. Transplantation 1992; 53(2):407. 19. Hering BRC. Islet transplantation for patients with type 1 diabetes: results, research priorities, and reasons for optimism. Graft 1999; 2(1):12. 20. Gross CR, Limwattananon C, Matthees BJ. Quality of life after pancreas transplantation: a review. Clin Transplant 1998; 12(4):351. 21. Secchi A, Di Carlo V, Martinenghi S, et al. Effect of pancreas transplantation on life expectancy, kidney function and quality of life in uraemic type 1 (insulin-dependent) diabetic patients. Diabetologia 1991; 34(suppl 1):S141.

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22. Benhamou PY, Oberholzer J, Toso C, et al. Human islet transplantation network for the treatment of type I diabetes: first data from the Swiss-French GRAGIL consortium (1999–2000). Groupe de Recherche Rhin Rhjne Alpes Geneve pour la transplantation d’Ilots de Langerhans. Diabetologia 2001; 44(7):859. 23. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343(4):230. 24. Shapiro AM, Ricordi C, Hering B. Edmonton’s islet success has indeed been replicated elsewhere. Lancet 2003; 362(9391):1242. 25. Goss JA, Schock AP, Brunicardi FC, et al. Achievement of insulin independence in three consecutive type-1 diabetic patients via pancreatic islet transplantation using islets isolated at a remote islet isolation center. Transplantation 2002; 74(12):1761. 26. Goss JA, Goodpastor SE, Brunicardi FC, et al. Development of a human pancreatic islet-transplant program through a collaborative relationship with a remote islet-isolation center. Transplantation 2004; 77(3):462. 27. Hering BJ, Kandaswamy R, Ansite JD, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA 2005; 293(7):830. 28. Hering BJ, Kandaswamy R, Harmon JV, et al. Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant 2004; 4(3):390. 29. Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005; 54(7):2060. 30. Ryan EA, Lakey JR, Paty BW, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 2002; 51(7):2148. 31. Contreras JL, Eckstein C, Smyth CA, et al. Brain death significantly reduces isolated pancreatic islet yields and functionality in vitro and in vivo after transplantation in rats. Diabetes 2003; 52(12):2935. 32. Sutherland DE, Matas AJ, Goetz FC, Najarian JS. Transplantation of dispersed pancreatic islet tissue in humans: autografts and allografts. Diabetes 1980; 29(suppl 1):31. 33. Matsumoto S, Okitsu T, Iwanaga Y, et al. Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet 2005; 365(9471):1642. 34. Gruessner RW, Sutherland DE, Dunn DL, et al. Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis. J Am Coll Surg 2004; 198(4):559. 35. Lakey JR, Warnock GL, Rajotte RV, et al. Variables in organ donors that affect the recovery of human islets of Langerhans. Transplantation 1996; 61(7):1047. 36. Tsujimura T, Kuroda Y, Avila JG, et al. Influence of pancreas preservation on human islet isolation outcomes: impact of the two-layer method. Transplantation 2004; 78(1):96. 37. Gruessner RW, Sutherland DE. Living donor pancreas transplantation. Transplant Rev 2002; 16(2):108. 38. Kosaka K, Kuzuya T, Hagura R, Yoshinaga H. Insulin response to oral glucose load is consistently decreased in established non-insulin-dependent diabetes mellitus: the usefulness of decreased early insulin response as a predictor of non-insulin-dependent diabetes mellitus. Diab Med 1996; 13(9 suppl 6):S109. 39. Franke B, Galloway TS, Wilkin TJ. Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies. Diab Metab Res Rev 2005; 21(5):395. 40. Barnett MJ, Zhai X, LeGatt DF, Cheng SB, Shapiro AM, Lakey JR. Quantitative assessment of collagenase blends for human islet isolation. Transplantation 2005; 80(6):723. 41. Lillemoe KD, Kaushal S, Cameron JL, Sohn TA, Pitt HA, Yeo CJ. Distal pancreatectomy: indications and outcomes in 235 patients. Ann Surg 1999; 229(5):693. 42. Slezak LA, Andersen DK. Pancreatic resection: effects on glucose metabolism. World J Surg 2001; 25(4):452. 43. Kendall DM, Sutherland DE, Najarian JS, Goetz FC, Robertson RP. Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med 1990; 322(13):898. 44. Robertson RP, Lanz KJ, Sutherland DE, Seaquist ER. Relationship between diabetes and obesity nine to 18 years after hemipancreatectomy and transplantation in donors and recipients. Transplantation 2002; 73(5):736. 45. Ryan EA, Shandro T, Green K, et al. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 2004; 53(4):955. 46. Villiger P, Ryan EA, Owen R, et al. Prevention of bleeding after islet transplantation: lessons learned from a multivariate analysis of 132 cases at a single institution. Am J Transplant 2005; 5(12):2992. 47. Shapiro AM, Lakey JR, Paty BW, Senior PA, Bigam DL, Ryan EA. Strategic opportunities in clinical islet transplantation. Transplantation 2005; 79(10):1304. 48. Kaplan B, Schold J, Srinivas T, et al. Effect of sirolimus withdrawal in patients with deteriorating renal function. Am J Transplant 2004; 4(10):1709. 49. Senior PA, Paty BW, Cockfield SM, Ryan EA, Shapiro AM. Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am J Transplant 2005; 5(9):2318. 50. Gruessner RW, Burke GW, Stratta R, et al. A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 1996; 61(2):261.

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51. Molinari M, Al-Saif F, Ryan EA, et al. Sirolimus-induced ulceration of the small bowel in islet transplant recipients: report of two cases. Am J Transplant 2005; 5(11):2799. 52. Kirk AD, Burkly LC, Batty DS, et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999; 5(6):686. 53. Kirk AD, Harlan DM, Armstrong NN, et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94(16):8789. 54. Kenyon NS, Chatzipetrou M, Masetti M, et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci USA 1999; 96(14):8132. 55. Li Y, Zheng XX, Li XC, Zand MS, Strom TB. Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 1998; 6610):1387. 56. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T-cells and induction of peripheral allograft tolerance. Nat Med 1999; 5(11):1298. 57. Smiley ST, Csizmadia V, Gao W, Turka LA, Hancock WW. Differential effects of cyclosporine A, methylprednisolone, mycophenolate, and rapamycin on CD154 induction and requirement for NFkappaB: implications for tolerance induction. Transplantation 2000; 70(3):415. 58. Sharland A, Yan Y, Wang C, et al. Evidence that apoptosis of activated T-cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance. Transplantation 1999; 68(11):1736. 59. Spitzer TR, Delmonico F, Tolkoff-Rubin N, et al. Combined histocompatibility leukocyte antigenmatched donor bone marrow and renal transplantation for multiple myeloma with end-stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation 1999; 68(4):480. 60. Seung E, Iwakoshi N, Woda BA, et al. Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. Blood 2000; 95(6):2175. 61. Contreras JL, Eckhoff DE, Cartner S, et al. Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. Transplantation 2000; 69(2):195. 62. Thomas JM, Eckhoff DE, Contreras JL, et al. Durable donor-specific T- and B-cell tolerance in rhesus macaques induced with peritransplantation anti-CD3 immunotoxin and deoxyspergualin: absence of chronic allograft nephropathy. Transplantation 2000; 69(12):2497. 63. Thomas JM, Contreras JL, Jiang XL, et al. Peritransplant tolerance induction in macaques: early events reflecting the unique synergy between immunotoxin and deoxyspergualin. Transplantation 1999; 68(11):1660.

Part VI

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LIVING-DONOR LUNG TRANSPLANTATION

Living Lobar-Lung Transplantation Mark L. Barr and Vaughn A. Starnes Department of Cardiothoracic Surgery, University of Southern California Keck School of Medicine and Children’s Hospital Los Angeles, Los Angeles, California, U.S.A.

INTRODUCTION The number of patients awaiting lung transplantation has steadily increased over the past two decades, as improvements in outcomes have made lung transplantation an accepted therapy for end-stage lung disease. Despite a steady increase in the potential recipient pool, the number of deceased-donor lung transplants performed has not increased accordingly due to a lack of donor lungs, despite liberalizing the standard donor criteria and considering older and sometimes more marginal donors (1–3). This donor-to-supply mismatch is even more severe in those who require bilateral lung transplantation because of suppurative lung disease, such as cystic fibrosis. With this disparity in mind, our group developed living-lobar lung transplantation as an alternative to deceased-donor lung transplantation (4,5). In living-lobar lung transplantation, two healthy donors are selected––one to undergo the removal of the right lower lobe and the other the removal of the left lower lobe. These lobes are then implanted in the recipient in place of whole right and left lungs. Although the number of living-lobar lung transplants performed each year remains small compared with kidney transplantation (where approximately 50% of transplants are now performed from living donors) and liver transplantation, living-lobar lung transplantation has clearly proven itself to be beneficial to a small group of patients who would have otherwise succumbed awaiting a deceased donor (5,6). Since 1992, our institution has performed 141 living lobar transplants, and other programs subsequently have been developed in North America, Europe, and Japan (7,8). RECIPIENT INDICATIONS AND DONOR SELECTION Living-lobar lung transplant candidates should meet the standard criteria for deceased-donor lung transplantation and be listed on the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network lung transplantation waiting list (9). Potential recipients should have the expectation that they would die or become unsuitable recipients before a deceased donor organ becomes available. Overall, cystic fibrosis has been the most common indication for living lobar-lung transplantation. However, other indications for living lobar-lung transplantation have included primary pulmonary hypertension, pulmonary fibrosis, bronchopulmonary dysplasia, and obliterative bronchiolitis, lymphangioleiomyomatosis, and idiopathic interstitial pneumonia (5,8). The goals of donor selection are to identify donors with excellent health, adequate pulmonary reserve for lobar donation, an emotional attachment to the recipient, and a willingness to accept the risks of donation without coercion. The criteria for donation have included an age between 18 and 55, no history of thoracic procedures on the side to be donated, and excellent general health. Donors taller than the recipient are favored over donors of the same or lower height, as they have the potential to provide larger lobes. Initially, only the mother and father of the recipient were considered as donors; however, lobes from siblings, extended family members, and unrelated individuals who can demonstrate an emotional attachment to the recipient are also presently considered. A psychosocial interview is then conducted. Potential donors are interviewed both with the recipient and the recipient’s family to ascertain interpersonal dynamics. Elements of the interview include the motivation to donate, pain tolerance, feelings regarding donation should the recipient expire, and the ability of the potential donor to

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be separated from family and career obligations. As an element of coercion can always exist between a potential donor and the recipient and/or the recipient’s family, any potential donor who discloses that they feel any pressure to donate after careful consultation and explanation of the procedure is denied for unspecified reasons, to prevent untoward feelings among the family, recipient, and potential donor. After the psychosocial evaluation, suitable potential donors undergo blood typing for compatibility and chest radiography and spirometry to assess the lung size and function. This preliminary screening reduces costs as it allows for the evaluation of only a limited number of potential donors. A more thorough medical work-up, including routine transplant serologies [human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis], electrocardiogram, echocardiogram, quantitative ventilation/perfusion scanning, and high-resolution chest-computed tomography, is completed after the preliminary screening is completed and is found to be acceptable (10,11). After the identification of two suitable donors, one is chosen to undergo right lower lobectomy and the other left lower lobectomy. The right lower lobe is usually selected from the larger donor; whereas, if the donors are of the same height, the donor with the more complete fissure on the left is chosen to donate that side. Occasionally, an acceptable donor will have a history of prior thoracic procedures, trauma, or infection. In this case, the contralateral side is chosen for donation. Currently, computed tomographic scanning and spirometry are used to estimate lung volume, although the optimal method of determining an appropriate size match between donor and recipient remains to be defined, and further improvements in this methodology are warranted. In children, care must be exercised to ensure that the lower lobe is not oversized. Although human leukocyte antigen (HLA) matching is not required for donor selection, a prospective crossmatch to rule out the presence of anti-HLA antibodies is performed. OPERATIVE TECHNIQUE The performance of living lobar-lung transplantation involves three simultaneous operations–– two donor lobectomies and the recipient bilateral pneumonectomy and lobar implantation. The operative goals of living-donor lung transplantation are to avoid morbidity to the healthy volunteer lobe donor-even as providing adequate tissue margins for implantation in the recipient (12). The lobar vascular and bronchial anatomy of the right and left lower lobes are the most suitable for lobar transplantation. The important difference in performing a lobectomy for lobar transplantation, as opposed to a lobectomy for cancer or infection, is that the lobe must be removed with adequate cuffs of bronchus, pulmonary artery, and pulmonary vein to allow successful reimplantation in the recipient, at the same time as allowing closure of these structures in the donor without compromise. DONOR RIGHT LOWER LOBECTOMY The donor lung is deflated and the chest is entered through a standard posterolateral thoracotomy through the fourth or fifth interspace. The lung is carefully inspected to exclude unsuspected pathology. Excellent exposure is mandatory, allowing the dissection of hilar structures without excessive manipulation of the graft. The inferior pulmonary ligament is incised with electrocautery, and the mediastinal pleura is dissected around the pleura anteriorly and posteriorly. Dissection in the fissure characterizes anatomic variants and identifies the pulmonary arteries to the right lower and right middle lobes. The relationship between the superior segmental artery to the right lower lobe and middle lobe artery should be visualized. Commonly, the middle lobe has two arteries, with the smaller artery having a more distal origin than the superior segmental artery to the lower lobe. In this case, the smaller artery may be ligated and divided. Ideally, there will be sufficient distance between the takeoff of the middle-lobe artery and the superior segmental artery of the right lower lobe to allow the placement of a vascular clamp distal to the middle lobe artery. This enables a sufficient vascular cuff for the pulmonary arterial anastomosis at implantation. After confirming that the inferior pulmonary vein does not receive venous drainage from the right middle lobe, the pericardium surrounding the inferior pulmonary vein is incised. This dissection allows a vascular clamp to be placed on the left atrium and the inferior pulmonary

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vein to be cut with an adequate cuff on the donor lobe. When the vascular dissections are complete, the fissures are divided using a 75-mm nonvascular stapler or a 45-mm GIA thoracoscopic stapler. Heparin and methylprednisolone are administered intravenously, and the lung is reinflated and ventilated for five to 10 minutes to allow the circulation of the drugs through the lung. The lung is then deflated. To avoid vascular congestion of the pulmonary allograft, a vascular clamp is placed first on the pulmonary artery and subsequently on the left atrial side of the inferior pulmonary vein, optimizing the length of the venous cuff for pulmonary venous anastomosis. The pulmonary artery is transected at a point that would allow an adequate vascular cuff for anastomosis at the same time as leaving enough length to permit repair without compromising the remaining pulmonary arterial branches. The inferior pulmonary vein is transected with a small cuff of left atrium. The bronchus to the right lower lobe should now be exposed. Minimizing dissection around the bronchus preserves blood supply to both the donor lobe and the remaining lung. The right middle-lobe bronchus is identified and the bronchus to the lower lobe is tangentially transected. The incision begins in the bronchus intermedius above the bronchus to the superior segment of the right lower lobe, and moves obliquely to a point just below the takeoff of the right middle lobe bronchus. Division of the pulmonary vessels and bronchus should be performed expeditiously to limit the warm ischemic time of the allograft. When separated, the donor lobe is wrapped in a cold, moist sponge, and taken to a separate, sterile table for preservation. The donor’s pulmonary artery is repaired in two layers with a running polypropylene suture, and the pulmonary vein/left atrium is closed in a similar fashion. The bronchus is closed with interrupted polypropylene, being careful to avoid the narrowing of the bronchus intermedius or infolding of the middle lobe carina. Resecting a small wedge of cartilage at the orifice of the middle lobe may facilitate closure. The bronchial suture line is covered with a pleural flap to separate the arterial and bronchial suture lines. Two chest tubes are placed in the pleural space, and the chest is closed in the standard fashion. DONOR LEFT LOWER LOBECTOMY The chest is opened using a standard posterolateral thoracotomy through the fourth or fifth interspace. The lung is examined in a similar fashion to that described for the right side. The inferior pulmonary ligament is taken down and the pleura is opened around the hilum. Dissection in the fissure defines the vascular anatomy. The relationship between the superior segmental artery to the lower lobe and the anteriorly positioned lingular artery is evaluated. The lingular artery may be ligated and divided if it is of small size and its origin is too far distal to the artery to the superior segment of the lower lobe. If the significance of this artery is uncertain, the anesthesiologist can inflate and deflate the lung when this artery is occluded. If the lingular segment becomes atelectatic, reflecting impaired absorption atelectasis secondary to poor blood flow, reimplantation of the lingular artery is suggested. Dissection of the pulmonary artery to the lower lobe should enable the placement of a vascular clamp proximal to the artery supplying the superior segment of the lower lobe. The pericardium around the inferior pulmonary vein is opened circumferentially and the fissures are divided with a nonvascular stapler. When the dissection is complete, the lung is reinflated and ventilated for five to 10 minutes as described for the right side. Heparin and methylprednisolone are administered. The lung is subsequently deflated, and the pulmonary artery and vein are clamped and transected in the sequence described for the right lung. The exposed bronchus is followed upward until the lingular bronchus is identified. Care must be taken to avoid skeletonizing the bronchus, as this may compromise healing in the recipient. The tangential transection begins at the base of the upperlobe bronchus and ends superiorly to the bronchus to the superior segment of the left lower lobe. The donor lobe is then taken to a separate table for preservation and storage. The pulmonary vessels and bronchus are repaired in a manner similar to that described for the right side. ALLOGRAFT PRESERVATION Preparation of the donor lobe begins at the start of the donor operation with a continuous prostaglandin infusion and meticulous attention to operative technique during the lobectomy.

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In contrast to deceased donor lung explantation, the preservation of the live donor lobe does not permit in vivo flushing and cooling of the graft with high-potassium containing preservation solutions. Therefore, after the donor lobe is removed, it is taken to a separate, sterile table for preservation. The allograft is immersed in cold crystalloid solution. The pulmonary artery and vein are cannulated in an alternating fashion and flushed with 1–2 l of cold, pulmonary preservation solution (Perfadex®) until the pulmonary venous and arterial effluents are clear and the parenchyma is blanched white. During perfusion, the lobe is gently ventilated with room air. A ventilation bag with different-sized endotracheal tubes should be available. Using an appropriately-sized endotracheal tube would allow an adequate seal to be formed when ventilating the bronchus, and would prevent potential damage to the bronchus caused by crushing or squeezing the bronchus in order to obtain an adequate seal. Depending on the length of the bronchus, it may be necessary to intubate the superior segment bronchus separately with a smaller tube to ventilate that portion of the lobe. The superior segment artery may have to be perfused separately as well. Care must be taken to prevent the crystalloid bath or the preservation solution effluent from entering the bronchus. In addition, a manometer is fastened to the ventilation apparatus, and the lobe is inflated to a pressure of 20–25 mmHg, being careful to avoid overpressurizing the lung. After adequate perfusion and ventilation, a final breath is administered to achieve approximately 75% maximum inflation, the endotracheal tube is quickly removed, and the bronchus is occluded with a noncrushing clamp. The donor lobe is placed in sterile bags with cold storage solution, and transported to the recipient operating room in an ice-filled cooler. RECIPIENT PNEUMONECTOMY AND ALLOGRAFT IMPLANTATION The recipient operation commences in a third operating room at the same time as the donor operations are being performed. The patient is positioned supine, and the arms padded and placed in an extended and abducted position on an overhead frame. The operation is performed through a transverse thoracosternotomy (clam-shell) incision, which provides exposure for cardiac cannulation and adequate access to the pleural spaces. The procedures are performed with cardiopulmonary bypass often because of the recipient’s critical condition and the risk of reperfusion pulmonary edema when exposing one lobe to the entire cardiac output at the same time as the other lobe is implanted. Cardiopulmonary bypass allows simultaneous reperfusion of both lobes in a controlled fashion. Hilar dissection and lysis of adhesions are completed prior to heparinization and cardiopulmonary bypass. The pleural cavity of cystic fibrosis patients is irrigated thoroughly with an aminoglycoside and amphotericin B solution. The dissection of the pulmonary artery and veins is performed as distally as possible to optimize the cuff length for the anastomosis. When the dissection is complete, cardiopulmonary bypass is initiated, and the pulmonary vasculature is divided. The pulmonary veins are divided between stapling devices even as the pulmonary artery is doubly ligated and divided. The bronchus is divided with a stapling device at the level of the takeoff of the upper lobe bronchus. After the onset of bypass, the anesthesiologist suctions the lungs and removes the endotracheal tube. The first allograft is placed on a cooling jacket within the pleural space, and the exposed lung is wrapped in iced-saline-soaked sponges. The bronchial anastomosis is performed with running 4-0 polypropylene suture. Care is taken to limit the amount of peribronchial dissection. The bronchial anastomosis places the donor lobar vein in close approximation to the superior pulmonary vein of the recipient, and the venous anastomosis is performed in a running fashion with 5-0 polypropylene suture. The short length of the donor vein makes anastomosis directly to the left atrium difficult and underscores the importance of leaving an adequate length of recipient pulmonary vein during pneumonectomy. The pulmonary artery anastomosis is performed end to end with 5-0 polypropylene suture. A similar procedure is performed for the second allograft. After completing the bilateral implantations, the arterial vascular clamp is slowly removed. The preservation perfusate is allowed to egress from the venous anastomosis prior to tying the venous sutures, and ventilation is begun gently. Continuous nitric oxide starting at 20 ppm and intermittent aerosolized bronchodilator therapy are both administered via the anesthesia circuit. Blood volume is gradually returned allowing increased cardiac ejection and

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pulmonary blood flow to occur with subsequent weaning from cardiopulmonary bypass. At the completion of implantation, transesophageal echocardiography (checking for patency of the one pulmonary vein on each side draining into the left atrium) and bronchoscopy are performed to exclude technical complications. POSTOPERATIVE MANAGEMENT Although the immunosuppression, antibiotic therapy, and prophylaxis, long-term management of the lobar recipient are very similar to the standard deceased-donor transplantation, the perioperative management can be quite challenging given the unique lobar physiology. The lobar physiology of the recipient presents unique challenges compared with standard deceaseddonor lung transplantation, as the entire cardiac output is flowing through two relatively undersized lobes. In an attempt to decrease atelectasis and optimize the expansion of the lobes, the recipient is kept sedated and ventilated through a single lumen endotracheal tube with positive end-expiratory pressures of 5- to 10-cm water for at least 48 hours. Additionally, efforts are undertaken to decrease the pulmonary artery pressures and minimize the risk of reperfusion injury and pulmonary edema. This is accomplished by maintaining the recipient in a relatively hypovolemic state, the use of nitroglycerin infusion, and the use of aerosolized nitric oxide for the first 48 to 72 hours. Another unique aspect of managing the lobar recipient in the perioperative period is chesttube management. Depending on the degree of size mismatch between the donor lobe and the recipient pleural cavity, conventional chest tube suction in the postoperative period can result in impaired deflation mechanics. This can lead to air trapping with increasing airway pressures, a rise in pulmonary vascular resistance, and subsequently an acute rise in pulmonary arterial pressure. This problem is exaggerated as the discrepancy between the size of the lobe and the thoracic cavity increases. In an effort to avoid this problem, suction is applied at low levels (10-cm water) to each tube sequentially for one-hour intervals, in a rotational fashion for the first 24 hours postoperatively. Subsequently, each of the four chest tubes is placed on continuous suction that is gradually increased to 20-cm water over the next 48 hours. The chest-tube output can be much greater than that seen after the deceased donor implantation, as there is an obligatory space filling of the pleural cavity with fluid, which can be exacerbated by greater topographical mismatches. The question of whether these tubes can be removed despite these higher-than-normal outputs is unclear. However, because of concerns of lobe compression by the pleural fluid, the chest tubes are left in place for two to three weeks, which is significantly longer than in conventional deceased donor transplantation. Any air leaks typically resolve in this time period as well. The management of the lobar recipient regarding immunosuppression, antibiotic therapy and prophylaxis, and long-term follow up, is very similar to deceased donor recipients. All patients have received triple-drug immunosuppression (tacrolimus/cyclosporine, mycophenolate mofetil/azathioprine, and prednisone) without induction therapy. Antibiotic use based on preoperative, intraoperative, and postoperative cultures is common in cystic fibrosis recipients because of the nearly universal presence of pathogenic bacterial and/or fungal species. Prophylaxis for Pneumocystis carinii and cytomegalovirus is given to all recipients. In all recipients, pulmonary function testing and chest roentgenography are performed with each clinic visit; however, bronchoscopy is performed only when clinically indicated by symptoms, radiography, or a decrease in spirometric results. Transbronchial biopsy is performed sparingly due to the perceived increased risk of bleeding in the lobar recipient. RESULTS AT UNIVERSITY OF SOUTHERN CALIFORNIA Although the use of live donor organs is considered ethically acceptable at most transplant centers, it creates the unique situation whereby the treatment approach affects not only the patient with end-stage organ disease, but also the live organ donor (13). The deaths of both liver and kidney donors have highlighted this issue, and have brought increased public attention to live organ donation (14). The need for donor safety is accentuated with living-lobar lung transplantation because of the necessity of placing two donors at risk for each recipient. For these reasons, careful scrutiny of living-lobar lung transplantation is needed to justify its use as a treatment for patients with end-stage lung disease.

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Since our last formal report in the literature (5), we have performed 141 living-lobar lung transplants on 136 patients at the University of Southern California and Children’s Hospital Los Angeles. Ninety recipients were adults (mean age 27 ± 7 years) and 46 were pediatric (mean age 14 ± 3 years of age). The main indication for transplantation was cystic fibrosis (86%); the remaining 14% of recipients had a variety of other diagnoses, including primary pulmonary hypertension, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, and obliterative bronchiolitis. At the time of transplantation, many of the patients were critically ill, with 67% hospital bound, and 20% ventilator dependent, including three on jet ventilation and one patient on ECMO. RECIPIENT OUTCOMES The overall recipient actuarial for one-, three-, and five-year survival are 73%, 58%, and 48%, respectively, and there has been no difference in actuarial survival between adult or pediatric recipients. This actuarial survival compares favorably with the International Society for Heart and Lung Transplantation (ISHLT) registry data of one, three, and five-year survival of 74%, 58%, and 47% (2). The mean follow-up is 3.6 ± 3.3 years (range 0–11.8 years). Deaths occurring within 30 days of transplantation have been largely related to infection and primary graft failure. Deaths occurring between 30 days and one year after transplantation have been usually related to infectious etiologies. Late death (greater than one year after transplantation) is predominantly related to infection and obliterative bronchiolitis. The predominant infections seen have presented as sepsis and/or pneumonia from Pseudomonas sp., Staphylococcus sp., and Aspergillus sp. As opposed to deceased-donor double lung transplantation, in which rejection almost always presents in a bilateral fashion, rejection episodes in the lobar recipients have been predominantly unilateral (72%), whereas only 28% presented bilaterally. Fifty-three percent of rejection episodes were classified as grade A2 according to the ISHLT grading system, whereas 35% were grade A1, and 12% were grade A3. In adult recipients, overall freedom from bronchiolitis obliterans syndrome (BOS) are 98%, 82%, and 76% at one, three, and five years, respectively. Age, gender, etiology, donor relationship, preoperative hospitalization status, use of preoperative steroids, and human leukocyte antigent (HLA) A, B, and DR matching did not influence survival or rejection. Patients undergoing retransplantation had an elevated risk of death (odds ratio 2.50, P = ns). Those patients on ventilators preoperatively had significantly worse outcomes (odds ratio for death at one year 4.9, P = 0.0015; overall odds ratio 3.06, P = 0.03). One question that has been raised regarding to living-lobar lung transplantation is whether the relatively undersized bilateral lobar grafts would provide comparable pulmonary function to full-sized bilateral deceased donor grafts in adult recipients. In an attempt to address this question, we recently compared serial postoperative pulmonary function tests in a deathcensored analysis of our initial cohort of 79 adult patients undergoing living-lobar lung transplantation and 46 adult patients undergoing bilateral deceased donor lung transplantation who survived at least three months after transplantation (15). There was no significant difference in the overall survival between these two groups of patients surviving at least three months after either living lobar or deceased donor lung transplantation: conditional one-, three-, and five-year actuarial survival were 83%, 81%, and 75% in deceased donor recipients and 83%, 64%, and 62% in lobar recipients (P = 0.32). The analysis of the pulmonary functions after both living-lobar and bilateral deceaseddonor lung transplantation showed that both groups of recipients demonstrated improvement during the first year after transplantation, and that pulmonary function was equivalent between the groups by six months after transplantation. Lobar recipients demonstrated an improvement in both forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) by six months after transplantation, whereas the deceased donor recipients had an improvement in FVC by 12 months after transplantation and maintained a stable FEV1. These results are similar to those reported in bilateral deceased-donor transplantation, which have shown improvements in FEV1, FVC, and diffusing capacity for the first six to 12 months after transplantation, after which time, lung function tends to decline at a variable rate and is highly influenced by the presence or absence of complications (16–18). The Okayama University group has seen similar

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improvements in FVC and FEV1 during the first year after transplantation in their series of living-lobar lung transplant recipients (8). The comparison of pulmonary functions between the living-lobar and deceased-donor recipients at various time points demonstrated that FVC and FEV1 were significantly lower at one and three months after transplantation in the living-lobar group compared with the deceased-donor group. However, by six months after transplantation, this difference had resolved and the values then remained equivalent. These results are somewhat intriguing but not entirely unexpected. It is generally accepted that the initial improvement seen in pulmonary function over the first year after transplantation is, in large part, related to improved chest wall mechanics and alveolar recruitment, which occur with operative recovery (19,20). However, the process is undoubtedly multifactorial and influenced by other factors, such as pulmonary compliance, episodes of infection and rejection, and other postoperative complications. Although one might have expected the lobes in the lobar recipients to have persistently decreased flows, as compared with bilateral deceased donor grafts from a strict physiologic standpoint. It seems likely that the lobes are able to provide similar flows through both careful donor and recipient selection (whereby, a relatively large lobe is placed in a relatively small recipient), and through continued alveolar dilatation and recruitment in the graft, as opposed to growth (21). The explanation of the lower FVC and FEV1 seen at one and three months in lobar recipients, compared with bilateral deceased-donor recipients, is likewise multifactorial, but is likely to be related to topographic and resulting mechanical issues because of the fact that the lobe is not perfectly opposed to the chest wall, as occurs with bilateral deceased donor grafts. It is possible that with time and scarring, the mechanics between the chest wall and lobe improve, resulting in an improvement in pulmonary flows as demonstrated in this study. Exercise capacities were also comparable in the lobar and deceased-donor lung transplant recipients when assessed by exercise stress testing. Although the peak oxygen consumption achieved by both groups of transplant recipients are below 80% of the normal predicted value, they are certainly adequate to permit a comfortable lifestyle and at least moderate levels of work and exercise (22). These peak exercise capacities are similar to those previously reported for the recipients of double-lung and heart–lung transplants (18,23). These results show that, despite the relatively undersized grafts, lobar transplantation provides adequate pulmonary function and exercise capacity––three female recipients have even gone through full-term pregnancy without any untoward events during gestation or delivery. DONOR OUTCOMES There has been no perioperative or long-term mortality in the total cohort of 279 lobar donors. In a detailed study of the first 253 donors, 80.2% had no perioperative complications (24). Fifty (19.8%) of the 253 donors had one or more perioperative complications. The overall length of stay was 9.4 ± 4.8 days. Right-sided donors were more likely to have a perioperative complication than left-sided ones (odds ratio 2.02, P = 0.04), probably related to right-lower and middlelobe anatomy. Intraoperative complications occurred in nine (3.6%) donors, and were primarily related to the right-middle lobe. The right-middle lobe was sacrificed in four donors because of variations in either arterial or venous anatomy, whereas three patients required reimplantation of the right middle-lobe bronchus. In addition, one donor required one packed red-blood cell unit secondary to blood loss after the clamp on the left atrium was inadvertently displaced. One patient with a history of Wolf-Parkinson-White syndrome developed a persistent supraventricular tachycardia, which eventually responded to medical therapy; however, the patient subsequently required pacemaker placement. Complications requiring reoperation occurred in eight (3.2%) donors. Three donors required reoperation for bleeding; however, none required red blood cell transfusion. The source of bleeding in these patients was most commonly an intercostal artery. One patient underwent video-assisted thoracoscopy for the evacuation of a loculated pleural effusion, whereas one required pericardiectomy for pericarditis unresponsive to medical management. The remaining three patients required reoperation for a sterile empyema, a retained sponge, and a bronchopulmonary fistula, respectively. Other perioperative complications occurred in

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38 (15.0%) donors. The most common complication in this group, and overall, was the need for a thoracostomy tube for more than 14 days postoperatively, either for persistent drainage or airleaks, or the placement of an additional thoracostomy tube. The most significant complication in this group occurred in two patients who developed pulmonary artery thrombosis. Both patients presented with severe respiratory distress; however, neither required intubation. Both patients had positive ventilation-perfusion scans, negative lower-extremity duplex scans, and contrast magnetic resonance imaging and angiography studies consistent with thrombus at the pulmonary artery suture line. Both patients were successfully managed with systemic anticoagulation, and suffered no long-term sequelae. Other complications included medically-treated arrhythmias and pericarditis, in addition to two minor epidural-related complications (hypotensive episodes resulting in syncope in two donors). One donor required bronchoscopy for right middle-lobe collapse, but did not require reoperation. Four donors required readmission within 30 days of lobectomy––one for dehydration, one with shortness of breath, one with a pleural effusion managed conservatively, and one for presumed pneumonia without positive cultures. OTHER CENTERS The results in pediatric and adult-living lobar transplantation from other centers are sparse, although programs do exist in North America, Europe, and Japan. The Washington University Group at St. Louis Children’s Hospital has reported results from 31 pediatric patients in an unstable condition, or in a condition where survival was unlikely during the wait for a deceased donor organ (7,25). In this series, 22 (71%) patients recovered and were discharged from the hospital, whereas nine (29%) died during the early postoperative period. The overall one-year survival was 63.7%. The group at Okayama University in Japan recently reported their early experience with 30 patients with end-stage lung disease who received living-lobar lung transplants (8). This technique is particularly attractive in Japan because of an extreme shortage of deceased donors. All patients in this series were alive at the time of their report, with a mean follow-up of 22.2 months (range 1–66 months). There have been two other reports of perioperative complications in living donor lobectomy (25,26). The Washington University group reported on 62 donors utilized for 31 livinglobar lung transplants in children. In this series, 10 donors (16.1%) had 12 major complications requiring subsequent intervention, three of which resulted in permanent loss of function (phrenic nerve paralysis, loss of right-middle lobe, and the development of a bronchial stricture). Eleven of the 27 donors in the Okayama University group had perioperative complications; however, there has been no mortality, and all donors have returned to their previous lifestyles (8). SUMMARY A constant awareness of the risk to the living donors must be maintained with any live-donor organ transplantation program, and comprehensive short- and long-term follow-up should be strongly encouraged to maintain the viability of these potentially life-saving programs. There has been no perioperative or long-term mortality following lobectomy for living-lobar lung transplantation, and the perioperative risks associated with donor lobectomy are similar to those seen with standard lung resections. However, these risks might increase if the procedure is offered on an occasional basis and not within a well-established program. An important question, which remains unanswered, concerns the long-term outcomes and functional effects of lobar donation. This has proven difficult to follow closely because of the fact that many donors live far away from the medical center, and are reluctant to return for routine follow-up evaluation. The death of a recipient further exacerbates this situation, as there is reluctance to insist on further routine exams for a grieving donor. Further long-term outcome data are ideally needed, similar to live-donor renal and liver transplantation. Although this may not reflect the postoperative pulmonary function of the entire group of donors, initial one- and two-year postoperative pulmonary function testing demonstrated an average decrease of 17% in forced vital

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capacity, 15% in forced expiratory volume in one second, and 16% in total lung capacity from preoperative values (27). Despite these results, we still favor performing living-lobar lung transplantation in the patient with a clinically deteriorating condition. We feel that prospective donors should be informed of the morbidity associated with donor lobectomy and the potential for mortality, in addition to the potential recipient outcomes regarding to life expectancy and quality of life after transplantation. A major question regarding lobar lung transplantation that has been unanswered during the last decade is defining when a potential recipient is too ill to justify placing two healthy donors at risk for donor lobectomy. The recipient age, gender, indication for primary transplant, prehospitalization status, steroid usage preoperatively, relationship of donor to recipient, and the presence or absence of rejection episodes postoperatively, all do not appear to influence the overall mortality (5). However, those patients on ventilators preoperatively, and those undergoing retransplantation after either a previous deceased-donor or lobar-lung transplant, have significantly elevated odds ratios for postoperative death. We would therefore recommend caution in these subgroups of patients. This experience is not that dissimilar to the deceased donor experience where intubated patients have higher one-year mortality and retransplants have decreased three- and five-year survival (2,3). A similar experience with a smaller number of lobar transplants has been reported by the Washington University group (28). Despite this high-risk patient group, this alternative procedure has been life-saving in severely ill patients who would either die or become unsuitable recipients before a deceased donor organ becomes available. Although deceased donor transplantation is preferable because of the risk to the donors, living-lobar lung transplantation should continue to be utilized under properly selected circumstances. Although there have been no deaths in the donor cohort, a risk of death between 0.5% and 1% should be quoted pending further data. The loss of lung function should be considered an expected aspect of this procedure, and is explained as such to the potential donor during the process of obtaining informed consent. The results reported by our group and others are important if this procedure is to be considered as an option at more pulmonary transplant centers, given the institutional, regional, and intra- and international differences in the philosophical and ethical acceptance of the use of live organ donors for transplantation. REFERENCES 1. Rosengard BR, Feng S, Alfrey EJ, et al. Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor. Am J Transplant 2002; 2(8):701–711. 2. Trulock EP, Edwards LB, Taylor DO, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult lung and heart-lung transplant report––2004. J Heart Lung Transplant 2004; 23(7):804–815. 3. Barr ML, Bourge RC, Orens JB, et al. Thoracic organ transplantation in the United States, 1994–2003. Am J Transplant 2005; 5(4 Pt 2):934–949. 4. Starnes VA, Barr ML, Cohen RG. Lobar transplantation. Indications, technique, and outcome. J Thorac Cardiovasc Surg 1994; 108(3):403–410; discussion 410–411. 5. Starnes VA, Bowdish ME, Woo MS, et al. A decade of living-lobar lung transplantation: recipient outcomes. J Thorac Cardiovasc Surg 2004; 127(1):114–122. 6. Danovitch GM, Cohen DJ, Weir MR, et al. Current status of kidney and pancreas transplantation in the United States, 1994–2003. Am J Transplant 2005; 5(4 Pt 2):904–915. 7. Mendeloff EN, Huddleston CB, Mallory GB, et al. Pediatric and adult lung transplantation for cystic fibrosis. J Thorac Cardiovasc Surg 1998; 115(2):404–413; discussion 413–414. 8. Date H, Aoe M, Sano Y, et al. Improved survival after living-donor lobar lung transplantation. J Thorac Cardiovasc Surg 2004; 128(6):933–940. 9. Maurer JR, Frost AE, Estenne M, et al. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. J Heart Lung Transplant 1998; 17(7):703–709. 10. Schenkel FA, Barr ML, Starnes VA. Living-donor lobar lung transplantation: donor evaluation and selection. In: Turka LA, ed. Primer on Transplantation. Moorestown, NJ: American Society of Transplantation, 2001. 11. Schenkel FA, Horn MV, Woo MS, et al. Screening potential donors for living-donor lobar lung transplantation. J Heart Lung Transplant 2003; 22(1S):S86.

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12. Bowdish ME, Barr ML, Starnes VA. Living lobar transplantation. Chest Surg Clin N Am 2003; 13(3):505–524. 13. Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000; 284(22):2919–2926. 14. Ellison MD, McBride MA, Edwards LB, et al. Living organ donation: mortality and early complications among 16,395 living donors in the U.S. Am J Transplant 2003; S:Abstract 517. 15. Bowdish ME, Pessotto R, Barbers RG, et al. Long-term pulmonary function after living-donor lobar lung transplantation in adults. Ann Thorac Surg 2005; 79(2):418–425. 16. Montoya A, Mawulawde K, Houck J, et al. Survival and functional outcome after single and bilateral lung transplantation. Loyola Lung Transplant Team. Surgery 1994; 116(4):712–718. 17. Cooper JD, Patterson GA, Trulock EP. Results of single and bilateral lung transplantation in 131 consecutive recipients. Washington University Lung Transplant Group. J Thorac Cardiovasc Surg 1994; 107(2):460–470; discussion 470–471. 18. Schwaiblmair M, Reichenspurner H, Muller C, et al. Cardiopulmonary exercise testing before and after lung and heart-lung transplantation. Am J Respir Crit Care Med 1999; 159(4 Pt 1):1277–1283. 19. Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1999; 340(14):1081–1091. 20. Chaparro C, Scavuzzo M, Winton T, et al. Status of lung transplant recipients surviving beyond five years. J Heart Lung Transplant 1997; 16(5):511–516. 21. Sritippayawan S, Keens TG, Horn MV, et al. Does lung growth occur when mature lobes are transplanted into children? Pediatr Transplant 2002; 6(6):500–504. 22. Wasserman K, Hansen J, Sue D, Whipp B. Principles of exercise testing and interpretation. Philadelphia: Lea & Febiger, 1987. 23. Levy RD, Ernst P, Levine SM, et al. Exercise performance after lung transplantation. J Heart Lung Transplant 1993; 12(1 Pt 1):27–33. 24. Bowdish ME, Barr ML, Schenkel FA, et al. A decade of living-lobar lung transplantation: perioperative complications after 253 donor lobectomies. Am J Transplant 2004; 4(8):1283–1288. 25. Battafarano RJ, Anderson RC, Meyers BF, et al. Perioperative complications after living donor lobectomy. J Thorac Cardiovasc Surg 2000; 120(5):909–915. 26. Date H, Aoe M, Nagahiro I, et al. Living-donor lobar lung transplantation for various lung diseases. J Thorac Cardiovasc Surg 2003; 126(2):476–481. 27. Starnes VA, Barr ML, Cohen RG, et al. Living-donor lobar lung transplantation experience: intermediate results. J Thorac Cardiovasc Surg 1996; 112(5):1284–1290; discussion 1290–1291. 28. Huddleston CB, Bloch JB, Sweet SC, et al. Lung transplantation in children. Ann Surg 2002; 236: 270–276.

Part VII

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LIVING-DONOR INTESTINAL TRANSPLANTATION

Intestinal Transplantation from Living Donors: Specific Issues and Donor/Recipient Evaluation Luca Cicalese Liver and Intestinal Transplantation, Department of Surgery, University of Massachusetts, Worcester, Massachusetts, U.S.A.

BACKGROUND Small bowel transplantation represents the physiologic alternative to total parenteral nutrition (TPN), and it has recently become a valid therapeutic option for patients with intestinal failure, with one-year graft survival rates now higher than 80% (1). However, this procedure is still associated with a relatively high rate of complications. A higher incidence of infections, acute rejection, and post-transplant lymphoproliferative disorder (PTLD) is observed following intestinal transplantation compared with the transplantation of other organs (1–5). These may be, at least in part, the consequence of the peculiarity of this graft that contains gut-associated lymphoid tissue and potential pathogenic enteric flora. Furthermore, in these patients, the existing disease and the relative malnutrition may predispose them to infectious complications. Additionally, other factors associated with the procedure, such as laparotomy, preservation injury, abnormal motility, lymphatic disruption, systemic venous drainage, antibiotic therapy, and the potent immunosuppressive agents can all be implicated in the development of infections in these patients. Most intestinal transplantations have been performed using whole small-bowel grafts obtained from deceased donors. Morris et al. reported the first successful clinical intestinal transplantation performed from a living donor between identical twins (6), whereas the first successful transplant using a human leukocyte antigen (HLA) nonidentical living donor was performed in 1988 (7). During the last decade, several groups worldwide embarked in this procedure, using different approaches and surgical techniques (8–12). However, the experience with living donors is still limited in intestinal transplantation, with only 32 cases reported up to 2003 at the Intestinal Transplant Registry (1). The indications for living donor intestinal transplantation are not different from those for deceased donors. In the cases reported from the registry, the patients were affected by short-gut syndrome secondary to volvulus, ischemia, trauma, and gastroschisis––other indications were desmoid tumor, pseudo-obstruction, and microvillus inclusions (1). Patients transplanted with this technique have been mostly young adults or children; however, older recipients can be considered as well. The widespread use of living donors for intestinal transplant, compared with other organs, has been limited mostly because, at the present time, there is no shortage of deceased intestinal donors. However, optimal deceased donors are not common either, and despite the limited number of patients waiting for a transplant, a long waiting time averaging over 200 days is reported with an associated high mortality rate, especially in pediatric patients (13). In a series of 257 patients evaluated for transplantation in a single center, only 82 (32%) received transplants from deceased donors. Another 120 of 178 listed patients were not transplanted and died awaiting transplantation. Factors predicting death on the list included age less than one year, prior surgical procedures, the presence of bridging fibrosis on liver biopsy examination, bilirubin levels greater than 3 mg/dL, and thrombocytopenia (14). From the European experience, there were similar findings among 42 patients referred for transplantation, with

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death within six months in 90% of short-bowel patients, 50% of those with mucosal lesions, and 40% of those with motility disorders (15). Data from the United Network of Organ Sharing on death rates for candidates awaiting intestinal transplants reported that 86% of deaths were among patients awaiting liver and intestine transplants, of which 83% were children; candidates less than one year old and adults 35–65 years of age had mortality rates three to six times those seen in patients waiting for liver transplantation alone (16). Eighty-six percent of recent pooled data confirm the high death rate of intestinal candidates when compared with those awaiting liver transplantation alone (17). These data suggest that early referral and a shorter waiting time should affect the outcome, and live donation certainly favors this approach. RATIONALE In intestinal transplantation, the driving force in considering the use of live donors is not so much the paucity of deceased donors, as seen in other organs, but the potential advantages available with grafts obtained from such donors. However, several possible disadvantages also exist and should be carefully considered. Potential advantages and disadvantages using intestinal grafts from live donors compared with deceased donors are summarized in Table 1. ADVANTAGES The mortality on the waiting list observed suggests that, despite the existence of a theoretically large number of deceased donors, this is not so true in clinical practice. This is related to strict exclusion criteria in using such donors. Often, family consent is a problem because intestinal transplantation is not well-known in the community, and it is considered experimental. Also, elderly donors are often excluded, in addition to abdominal trauma victims. Donors with extensive down time or hypotension are also not considered, in addition to those who become available at a great distance from the transplant hospital. These exclusions, less commonly seen in the selection of donors for other organs, significantly limit the intestinal donor pool. Additionally, the lack of deceased donors related to religious beliefs or the organization of health care in certain countries play a role. Finally, the diminished need for resources for longterm parenteral nutrition are advantages afforded to a recipient of a live donor intestinal transplant. The advantage in using living donors because of the aforementioned problems is obvious, and the mortality observed in the waiting list could be significantly reduced using this alternative source of grafts. Intestinal grafts are extremely sensitive to preservation injury. In an analysis of 50 pediatric intestinal transplant recipients, it has been shown that the ischemia time was the most significant factor in inducing bacterial translocation (18). This phenomenon can contribute to the high rate of infections seen during the early post-transplant period, and coincides with the timing of maximum amount of immunosuppression given to the patient. Deceased donors are often subject to either an episode of cardiac arrest and resuscitation or to hypotension. This results in splanchnic hypoperfusion that can trigger ischemia/reperfusion

TABLE 1 Potential Advantages and Disadvantages Using Intestinal Grafts from Live Compared with Deceased Donors Advantages Eliminates waiting time in deceased donor list Can be used in countries where TPN and deceased donors are not available Use of hemodynamically stable donor Optimal donor–recipient HLA matching Short cold ischemia time Elective case, allows better donor bowel preparation and optimization of recipient clinical condition Small graft can be accommodated in retracted abdominal cavity Disadvantages Risk for the donor Short graft and smaller vascular pedicle Abbreviations: HLA, human leukocyte antigen; TPN, total parenteral nutrition.

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injury even before the intestine is recovered from the donor. Cold preservation of the obtained graft can also be extended because of the distance between the donor and the transplant hospitals; in addition, specific preservation solutions designed for intestinal grafts are not yet available. Using live donors, these problems can be obviated, as the donor is a healthy individual without hemodynamic instability and consequent recovery graft hypoperfusion. Furthermore, the short cold ischemic time prior to revascularization also improves graft quality, virtually eliminating ischemia/reperfusion injury, and may reduce the rate of post-transplant infections (19). The use of deceased donors is also linked to the need of performing the transplant based on donor availability. This is not always associated with the best timing for the recipient, who might require the optimization of his or her clinical condition when a donor becomes available. Also, the intestine cannot be prepared adequately in the donor as the time is limited between the organ offer and recovery, and also because a multiorgan recovery is often performed in association with deceased intestinal donation related to the overall good quality of these donors. The use of living donors offers an advantage as the recovery is performed as an elective operation; and consequently, the donor bowel preparation and recipient medical conditions can be adequately optimized. Another aspect of intestinal transplantation where the use of living donors might be beneficial is immunologic. The rate of rejection in intestinal transplantation is higher than in any other organ. The grafts obtained from deceased donors have not been HLA matched, mostly because the intestinal grafts were transplanted in association with the liver in the early experience. To date, no scientific information is available in this regard as the donor- and recipient-tissue typing data have not been collected and analyzed in the cases performed. A living donor is often a relative of the recipient because of the strong emotional involvement that justifies the donation. Living related donors are generally better HLA-matched, and this could contribute to an immunologic advantage. This is supported by the experience of HLA-matched transplants performed between homozygote twins (20). This point might be challenged, as in recent times, a significantly decreased rate of rejection has been observed using poorly HLA-matched deceased donors (1). However, this improvement has been accomplished using more potent immunosuppression and antibody induction immunosuppression with monoclonal IL-2 receptor or polyclonal antilymphocyte antibodies, and relatively high levels of tacrolimus (1). A similarly low rate of rejection was seen using living related HLA-matched donors using a less potent immunosuppressive regimen and lower serum target levels of tacrolimus (12). An additional benefit can be offered performing intestinal transplants with living donors at an earlier stage of the disease, as long-term TPN and indwelling venous catheters can be associated with an effect on the immune system (21–23). Early transplantation can also benefit outcome, as evident in the improved survival seen in patients transplanted when waiting at home compared with hospitalized patients (1). The graft transplanted from a deceased donor is usually the whole small intestine with a vascular pedicle consisting of the superior mesenteric artery (SMA) and portal vein or superior mesenteric vein (SMV). The segmental intestinal graft used from living donor is usually between 60 and 200 cm length, and is obtained by the resection of the distal ileum, and has a simple vascular pedicle containing the distal SMA and SMV. This small intestinal mass can be easily accommodated in a small and retracted abdominal cavity, as is often seen in these patients, especially if they have undergone numerous intestinal resection procedures over a long period of time; in addition, adult to pediatric donation is possible because of the size match. Naturally, a reduced size graft from a deceased donor can also be obtained to offer similar advantages, but this is not usually performed. It has been recently suggested that using combined liver/intestine grafts from live donors may offer particular advantages in small infants who have otherwise a high mortality on the waiting list (24). All these benefits could allow an easier management of intestinal transplant recipients and contribute to an improvement in the outcomes of this transplant, but whether HLA matching or reduced preservation times are truly beneficial is unproven and requires further study at the moment.

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DISADVANTAGES Naturally, potential disadvantages are associated with the use of living donors. The main disadvantage is the risk for the donor, which includes the early and late surgical complications of bowel resection and potential long-term impairment of intestinal absorption. The procedurespecific risk for the live intestinal donor is given in Table 2. The risk of perioperative death is probably similar to the risk of general anesthesia, and can be estimated to be approximately 0.03%. Specific data on living intestinal donors are limited at this time, and no serious complications have been reported. The potential risk can be hypothetically calculated looking at the general surgery-related data of small bowel resection, with about 3% to 5% of the donors developing a small bowel obstruction (25–30). In a large series, the mortality rate for patients with small bowel obstruction is approximately 2% for the lifetime of the patient (31). A brief and self-limited period of diarrhea has been reported after intestinal donation (12). Although weight loss and dysvitaminosis are not reported, they represent potential risks of this procedure. Another potential risk is associated with the length of the intestinal graft and the increased risk of vascular thrombosis related to the smaller vascular pedicle used. Although the latter can be circumvented with a careful and accurate surgical technique, the length of the graft and the possible reduced absorptive capacity have not been reported to be the limiting factors as morphologic and functional adaptation occur (32,33––see Chapter 26). In conclusion, live-donor intestinal transplantation is not experimental, but this procedure should be regarded as an innovative and an evolving technology. Because of the evolving nature of this procedure and the paucity of the data available, a recent forum of international experts recommended that the centers performing live-donor intestinal transplantation should submit their protocols for ethical review and report outcomes to the international registry (34). DONOR SELECTION AND EVALUATION Special Considerations The potential donor should be an individual in good health with no underlying chronic medical illnesses that would increase the surgical operative risk. There should be no history of intestinal surgery. Special considerations apply to these donors. Age There are no available data to define the upper age limit for living intestinal donation. Based on published general surgery data on the surgical risk of intestinal resection and on the available clinical experience with intestinal transplants from living donors, a limit of 60 years of age is advisable. The lower age limit is determined by legal age to consent to the procedure. Relationship Living donors are preferentially the relatives of the recipients, but can also be unrelated with a close emotional relationship. This condition and the absence of any financial interest for donation are evaluated by a physician team that is not part of the transplant program.

TABLE 2

Procedure-Specific Risk for the Live Intestinal Donor

Short bowel syndrome Small bowel obstruction 3–8% 3% mortality Dysvitaminosis Weight loss Diarrhea

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Psychosocial Assessment Live intestinal donation should be voluntary without coercion. There should be no psychosocial, ethical issues, or other concerns about the motivations of the donor. The screening process should exclude active or uncontrolled psychiatric disorders, and ensure the altruistic nature of the donation. The institutional ethics committee should separately evaluate the donor to ensure that there is full understanding of the limited information regarding the short- and long-term risks associated with intestinal donation, and that all the steps of the potential donation conform to ethically acceptable principles. Body Mass Index General surgical experience indicates that a high body mass index (>30 kg/m2) may increase the risk of surgical complications after intestinal resection. However, a body mass index of >30 may not affect the graft quality and does not constitute per se an absolute contraindication to live donation. ABO Blood Type Identical or compatible ABO blood type is recommended. Laboratory Blood Tests A comprehensive metabolic panel should be obtained. Blood test results that confirm donor infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) (HBsAg+) are a contraindication for living intestine donation. Recipients with Genetic Disorder Specific consideration must be given for related intestinal donors for potential recipients who have a genetic or familial intestinal disease. Despite the lack of data, it is possible that the related donor might develop the same condition later in life. At the present time, it is advisable not to consider these donors, and eventually, to screen them to rule out the same genetic disorder. Initial Donor Screening and Evaluation Once a potential donor is identified, the initial step should be a meeting with the surgeon to describe the procedure and the steps involved in the work-up. Also a psychosocial evaluation should be performed, as indicated earlier. During this initial visit, the potential donor can be screened with an ABO blood type determination. If this is compatible and the candidate is willing to continue the work-up, an HLA test and histocompatibility testing by T-cell crossmatching should be performed. The crossmatch should be negative, and among multiple donor candidates, the one with the best HLA match should be preferred and should be directed to continue the work-up. This might be particularly important if a presensitized candidate for whom a crossmatch negative donor has been identified. Full Evaluation Once the potential donor has completed these initial steps, the following tests are performed for the live donor evaluation as follows: ■ ■ ■ ■

Physical examination Formal psychosocial assessment Ethics committee evaluation Gastroenterological assessment: ❏ d-xylose and fecal fat absorption studies ❏ screen for Celiac Sprue

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Laboratory tests ❏ Complete blood count (CBC), prothrombin time (PT)/international normalized ratio (INR) partial thromboplastin time (PTT), total protein, and albumin ❏ Liver chemistries, amylase, renal chemistries, random glucose ❏ Vitamin A, D, E, K, and B12 ❏ Ammonia, alpha fetoprotein, lipid profile Infectious disease assessment ❏ Hepatitis screen, HIV, cytomegalovirus (CMV) (IgM and IgG) ❏ Epstein-Barr virus (EBV) (IgM and IgG), varicella zoster virus (VZV) (IgA EIA) ❏ Urinalysis and culture; stool culture Chest radiography (CXR) and electrocardiography (ECG) Imaging studies ❏ Abdominal computed tomography (CT) scan, three-dimensional (3D) angio CT scan ❏ Alternatively, SMA angiogram

Imaging Studies The imaging studies of the abdomen are performed last if the candidate has no contraindications to become a donor. These are performed to rule out underlying or occult pathology, and CT scan, magnetic resonance imaging (MRI), or ultrasound is indicated. Specifically, to delineate the vascular anatomy, either CT or MR angiography is performed with computerized 3-D reconstruction, if available. In case these techniques are not available or inadequate, a traditional angiogram can be performed. However, in this instance, the patients must be informed of the higher risks of this procedure. Angiography is performed to evaluate the SMA to ensure a normal vascular distribution to the small bowel, to exclude atherosclerotic disease and abnormal anatomy. Particular attention is placed on identifying a normal distribution of the right colic and ileocolic arteries with adequate blood supply to the cecum and terminal ileum, and that allows a safe transection of the distal SMA pedicle. If more than one donor is available, patients with a single artery should be preferred to patients with multiple vessels originating caudal to the takeoff of the right colic artery that must be spared during recovery to provide adequate blood supply to the cecum, terminal ileum, and ileocecal valve, as these structures are carefully preserved in the donor (Figs 1 and 2). Responsibility and Duration of Donor Follow-Up The world experience with live intestinal donation is limited. At this time, no donor deaths or long-term complications in intestinal donors have been reported. However, owing to the limited

FIGURE 1 Conventional angiography and computed tomography angiography are used to evaluate the superior mesenteric artery for normal vascular distribution to the small bowel, and a normal ileocolic artery with adequate descending branch of the right colic artery to assess adequate blood supply to the areas of the terminal ileum and ileocecal valve.

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FIGURE 2 Conventional angiography and computed tomography angiography are used to evaluate the superior mesenteric artery for normal vascular distribution to the small bowel, and a normal ileocolic artery with adequate descending branch of the right colic artery to assess adequate blood supply to the areas of the terminal ileum and ileocecal valve.

data available, the center performing the donor procedure should maintain responsibility to ensure long-term medical care of any procedure-related complication in these patients. The recommended minimum follow-up schedule includes a postoperative visit at two and four weeks. There are several risks potentially associated with the procedure and that could occur early in the postdonation period, such as diarrhea, weight loss, dysvitaminosis, and small bowel obstruction, whereas the long-term risk primarily involves small bowel obstruction. Donors should be followed until all procedure-related symptoms have been resolved. The donor team needs to be wary of a B12 deficiency. B12 monitoring can be performed with serum levels at six months and annually for three years. Recommendations In a recent meeting of a group of experts, organized by United Network Organ Sharing (UNOS) in Vancouver, Canada, (34), the intestinal group made the following action plans and recommendations in regard to live-donor intestinal transplant: 1. Creation of a donor registry in conjunction with the existing International Intestinal Transplant Registry. 2. Data collection to study the effect of organ preservation time, and HLA matching results with next International Intestinal Transplant Registry Report. 3. Collect and share with intestine transplant centers the UNOS data on waiting list death/ withdrawals for patients waiting for isolated intestine grafts. Recipient Selection and Evaluation Indications The indication of intestinal transplantation is identical using either a living or deceased donor. This transplant should be considered for patients with irreversible intestinal failure requiring TPN. The most common causes of intestinal failure are “short gut syndrome” related to the loss of over 70% of the native small bowel length (<100 cm of residual intestine) and, less commonly, to defective gastrointestinal (GI) motility and impaired enterocyte absorptive capacity or neoplastic disease. The irreversibility of intestinal failure is based on the length and function of

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TABLE 3 Conditions and Their Frequency Leading to Intestinal Failure and Transplantation in Pediatric and Adult Patients Pediatric

Frequency (%)

Gastroschisis Volvulus Necrotizing enterocolitis Pseudo-obstruction Intestinal atresia Retransplantation Aganglionosis/ Hirshsprung’s Microvillus inclusion disease Short gut syndrome Malabsorption Motility disorders Tumor Other

21 17 12 9 8 8 7 6 5 3 1 1 2

Adults Ischemia Crohn’s Trauma Short gut syndrome Desmoid Motility Volvulus Retransplant Other tumor Gardner’s-fam. polyposis Other

Frequency (%) 23 14 10 9 9 8 7 6 5 3 5

Source: Data from the International Transplant Registry 2003.

the remaining native bowel and its inability to provide sufficient fluid and nutritional support. Intestinal rehabilitation can correct this condition in up to 50% of patients requiring chronic TPN, and should be considered before transplantation (35,36). Conditions leading to intestinal failure and intestinal transplantation are summarized in Table 3. INCLUSION CRITERIA Once a patient with intestinal failure develops these conditions, he or she is not automatically considered an intestinal transplant candidate. TPN is started and intestinal rehabilitation is attempted first. Usually these patients are considered transplant candidates when TPN fails or complications arise. The criteria for inclusion for intestinal transplant are summarized in Table 4. Impending Liver Failure Due to Total Parenteral Nutrition-Induced Cholestasis The clinical manifestations include elevated serum bilirubin and/or liver enzymes, splenomegaly, thrombocytopenia, gastroesophageal varices, coagulopathy, stomal bleeding, or hepatic fibrosis/cirrhosis. Limited Vascular Access This can be consequent to the thrombosis of the major central venous channels, such as jugular, subclavian, and femoral veins. Thrombosis of two or more of these vessels is considered a life-threatening complication and a failure of TPN therapy. The sequelae of central venous thrombosis are the lack of access for TPN infusion, fatal sepsis secondary to infected thrombi, pulmonary embolism, superior vena cava syndrome, or chronic venous insufficiency.

TABLE 4

Inclusion Criteria for Live Donor Intestinal Transplantation

Failed intestinal rehabilitation Total parenteral nutrition (TPN) failure TPN-induced cholestasis and impending liver failure Premalignant (extensive polyposis) or locally aggressive (desmoids) small bowel tumors Limited venous access Frequent line sepsis Frequent episodes of severe dehydration in spite of TPN and fluid supplementation Significant limitation in quality of life owing to TPN restrictions on daily activities

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Frequent Line Infections and Sepsis The development of two or more episodes per year of systemic sepsis, secondary to line infection that requires hospitalization, indicates failure of TPN therapy. A single episode of linerelated fungemia, septic shock, and/or acute respiratory disease syndrome (ARDS) is considered an indication of TPN failure. Frequent Episodes of Severe Dehydration Despite Intravenous Fluid Supplement in Addition to Total Parenteral Nutrition Under certain medical conditions, such as secretory diarrhea and nonreconstructable GI tract, the loss of the GI and pancreatobiliary secretions exceeds the maximum intravenous infusion rates that can be tolerated by the cardiopulmonary system. EXCLUSION CRITERIA Several conditions also preclude intestinal transplant. The exclusion criteria are summarized in Table 5. PREOPERATIVE WORK-UP Once a patient with intestinal failure is considered for a transplant, a specific evaluation should be performed. The purpose of the evaluation is to determine if the patient would benefit from transplantation; to rule out contraindications; and to improve, if possible, the current medical management of these patients. The work-up performed in the recipient is similar for either a deceased donor or live donor. The work-up is performed by a multidisciplinary team consisting of transplant surgeon, gastroenterologist, nutrition specialist, cardiologist, anesthesiologist, infectious disease specialist, psychiatrist, and social worker. A multidisciplinary discussion and presentation of each case is advisable. The following tests are performed: ■ ■ ■ ■ ■ ■ ■ ■ ■

Laboratory tests CXR EKG 12 lead and ECHO CT abdomen with intravenous contrast Barium enema Upper GI with small bowel follow through Gastric emptying study d-Xylose and fecal fat absorption studies Venogram

Laboratory Studies ■

CBC with differential and platelets

TABLE 5 Contraindications for Live-Donor Intestinal Transplant Relative contraindications Age less than six months or greater than 70 years Human immunodeficiency virus (HIV) seropositive Active substance abuse Absolute contraindications Significant uncorrectable cardiopulmonary insufficiency Incurable malignancy Active systemic infections Severe systemic autoimmune disease Acquired immune deficiency syndrome

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Total and fractionated bilirubin, aspartate amino transferase (AST), aladine amino transferase (ALT) alkaline phosphatase, gamma-glutomyl transpeptidase (GGTP) amylase, lipase, electrolytes, blood urea nitrogen (BUN), creatinine, CO2, calcium, phosphorus, magnesium, NH3, total protein (TP), albumin, and glucose Prothrombin time (PT) and activated PTT (aPTT) Blood group system (ABO), and HLA Vitamin A, D, E, K, and B12 Baseline serum citrullin level Ammonia, alpha fetoprotein, lipid profile Serologic testing for: HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), CMV (IgM and IgG), EBV (IgM and IgG), syphilis, VZV (IgA EIA) For pediatric patients also: IgG and IgM titers for herpes, varicella, mumps, measles, and rubella Urinalysis and culture; stool culture Hypercoagulable work-up (i.e., protein C, protein S, antithrombin III, factor V mutation) when indicated

Radiographic Imaging Studies It is imperative to know the anatomy of the recipient pretransplant. If numerous intestinal resections have been performed over a long period of time, often previous medical records are not available or are inaccurate in recording the remaining portion of the intestine and its length after each surgery. Also, intraoperative evaluation of the anatomy is often difficult due to the scarring and adhesions found. Upper and lower GI series with contrast will allow to visualize the portion of residual gut, its position in the abdominal cavity, and its length. It is not uncommon that during a work-up, a longer-than-expected segment of small or large intestine is identified, and this might allow different strategies than transplantation, such as surgical recanalization of the residual intestine and intestinal rehabilitation or different surgical elongation procedures. ACT (or MRI) with contrast is also used to rule out malignancies or other undiagnosed disease. Patency of the upper and lower body veins must be established by venogram. Ultrasound (duplex) is not sufficiently sensitive for this purpose. Thrombosis of these vessels is not uncommon in patients receiving TPN. Thrombosis can cause inability to cannulate the vessels, and can cause superior vena cava syndrome when the inferior vena cava (IVC) is clamped. The patient may have patency only of the femoral veins. Complete lack of venous access could be a contraindication for intestinal transplantation. Electrocardiography and echocardiogram are used to determine the cardiac function and any valvular lesions, and should be accompanied by a cardiologic evaluation and clearance for surgery. Stress test or cardiac catheterization may also be performed if indicated. Additional Diagnostic Procedures Liver biopsy may be indicated in patients with intestinal failure and hepatic insufficiency. TPN-induced cholestatic liver injury can be reversed by isolated intestinal transplant or by restoring intestinal integrity (37). However, in the presence of liver cirrhosis or portal hypertension, a patient with intestinal failure requires a combined liver–intestinal transplant. This can be performed using deceased donor. However, as an option, liver transplant from a deceased donor can be followed by intestinal transplant from a living donor if an intestinal graft is not attainable at the same time. Also, in pediatric patients, combined liver and intestinal transplant from a living donor has been recently reported (24). Further assessment of associated liver disease (portal hypertension, coagulopathy, ascites, hyperdynamic circulation, hepatopulmonary syndrome, and hepatic encephalopathy) should be assessed if indicated. Patients with familial polyposis should be evaluated for the presence of polyps in the remaining portion of the GI tract. Patients with dysmotility disorders may require an assessment of the stomach to evaluate functional abnormalities. Children with pseudo-obstruction may require urologic assessment because as many as a third may have a dysfunctional urinary tract. Children with necrotising entero colitis (NEC) may require a full neurologic and pulmonary

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work-up to exclude the possibility of associated intraventricular hemorrhage and bronchopulmonary dysplasia. REFERENCES 1. Grant D, Abu-Elmagd K, Reyes J, et al. on behalf of the Intestine Transplant Registry. 2003 report of the intestine transplant registry: a new era has dawned. Ann Surg 2005; 241(4):607–613. 2. Adam R, McMaster P, O’Grady JG, et al. European Liver Transplant Association. Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry. Liver Transpl 2003; 9(12):1231–1243. 3. Dharnidharka VR, Sullivan EK, Stablein DM, et al. North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001; 71(8):1065–1068. 4. Caillard S, Lachat V, Moulin B. Posttransplant lymphoproliferative disorders in renal allograft recipients: report of 53 cases of a French multicenter study. PTLD French Working Group. Transplant Int 2000; 13 (suppl 1):S388–393. 5. Loinaz C, Kato T, Nishida S, et al. Bacterial infections after intestine and multivisceral transplantation. The experience of the University of Miami (1994–2001). Hepatogastroenterology 2006; 53(68):234–242. 6. Morris JA, Johnson DL, Rimmer JA, et al. Identical-twin small-bowel transplant for desmoid tumor. Lancet 1995; 345:1577–1578. 7. Deltz E, Schroeder P, Gundalach M, et al. Successful clinical small bowel transplantation. Transplant Proc 1990; 22:2501. 8. Calne R, Friend P, Middleton S, et al. Intestinal transplant between two of identical triplets. Lancet 1997; 350:1077–1078. 9. Jaffe BM, Beck R, Flint L, et al. Living-related small bowel transplantation in adults: a report of two patients. Transplant Proc 1997; 29:1851–1852. 10. Gruessner RWG, Sharp HL. Living-related intestinal transplantation: first report of a standardized surgical technique. Transplantation 1997; 64:1605–1607. 11. Morel P, Kadry Z, Charbonett P, et al. Pediatric living-related intestinal transplantation between two monozygotic twins: a 1-year follow-up. Lancet 2000; 355:723–724. 12. Cicalese L, Rastellini C, Sileri P, et al. Segmental living-related small bowel transplantation in adults. J Gastrointest Surg 2001; 5(2):168–172. 13. Howard L, Heaphey L, Fleming CR, et al. Four years of North American registry home parenteral nutrition outcome data and their implications for patient management. JPEN J Parenter Enteral Nutr 1991; 15:384–393. 14. Bueno J, Ohwada S, Kocoshis S, et al. Factors impacting the survival of children with intestinal failure referred for intestinal transplantation. J Pediatr Surg 1999; 34:27–33. 15. Beath SV, Brooks GA, Kelly DA, et al. Demand for pediatric small bowel transplantation in the United Kingdom. Transplant Proc 1998; 30:2531–2532. 16. Fryer J, Pellar S, Ormond D, et al. Mortality in candidates waiting for combined liver-intestine transplants exceeds that for other candidates waiting for liver transplants. Liver Transpl 2003; 9:748–753. 17 Hanto DW, Fishbein TM, Pinson CW, et al. Liver and intestine transplantation: summary analysis, 1994–2003. Am J Transplant 2005; 5:916–933. 18. Cicalese L, Sileri P, Green M, et al. Bacterial translocation in clinical intestinal transplantation. Transplantation 2001; 71(10):1414–1417. 19. Cicalese L, Sileri P, Asolati M, et al. Low infectious complications in segmental living related small bowel transplantation in adults. Clin Transplant 2000; 14(6):567–571. 20. Berney T, Genton L, Buhler LH, et al. Five-year follow-up after pediatric living-related small bowel transplantation between two monozygotic twins. Transplant Proc 2004; 36(2):316–318. 21. Okada Y, Klein NJ, van-Saene HK, Webb G, Holzel H, Pierro A. Bactericidal activity against coagulasenegative staphylococci is impaired in infants receiving long-term parenteral nutrition. Ann Surg 2000; 231:276–281. 22. Okada Y, Papp E, Klein NJ, Pierro A. Total parenteral nutrition directly impairs cytokine production after bacterial challenge. J Pediatr Surg 1999; 34:277–280. 23. Okada Y, Klein NJ, Pierro A. Neutrophil dysfunction: the cellular mechanism of impaired immunity during total parenteral nutrition in infancy. J Pediatr Surg 1999; 34:242–245. 24. Testa G, Holterman M, John E, et al. Combined living-donor liver/small bowel transplantation. Transplantation 2005; 79(10):1401–1404. 25. Ellozy SH, Harris MT, Bauer JJ, et al. Early postoperative small-bowel obstruction: a prospective evaluation in 242 consecutive abdominal operations. Dis Colon Rectum 2002; 45(9): 1214–1217. 26. Fraser SA, Shrier I, Miller G, et al. Immediate postlaparotomy small-bowel obstruction: a 16-year retrospective analysis. Am Surg 2002; 68(9):780–782.

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27. Matter I, Khalemsky L, Abrahamson J, et al. Does the index operation influence the course and outcome of adhesive intestinal obstruction? Eur J Surg 1997; 163(10):767–772. 28. Menzies D, Ellis H. Intestinal obstruction from adhesions—how big is the problem? Ann R Coll Surg Engl 1990; 72(1):60–63. 29. Ellis H, Moran BJ, Thompson JN, et al. Adhesion-related hospital admission after abdominal and pelvic surgery: a retrospective cohort study. Lancet 1999; 353(9163):1476–1480. 30. Fevang BT, Fevang J, Lie SA, Soreide O, Svanes K, Viste A. Long-term prognosis after operation for adhesive small bowel obstruction. Ann Surg 2004; 240(2):193–201. 31. Miller G, Boman J, Shrier I, Gordon PH. Natural history of patients with adhesive small bowel obstruction. Br J Surg 2000; 87(9):1240–1247. 32. Benedetti E, Baum C, Cicalese L, et al. Progressive functional adaptation of segmental bowel graft from living related donor. Transplantation 2001; 71(4):569–571. 33. Jao W, Sileri P, Holaysan J, et al. Morphologic adaptation following segmental living related intestinal transplantation. Transplant Proc 2002; 34(3):924. 34. Barr ML, Belghiti J, Villamil FG, et al. A report of the Vancouver forum on the care of the live organ donor: lung, liver, pancreas and intestine: data and medical guidelines. Transplantation 2006 Transplatation 2006; 81(10):1373–1385. 35. Fishbein TM, Matsumoto CS. Intestinal replacement therapy: timing and indications for referral of patients to an intestinal rehabilitation and transplant program. Gastroenterology 2006; 130(2 suppl 1):S147–151. 36. DiBaise JK, Young RJ, Vanderhoof JA. Intestinal rehabilitation and the short bowel syndrome part 1. Am J Gastroenterol 2004; 99(7):1386–1395; part 2, Am J Gastroenterol 2004; 99(9):1823–1832. 37. Scolapio JS, Fleming CR, Kelly DG, et al. Survival of home parenteral nutrition-treated patients: 20 years of experience at the Mayo Clinic. Mayo Clin Proc 1999; 74:217–222.

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Living-Donor Intestinal Transplantation: Surgical Technique Luca Cicalese Liver and Intestinal Transplantation, Department of Surgery, University of Massachusetts, Worcester, Massachusetts, U.S.A.

BACKGROUND The transplantation of an intestinal graft from a live donor, by definition, involves the transplantation of a segment of the small intestine. Determining the appropriate length and the anatomic origin of the segmental graft have been issues from the beginning of the early experience. Early attempts have established the approach now used by most surgeons. Blood Supply to the Small Intestine The arterial blood supply to the small intestine is from the superior mesenteric artery (SMA). The basic pattern of distribution of the intestinal arteries generally includes five arteries arising on the left of the SMA above the origin of the ileocolic artery and 11 below that level. Eight additional arteries usually originate from the ileal branch of the ileocolic artery (1). These intestinal vessels branch a few centimeters from the border of the intestine to form arterial arcades connecting the intestinal arteries with one another. Proximally, a single set of arcades is present; distally, there are usually several sets of arcades. These arches form the primary interconnections of the arterial supply. From arches and arcades, the vasa recta arise and pass without cross-communication to enter the intestinal wall. A complete channel may also exist from the posteroinferior pancreaticoduodenal artery that is parallel to the intestine and joins the marginal artery of Drummond of the colon. The terminal ileum, ileocecal valve, and right colon receive blood supply also from the right colic artery and ileocolic artery, often sharing a common origin, connected by the marginal artery of Drummond to the terminal branches of the SMA (Fig. 1). In 5% of the population, blood supply to these structures is guaranteed only by the ileocolic artery as the marginal artery is incomplete (Fig. 1B). The venous drainage of the small intestine is less complex than the arterial vessels, merging in the jejunal and ileal veins, and into the superior mesenteric vein and portal vein. Jejunum or Ileum? In the early clinical experience, both types of grafts were used, either a segment of jejunum or ileum. The choice was linked mainly to two factors––technical and immunologic. From a technical standpoint, the ileum offers the advantage of a larger vascular pedicle if the distal portion of the SMA is used. This vessel can be transected below the takeoff of the right colic artery to avoid hypoperfusion of the terminal ileum, and the preservation of the ileocecal valve in the donor (Fig. 2). At this level, this artery is commonly single, but could also consist of two or more branches. As previously discussed in the donor work-up, the anatomy of the vasculature should be assessed and identified prior to surgery. Additionally, despite the fact that both jejunum and ileum have the ability to adapt following intestinal resection, the ileum has the advantage of allowing structural and functional adaptation (2,3). Despite these advantages, the jejunum has been also used in early experience, particularly for the possible immunologic advantages (4). Evidence exists from small-animal studies that acute rejection is more severe in the ileum (5). However, the vascular distribution to the jejunum makes the operation more complex, as the segmental graft obtained has numerous arterial branches needing multiple anastomoses in the recipient to obtain adequate revascularization for the graft (Fig. 3). Jaffe reported attempts at proximal small bowel transplantation involving complex vascular reconstruction that resulted in vascular complications (4). In addition, the

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FIGURE 1 (A) Vascular supply to the small intestine from the SMA. The terminal ileum, ileocecal valve, and right colon receive blood supply also from the right colic and ileocolic arteries, and are connected by the marginal artery of Drummond. (B) The marginal artery is incomplete in 5% of the population. Abbreviations : *, incomplete marginal artery; CB, colic branches; ICA, ileocolic artery; MCA, middle colic artery; RCA, right colic artery; SMA, superior mesenteric artery.

early clinical experience from the same group did not show an immunologic advantage with the use of jejunal segmental grafts. Optimal Length of the Segmental Graft The length of the human alimentary tract is proven to be surprisingly difficult to measure. The length of the small intestine in deceased donors was reported to be from 10 to 40 feet with an average of 20.5 feet or 624.8 cm (6). In vivo measurements using an intraluminal method provided an average of 8.5 feet or 258 cm (7). This discrepancy is attributed to the postmortem loss of longitudinal muscle tone of the small intestine that can lead to an increase in length, up to 135% in few

FIGURE 2 From a technical standpoint, the ileum offers the advantage of a larger vascular pedicle if the distal portion of the superior mesenteric artery is used. This vessel can be transected below the takeoff of the right colic artery to avoid hypoperfusion of the terminal ileum and ileocecal valve, which are always preserved in the donor.

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FIGURE 3 The vascular distribution to the jejunum makes the operation more complex as the segmental graft obtained has numerous arterial branches needing multiple anastomoses in the recipient to obtain adequate revascularization of the graft.

hours, as shown in animal studies (8). For the purpose of intestinal transplantation, intestinal measurements are performed in a live subject, but being under general anesthesia, the effect of the pharmacologic agents used might affect the intestinal distension, motility, and length (9–12). For these reasons, the calculation of a generic optimal length of small bowel graft to resect can be difficult. In each individual case, the entire small bowel should be measured from the ligament of Treitz to the ileocecal valve, using a sterile surgical tape. Once the length of the entire small bowel is determined in a particular patient under a specific anesthetic agent, a final determination of the segment to be removed is made. Although it is relatively easy to determine when an intestinal segment is too short, the long-term impact to the donor of the resection of a longer segment is unknown. Deltz reported a transplant of a 60-cm segment of distal jejunum and proximal ileum, whereas Morris used a similarly long segment of distal ileum, ileocecal valve, and a portion of the cecum (13,14). Despite these early successes, a length of 60-cm small bowel has been generally inadequate to provide a total parenteral nutrition (TPN)-free condition (13), and resection of the ileum, ileocecal valve, and cecum, can have a negative impact on the function of the remaining donor bowel (e.g., increased transit time, vitamin B12 deficiency) (14). From the short-bowel syndrome literature, a segment of approximately 1 m has been reported to be sufficient to ensure adequate absorption (15). However, this depends on the presence of the ileocecal valve or part of the colon. Considerations in the recipient anatomy also play an important role in determining the length of the intestinal segment to remove in the donor. A recipient with no colon or ileocecal valve, for example, will require a longer segment compared with a patient where these structures are present. Donor safety is of course paramount, and this will determine the upper limit of the length of resection. The resection of a long segment might induce malabsorption and weight loss, and the removal of terminal ileum might induce the malabsorption of bile salts, vitamin B12, and chronic diarrhea. It is clear that the ileocecal valve and terminal ileum should be preserved in the donor, and that the segment of intestine to be removed should be the ileum. Only 20% to 30% of the total length of the small intestine should be resected to minimize risk to the donor, as no data are available to determine the ideal length of the intestine to preserve. The successful use of ileal segments between 150- and 200-cm length has been reported, with no sign of long-term complications in the donors (16). Generally, the expectation is that the adaptation of the residual intestine will take place, compensating for the segment removed, and re-establishing a completely normal functional condition. However, although data exist about post-transplant adaptation in the recipient, such evidence is not yet available in the donor (17,18). Pollard was the first to report the use of a segment of ileum with the distal SMA and vein for a living-related intestinal transplant; however, no information was given regarding the distal terminal ileum and blood supply to the remaining cecum and ileocecal valve (19). Subsequently, Gruessner reported a case describing the surgical technique, with particular attention to preserving these structures (20).

284 TABLE 1

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DONOR Preoperative Orders Preoperative orders are individualized by each transplant center. A mechanical bowel preparation and preoperative intestinal decontamination is performed. A final crossmatch is also performed and stool cultures are obtained. An example of these orders is shown in Table 1. Surgical Procedure A schematic illustration of the donor operation is shown in Figure 4. The donor operation is performed with the patient in a supine position, using a midline incision from approximately 4 cm above the umbilicus to 2 cm above the pubis. The small intestine is inspected and measured from the ligament of Treitz to the ileocecal valve. The terminal ileum is identified, and a mark is placed at 15–20 cm from the ileocecal valve using a silk stitch in the serosal layer. This segment of terminal ileum is preserved and its blood supply is maintained by the ileal branches of the ileocolic artery, usually originating from the right colic artery. The total length of the intestinal segment to be removed is based on the recipient anatomic characteristics and donor total intestinal length. This measurement starts at the previously placed mark proceeding cranially in the ileum, and is marked with another silk stitch in the serosal layer. At this point, the segment of ileum to be removed is identified, and is included between the two marks. A different mark should be used proximally to identify later the orientation of the intestinal graft. The terminal branches of the SMA and vein are identified, and dissected from the surrounding tissue, and identified with vessel loops near the origin of the right colic artery (Fig. 5). The origin of the right colic artery is also identified with a vessel loop. The line of transection of the SMA will be below this point to preserve the right colic artery in order to provide blood supply to the terminal ileum, ileocolic valve, and cecum with its ileocolic branches. Careful inspection by transillumination of the vascular arcades is performed (Fig. 6). The peritoneum of the mesentery is initially scored with electrocautery, and the mesenteric tissue is dissected; the vascular arcades encountered are ligated and divided between silk ties. The line of dissection of the mesentery starts from the marks on the ileum and is directed toward the previously dissected and looped blood vessels. Once all the dissection is performed, the intestinal segment is still vascularized through a triangle of mesentery containing the distal superior mesenteric vessels (Fig. 7). Once the recipient is ready in the adjacent operating room, the intestine is transected using a GIATM stapler. Adequate blood supply to the proximal and the

FIGURE 4 A schematic illustration of the donor operation is shown.

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FIGURE 5 The terminal branches of the superior mesenteric artery and vein are identified and dissected from the surrounding tissue and identified with vessel loops near the origin of the right colic artery.

distal stumps of the ileum is confirmed when it is transected by GIA stapler (Fig. 8). The ileocolic vessels are clamped and transected, and the vasculature of the intestinal segment is flushed using 4°C cold preservation solution on the back table. As the graft is transported to the recipient operating room for transplantation, the vascular stumps in the donor are ligated using nonabsorbable monofilament stick ties. The proximal and distal segments of the ileum are reanastomosed primarily using either a GIA or manual technique. To avoid intraperitoneal spillage of intestinal content, the intestine is clamped using linen-shod noncrushing Doyen clamps closed at 1 to 2 clicks. If manual technique is used, our preference is to use an absorbable monofilament for the mucosal layer and a nonabsorbable monofilament for the seromuscular layer using Lembert or Cushing stitches. A side-to-side technique is preferred to minimize the risk of stenosis. The mesenteric defect should, of course, be closed carefully. The abdomen is then closed using absorbable monofilament for the fascia and a subcuticular skin closure without surgical drainage. Postoperative Orders Postoperative orders are substantially similar to the orders used for a general surgical patient undergoing small intestinal resection. An example of these orders is shown in Table 2. Postoperative Follow-Up The recommended minimum follow-up includes postoperative visits at two and four weeks. There are several risks potentially associated with the donor operation that could occur early in the postoperative period, such as diarrhea, weight loss, dysvitaminosis, and small bowel

FIGURE 6 Careful inspection by transillumination of the vascular arcades is performed.

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FIGURE 7 Once all the dissection is completed, the intestinal segment is still vascularized through a triangle of mesentery containing the distal superior mesenteric vessels.

obstruction, whereas the long-term risk of small bowel resection primarily involves small bowel obstruction. Donors should be followed until all procedure-related symptoms have been resolved. B12 deficiency can be monitored by performing serum levels at six months and annually for three years. Donor data should be collected and submitted to the intestinal transplant registry. RECIPIENT Preoperative Orders Preoperative orders are, again, individualized by each transplant center. Our preference is shown in the preoperative orders exhibited in Table 3. Surgical Procedure A schematic illustration of the recipient operation is shown in Figure 9. The recipient operations for isolated intestinal transplantation from living or deceased donors are not different, except

FIGURE 8 Adequate blood supply to the proximal and distal stumps of the ileum is confirmed when it is transected by GIA stapler.

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for the length of the intestinal graft and the vascular pedicle. These patients can present with a variety of anatomic differences in their native intestine. These can go from the presence of the entire dysfunctional intestine in patients with pseudo-obstruction, to the ultrashort gut syndrome with only a portion of the duodenum intact. In all cases, the anatomy should be wellidentified pretransplantation to evaluate the best surgical approach. The goal of the operation is to re-establish intestinal continuity by transplanting the segment of ileum recovered from the donor. The proximal and distal (if present) segments of intestine in the recipient should be used for the anastomosis. The presence of a segment of colon or ileocecal valve in these patients would decrease the transit time and increase absorption. Often, these patients develop short bowel syndrome as a consequence of multiple surgical resections. In this case, the presence of diffuse intra-abdominal adhesions requires a long and careful dissection to identify vascular and intestinal anomalies. For this reason, we start the recipient operation first and initiate the procedure in the donor in the adjacent operating room only when the recipient anatomy is identified. A midline incision from the xiphoid process to the pubis is used. The operation is carried out to identify the aorta, vena cava, and the proximal and distal intestinal stumps. Once this is accomplished, the graft is removed from the donor and is transported in the recipient operating room. The previously dissected aorta and vena cava are used for the anastomoses. The vein is clamped in its infrarenal portion with a Satinsky vascular clamp. The ileocolic vein is anastomosed end to side with running nonabsorbable monofilament. The mesenteric artery is anastomosed end to side to the aorta after this vessel is also clamped using a vascular clamp. In this case, a running or interrupted anastomosis is performed, depending on the size of the vessel using nonabsorbable monofilament. If the vascular pedicle consists of multiple arteries, they are anastomosed individually. Once the vascular anastomoses have been completed, the intestinal graft is reperfused (Fig. 10). The proximity of the vena cava and aorta allow anastomosis without tension, as the vascular pedicle of the graft can be short. However, an alternative venous drainage, for example, using the portal vein, could also be utilized. Intestinal continuity is immediately re-established anastomosing the proximal end of the graft, previously marked in the donor, to the proximal intestinal stump available in the recipient. Often, this is the duodenum or the proximal jejunum. Care should be taken not to shorten the native intestine unless pseudo-obstruction or motility disorder is present. The intestine is anastomosed using a hand-sewn technique side to side along its antimesenteric border. Our preference is to use absorbable monofilament for the mucosal layer and a nonabsorbable monofilament for the seromuscular layer using Lembert or Cushing stitches. The same is done for the distal portion of the graft if a segment of colon is available. To avoid intraperitoneal spillage of the intestinal content, the intestine is clamped using linen-shod noncrushing Doyen clamps closed at one to two clicks. A temporary loop ileostomy is constructed and is maintained for six months. This is used for endoscopy, stool collection, and the evaluation of the graft mucosa visible in the stoma. Construction of the loop ileostomy is performed after the intestinal anastomoses have been completed, and intestinal continuity is re-established. At this point, a site in the lower quadrant is identified to perform the ileostomy without tension, depending on the length of the mesenteric vessels, the anatomy of the recipient, and the intestinal reconstruction performed. This is performed excising a 2-cm diameter circle of skin followed by a 2-cm incision of the fascia. The muscle fibers are spread and the tips of two fingers should be easily introduced into the opening. The loop should be gently exteriorized using a Babcock clamp, and a rod is introduced in a small opening of the mesentery to keep the loop in position. The anterior wall of the ileum is opened slightly more than 50% of its circumference. The proximal stoma is larger and is kept cephalad. The ileostomy is matured with mucocutaneous fixation using interrupted sutures. Sutures are also used to secure the graft to the peritoneum to prevent herniation, and to help in identifying the proximal and distal end of the ileostomy for future endoscopy. If no colon is available, a permanent end ileostomy is constructed. If possible, this is performed approximately 5 cm to the right of the midline incision and about 4 cm below the umbilicus. The presence of scar from previous surgeries might mandate a different location. The end ileostomy is performed excising a 2-cm diameter circle of skin followed by a 2-cm incision of the fascia. After spreading the muscle, two fingers should be easily introduced into

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FIGURE 9 shown.

A schematic illustration of the recipient operation is

the opening. The distal end of the graft should be gently exteriorized using a Babcock clamp, preserving the marginal artery and with the mesentery cephalad. The end ileostomy is matured with mucocutaneous fixation using interrupted sutures. Intraperitoneal sutures are used to secure the graft to prevent herniation or prolapse of the stoma. Abdominal closure is performed in two layers using nonabsorbable monofilament for the fascia and surgical staples for the skin. If tension exists on the fascia at the time of closure, this should not be attempted to reduce the risk of thrombosis. The skin can be approximated leaving the fascia open. This approach may require a complex plastic reconstruction later (21). The abdominal wall fascia can be alternatively closed without tension using an acellular dermal matrix that has been previously described to be safe in this setting (22). Postoperative Orders Postoperative orders are individualized by each transplant center. Several protocols of immunosuppression can be used. Our preference is shown in the postoperative and transfer orders shown (Tables 4 and 5).

FIGURE 10 Once the vascular anastomoses have been completed, the intestinal graft is reperfused.

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Postoperative Orders for Intestinal Treatment Recipient

(Continued )

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TABLE 4

Postoperative Orders for Intestinal Treatment Recipient (Continued )

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294 TABLE 5

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Transfer Orders from Intensive Care Unit to Floor Room for Intestinal Transplant Recipient

(Continued )

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TABLE 5

Transfer Orders from Intensive Care Unit to Floor Room for Intestinal Transplant Recipient (Continued )

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REFERENCES 1. Michels N, Siddhart P, Kornblith L, et al. The variant blood supply to the small and large intestines: its import in regional resections. J Int Coll Surg 1963; 39:127. 2. Dowling RH, Booth CC. Structural and functional changes following small bowel resection in the rat. Clin Sci 1967; 32:139–149. 3. Thompson JS, Ferguson DC. Effect of the distal remnant on ileal adaptation. J Gastrointest Surg 2000; 4:430–434. 4. Tesi R, Beckj R, Lamblase L, et al. Living-related small bowel transplantation: donor evaluation and outcome. Transplant Proc 1997; 29:686–687. 5. Kimura K, Money S, Jaffe B. The effects of size and site of origin of intestinal grafts on small-bowel transplantation in the rat. Surgery 1987; 101:618–622. 6. Bryant J. Observations upon the growth and length of the human intestine. Am J Med Sci 1924; 167:499. 7. Blankehorn DH, Hirsh J, Ahrens EH. Transintestinal intubation: technique to measure the gut length and physiologic sampling of known loci. Proc Soc Exp Biol Med 1995; 88:356. 8. Reis Van der V and Schembra FW. Lange and Lage des verdauungsrohres beim lebenden. Z Ges Exp Med 1924; 43:94. 9. Reinelt H, Schirmer U, Marx T, Topalidis P, Schmidt M. Diffusion of xenon and nitrous oxide into the bowel. Anesthesiology 2001; 94:475–477; discussion 6A. 10. Akca O, Lenhardt R, Fleischmann E, et al. Nitrous oxide increases the incidence of bowel distension in patients undergoing elective colon resection. Acta Anaesthesiol Scand 2004; 48:894–898. 11. Ogilvy AJ, Smith G. The gastrointestinal tract after anaesthesia. Eur J Anaesthesiol Suppl 1995; 10:35–42. Review. 12. Torjman MC, Joseph JI, Munsick C, Morishita M, Grunwald Z. Effects of isoflurane on gastrointestinal motility after brief exposure in rats. Int J Pharm 2005; 294(1–2):65–71. 13. Deltz E, Schroeder P, Gehbardt H, et al. Successful clinical bowel transplantation. Clin Transplant 1989; 3:89. 14. Morris JA, Johnson DL, Rimmer JA, et al. Identical-twin small-bowel transplant for desmoid tumor. Lancet 1995; 345:1577–1578. 15. DiBaise JK, Young RJ, Vanderhoof JA. Intestinal rehabilitation and the short bowel syndrome part 1. Am J Gastroenterol 2004; 99:1386–1395: part 2, 1823–1832. 16. Cicalese L, Rastellini C, Sileri P, et al. Segmental living-related small bowel transplantation in adults. J Gastrointest Surg 2001; 5:168–172. 17. Benedetti E, Baum C, Cicalese L, et al. Progressive functional adaptation of segmental bowel graft from living related donor. Transplantation 2001; 71:569–571. 18. Jao W, Sileri P, Holaysan J, et al. Morphologic adaptation following segmental living-related intestinal transplantation. Transplant Proc 2002; 34:924. 19. Pollard SG, Lodge P, Selvakumar S, et al. Living-related small bowel transplantation: the first United Kingdom case. Transplant Proc 1996; 28:2733. 20. Gruessner R, Sharp H. Living-related intestinal transplantation: first report of a standardized surgical technique. Transplantation 1997; 64:1605–1607. 21. Tzoracoleftherakis E, Cohen M, Sileri P, Cicalese L, Benedetti E. Small bowel transplantation and staged abdominal wall reconstruction after shotgun injury. J Trauma 2002; 53:770–776. 22. Asham E, Uknis M, Rastellini C, Elias G, Cicalese L. Acellular dermal matrix provides a good option for abdominal wall closure following small bowel transplantation: a case report. Transplant Proc 2006, Transpl Proc 2006; 38(6):1770–1771.

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Living-Donor Intestinal Transplantation: Clinical Outcomes Luca Cicalese and Shimul A. Shah Liver and Intestinal Transplantation, Department of Surgery, University of Massachusetts, Worcester, Massachusetts, U.S.A.

CURRENT STATUS OF DECEASED-DONOR INTESTINAL TRANSPLANTATION Intestinal transplantation has become the treatment of choice for patients with end-stage intestinal failure and life-threatening complications of parenteral nutrition. As the results improve, this procedure is becoming the preferred treatment for intestinal failure, much as kidney transplantation is preferred to dialysis for the treatment of end-stage renal disease. Two factors currently limit deceased donor intestinal transplantation (DDIT) from more widespread application: (i) a shortage of good deceased donor organs that correlates with a high mortality rate on the waiting list, and (ii) high rates of late graft and patient loss because of rejection and infection (1–3). The inability to completely control rejection has resulted in heavier immunosuppression; unfortunately, the consequence of attempting to prevent graft loss has led to sepsis, malignancy, and death in a substantial percentage of patients. Newer immunosuppressive regimens and living donor intestinal transplantation (LDIT) may offer theoretical advantages that could help address these problems. Patients awaiting intestine transplants in the United States have the highest mortality of any group on the waiting list based on the United Network for Organ Sharing (UNOS) registry (4). Although there are a small number of patients on the waiting list for intestinal transplantation, the waiting time is long, averaging 220 days. The mortality on the waiting list for a deceased donor graft is as high as 25% for adult recipients, and 60% for pediatric recipients (2,5), and appears to be highest in the youngest children and older adult candidates. Early referral and LDIT can reduce waiting time, thus decreasing mortality and preventing progression of the complications associated with total parenteral nutrition (TPN) (5,6). UNOS has recently allocated more points to patients waiting for intestine and liver grafts; whether this change in practice will significantly improve mortality rates remains to be seen. Currently, the five-year patient survival rates for all types of intestinal transplants are approximately 50%. In contrast to the dramatic improvement in short-term survival, the long-term survival of grafts in patients who have lived for more than one year has failed to improve (7). Graft rejection and/or infection are still the most common causes of early and late deaths. The surgical techniques for intestinal transplantation were first established in dogs (8–10). Early experiments in rodent, dog, and pig models of intestinal transplantation demonstrated a survival advantage with matching of histocompatibility antigens (11,12). These advantages were subsequently confirmed in mice as well (11,13). Seven attempts were made to transplant the intestine in the 1960s and early 1970s in the precyclosporine era, with limited success. Most failed because of technical complications. It is noteworthy, however, that the longest survivor (76 days after transplantation) during this early period received an human leukocyte antigen (HLA)-identical ileal segment from her sister (14). Current Outcomes of Intestinal Transplantation Over the last 20 years, there has been a remarkable improvement in short-term graft and patient survival rates after intestinal transplantation, and a resulting growth in the application of this procedure (Figs. 1 and 2). Improved outcomes in intestinal transplantation have led to the performance of over 170 cases per year worldwide (2006 estimate). Despite this growth, the

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700

# of Patients

600 500

LD DD

400 300 200 100 0 <= 1990

1991 - 95 1996 - 00 Transplant Era

>2000

FIGURE 1 Growth of living donor and deceased donor intestinal transplantation worldwide by era. Abbreviations: DD, deceased donor; LD, living donor.

experience remains skewed; only 25% of the centers have performed more than 10 cases each. In the United States, only nine centers performed five or more intestinal transplants (15). The Intestinal Transplant Registry contains data on 1292 transplants performed in 1210 patients in 65 centers from 20 countries. Over half of the recipients are still alive today, with the longest patient surviving 16 years with a functioning graft. In the United States, only 65 patients were alive with a functioning graft in 1995, compared with 443 in 2004 (15). The number of patients on the intestine waiting list has more than doubled from 1995 (n = 69) to 2004 (n = 194); 70% of the patients on the waiting list were in the pediatric group (15). The types of intestine transplants performed include small intestine only (44%), liver and small intestine (38%), and multivisceral (18%). There has been an equal gender distribution, and 60% of the transplants have been performed in the pediatric population. The most common indication in both children and adults is short-gut syndrome. Isolated intestine transplant is the most common procedure in adults (56%), while combined liver and intestine is the most frequent type of intestinal transplant in children (50%) (Fig. 3). Table 1 outlines the multivariate analysis of factors associated with accelerated graft failure. Early referral and listing are important to ensure successful outcomes after intestinal transplant: Patients who are called in from home for their intestinal transplant have significantly higher survival rates, regardler of the type of transplant performed (Fig. 4A) (1). Center experience with more than 10 intestinal transplants also leads to improved survival rates (Fig. 4B). Because of the large lymphoid mass in the graft, the use of antibody induction therapy appears to be particularly important after intestinal transplantation (Fig. 4C). Either Campath 1-H or anti-interleukin (IL)-2 receptor antibodies have been shown to improve both graft and patient survival in single center series (1,2,16–18). Combined liver and intestine grafts appear to have a slightly higher survival rate (Fig. 4D), but single center experiences have not always had the same results (2).

FIGURE 2 Comparison of graft survival of all intestinal transplants by era.

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Pediatric

MVT 13.3%

MVT 24.8%

SB/LIV 19.4%

TABLE 1

SBT 55.8%

SBT 36.3

FIGURE 3 Types of intestinal transplants performed for adults and children. Abbreviations: MVT, multivisceral; SB/LIV, small bowel liver; SBT, small bowel alone.

SB/LIV 50.4%

Multivariate Analysis of Factors Affecting Survival After Intestinal Transplantation Graft survival

Grouped transplant yearb Center size: ≤10 transplants Pretransplant status—at home First transplant FK506 alone induction

Patient survival

P value

AFa

P value

AFa

0.0308 0.0530 0.0006 0.0024 NS

0.58 2.11 0.43 0.29 —

NS 0.0530 0.0004 0.0040 0.0098

— 2.14 0.40 0.30 3.92

aLog

normal accelerated failure model. <1990; 1990–1995; 1996–2000; 2000–2005. Abbreviation: NS, not significant.

bGroups:

FIGURE 4 Effect of different factors on patient survival. (A) Pretransplant status. (B) Center size. (C) Type of induction. (D) Transplant type.

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In the pediatric population, survival results have improved steadily over time, with 55% (400/721) of recipients alive today. In patients surviving beyond six months after transplantation, more than 70% enjoy excellent graft function. Improvements in immunosuppressive regimens have led to a significant decline in post-transplant lymphoproliferative disease (PTLD) over time. Infants less than one year old have survival outcomes similar to those older than one year. One-year graft survival in the United States has increased over time and now exceeds 80% (15). Unfortunately, longer-term outcomes have failed to improve over time. No differences were found when conditional survival analyses were performed in three-month, six-month, or one-year survivors grouped according to era, donor type, or graft type. The most common cause of death in recipients surviving beyond one year is sepsis, followed by rejection and lymphoma. Rejection can be a fatal complication for the recipient, or can at least require re-transplantation. This emphasizes the need for prompt diagnosis and control of earlier stages of acute rejection so that severe rejection or graft failure does not take place (19). Intestinal transplantation is a life-saving procedure and can prevent the long-term complications from TPN, such as sepsis, loss of central venous access, thrombosis, and liver failure. In patients with short bowel syndrome and permanent intestinal failure, the survival rate after long-term parenteral nutrition is reported to be 87%, 77%, and 44% at one, two, and five years, respectively (20,21). After intestinal transplantation, one-year patient survival rates of more than 80% are now being achieved. Numerous studies have shown that the quality of life in intestine recipients is excellent, and successful intestinal transplant is less expensive than maintenance home parenteral nutrition (22–24). Based on the International Transplant Registry, more than 90% of the survivors stop parenteral nutrition, resume oral intake, and return to normal daily activities (1,25). LIVE-DONOR INTESTINAL TRANSPLANTATION The potential benefits of live donation must be weighed against the potential disadvantages of LDIT, which include risk to the donor, poorer function, as a shorter segment of the bowel is transplanted, and as there is limited experience to date, largely confined to adolescents and identical twins (2,23). Centers and Demographics of Transplants Performed Of 1292 intestinal transplants performed to date, 41 grafts (3.2%) have come from living donors at 17 centers in seven different countries (Table 2). Living-related intestinal transplants were

TABLE 2

Living Donor Intestinal Transplantation Centers Country

Asia Jinling Hospital, Nanjing Tianjin University Medical Hospital, Tianjin Kyoto University, Kyoto Osaka University Medical School, Osaka Tohoku University Hospital, Sendai Shahid Beheshti Medical University, Tehran Europe Hospitaux Universitaires de Geneve, Geneva University Hospital, Innsbruck Friedrich-Ebert Hospital, Neumunster Addenbrooke’s Hospital, Cambridge St. James University Hospital, Leeds North America University of Illinois at Chicago, Chicago Northwestern Memorial Hospital, Chicago University of Minnesota, Minneapolis University of Massachusetts, Worcester Stanford University Medical Center, Palo Alto Tulane Univ. School of Medicine, New Orleans

China China Japan Japan Japan Iran Switzerland Austria Germany UK UK USA USA USA USA USA USA

Living-Donor Intestinal Transplantation: Clinical Outcomes Tumor Pseudo-obstruction 10% 5%

Re-Tx Other 2% 2%

301

Volvulus 34%

Malabsorption 2% Short Gut Other 2% Crohn's 2%

Ischemia 19%

Gastroschisis 10% Trauma 10%

Necrotizing Enterocolitis 2%

FIGURE 5 Indication for live-donor intestinal transplantation.

performed more commonly in males (male 63%) and in the pediatric population (≤18 years). Volvulus, followed by intestinal ischemia, is the most common indication for live-donor intestine grafts, which is a function of the procedure being performed more commonly in children (Fig. 5). Donors At this time, no donor deaths or long-term morbid complications in intestinal donors have been reported. Only a one- to two-week period of postoperative diarrhea has been described (26). However, this is usually self-limited and does not require aggressive therapy. In our experience, donors maintain their presurgical weight and, in some instances, tend not to gain weight even after increasing their caloric intake during the first few months. This is probably because of an adaptation of the remaining shorter segment of ileum left in the donor. No studies have been published at this time regarding to bowel adaptation or absorption in donors following the donor enterectomy, probably a function of lack of symptoms and an understandable desire to minimize postoperative visits in these otherwise healthy individuals. Additionally, no data have been collected on vitamin absorption. However, even if the distal ileum has been utilized, most of the transplants performed in recent years have been performed with careful preservation of the terminal ileum, which should prevent these problems. Unfortunately, these patients are followed only for a limited time. It has been recently recommended that data on long-term follow-up of these donors should be collected. For example, B12 should be monitored with serum levels at six months, and annually for three years. In addition, recent recommendations have been developed to create a donor registry in conjunction with the existing International Intestinal Transplant Registry to evaluate the longterm risk of the procedure to the donor (27). Recipient Outcomes LDIT is not routinely performed and; therefore, few reports of short- and long-term outcomes exist. The largest series, reported by the University of Illinois at Chicago, included nine patients who underwent transplantation of 150 to 200 cm of terminal ileum proximal to the ileocecal valve. The one- and three- year actuarial patient and graft survival rates were 78% and 67%, respectively (4). No rejection has been documented in six or seven living-donor HLA-matched intestinal grafts during the first year post-transplantation at their institution, and all have achieved good long-term graft function (5,26). Four identical-twin intestinal transplants have been associated with complete recovery of the recipient and with no adverse long-term side effects. Case reports of LDIT at other centers have described outcomes similar to the larger programs (6,28–30). None of the reports of LDIT has described any serious, long-term adverse effects in the donor, and no donor deaths have been reported. Intestinal graft survival has steadily improved over time. Close to half of the patients who have undergone LDIT are currently alive today (21/41; 51%). This is probably an underestimated survival, considering the high rate of failure of the early attempts (historical data). Causes of

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FIGURE 6 (A) Graft and (B) recipient survival comparing deceased and living donor intestinal transplants. Abbreviations: DD, deceased donor; LD, living donor.

death included sepsis (29%), liver failure (5%), rejection (5%), and other causes (10%). Only one patient lost the intestinal graft to vascular thrombosis (2.5%). This suggests that the small vascular pedicle in LDIT is not a significant risk factor for graft loss when compared with deceased donor grafts, as the technical results are at least comparable with those seen with deceased donors (2.5% versus 15–20% graft loss, respectively). Center volume had no effect on graft survival, but this may reflect the small number of procedures performed worldwide. There was no difference in graft survival or patient survival (Fig. 6A,B) when comparing LDIT and DDIT. Historical Data Morris et al. reported the first successful living-donor intestinal transplant, between identical twins (31), while the first successful transplant using a non-HLA identical living donor was performed in 1988 (9). However, many of the early clinical cases of LDIT were plagued by poor function. In one case, only 60 cm of the distal jejunum and proximal ileum was removed and this graft never functioned well (32). In another case, the ileocecal valve was removed along with the terminal ileum, resulting in diarrhea in the donor-related to increased transit times and a vitamin B12 deficiency (31). Two other early cases of proximal small bowel transplantation failed because of vascular complications. In both these cases, recovery of the jejunum necessitated a complex vascular reconstruction of several small jejunal vessels to create a single arterial and venous anastomosis with the recipient vessels with anastomotic vascular stenosis and graft failure (29). Based on this experience, most centers currently prefer to recover a jejunal graft that has a vascular pedicle with a single artery that can be easily anastomosed to the recipient vessels. Rejection and Immunosuppression The rate of rejection in intestinal transplantation from deceased donors has been higher than that observed with other organs, and possible benefits may exist with HLA-matched live donors. Grafts obtained from deceased donors have not been HLA-matched, mostly because intestinal grafts have been at least initially transplanted in association with the liver. However, living-related donors will generally have a better HLA match. This benefit is supported by the experience of intestinal transplants performed between homozygous twins (22). In addition, no rejection has been documented in six or seven living-donor HLA-matched intestinal grafts during the first year post-transplantation by the Chicago group, and have had good long-term graft function (5,26). Rejection was a cause of death in 3.8% of the patients transplanted with deceased donor organs, and 4.8% in patients transplanted with intestinal segments from living donors. However, graft loss was related to rejection in 56% of the transplants performed from deceased donors and 30% in patients transplanted from living donors (2005 registry data).

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To date, no additional data are available, as donor and recipient tissue typing information has not been collected and analyzed. A recent improvement in the rate of rejection has been reported in deceased donor transplants using antibody induction therapy with monoclonal IL-2 receptor blockers or polyclonal antilymphocyte agents and relatively high levels of tacrolimus (1). In the reported clinical experience, most transplants from live donors have been with HLA-matched donors using less potent immunosuppression and lower target levels of tacrolimus (14). Infections Infections seem to affect living donor and deceased donor recipients almost equally. Sepsis was a cause of death in 22.7% of the deceased donor recipients and 29.2% of the the living donor recipients. Graft loss to sepsis occurred in 8.8% of the deceased donor transplants and 0% of the living donor recipients. POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE PTLD is a serious complication of intestinal transplantation, and is related to the heavy immunosuppression that is required to prevent rejection. In living donor transplants, the ability to use a less aggressive immunosuppressive regimen could have a beneficial impact on the incidence of PTLD. The registry data show that PTLD was a cause of death in 2.7% of the deceased donor transplants and constituted 10.2% of the causes of death. In contrast, PTLD was never reported as cause of death in living-donor transplant recipients. The incidence of PTLD in deceased donor transplants is progressively falling, although follow-up in the more recent cohorts is short (Fig. 7). Graft Adaptation Deltz et al. reported a successful transplant of a 60-cm segment of distal jejunum and proximal ileum, and Morris et al. successfully used a 60-cm segment of distal ileum, ileocecal valve, and a portion of the cecum (31,32). Despite these early successes, a length of 60 cm of the bowel is generally inadequate (32). From the short-bowel syndrome literature, a segment of approximately 1 m has been reported to be sufficient to ensure adequate absorption (33) depending on the presence of ileocecal valve or part of the colon. The successful use of ileal segments of length between 150 and 200 cm have been reported, with no sign of long-term complication for either the donors or recipients (29). Furthermore, adaptation of the remaining intestine occurs, compensating for the segment removed, and re-establishing completely normal function. Intestinal grafts show evidence of functional adaptation in recipients (Table 3). This occurs because of a morphologic adaptation characterized by increased length and size of the villi (Figs. 8 and 9) (34). Given the experience reported thus far, it seems that ileal grafts measuring 150–200 cm of the distal ileum (without the ileocecal valve) will provide sufficient nutrient absorption to

50 45 40 35 30 25 20 15 10 5 0 <= 1990

1991-95 SBT

1996-2000 SB/LIV

MVT

>2000

FIGURE 7 Rate of post-transplant lymphoproliferative disease (PTLD) following intestinal transplantation per era. Despite the use of more intense immune suppression in the recent era, rates of PTLD appear to have decreased over time, although we cannot be confident of this finding when using the registry data for analysis as the length of follow-up is different in the four groups. Abbreviations: SB/LIV, small bowel liver; SBT, small bowel alone; MVT multivisceral.

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TABLE 3 Functional Adaptation of the Graft: Absorption Tests Following Living-Donor Intestinal Transplantation

72-Hour fecal fat Three-day fat intake (g) Percent of lipid excreted Stool weight (kg) D-xylose absorption test Two-hour blood (mg/100 mL) Five-hour urine excretion (g) Percent of excretion

Normal

One month

Six months

Twelve months

— 6 0.2–0.3

159.5 64 3.3

112 7 1.6

Not done 6.5 0.5

32–58 4–10 16–40

16 1.2 5

37 3.6 14

29 2.2 9

FIGURE 8 Morphologic adaptation of the intestinal graft mucosa. The mean length of the villi appears to increase immediately post-transplant (left ) to six months after transplantation (right ).

Morphologic adaptation (mean % of increase of villi length) 70 *

60 50

* *

*

40 30 20 10 0 1 week

* p < 0.05 1 month

3 months

6 months

1 year

3 years

FIGURE 9 Morphologic adaptation of the graft mucosa. Measurements of the villi confirm that a mean 50% increase length occurs within six months post-transplant, thus doubling the absorptive surface of the graft mucosa.

achieve independence from TPN, once adaptation is complete approximately six months after transplantation. Ischemic Injury Intestinal grafts are extremely sensitive to preservation injury. In an analysis of 50 pediatric intestinal transplant recipients, it has been shown that the ischemia time was the most significant factor in inducing bacterial translocation (35). This phenomenon can contribute to the high rate of infections seen during the early post-transplant period, and, of course, also coincides with the timing of the maximum amount of recipient immunosuppression. With living donation, this

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problem is obviated, as the donor is a healthy individual who is hemodynamically stable, and this minimizes prerecovery gut hypoperfusion. Furthermore, the short cold ischemia time, limited to a few minutes transports the graft between donor- and recipient-operating rooms, virtually eliminating ischemia/reperfusion injury. This is documented by the fact that mucosal biopsies and zoom-endoscopy evaluation performed early after living donor transplantation show no evidence of ischemic injury (36). Ileal Compared with Jejunal Segmental Graft In the early clinical experience, both jejunum and ileum were used. Jaffe et al. (29) reported attempts at proximal small bowel transplantation involving complex vascular reconstruction, which resulted in vascular complications. Furthermore, the early clinical experience from the same group did not show an immunologic advantage for jejunal grafts. Currently, most transplant surgeons prefer using distal ileal grafts. Cost-Effectiveness A cost analysis in the United States for TPN reveals that the cost per patient in 1992 was approximately $150,000 per year only for supplies, not including the cost of frequent hospitalizations, medical equipment, nursing care, and that the national cost of home TPN for Medicare was $780 million in 1992 (37). The cost of an intestinal transplantation performed from a deceased donor has been analyzed in the United States and varies according to the type of transplant performed. This was estimated in 1994–1998 to average $132,285 for isolated intestinal transplant, $214,716 for combined liver–intestinal transplant, and $219,098 for multivisceral transplants (38). The cost of LDIT was estimated to be $16,000 ± 2000 for the donor work-up and hospitalization, $113,000 ± 26,000 for the recipient hospitalization, $3900 ± 750 for yearly routine follow-up, and $20,000 for the first year, followed by $3000 per year thereafter for immunosuppression (23). Compared with the cost of TPN, LDIT is similar or less expensive, and is also less expensive than deceased donor-isolated intestinal transplant. Quality of Life The quality of life of recipients undergoing LDIT has been evaluated (39–44): before the injury, while TPN-dependent, and following intestinal transplantation (41). The premorbid period was defined as the patient’s normal state of health prior to becoming TPN-dependent. The morbid phase was the period when patients were TPN-dependent. Quality of life was measured with the Quality of Life Inventory (QOLI), designed for transplant recipients, and previously validated in liver transplant patients and in intestinal transplant patients at the Starzl Transplantation Institute at the University of Pittsburgh Medical Center (45,46). These patients, when comparing “before illness” with “during illness” (while on TPN), reported disruption in most areas of their lives, except for marital relationships, medical compliance, and medical satisfaction, which were unchanged from before illness. After transition from TPN-dependence to post-transplant TPN-independence, when comparing post-transplant status with that during illness (while on TPN), patients reported a significant improvement in most areas of quality of life: psychological (less anxiety, less depression, better mental status, decreased stress experience, improved optimism, less impulsiveness and improved control, increased sexuality, and improved coping); physical (better mobility, better appearance, decreased gastrointestinal and genitourinary symptoms, improved sleep, improved energy); and social (more ability to perform and enjoy recreation activities, improved quality of social support, and improved quality of relationships). The patients did not report worsened quality of life in any area. These patients reported that their post-transplant status compared favorably with their pre-illness condition. Of the 26 domains, only five areas of functioning were statistically worse: loss of control, poorer sleep, increased pain and discomfort, poor quality of social supports, and difficulty in parenting. Regarding to employment, all were working full time before becoming TPN-dependent. When they became TPN-dependent, none maintained his or her working status. These data are summarized in Table 4. All these patients recovered their working status, and one also achieved paternity by 36 months after the transplant.

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TABLE 4 Quality of Life Analysis for Recipients of Intestinal Grafts from Live Donors Total parenteral nutrition (TPN) versus pre-TPN-dependance: worse Anxiety P = 0.001 Depression P = 0.001 Drug use P = 0.01 Cognitive/emot. P = 0.01 Mental status P = 0.01 Physical mobility P = 0.001 Appearance P = 0.002 Pain and discomfort P = 0.001 Stress experience P = 0.001 Coping P = 0.01 Finance P = 0.01 Sexuality P = 0.002 Digestive and ur. sx P < 0.001 Sleep P < 0.001 Energy P < 0.001 Optimism P < 0.001 Impulsiveness P < 0.001 Quality relation P = 0.01 Quality social support P = 0.001 Leisure/recreation P = 0.002 Parenting P = 0.01 Post-Transplant versus TPN-dependance: better Depression P < 0.001 Optimism P = 0.001 Dig. and ur. sx P = 0.002 Social support P = 0.002 Coping P = 0.004 Control P = 0.006 Relationship P = 0.006 Energy P = 0.008 Appearance P = 0.009 Stress P = 0.014 Leisure P = 0.015 Mental stat. P = 0.016 Sleep P = 0.026 Sexuality P = 0.027 Physical mo. P = 0.031 Anxiety P = 0.033 Post-Transplant versus pre-TPN-dependance: worse Control P = 0.001 Sleep P = 0.001 Pain P = 0.01 Social support P = 0.01 Parenting P = 0.02

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39. O‘Keefe SJ, Buchman AL, Fishbein TM, et al. Short bowel syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol Hepatol 2006; 4:6–10. 40. Todo S, Reyes J, Furukawa H, et al. Outcome analysis of 71 clinical intestinal transplantations. Ann Surg 1995; 222:270–280. 41. Rovera GM, Sileri P, Rastellini C, et al. Quality of life after living-related small bowel transplantation. Transplant Proc 2002; 34:967–968. 42. DiMartini A, Rovera GM, Graham TO, et al. Quality of life after small intestinal transplantation and among home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 1998; 22:357–362. 43. Abu-Elmagd KM. Intestinal transplantation for short bowel syndrome and gastrointestinal failure: current consensus, rewarding outcomes, and practical guidelines. Gastroenterology 2006; 130: S132–S137. 44. Rovera GM, DiMartini A, Graham TO, et al. Quality of life after intestinal transplantation and on total parenteral nutrition. Transplant Proc 1998; 30:2513–2514. 45. DiMartini A, Rovera GM, Graham TO, et al. Quality of life after small intestinal transplantation and among home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 1998; 22:357–362. 46. Rovera GM, DiMartini A, Schoen RE, Rakela J, Abu-Elmagd K, Graham TO. Quality of life of patients after intestinal transplantation. Transplantation 1998; 66:1141–1145.

Part VIII

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HEMATOPOIETIC STEM-CELL TRANSPLANTATION

Collection, Processing, and Infusion of Adult Hematopoietic Stem Cells (Bone Marrow and Peripheral Blood Stem Cells) Leslie A. Andritsos Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, Tucson, Arizona, U.S.A.

Candace Paprocki University Medical Center, Tucson, Arizona, U.S.A.

Andrew M. Yeager Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, Tucson, Arizona, U.S.A.

INTRODUCTION Adult hematopoietic stem cells (HSCs) are capable of either self-replication or differentiation into mature peripheral blood cells. Although controversy exists regarding the exact phenotype of HSCs, expression of the CD34 antigen on the cell surface is considered a marker of HSCs and their early progeny. Using flow cytometry, CD34+ cells can be enumerated in a single-cell suspension. HSCs are found primarily in the bone marrow, but low levels of CD34+ cells are present in the peripheral blood of healthy adults and children (1). The intent of HSC transplantation (HSCT) is to provide a source of normal CD34+ HSCs that will engraft and repopulate the lymphohematopoietic system of the recipient. TYPES OF HEMATOPOIETIC STEM CELL TRANSPLANTS Hematopoietic stem cell transplantation has been used to treat a variety of both malignant and nonmalignant hematologic disorders. Depending on the disease being treated by HSCT, there are three potential types of HSCTs: (i) autologous, in which the patient receives his or her own HSCs; (ii) syngeneic, in which the patient receives HSCT from a healthy identical twin; or (iii) allogeneic, in which the patient receives HSCT from a related or unrelated HLA-compatible donor. The type of HSCT is determined by factors such as the disease being treated, the patient’s overall health, and donor availability. Autologous HSCT has been effective in patients with malignancies that are sensitive to chemotherapy and may potentially be eradicated by high-dose myeloablative chemotherapy with or without total body irradiation. Allogeneic HSCT is used in patients with hematologic, immunologic, or metabolic disorders, and is usually recommended instead of autologous HSCT in malignancies with lower chemosensitivity and higher potential for relapse, such as poor-risk acute leukemia. The rationale for allogeneic HSCT in hematological malignancies is not only to infuse a graft that is not contaminated by neoplastic cells, but also to harness the potential graft-versus-tumor effect, in which the donor’s immune system recognizes and destroys the recipient’s malignant cells (2). The application of allogeneic HSCT is limited by the requirement for long-term immunosuppression to prevent graft-versus-host disease (GVHD), with the accompanying risks of opportunistic infections. Chapter 28 discusses in detail the rationale for and outcomes of autologous and allogeneic HSCT. Suitable allogeneic donors are identified by their compatibility with the recipient for class I and class II human leukocyte antigens (HLA). Improvements in donor selection by molecular

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identification of HLA antigens and alleles have significantly improved post-transplant survival by reducing the risks of GVHD and graft rejection (3). Most related allogeneic HSCTs are performed from HLA-identical siblings. Most unrelated allogeneic HSCTs may be performed from HLA-compatible adult volunteer donors of either bone marrow or peripheral blood stem cells (PBSCs). Another source of allogeneic HSCs is umbilical cord blood, and this topic is discussed in detail in Chapter 29. ADULT HEMATOPOIETIC STEM CELLS Sources Hematopoietic stem cells for clinical transplantation may be obtained directly from the marrow cavity by aspiration from the posterior iliac crest, or by the collection of HSCs mobilized from the bone marrow to the peripheral blood. The choice of stem cell source depends on both donor and recipient factors, including donor preference, donor comorbidities that would preclude either marrow collection or administration of cytokines for HSC mobilization, and the underlying disease for which the recipient is undergoing HSCT. Because peripheral blood HSC grafts result in a somewhat higher incidence of chronic GVHD, bone marrow grafts are sometimes chosen to treat nonmalignant diseases or those malignant hematological diseases known to be extremely sensitive to the graft-versus-tumor effect. Dose Requirements for Transplantation The HSC product (bone marrow or PBSCs) contains not only CD34+ cells but also additional mononuclear cells such as lymphocytes. Bone marrow collections, but not PBSC products, contain a substantial number of erythrocytes, and PBSC products have a high content of granulocytes. Measures of the adequacy of an HSC graft include in vitro colony-forming assays (e.g., CFU-GM), total number of mononuclear cells, or the total number of CD34+ cells; in clinical practice, the CD34+ cell dose is most commonly used. Wide experience with both autologous and allogeneic HSCTs has shown that a product containing between 2.0 and 8.0 × 106 CD34+ cells per kilogram of recipient weight will consistently result in complete and sustained hematopoietic reconstitution, with neutrophil engraftment first detected within 10 to 14 days after the infusion of HSCs (4). This is considered a reasonably brief and relatively safe duration of cytopenia. Total CD34+ cell doses below 2.0 × 106/kg recipient weight may result in prolonged cytopenias, increasing the risks of infectious complications, bleeding because of thrombocytopenia, and increased erythrocyte transfusion requirements. Paradoxically, allogeneic HSC products containing total CD34+ cell doses greater than 8.0 × 106/kg recipient weight have been associated with inferior outcomes because of increased risks of moderate and severe acute GVHD and extensive chronic GVHD (5). DONOR EVALUATION General Considerations When selecting an allogeneic donor, the transplant team must not only find the most suitable donor available for the recipient but also safeguard the health and safety of the donor. The donor evaluation includes an assessment of overall health and eligibility for collection of either bone marrow or PBSCs, an assessment for presence of potentially transmissible infectious agents, and confirmation of HLA compatibility. Once a potential allogeneic donor is identified, he or she undergoes evaluation at the transplant center (in the case of related donors), or the donor evaluation center (in the case of unrelated volunteer donors). Adult donors must be able to provide informed consent or have consent given by a surrogate medical decision maker. A complete medical history is obtained, and the donor is thoroughly evaluated for any history of malignancy, known or suspected genetic disorders that could be transmitted by HSCs (e.g., thalassemia, sickle cell anemia), and comorbidities that would increase the risk of general anesthesia or granulocyte-colony stimulating factor (G-CSF) administration, such as coronary artery disease with unstable angina, recent acute coronary syndrome, or sickle cell trait (6,7). In addition, a thorough social history is reviewed to identify potential risk factors for transmissible infections, such as skin-breaching procedures

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(e.g., tattoos, body piercings), use of injected drugs, high-risk sexual behavior, residence in areas endemic for malaria or West Nile virus, or exposure to bovine spongiform encephalopathy (BSE). All donors undergo a complete physical examination by a member of the transplant team. Potential PBSC donors are also assessed for adequacy of peripheral venous access for the apheresis procedure (see later). Most centers perform a complete blood count, electrocardiogram, and chest X ray, with additional donor testing as indicated. Female donors of childbearing potential are tested for pregnancy, which is a contraindication to HSC donation. Screening of Donors for Infectious Diseases All HSC donors undergo comprehensive screening for infectious disease markers. These include testing for human immunodeficiency viruses (HIV) 1 and 2, human T-cell lymphotrophic viruses I and II, hepatitis B, hepatitis C, cytomegalovirus, syphilis, Epstein-Barr virus (EBV), and varicella-zoster virus (8). Donor HIV infection is considered an absolute contraindication to donation, while positive hepatitis serologies are relative contraindications to donation, depending on the urgency of the recipient’s situation and availability of other HLA-compatible donors (9). Specific Assessment of Bone Marrow Donors In addition to the previous studies and procedures, assessment of a bone marrow donor includes obtaining a thorough surgical history, paying close attention to any history of adverse reactions to anesthetic agents, and evaluating for potential indicators of a difficult airway such as micrognathia or obstructive sleep apnea. Marrow donors undergo the same preoperative evaluation for noncardiac surgery as other surgical patients, with particular attention to potential cardiac risk factors, personal or family history of a bleeding diathesis, signs or symptoms of chronic pulmonary disease, neurovascular symptoms, or musculoskeletal disorders (10). Although obesity in marrow donors can lead to difficulty palpating the posterior iliac crests, there is variability in ease of palpating the iliac crests in nonobese individuals as well. Therefore, obesity in and of itself is not considered a contraindication to marrow donation. Ultimately, the determination of a potential donor’s eligibility for general or regional anesthesia rests with both the transplant team and the anesthesiologist, and may require additional evaluation such as stress testing to stratify cardiac or other risk factors. COLLECTION OF HEMATOPOIETIC STEM CELLS Bone Marrow Collection Technique Bone marrow collection (“harvesting”) is performed in the operating room under regional or general anesthesia. Under sterile conditions, a small puncture incision may be made in the skin overlying the posterior iliac crest, using a #11 scalpel blade, or the skin may be punctured by the wide-bore bone marrow aspiration needle itself. The aspiration needle is then advanced through the cortical bone into the medullary cavity. Approximately 5 to 10 mL of bone marrow is rapidly aspirated into a syringe that has been flushed with a heparinized solution to prevent coagulation. Rapid aspiration is felt to decrease peripheral blood contamination of the marrow product and increase the yield of HSCs. The same percutaneous puncture site may be used for multiple aspirations by redirecting the aspiration needle to other areas of the posterior iliac crest. However, depending on the cell yield and required cell dose, several percutaneous puncture sites may be needed. Very rarely, the anterior iliac crests and/or the sternum may be used for marrow collection if inadequate cells are obtained from the posterior iliac crests, but these two sites necessarily contribute a minimal number of marrow cells to the final product. The aspirated marrow is placed into a sterile closed collection system, which contains sterile mesh filters that eliminate bone spicules and fat globules from the final product and create a single-cell suspension. The total volume of marrow to be collected from the donor depends on the target dose of nucleated marrow cells per kilogram of recipient weight, and can be estimated from the recipient’s weight and an intraoperative determination of nucleated cell count of the aspirated marrow. To decrease risks to volunteer bone marrow donors, the National

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Marrow Donor Program (NMDP) limits the volume of the marrow collection to no more than 20 mL/kg of donor weight. Enumeration of nucleated marrow cells by standard automated particle counter methods is performed because real-time determination of CD34+ content during collection is not practical, as the flow cytometric procedure takes one to two hours. The adequacy of the marrow collection is ultimately determined by retrospective analyses in the HSC-processing laboratory, where formal quantification of nucleated cells and CD34+ cells is performed. Risks and Postoperative Management Serious complications after marrow donation are rare. Most marrow donors report some symptoms after marrow donation, notably fatigue and pain at the aspirate sites. Symptoms related to general anesthesia, such as postintubation throat soreness and postoperative nausea and vomiting, are also observed. Donors who undergo spinal anesthesia may experience postprocedure headache, hypotension, or syncope. Other commonly reported postoperative symptoms include back pain, especially with sitting, and pain at the site of intravenous catheter insertion. Donors less commonly experience postoperative fever, bleeding at the procedure sites, and rarely, infections at the procedure site. Although uncommon, mechanical injuries can occur during the marrow collection such as nerve or visceral damage, hemorrhage, or direct damage to bone (11). Unless the volume of marrow collected is quite small, as in a large adult donating for a small pediatric patient, most donors are instructed to take oral iron supplements for three months after marrow collection to replete the iron stores lost during donation. Donors rarely require blood transfusion during or after donation, and if this can be anticipated several weeks preoperatively (e.g., need for a large number of nucleated marrow cells on the basis of recipient weight), some transplant centers will arrange for collection and storage of one or more units of autologous donor blood, which can be infused intra- or postoperatively. Peripheral Blood Stem Cell Collection Rationale The bone marrow is obviously the source of HSCs, but the peripheral blood of normal individuals contains CD34+ HSCs at very low levels. The proportion of CD34+ cells in the circulation can be increased, or mobilized, by the administration of chemotherapy (most commonly intravenous cyclophosphamide), hematopoietic growth factors (most commonly G-CSF), chemotherapy followed by growth factors, or other agents known to directly or indirectly inhibit the interaction between stromal derived factor-1 (SDF-1) and its ligand CXCR4, which is increasingly felt to represent the most important anchoring mechanism for HSCs in the bone marrow microenvironment (12,13). These mobilized CD34+ cells, or PBSCs, are then collected by apheresis. For autologous PBSC mobilization, where additional anti-tumor effects may be desirable, the combination of chemotherapy and G-CSF is most often used. For allogeneic PBSC mobilization, to minimize risks of unnecessary chemotherapy administration, G-CSF is usually administered daily for four or five days before PBSC collection by apheresis. PBSCs are currently used for more than 90% of autologous HSCTs in adults and children, and are being increasingly used for allogeneic donation, especially in adults. Advantages of PBSC donation over marrow donation include higher CD34+ cell yields, less potential for tumor contamination of autologous HSC products, and fewer restrictions for comorbidities that would otherwise preclude marrow donation (14). Peripheral blood HSC collection can be performed as an outpatient procedure and does not require general or regional anesthesia. These features may make PBSC collection more palatable to prospective HSC donors than marrow donation. Technique PBSCs are collected by apheresis, which is a sterile, closed-system centrifugation process that separates whole blood into plasma, platelet-rich plasma, buffy coat (in which the HSCs reside), and red blood cells. The buffy coat layer is collected in a sterile transfer pack, and the remainder of the blood and plasma is returned to the patient. Satisfactory apheresis procedures require placement of either two large-bore peripheral intravenous lines, or a central venous apheresis catheter. Most patients undergoing PBSC collection have central apheresis catheters, but most allogeneic PBSC donors undergo apheresis through

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peripheral venous access. For peripheral access, usually one intravenous line is placed in each antecubital vein; one of these lines provides outflow of blood to the apheresis machine, and the other returns the apheresed blood to the donor. Potential allogeneic PBSC donors are assessed for adequacy of peripheral venous access during the initial evaluation process. If a donor lacks sufficiently large veins for peripheral intravenous access or is unable to tolerate prolonged immobilization during the apheresis procedure, a temporary apheresis catheter is placed in the internal jugular or subclavian vein. This procedure not only guarantees venous access for the duration of apheresis, but also allows for greater freedom of movement during the procedure. A single PBSC apheresis session is approximately four hours in adults. During that time, a total of approximately 20 L of blood is centrifuged and is referred to as large-volume apheresis. The total number of CD34+ cells in the collected apheresis product is determined by flow cytometry. The donor may return daily for additional collections until the target dose of CD34+ cells has been met. In allogeneic PBSC transplantation from healthy donors, a single apheresis procedure is usually sufficient to collect an adequate stem cell product. In autologous PBSC transplantation, more apheresis sessions may be needed to attain the target CD34+ cell dose because these patients often have had extensive previous chemotherapy and/or radiotherapy. Risks The risks of apheresis are low. In contrast to bone marrow collection, apheresis does not result in any significant blood loss, as very few erythrocytes are collected in the buffy coat. Some patients may experience bruising or rarely infection at the sites of peripheral venous access. Placement of central venous apheresis catheters is associated with risks of bleeding, pneumothorax, hemothorax, and infection (15). Because a calcium-binding solution (e.g., acid citrate dextrose) is used for anticoagulation of the apheresis product, some patients may experience transient and usually mild symptoms of hypocalcemia, such as circumoral paresthesias, muscle cramps, and rarely, tetany. Hypocalcemia can be treated with intravenous administration of calcium gluconate and/or oral administration of calcium supplements, often in the form of over-the-counter antacids (e.g., Tums®). Thrombocytopenia can occur even after one apheresis procedure, so patients undergoing more than one apheresis session should have platelet levels monitored daily and should receive platelet transfusions as needed. A small proportion of patients (<5–10%) will fail to mobilize adequate numbers of CD34+ cells into the circulation, and in these instances bone marrow collection is performed. PROCESSING OF MARROW OR PERIPHERAL BLOOD STEM CELLS Donated bone marrow or PBSCs may be manipulated ex vivo before infusion for a variety of reasons. The most common ex vivo manipulations include removal of incompatible erythrocytes, depletion of T-cells, selection of CD34+ cells, and cryopreservation. Erythrocyte Depletion As the HLA locus is on chromosome 6, and the ABO blood group locus is on chromosome 9, donor and recipient may be HLA-identical, but differ in major blood groups. ABO incompatibility is classified as either major or minor. In the case of minor ABO incompatibility, type O donor erythrocytes are infused into type A, AB, or B recipients. The donor stem cell product may ultimately produce antirecipient isoagglutinins, but because there is little risk for hemolysis during infusion of donor HSCs, erythrocyte depletion is usually not indicated in these cases. In contrast, major ABO incompatibility refers to infusion of donor erythrocytes that would be destroyed by preformed recipient isoagglutinins, leading to massive and potentially fatal hemolysis. Examples of major ABO incompatibility are infusions of type A, AB, or B erythrocytes into type O recipients, infusion of type A erythrocytes into type B recipients, or infusion of type B erythrocytes into type A recipients (16). In the case of HSCT between ABO-incompatible donors and recipients, the allogeneic bone marrow product must be processed to remove donor erythrocytes. Because they usually contain very low amounts of donor erythrocytes, allogeneic PBSC products do not require further reduction of erythrocyte content after collection. Several methods are used for depletion

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of erythrocytes from bone marrow suspensions, including mechanical cell separators (analogous to apheresis machines), dextran sedimentation, and buffy coat removal; automated cell separators are most commonly used (17–19). It is not necessary to remove all erythrocytes from the product, as up to 20 mL of ABO-incompatible erythrocytes can be infused safely, depending on the recipient’s isoagglutinin titer. T-Cell Depletion and CD34+ Selection T-cell depletion and CD34+ cell selection are used to decrease the risks of acute and chronic GVHD, which can be major limitations to the success and application of allogeneic HSCT. These techniques are usually used when the available donor is haploidentical and/or the risks of GVHD are felt to be prohibitive to transplantation. T-cells are present in both bone marrow and peripheral blood HSC products, and their number may be decreased by a variety of different mechanisms, which may be physical or immunological. Physical methods of Tcell depletion are performed ex vivo and include photoinactivation, counterflow centrifugal elutriation, density gradient centrifugation, and lectin agglutination followed by E-rosette depletion (20). Immunological T-cell depletion may be performed either ex vivo or in vivo. Ex vivo methods may consist of incubating the HSC product with either monoclonal antilymphocyte antibodies, with or without rabbit complement, or immunomagnetic beads specific for T-cells. In vivo T-cell depletion can be achieved by administration of agents directed against T-cells during the preparative regimen, such as monoclonal antibodies (alemtuzumab) or polyclonal rabbit or horse antithymocyte globulin. Advantages of in vivo T-cell depletion include the ease of administration and the lack of requirements for specialized laboratory personnel and equipment for HSC processing. However, HSCT with T-cell depleted grafts carries increased risks of graft rejection, especially in haploidentical transplants, and the potential for the loss of the graft-versus-tumor response, which may increase the risk of relapse (21). T-cell depletion also leads to delayed post-transplant immune reconstitution (22), which increases the risks of serious infections, especially by reactivation of cytomegalovirus (CMV) and EBV. The latter is of importance because post-transplant EBV infection is sometimes associated with post-transplantation lymphoproliferative disorder (PTLD), a type of lymphoma that may necessitate withdrawal of immunosuppression and institution of specific antilymphoma therapy (23). CD34+ cell selection is an alternative method for T-cell depletion. CD34+ cells may be positively selected by passing the product through commercially available anti-CD34 antibodycoated columns or by incubating the unfractionated HSC product with immunomagnetic beads coated with anti-CD34 antibody (24). An advantage of CD34+ cell selection is that fewer HSCs are lost during cell processing. However, the potential long-term risks associated with this form of HSC processing are similar to other methods for in vivo or ex vivo T-cell depletion. Storage and Cryopreservation After collection, HSC products must be stored, whether they are intended for short-term infusion or later use. Allogeneic bone marrow or PBSC products are usually infused without previous cryopreservation and may be stored at 4°C for up to 24 to 48 hours. However, with longer intervals between collection, storage, and infusion, there is progressive loss of HSCs because of degradation. For this reason, most centers will cryopreserve the allogeneic HSC product if infusion of that product is to be delayed for more than 48 hours after collection. During the freezing process, ice crystals form in and around the cells and can cause cell damage and death. Two different mechanisms account for freezing-associated cytotoxicity. Mechanical disruption may occur during rapid cooling because of formation of intracellular ice crystals, and leads to immediate cell death. Increased extracellular osmolality may occur at slower rates of cooling, and cause cellular dehydration and death. As ice crystals form in the extracellular spaces during slow cooling, the decrease in free-liquid-state water increases the extracellular osmolality and results in an osmotic gradient with shifting of free water from the intracellular to the extracellular spaces and ultimately intracellular dehydration (25). Strategies to preserve cell viability during freezing have focused on prevention of dehydration injury at slower cooling rates. Certain solutes may prevent dehydration injury by

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decreasing the concentration of extracellular solutes during ice formation and by decreasing the amount of water incorporated into ice crystals at specific temperatures. Glycerol was one of the earliest compounds that could improve the viability of frozen HSCs. Later studies showed that dimethyl sulfoxide (DMSO), an organic solvent, is a cryoprotectant that rapidly diffuses through the cell membrane and preserves cell viability during freezing and thawing. Other cryoprotective agents include hydroxyethyl starch (HES), plasma proteins, bovine serum albumin, dextran, and saline, but most transplant centers use a 10% solution of DMSO with or without HES for cryopreservation of HSCs (26). INFUSION OF HEMATOPOIETIC STEM CELLS Either cryopreserved or freshly donated HSC products are transported to the recipient’s bedside and infused intravenously, in a manner similar to a blood transfusion. Most infused HSCs migrate to the marrow spaces and begin differentiating into mature blood cells that appear in the peripheral circulation in approximately eight to 14 days. However, this time frame for hematopoietic reconstitution depends on the number of CD34+ cells infused and certain postinfusion medications administered to prevent GVHD, if indicated. The anticipated complications during infusion depend on whether the product is cryopreserved, whether it is marrow or peripheral blood, the content of mature peripheral blood cells, and, in allogeneic HSCT, whether the donor and recipient are ABO compatible. Cryopreserved Hematopoietic Cells Cryopreserved HSCs are thawed in a warm water bath at or near the patient’s bedside. To prevent post-thawing degradation of HSCs, the time between thawing and infusion is minimized and the product is infused as quickly as tolerated by the patient. Side effects of infusion of HSCs cryopreserved in DMSO may be related to the pharmacological effects of DMSO, the presence of lysed erythrocytes or degraded leukocytes, or the presence of other agents used for tumor cell purging or cell processing. These side effects are usually transient and attributed to DMSO-induced histamine release, and include flushing, nausea, vomiting, abdominal cramping, and dyspnea (27). Most patients experience an unusual taste in the mouth that is caused by the pulmonary excretion of DMSO, often described by patients as resembling the taste of creamed corn or garlic. Volume overload may be a significant problem in patients receiving infusions of multiple HSC products. The majority of symptoms related to DMSO infusion can be prevented and/or treated with premedications including acetaminophen, diphenhydramine, and antiemetics, and diuretics may be needed in patients receiving large volumes of HSCs. The infusion rate is determined by patient symptomatology and may need to be decreased in patients who develop intractable or serious side effects. Serious adverse effects may include anaphylaxis or anaphylactoid reactions, bradycardia, or hypotension. For this reason, patients are monitored continuously with telemetry and continuous oxygen saturation monitoring, and nursing personnel are present during all phases of infusion. Serious adverse effects are treated with standard resuscitation techniques and may require temporary interruption of the HSC infusion. However, because of the absolute requirement for marrow repopulation, the infusion is continued or restarted if at all possible. Fresh Hematopoietic Cells Allogeneic bone marrow or PBSC products may be cryopreserved if necessary, but are usually collected, refrigerated, and transported to the recipient’s location for infusion. The marrow product consists of HSCs as well as mature leukocytes, erythrocytes, fat, and other cellular debris. As described before, erythrocyte depletion may be needed in the case of major ABO incompatibility between donor and recipient. After processing, the marrow product is transported to the recipient’s hospital room and infused at the bedside. Side effects during infusion may include symptoms similar to blood transfusion reaction, such as fever, chills, abdominal pain or cramping, back pain, restlessness, apprehension, or chest tightness. These symptoms are more likely to occur when there is major ABO incompatibility between the donor and the recipient, but may occur with any allogeneic HSCT. As with HSCTs using cryopreserved

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products, patients receive premedication with acetaminophen, diphenhydramine, and antiemetics before infusion of fresh HSCs. Marrow products are often large volumes (1500–3000 mL), so patients may require diuretics for volume overload. Other symptoms, particularly dyspnea, may be attributable to infusion of marrow fat or cellular debris. Continuous cardiac and oxygen saturation monitoring are standard procedures, and nursing personnel are present throughout the duration of the marrow infusion. Most side effects are transient and resolve soon after completion of the infusion. As with cryopreserved products, anaphylactoid reactions are possible and are treated with standard resuscitation techniques, with continuation of the infusion if possible. Post-transplant Care Following HSC infusion, patients are managed with supportive care over the ensuing one to two weeks. Most recipients who receive high-dose chemotherapy or radiation develop pancytopenia in the days after HSC infusion and may be at risk for serious infections or bleeding. Most patients require transfusion support during this time. All patients are treated with prophylactic antimicrobials including gram-negative, antiviral, and antifungal agents. Many adverse effects caused by the preparative regimen will begin to resolve when neutrophil engraftment occurs. In most centers, engraftment is defined as an absolute neutrophil count of >0.5 × 109/L and a platelet count >20 × 109/L, which are sustained without transfusion or growth factor support.

REFERENCES 1. Barr RD, Whang-Peng J, Perry S. Hemopoietic stem cells in human peripheral blood. Science 1975; 190(4211):284–285. 2. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300:1068–1073. 3. Hurley CK, Wagner JE, Setterholm MI, et al. Advances in HLA: practical implications for selecting adult donors and cord blood units. Biol Blood Marrow Transplant 2006; 12(Suppl 1):28–33. 4. Pecora AL. Impact of stem cell dose on hematopoietic recovery in autologous blood stem cell recipients. Bone Marrow Transplant 1999; 23(Suppl 2):7–12. 5. Diez-Campelo M, Perez-Simon JA, Ocio EM, et al. CD34 + cell dose and outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation. Leuk Lymphoma 2005; 46(2):177–183. 6. Bensinger W, Buckner W, Rowley S, et al. Treatment of normal donors with recombinant growth factors for transplantation of allogeneic blood stem cells. Bone Marrow Transplant 1996; 17:S19–S21. 7. Kang E, Areman E, David-Ocampo V, et al. Mobilization, collection, and processing of peripheral blood stem cells in individuals with sickle cell trait. Blood 2002; 99:850–855. 8. Human cells, tissues, and cellular and tissue-based products; donor screening and testing, and related labeling. Federal Register 2005; 70(100):29949–29952. 9. Strasser SI, McDonald GB. Hepatitis viruses and hematopoietic cell transplantation: a guide to patient and donor management. Blood 1999; 93:1127–1136. 10. Eagle KA, Berger PB, Calkins H, et al. Perioperative cardiovascular evaluation for noncardiac surgery update. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). http://www.acc.org/clinical/guidelines/perio/update/ periupdate_index.htm. 11. Stroncek DF, Holland PV, Bartch G, et al. Experiences of the first 493 unrelated marrow donors in the National Marrow Donor Program. Blood 1993; 81:1940–1946. 12. Cottler-Fox MH, Lapidot T, Petit I, et al. Stem cell mobilization. Hematology, 2003:419–427. 13. DeClercq, E. Timeline: The bicyclam AMD3100 story. Nat Rev Drug Discov 2003; 2:581–587. 14. Hartmann O, Le Corroller AG, Blaise D, et al. Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas; hematologic recovery and costs. A randomized, controlled trial. Ann Intern Med 1997; 126:600–607. 15. Rowley SC, Donaldson G, Lilleby K, et al. Experiences of donors enrolled in a randomized study of allogeneic bone marrow or peripheral blood stem cell transplantation. Blood 2001; 97: 2541–2548. 16. Kim JG, Sohn SK, Kim DH, et al. Impact of ABO incompatibility on outcome after allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 2005; 35:489–495.

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17. Rosenfeld CS, Tedrow H, Boegel F, et al. A double buffy coat method for red cell removal from ABO-incompatible marrow. Transfusion 1989; 29:415–417. 18. Tsang KS, Li CK, Wong AP, et al. Processing of major ABO-incompatible bone marrow for transplantation by using dextran sedimentation. Transfusion 1999; 39:1212–1219. 19. Larghero J, Rea D, Esperou H, et al. ABO-mismatched marrow processing for transplantation: results of 114 procedures and analysis of immediate adverse events and hematopoietic recovery. Transfusion 2006; 46:398–402. 20. Ho VY, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001; 98:3192–3204. 21. Patterson J, Prentice HG, Brenner MK, et al. Graft rejection following HLA matched T-lymphocyte depleted bone marrow transplantation. Br J Hematol 1986; 63:221–225. 22. Roux E, Helg C, Dumont-Girard F, et al. Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts. Blood 1996; 87:3984–3989. 23. Kuehnle I, Huls MH, Lui Z, et al. CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hematopoietic stem-cell transplantation. Blood 2000; 95:1502–1506. 24. Urbano-Ispizua A, Solano C, Brunet S, et al. Allogeneic transplantation of selected CD34+ cells from peripheral blood: experience of 62 cases using immunoabsorption or immunomagnetic technique. Bone Marrow Transplant 1998; 22:519–524. 25. Karow AM, Webb WR. Tissue freezing. A theory for injury and survival. Cryobiology 1965; 2:99–108. 26. Rowley SD, Feng Z, Chen L, et al. A randomized phase III clinical trial of autologous blood stem cell transplantation comparing cryopreservation using dimethylsulfoxide versus dimethylsulfoxide with hydroxyethylstarch. Bone Marrow Transplant 2003; 31:1043–1051. 27. David NA. The pharmacology of dimethyl sulfoxide 6544. Ann Rev Pharmacol 1972; 12:353–374.

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Applications and Outcomes of Autologous and Allogeneic Hematopoietic Stem-Cell Transplantation Gregory Gerstner Section of Hematology/Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona, U.S.A.

Jennifer Christian Blood and Marrow Transplantation Program, University Medical Center, Tucson, Arizona, U.S.A.

Andrew M. Yeager Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, Tucson, Arizona, U.S.A.

HISTORY AND RATIONALE FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION The first successful allogeneic hematopoietic stem cell transplantation (HSCT) was reported in 1968, when three children with congenital immunodeficiency diseases received bone marrow transplants (BMT) from human leukocyte antigens (HLA)-compatible healthy sibs (1,2). Pioneering studies of Dr. E. Donnall Thomas and colleagues, reported in the early 1970s, showed that BMT from HLA-matched sibs after high-dose chemotherapy and total body irradiation (TBI) could provide long-term, relapse-free survival in patients with refractory acute leukemia (3,4). Experience soon showed that better relapse-free survival occurred when the BMT was carried out in patients with first- or second-remission acute leukemia (5,6). In the late 1970s and early 1980s, allogeneic BMT was established as the only curative therapy for chronic myeloid leukemia (CML) (7). Initially, the vast majority of allogeneic HSCTs used HLA-identical sibling donors, but currently approximately 35% of all allogeneic HSCTs are carried out using unrelated volunteer donors identified through national or international registries. The first studies demonstrating the effectiveness of autologous HSCT in acute myeloid leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma were reported in the mid-1980s (8–10). As a result of its widespread use for the treatment of breast cancer, autologous HSCT surpassed allogeneic HSCT in the mid-1990s, when breast cancer accounted for 40% of all autologous HSCTs (11). However, as the results of randomized trials showed no overall survival benefit in recipients of autologous HSCT for either early or advanced breast cancer (12), the number of autologous HSCTs for breast cancer has decreased significantly and now accounts for less than 5% of all autologous HSCT procedures. In contrast, several randomized trials since the mid-1990s have shown that high-dose therapy and autologous HSCT provide improved relapse-free survival in patients with multiple myeloma compared with conventional therapy (13). Consequently, 30% to 40% of all autologous HSCTs are now performed for multiple myeloma. The initial reports of allogeneic and autologous HSCT universally used bone marrow as the source of hematopoietic stem cells. By the early 1990s, the use of peripheral blood stem cells (PBSCs) for transplantation grew, especially in the autologous HSCT setting. Currently, more than 95% of all autologous HSCTs and more than 50% of allogeneic-related HSCTs are carried out using PBSCs. The main causes of treatment failure differ between allogeneic and autologous HSCT. The major cause of treatment failure in allogeneic HSCT is acute or chronic graft-versus-host disease and opportunistic infections, including cytomegalovirus and invasive fungus (notably Aspergillus). Graft-versus-host disease is an immunological attack by donor immune cells, especially T-cells, against recipient organs and tissues. The fact that graft-versus-host disease occurs in the setting of allogeneic HSCT from HLA-identical siblings indicates that minor

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histocompatibility antigenic disparities are the likely underlying cause of graft-versus-host reactions. In contrast, the major cause of treatment failure after autologous HSCT for neoplastic diseases is failure to eradicate residual tumor in the recipient. The higher relapse rates after autologous HSCT, in part. reflect the absence of cellular antitumor immune responses, which have been well-recognized in the allogeneic setting as graft-versus-malignancy effects and that vary in potency among hematological malignancies treated with HSCT. Rationale for Hematopoietic Stem Cell Transplantation in Neoplastic Diseases The availability of HSCs for infusion allows the administration of high-dose antitumor chemotherapy (with or without TBI) that should eradicate neoplastic cells, but would otherwise be lethal to normal hematopoietic cells. The infusion of fresh or (especially in the autologous setting) cryopreserved HSCs “rescues” the patient from otherwise fatal aplasia resulting from intensive chemo(radio)therapy and restores normal hematopoiesis. In theory, allogeneic, autologous, or syngeneic HSCT could be used to restore hematopoiesis but, in practice, most HSCTs for neoplastic diseases are performed with autologous stem cells because of efficacy and safety considerations. As noted before, in some cancers, especially those of the lymphohematopoietic system, the use of allogeneic HSCT may also provide adoptive cellular immune antitumor responses, the “graft-versus-malignancy” effect. Rationale for Hematopoietic Stem Cell Transplantation in Hematologic, Immunologic, and Genetic Diseases Diseases such as severe aplastic anemia, hemoglobinopathies, congenital cellular immunodeficiency states, and inborn errors of metabolism (e.g., lysosomal storage disorders) are characterized either by defective or deficient hematopoietic and/or lymphoid cell populations or by cells that lack specific metabolic activity (e.g., deficiency of a certain lysosomal hydrolase or other enzymes). The goal of HSCT is to eradicate the defective/deficient lymphohematopoietic system with chemoradiotherapy and to repopulate that system with normal cells. Insertion of functional genes into nonfunctioning autologous stem cells may be a promising approach for some of these disorders, as shown by correction of X-linked severe combined immunodeficiency syndrome (SCIDS) by infusion of genetically modified autologous stem cells containing the common cytokine gamma chain gene (14). For most hematologic, immunologic, and metabolic disorders, however, the practical approach warrants HSCT with cells from related or unrelated normal allogeneic donors. A more recent application of this rationale is in the use of autologous HSCT for the treatment of severe autoimmune diseases that are not controlled with conventional immunosuppressive treatment, in which the goal of HSCT is to eradicate a dysregulated immune system by administration of high-dose immunosuppressive and cytoreductive agents, and then to infuse immunologically naïve lymphohematopoietic stem cells for reconstitution of a normally responsive immune system. PREPARATIVE REGIMENS FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION Conventional Myeloablative Regimens Patients undergoing HSCT require a preparative regimen. Conventional HSCT requires that the preparative regimen provides antineoplastic and/or myeloablative effects and, in the case of allogeneic HSCTs, provides satisfactory immunosuppression of the recipient to decrease the risk of graft rejection (host-versus-graft reaction) (15,16). The most commonly used myeloablative preparative regimens include combinations of high-dose chemotherapy, such as busulfan plus cyclophosphamide, or high-dose chemotherapy, such as cyclophosphamide, melphalan, etoposide, or cytarabine, with TBI. Some randomized studies have compared outcomes of HSCT after different preparative regimens. For example, the combination of busulfan plus cyclophosphamide has been shown to be as effective as cyclophosphamide plus TBI in patients with acute myeloid leukemia receiving HLA-matched allogeneic HSCT (17). Another polychemotherapy regimen, commonly used before autologous HSCT in Hodgkin’s disease and nonHodgkin’s lymphoma, combines BCNU (carmustine), etoposide, cytarabine, and melphalan (the BEAM regimen). Most autologous HSCTs for myeloma are carried out after single-agent

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high-dose melphalan. In addition to myeloablation or profound myelosuppression, conventional preparative regimens have substantial extramedullary toxicities, including mucositis, idiopathic pneumonitis, hepatic veno-occlusive disease, sterility and, in young patients, growth retardation (18). These regimen-related toxicities are substantial enough to exclude elderly patients, patients with comorbidities, and patients who have had previous HSCTs from eligibility for conventional myeloablative allogeneic HSCT. Nonmyeloablative Regimens The allogeneic graft-versus-tumor effect and the observation that gradual, complete, and durable allogeneic donor cell engraftment can occur after an immunosuppressive but not myeloablative preparative regimen have resulted in a paradigm shift in allogeneic HSCT. A growing number of allogeneic HSCTs from related or unrelated donors are being carried out with nonmyeloablative reduced-intensity preparative regimens (19). Instead of providing myeloablation and intensive antineoplastic activity, the goal of the nonmyeloablative preparative regimen is to provide sufficient immunosuppression to prevent host rejection of the allogeneic HSCT and thus to allow engraftment of those donor cells. In time, those donor cells will provide a graft-versus-tumor immune response. Not surprisingly, many of the toxicities seen after conventional myeloablative regimens are either less severe or nonexistent in recipients of nonmyeloablative preparative regimens. The reduction in regimen-related toxicities now allows some patients to undergo reduced-intensity allogeneic HSCT who would not have been candidates for conventional HSCT because of increased age, organ dysfunction, or previous HSCT. Currently, popular nonmyeloablative regimens include low-dose (e.g., 200 cGy) TBI with or without fludarabine, or the combination of fludarabine and melphalan. OUTCOMES OF HEMATOPOIETIC STEM CELL TRANSPLANTATION Hematologic Malignancies Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL) is more common in children, especially those aged five years or less, but is also seen in adults. Cures of ALL can be obtained with chemotherapy regimens alone in about 70% of the children but fewer than 30% of the adults. The probabilities for long-term relapse-free survival with conventional chemotherapy alone are worse for patients with T-cell lineage or Philadelphia chromosome-positive ALL, who have decreased response rates and higher relapse rates. HSCT is carried out for high-risk ALL in first remission or for ALL in second (or sometimes subsequent) remission. Because of limited efficacy, few autologous HSCTs are now performed for ALL outside of experimental protocols. Most series show that the overall survival after related donor allogeneic HSCT for first-remission high-risk ALL or second-remission standard-risk ALL is about 50%, with relapse rates of 25% to 35% and transplant-related mortality (TRM) of 20% to 25%. When patients with high-risk ALL undergo allogeneic HSCT in second remission, the event-free survival decreases to 25% to 30% and the relapse rate increases to 35% to 50% (20). Results of unrelated allogeneic HSCT are encouraging, but survival is compromised by higher risks of TRM. Recent studies have also begun to evaluate the role of nonmyeloablative stem cell transplants for ALL, which is appealing, given the potential long-term toxicities of conventional myeloablative regimens in children and the second peak incidence of ALL in the elderly. As with conventional myeloablative HSCTs for ALL, high relapse rates also appear to be a challenge after reduced-intensity HSCT. Acute Myelogenous Leukemia Acute myelogenous leukemia (AML) accounts for nearly 90% of acute leukemia in adults, and the median age at diagnosis is approximately 70 years. There are several phenotypic/genetic variants of AML, but cytogenetics is the most sensitive prognostic factor (21). Additionally, AML that arises from an antecedent myelodysplastic syndrome or is secondary to previous myelotoxic chemotherapy (secondary, or therapy-associated, AML) has an especially poor prognosis. Both allogeneic and autologous HSCTs for AML have been studied, and each has demonstrated durable remissions and cures. Currently, allogeneic HSCT in first remission is the preferred modality for patients under age 60 who have high-risk AML by cytogenetic features and who have HLA-matched related donors. In that setting, long-term relapse-free survival is

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approximately 40% to 50%, and the relapse rate is approximately 15% to 20%. For patients who lack HLA-matched related donors, autologous HSCT in first remission may be associated with relapse-free survival of 20% to 35% but with relapse rates of 50% to 60%. Several prospective studies have shown the superiority of allogeneic HSCT over autologous HSCT in terms of longterm relapse-free survival, and superiority of either allogeneic or autologous HSCT over conventional chemotherapy alone. Nonmyeloablative transplants are of great interest in AML, given the median age at diagnosis and its overall higher prevalence compared with ALL (19). Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL; also called small lymphocytic lymphoma) is often an indolent lymphoproliferative disorder involving clonal B-cells. Patients with high-stage (Rai III–IV) CLL often have an aggressive course and median survival of nine months. CLL can also transform to more aggressive types of leukemia and lymphoma. As most cases of CLL are not aggressive, front-line therapy is more conservative, with low-toxicity medications such as chlorambucil. More aggressive frontline treatments include alkylating agents and fludarabine. Despite the apparent clinical response of many patients to chemotherapy, few achieve complete remission. It is unclear which patients are best suited for HSCT. Younger patients who have failed chemotherapy have fewer options and would seem to be good candidates. However, no definitive studies have shown the superiority of allogeneic HSCT over autologous HSCT. Outcomes have varied widely, with overall (not event-free) survivals reported as 40% after allogeneic HSCT and ranging from 20% to 85% after autologous HSCT. The advanced age of this patient population, adverse selection (i.e., advanced and often chemorefractory CLL), and the high TRM associated with conventional allogeneic HSCT are factors to consider in evaluating these data. However, given the high TRMs (especially with unrelated HSCT), allogeneic HSCT with conventional preparative regimens remains as salvage therapy for patients with aggressive CLL and is not appropriate for younger patients with low-grade, indolent disease (22,23). The graft-versus-CLL effect has been demonstrated in several series, so that the application of nonmyeloablative HSCT in this patient population may be attractive. Chronic Myelogenous Leukemia Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder with a characteristic cytogenetic abnormality, the 9:22 translocation (Philadelphia chromosome; Ph), and the product of this translocation, the bcr-abl kinase. The recent discovery of imatinib (Gleevec), a targeted therapy against bcr-abl gene product, has revolutionized the treatment of CML and has led to a reassessment of the role of and timing of allogeneic HSCT for this chronic leukemia. Before imatinib, allogeneic HSCT was uniformly recommended for young patients with CML in the first chronic phase; five-year survival reported by the Center for International Blood and Marrow Transplant Research (CIBMTR) in such patients was 75% after related allogeneic HSCT and 50% after unrelated allogeneic HSCT. Allogeneic HSCT has been less effective for CML in accelerated phase or blast crisis. In contrast, no studies have consistently shown effectiveness of autologous HSCT for CML. Although imatinib can lead to sustained hematologic, cytogenetic, and molecular remissions of CML, resistance to this agent is also well recognized. Preliminary data suggest that patients who have failed imatinib are not at high risk from TRM following salvage treatment with allogeneic HSCT. The fact that CML is the prime example of graftversus-malignancy effect suggests that this disease would be an excellent one in which to evaluate nonmyeloablative HSCT. Indeed, one study has shown an encouraging 85% event-free survival in patients with CML in first chronic phase who underwent allogeneic HSCT after a reducedintensity regimen (24). Non-Hodgkin’s Lymphoma Low-Grade Non-Hodgkin’s Lymphoma

Low-grade lymphomas (follicular lymphomas) are indolent diseases with a median survival of at least nine years, but are usually incurable with conventional chemotherapy. HSCT offers the possibility of long-term disease control in these patients. Although initial responses are similar after allogeneic or autologous HSCT, the TRM is higher after allogeneic HSCT (30–40%) than after autologous HSCT (5%), and the relapse rate is higher after autologous HSCT (25). The fact

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that marrow involvement is common in low-grade lymphoma has been suggested as one reason for higher relapse rates after autologous HSCT in that disease. There is some controversy about the timing of HSCT in low-grade lymphoma. For older patients whose life expectancy does not exceed that of their disease, transplant offers little advantage over conventional chemotherapy. However, responses are better when patients undergo HSCT in first remission rather than later in the course of the disease. There is a risk of secondary myelodysplastic syndrome (MDS) in recipients of autologous HSCT for low-grade lymphoma, and this too must be factored into the treatment decision and timing of transplant. The limited data on unrelated allogeneic HSCT in low-grade lymphoma describe higher risks of TRM, which contribute to a lower survival after unrelated HSCT (30%, compared with 60% after related allogeneic HSCT). Studies are in progress to evaluate nonmyeloablative allogeneic HSCT for low-grade lymphoma, with encouraging survival (26). Intermediate and High-Grade Non-Hodgkin’s Lymphoma

Included in this category are mantle cell, diffuse large B-cell, and Burkitt’s lymphoma, as well as lymphoblastic and other T-cell lymphomas. In contrast to low-grade lymphoma, the intermediate/high-grade lymphomas are much more aggressive. As marrow involvement is less common in intermediate/high-grade lymphoma, results of autologous HSCT are encouraging in high-grade non-Hodgkin’s lymphoma. Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) indicate that overall survival after autologous HSCT for diffuse large B-cell lymphoma (DLBCL) in first remission is approximately 70% at five years, and in patients who never attained remission is approximately 45%. Patients undergoing autologous HSCT in second complete remission have relapse-free survival of 40 to 50% (12,27). Related or unrelated allogeneic HSCT for intermediate/high-grade lymphoma has been associated with high TRM, related to conventional preparative regimens, but low relapse rates, consistent with a graft-versus-lymphoma effect. In general, allogeneic HSCT is reserved for patients whose lymphomas relapse after autologous HSCT, and a growing number of these transplants are carried out with nonmyeloablative regimens (28). Data for highly aggressive lymphomas like Burkitt’s and lymphoblastic lymphoma are much more limited, and decisions on the type and timing of HSCT are made primarily on a case-by-case basis. Hodgkin’s Disease Hodgkin’s disease has a bimodal age distribution, with peak incidences at ages 20 to 30 and then after age 50. Although cure rates are high with conventional therapy in patients with favorable stage I/II disease (approximately 90% at five years), the cure rate is 50% in patients with advanced stage III/IV disease, and a substantial proportion of patients with stage III/IV Hodgkin’s disease never attain remission, or experience relapse. Autologous HSCT has been extensively evaluated in patients with recurrent or refractory Hodgkin’s disease, and five-year survival rates have been reported as 70 to 80% and 40 to 50% after autologous HSCT in first and second remission, respectively. Encouraging results have also been observed when autologous HSCT is carried out in first chemosensitive relapse. Much of the experience with autologous HSCT for Hodgkin’s disease is with the BEAM preparative regimen. Allogeneic HSCT has been reserved for relapses after autologous HSCT or for refractory disease, and it is this patient population in whom reduced intensity regimens are now being explored (29). Myelodysplastic Syndromes Myelodysplastic syndromes (MDSs), which are characterized by cytopenias and ineffective hematopoiesis, are most often seen in older patients [approximately 75% of patients with MDS are over the age of 60 (30)]. Because of the clonal nature of MDS, autologous HSCT is not effective. Most allogeneic HSCTs for MDS have been carried out in younger patients, using myeloablative regimens, although the application of nonmyeloablative regimens and allogeneic HSCT is now being studied in some older patients (who represent the bulk of MDS patients). Several studies indicate that the event-free survival after related or unrelated allogeneic HSCT is 35% to 50% in patients with early-stage MDS (refractory anemia, or refractory anemia with ringed sideroblasts) and 25% to 35% in patients with advanced MDS, with lower event-free survival in recipients of unrelated HSCTs. A recent decision analysis report indicates that

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delaying allogeneic HSCT in patients with low- or intermediate-1 MDS scores [using the International Prognostic Scoring System (30)] until later in the course of the disease but before progression to acute leukemia is associated with prolonged survival, whereas immediate allogeneic HSCT is recommended for patients under age 40 with intermediate-2 or high-risk MDS scores (31). Nonmyeloablative HSCTs for MDS have met with early success in significantly reducing transplant-related mortality and show promising early survival outcomes. Multiple Myeloma Multiple myeloma is a clonal proliferation of neoplastic plasma cells in the bone marrow with the production of monoclonal protein, often with anemia, thrombocytopenia, lytic bone lesions, and renal insufficiency. Median survival with conventional treatment ranges from 29 to 62 months, depending on the stage of the disease (I, II, or III). Multiple studies have shown that autologous HSCT after initial induction treatment (e.g., vincristine, doxorubicin, and dexamethosone, or thalidomide and dexamethasone) provides significantly greater time to disease recurrence/progression than conventional therapy alone. The current standard of care for most patients with myeloma incorporates autologous HSCT, usually after a preparative regimen of high-dose melphalan. However, it is important to point out that the autologous HSCT is not curative, and the fiveyear overall survival after transplant is approximately 45% (15,32). Some experts recommend that patients receive post-transplant maintenance therapy with agents like thalidomide. The use of a nonmyeloablative allogeneic HSCT as planned therapy after initial autologous HSCT, or as salvage therapy following relapse of myeloma after autologous HSCT, is another approach being evaluated to improve long-term relapse-free survival in patients with myeloma (33). Other Clonal Lymphohematopoietic Disorders Amyloidosis

Primary systemic amyloidosis (AL) is a disorder in which aberrant plasma cells deposit abnormal proteins (amyloid fibrils) into various tissues and organs, leading to organ dysfunction. Standard chemotherapy increases median survival from about one to two years. With autologous HSCT, the overall survival at three years ranges from 50% to 75%, with stabilization or reversal of organ dysfunction. The TRM in earlier reports of autologous HSCT for AL was high (20–40%), leading to more stringent criteria for patient selection based on the number and severity of organs involved by amyloid deposition. Patients with two or more organs involved or with severe cardiomyopathy are poor candidates for transplant, while patients with one or two organs involved have low TRM and are much better candidates for autologous HSCT. High-dose melphalan, with doses decreased in patients with more organ dysfunction, is the mainstay of the preparative regimen for autologous HSCT in AL (34). Myeloproliferative Syndromes

Myeloproliferative syndromes such as myelofibrosis, essential thrombocythemia (ET), and polycythemia vera (PV) have been treated with allogeneic HSCT. Data are limited in transplants for ET and PV secondary to their extremely chronic nature. In patients with myelofibrosis, allogeneic HSCT has been associated with overall survival of 88% in early-stage disease and 35% in more advanced disease (35). Hematologic Disorders Severe Aplastic Anemia Severe aplastic anemia (SAA) has a high mortality rate, with most deaths caused by bleeding and/or infection, if treated with supportive care alone (16,36,37). Treatment with immunosuppressive therapy (e.g., cyclosporine, steroids, and antithymocyte globulin) may lead to some responses, but recipients of immunosuppression alone are at risk of development of clonal hematopoietic disorders like MDS decades later. Allogeneic HSCT may be curative in patients with SAA, with 80% to 90% survival after related HSCT and 40% to 60% survival after unrelated HSCT. In general, young patients with SAA who have HLA-matched siblings should undergo allogeneic HSCT without a trial of immunosuppression. Those patients who are older and/or lack an HLA-identical related donor should have a trial of immunosuppression with

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cyclosporine and antithymocyte globulin, and unrelated allogeneic HSCT would be reserved for patients whose hematologic status does not improve after a course of immunosuppressive therapy. Limiting transfusions is important to prevent alloimmunization and graft rejection in those patients who do fail conservative measures and require transplantation. Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoietic disorder with a broad spectrum of clinical presentations. In addition to episodic hemolysis and hemoglobinuria, patients with PNH may develop thromboses, bone marrow failure, and recurrent infections. Standard management consists of transfusions and long-term anticoagulation therapy. Allogeneic HSCT may be curative in patients with PNH that is not well-controlled with standard therapy, and is definitely indicated in patients with PNH who develop severe aplastic anemia (38). Approximately, 50% of the patients with PNH are long-term survivors after allogeneic HSCT. Unrelated allogeneic HSCT (39) and nonmyeloablative preparative regimens (46) also have been used successfully to treat PNH. Hemoglobinopathies Allogeneic HSCT is the only curative treatment for thalassemia major. Proceeding with transplant before patients develop sequelae of iron overload from chronic transfusions, such as hepatic fibrosis or cardiac dysfunction, is associated with decreased TRM and improved overall survival. Both related and unrelated HSCTs have been carried out for thalassemia major (40). The experience with allogeneic HSCT is more limited in patients with high-risk sickle cell disease (i.e., those who have had cerebrovascular accidents, recurrent acute chest syndrome, or recurrent vaso-occlusive pain crises). Event-free survival exceeds 85%, but graft rejection (host-versus-graft) had been reported in approximately 10% of the children with high-risk sickle cell disease who underwent allogeneic HSCT from HLA-identical siblings (41,42). There are very limited data on the use of unrelated allogeneic HSCT to treat high-risk sickle cell disease, although unrelated cord blood cell transplantation has been successful in a small number of cases. Congenital Immunodeficiency Syndromes Congenital cellular immunodeficiency states may exist as pure lymphopoietic defects (such as SCIDS) or in combination with hematopoietic abnormalities (such as Wiskott-Aldrich syndrome and Chediak-Higashi syndrome). Pure B-cell immunodeficiency states can be managed with intravenous immunoglobulin infusions and, in general, are not treated with allogeneic HSCT. Allogeneic HSCT from HLA-identical siblings is highly effective in SCIDS, with 60% to 90% long-term survival. In most cases, a preparative regimen is not required because the SCIDS recipient cannot mount a host-versus-graft reaction. After HSCT, functional host-derived T-cells and, to a slightly lesser degree, B-cells are promptly reconstituted and fewer than 10% of SCID patients require long-term supplementation with intravenous immunoglobulin. The use of T-cell-depleted haploidentical parental HSCT has been shown to be effective in patients with SCIDS who lack healthy HLA-matched sibs (43). Unrelated allogeneic HSCT has also been shown to reconstitute immune function in infants and children with congenital immunodeficiency syndromes, although the survival is lower (approximately 50%) than after matched sibling allogeneic HSCT, largely as a result of fatal complications of graft-versus-host disease (44). Inborn Errors of Metabolism Allogeneic HSCT is the only known cure for lysosomal storage diseases, such as mucopolysaccharidoses and sphingolipidoses, or for adrenoleukodystrophy, which is a demyelinating disorder characterized by accumulation of high levels of saturated, very long chain fatty acids (VLCFA) (45,46). The rationale for HSCT in these disorders is to provide a self-renewing source of lymphohematopoietic cells that contain normal levels of the deficient enzyme, thus providing correction of the metabolic defect in the patient’s somatic cells. It is well-known that HSCT repopulates cells of the mononuclear phagocytic system, including splenic and fixed tissue

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macrophages, Kupffer cells in the liver, Langerhans cells in the skin, pulmonary alveolar macrophages, and microglia in the central nervous system. The largest experience of HSCT for storage diseases is in Hurler’s syndrome (mucopolysaccharidosis I), where more than 300 patients have undergone HSCT (mostly from HLA-matched siblings). When performed before irreversible organ damage has occurred, allogeneic HSCT can ameliorate the abnormal facies, limitation of joint mobility, hepatosplenomegaly, cardiac dysfunction, and hydrocephalus that are characteristic features and complications of Hurler’s syndrome. However, HSCT does not improve the skeletal manifestations (dysostosis multiplex) of this storage disease, and patients successfully treated with HSCT still have short stature and require ongoing orthopedic evaluations and interventions (45). In all of these metabolic diseases, the best outcomes are observed in patients who undergo HSCT well before onset of neurological deterioration; in patients with neurological manifestations at the time of HSCT, there is at best a chance of stabilization at the pretransplant level of dysfunction, or there can be progressive disability post-transplantation. Autoimmune Diseases The fundamental defect in autoimmune diseases is dysregulation of the immune system, with a loss of tolerance that allows T-cell-mediated attack on and destruction of autologous cells and tissues. The manifestations of these disorders can be protean, and can lead to multisystem dysfunction and death. The use of autologous HSCT after immunosuppressive and cytoreductive therapy has been evaluated in patients with progressive autoimmune diseases, especially rheumatoid arthritis, systemic lupus erythematosis, and multiple sclerosis (47–50). To provide a stem cell graft depleted of mature autoreactive lymphocytes, most HSCTs for autoimmune diseases have used autologous PBSCs that have been selected for primitive CD34+ cells, as lymphocytes do not express that cell surface antigen. HSCTs for autoimmune diseases are considered investigational at this time, and international collaborative research studies are underway to develop shared databases and treatment protocols, with common criteria for patient selection and assessment of endpoints. REFERENCES 1. Bach FH, Albertini RJ, Joo P, et al. Bone marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet 1968; 2(7583):1364–1366. 2. Gatti RA, Meuwissen HJ, Allen HD, et al. Immunological reconstitution of sex-linked immunological deficiency. Lancet 1968; 2(7583):1366–1369. 3. Thomas ED, Storb R, Clift RA, et al. Bone marrow transplantation. N Engl J Med 1975; 292(17): 832–843, 895–902. 4. Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977; 49(4): 511–533. 5. Thomas ED, Buckner CD, Clift RA, et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med 1979; 301(11):597–599. 6. Blume KG, Beutler E, Bross KJ, et al. Bone marrow ablation and allogeneic marrow transplantation in acute leukemia. N Engl J Med 1980; 302(19):1041–1046. 7. Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986; 104(2):155–163. 8. Philip T, Biron P, Maraninchi D, et al. Massive chemotherapy with autologous bone marrow transplantation in 50 cases of bad prognosis non-Hodgkin’s lymphoma. Br J Haematol 1985; 60(4):599–609. 9. Armitage JO, Gingrich RD, Klassen LW, et al. Trial of high-dose cytarabine, cyclophosphamide, total body irradiation and autologous marrow transplantation for refractory lymphoma. Cancer Treat Rep 1986; 70(7):871–875. 10. Philip T, Armitage JO, Spitzer G, et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade Hodgkin’s lymphoma. N Engl J Med 1985; 316(24):1493–1498. 11. Antman KH, Rowlings PA, Vaughan WP, et al. High-dose chemotherapy with autologous HSC support for breast cancer in North America. J Clin Oncol 1997; 15(5):1870–1879. 12. Armstrong DK, Davidson NE. Dose intensity for breast cancer. Oncology (Huntington) 2001; 15(6): 701–708, 712. 13. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335(2):91–97.

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14. Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002; 346(16):1185–1193. 15. Baron F, Storb R, Little M-T. Hematopoietic cell transplantation: five decades of progress. Arch Med Res 2003; 34(6):528–544. 16. Storb RF, Lucarelli G, McSweeney PA, et al. Hematopoietic cell transplantation for benign hematological disorders and solid tumors. Hematology 2003:372–397. 17. Gupta V, Lazarus HM, Keating A. Myeloablative conditioning regimens for AML allografts: 30 years later. Bone Marrow Transplant 2003; 32(10):969–978. 18. Bearman SI, Appelbaum FR, Buckner CD, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6(10):1562–1568. 19. Resnick IB, Shapira MY, Slavin S. Nonmyeloablative stem cell transplantation and cell therapy for malignant and non-malignant diseases. Transpl Immunol 2005; 14(3–4):207–219. 20. Avivi I, Rowe JM. Acute lymphocytic leukemia: role of hematopoietic stem cell transplantation in current management. Curr Opin Hematol 2003; 10(6):463–468. 21. Mrozek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev 2004; 18(2): 115–136. 22. Paneesha S, Milligan DW. Stem cell transplantation for chronic lymphocytic leukaemia. Br J Haematol 2005; 128(2):145–152. 23. Pavletic SZ, Khouri IF, Haagenson M, et al. Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant Research. J Clin Oncol 2005; 23(24):5788–5794. 24. Or R, Shapira MY, Resnick I, et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 2003; 101(2):441–445. 25. Freedman A, Friedberg JW, Gribben J. High-dose therapy for follicular lymphoma. Oncology 2000; 14(3):321–326, 329. 26. Morris EC, Mackinnon S. Reduced intensity allogeneic stem cell transplantation for low grade nonHodgkin’s lymphoma. Bailliere’s Best Pract Clin Haematol 2005; 18(1):129–142. 27. Holmberg LA, Stewart FM. Hematopoietic stem cell transplantation for non-Hodgkin’s lymphoma. Oncology (Huntington) 2003; 17(5):627–632, 635, 640. 28. Peggs KS, Mackinnon S, Linch DC. The role of allogeneic transplantation in non-Hodgkin’s lymphoma. Br J Haematol 2005; 128(2):153–168. 29. Reece DE. Hematopoietic stem cell transplantation in Hodgkin disease. Curr Opin Oncol 2002; 14(2):165–170. 30. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89(6):2079–2088. 31. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104(2):579–585. 32. Harousseau JL. Stem cell transplantation in multiple myeloma. Curr Opin Oncol 2005; 17(2):93–98. 33. Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102(9): 3447–3454. 34. Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood 2002; 99(12):4276–4282. 35. van Besien K, Deeg HJ. Hematopoietic stem cell transplantation for myelofibrosis. Semin Oncol 2005; 32(4):414–421. 36. Bacigalupo A, Brand R, Oneto R, et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy—the European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37(1):69–80. 37. Margolis DA, Casper JT. Alternative-donor hematopoietic stem-cell transplantation for severe aplastic anemia. Semin Hematol 2000; 37(1):43–55. 38. Saso R, Marsh J, Cevreska L, et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1999; 104(2):392–396. 39. Woodard P, Want W, Pitts N, et al. Successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. Bone Marrow Transplant 2001; 27(6):589–592. 40. Lucarelli G, Andreani M, Angelucci E. The cure of thalassemia by bone marrow transplantation. Blood Rev 2002; 16(2):81–85. 41. Yeager AM. Hematopoietic stem cell transplantation in children with sickle cell disease. Blood Ther Med 2004; 4:40–47. 42. Hoppe CC, Walters MC. Bone marrow transplantation in sickle cell anemia. Curr Opin Oncol 2001; 13(2):85–90. 43. Fischer A, Landais, P, Friedrich W, et al. European experience of bone marrow transplantation for SCID. Lancet 1990; 336(8719):850–854. 44. Filipovich AH, Shapiro RS, Ramsay NKC, et al. Unrelated donor bone marrow transplantation for correction of lethal congenital immunodeficiencies. Blood 1992; 80(1):270–276.

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45. Peters C, Steward CG, National Marrow Donor Program, et al. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant 2003; 31(4):229–239. 46. Peters C, Charnas LR, Tan Y, et al. Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 2004; 104(3):881–888. 47. Burt RK, Slavin S, Burns WH, et al. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Blood 2002; 99(3):768–784. 48. Gratwohl A, Passweg J, Bocelli-Tyndall C, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant 2005; 35(9):869–879. 49. Snowden JA, Passweg J, Moore JJ, et al. Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: a report from the EBMT and ABMTR. J Rheumatol 2004; 31(3):482–488. 50. Fassas A, Kimiskidis VK. Autologous hemopoietic stem cell transplantation in the treatment of multiple sclerosis: rationale and clinical experience. J Neurol Sci 2004; 223(1):53–58.

29

Umbilical-Cord Blood-Cell Transplantation Michael L. Graham and Martin Andreansky Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, and Department of Pediatrics, University of Arizona College of Medicine, Tucson, Arizona, U.S.A.

Andrew M. Yeager Blood and Marrow Transplantation Program, Arizona Cancer Center and University Medical Center, Tucson, Arizona, U.S.A.

INTRODUCTION AND BACKGROUND Attempts at transplantation of bone marrow to correct hematological abnormalities were first reported in the 1930s (1), although successful outcomes of this procedure did not occur until the late 1960s, largely as a result of understanding the importance of human leukocyte antigen (HLA) typing (2,3). For two decades, allogeneic hematopoietic stem cell transplantation was largely confined to patients with healthy HLA-identical-related donors, usually siblings. With the development of the National Marrow Donor Program (NMDP) in the 1980s, patients lacking family donors were sometimes able to undergo bone marrow transplantation from histocompatible unrelated-volunteer donors (4-5), although many other patients still did not have suitable unrelated bone marrow donors identified through the NMDP or other registries (6). Transfusion of umbilical cord (placental) blood was first described by Ende and Ende in 1972, although no clear evidence of sustained engraftment was presented (7). Early studies of cord blood revealed that very high quantities of hematopoietic progenitor cells are present at the time of birth (8–10), although these numbers decline rapidly within several hours after birth. It was subsequently recognized that the number of hematopoietic progenitors in a single cord blood could be used for successful transplantation (11-12). In 1988, the first successful related umbilical-cord blood transplant was performed in a patient with Fanconi anemia whose unaffected HLA-identical donor-sibling’s cord blood had been harvested and cryopreserved at birth (13). This report and others provided the proof of principle that allogeneic cord blood cells could engraft and restore normal hematopoiesis in human recipients. Recognizing that cord blood registries could offer the possibility of a transplant to patients who would otherwise lack donors, Rubinstein (14) and others developed the first unrelateddonor cord blood banks. Subsequently, donor banks throughout North America, South America, Europe, Asia, and Australia have been established. As of this writing, it is estimated that between 150,000 and 200,000 cord blood units are potentially available for use in patients requiring unrelated donor transplantation, in contrast to the more than seven million potential adult bone marrow/peripheral blood stem-cell donors who have been registered over the past 20 years. As discussed next, the possibility of using less than completely HLA-matched stem cells for cord blood transplantation allows this considerably lower number of available units to serve a large proportion of patients who require hematopoietic stem cell transplantation. BIOLOGY OF UMBILICAL CORD BLOOD CELLS Hematopoiesis Hematopoiesis is a complex process of cellular maturation from putative “stem cells” to mature, circulating committed cells, highly regulated by various chemical factors (15). The actual progenitor cell, or stem cell, has not been specifically identified by histologic or biochemical means, but populations of marrow cells that include such cells have been defined and are used to study hematopoietic differentiation. The most commonly used marker is CD34 (16),

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A Partial List of Identified Hematopoietic Colony Types

Colony type HPC-CFC CFU-GEMM CFU-GM CFU-G CFU-Mega BFU-E

Cell type(s) measured High proliferative potential Granulocyte, erythroid, macrophage, megakaryocyte Granulocyte/macrophage Granulocyte Megakaryocytes Erythroid

Abbreviations: BFU, burst forming unit; CFU, colony forming unit.

a glycophosphoprotein found in highest concentration in cell populations with very high quantities of early hematopoietic progenitor cells. Within the CD34-expressing (CD34+) population are CD34+ cells that are negative for the lineage differentiation antigen CD38; these CD34+ CD38-negative (CD38–) cells appear to be even earlier hematopoietic progenitors (17). Expression of CD34 identifies a surrogate population of hematopoietic stem cells, as small numbers of hematopoietic colonies can be developed from CD34– populations in vitro (18), and CD34 may also be expressed on some nonhematopoietic cells (19). One measure of the hematopoietic potential of cell populations is the ability to form specific colony types in semisolid media. A partial list of identified hematopoietic colony types is noted in Table 1. The number of nucleated cells required for reconstitution in adult marrow and stem cell transplants (between 1 and 5 × 108 cells per kg of recipient weight) is about 10 times the number of cells required for a cord blood (1 to 5 × 107 cells per kg) (20). Although the percentage of CD34+ cells in cord blood is actually lower than that in the marrow (21–23), the proportion of more primitive lineage-negative CD38– cells within that CD34+ cell population is higher (24). The CD34+ cells in cord blood have a much greater ability to proliferate in long-term cultures than adult cells (17). It is also possible that cord blood cells have an increased ability to populate marrow cavities (“homing”) (25), which may explain the dramatically increased ability of limited numbers of the cord blood cells to reconstitute hematopoiesis in the recipient. Immunology A leading cause of morbidity and mortality in stem cell transplantation is graft-versus-host disease (GVHD). Mediated by activated donor T-lymphocytes, GVHD clinically manifests as an injury to multiple organs, including skin, gastrointestinal tract, liver, lung, and the immune system. T-lymphocytes from cord blood have a lower likelihood of producing GVHD than marrow T-cells in animal models (26–28), and this has correlated in humans clinically with a lower incidence of GVHD and a significantly increased tolerance of HLA mismatches in cord blood transplantation (29–32). Several properties of fetal blood may be involved in limiting the immune responsiveness, and thus the GVHD-producing potential, of cord blood cells. Transforming growth factor-beta, a cytokine that suppresses immune responses, is found in very high levels in cord blood and clearly suppresses the cytotoxic responses of alloreactive CD8+ T-cells (33-34). Cord blood cells have lower ratios of CD8+:CD4+ (cytotoxic:helper) T-lymphocytes, leading to the possibility that the cytotoxicity induced by donor CD8+ cells, intimately related to cytotoxicity from GVHD, may be diminished (35). Cord blood units have higher percentages of CD45RA (naïve, or unprimed) T-cells compared with CD45RO (memory, or primed) T-cells, supporting the concept of a much more immature population (36). Cord blood cells also have lower levels of CD3- and CD28-induced signal transduction, resulting in diminished proliferation of and cytotoxic responses by CD8+ T-cells (37). Cord blood T-cells produce much lower levels of cytokines such as tumor necrosis factor-alpha and interferon-gamma, which are secreted by alloreactive T-lymphocytes and are involved in the development of GVHD (38). Studies have also shown that cord blood T-cells have diminished allogeneic cytotoxic responses to antigens that normally stimulate allogeneic responses in marrow-derived T-cells, and express lower levels of chemokine receptors that facilitate the development of cytoxic responses (28-39).

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In summary, immunological studies clearly demonstrate the diminished alloreactivity of cord blood cells compared with adult bone marrow and peripheral blood stem cells. Most clinical studies comparing patients undergoing cord blood transplants versus unrelated donor marrow transplants have shown lower rates of acute and chronic GVHD in recipients of cord blood. A report by Rocha et al. (40) from the Eurocord group noted a 58% incidence of grades 2 to 4 (moderate to severe) acute GVHD in the 262 patients, mostly children, who received unmanipulated matched bone marrow transplants, compared with 35% in the 99 patients who received cord blood transplants. In a matched-pair comparison analysis in a pediatric patient population, Barker et al. (41) saw comparable rates of grades 2 to 4 GVHD in each group of 57 patients. Although all of the bone marrow recipients had HLA-identical transplants, only 16% of the cord blood recipients did. Two studies of unrelated cord blood transplantation in adults have shown similar outcomes. Laughlin et al. (29) compared outcomes among adult patients undergoing mismatched unrelated-donor cord blood transplants (n = 150), mismatched unrelated marrow transplants (n = 83), or matched unrelated-donor marrow transplants (n = 367). The incidence of grade 2 to 4 GVHD was similar for mismatched cord transplants and matched marrow transplants (41% versus 48%, respectively) but was significantly higher for mismatched marrow transplants (52%). Rocha et al. (30) noted a 26% incidence of grade 2 to 4 GVHD in 98 adults who received mostly mismatched cord blood transplants and a 39% incidence in 584 adults who received completely HLA-matched marrow transplants. COLLECTION, PROCESSSING, AND INFUSION OF UMBILICAL CORD BLOOD CELLS Collection Placental cord blood are collected in one of the two settings: (i) for autologous use and (ii) for public use. In both settings, recruitment is followed by the specific process of collection. Most expectant mothers become aware of the possibility of autologous cord blood storage from word of mouth, sales brochures, or from obstetricians. In these cases, arrangements for cord blood collection, shipment, and storage are usually made with the mother’s obstetrician and a private for-profit company. Donor recruitment for storage of cord blood in a public bank involves several steps. In the prenatal period, the expectant mother may be offered a brochure and contact information for the cord blood bank for explanations of the purpose and procedure of cord blood donation. All recruitment materials for voluntary cord blood donation must be reviewed and approved by an institutional review board. Ideally, recruitment of mothers for public cord blood donation takes place in the weeks to months before delivery, but at many centers the recruitment occurs during the early phase of labor. Very young mothers (<18 years), those delivering prematurely, those who are at high risk for infections, or those who are physically or emotionally unable to give consent are excluded from donating cord blood to public banks. In general, term infants over 2500 g who appear healthy at birth are suitable cord blood donors. One significant concern in cord blood transplantation is the possibility that the transplanted cells will transmit a hematologic, immunologic, or metabolic disease into the recipient. In an effort to limit this possibility, thorough maternal and family histories are obtained. Routine screening includes studies for potentially transmissible infections and abnormal hemoglobins (e.g., sickle hemoglobin). Some cord blood banks contact the parents six months after the cord blood donation to determine whether the infant has any medical problems, such as immunodeficiency or other congenital or heritable diseases. This policy must be balanced against the general assumption of anonymity in the donation of cord blood. Cord blood can be extracted in utero or ex utero. In general, when cord blood is obtained by physicians or midwives, it is collected in utero. After the umbilical cord has been clamped and cut, the blood remaining in the placenta and cord can be drained. In general, an insertion site for a needle is found near a visible umbilical vein, and the site is sterilized with an iodine solution. The vein is cannulated by a needle, which is connected by sterile tubing to a sterile collection bag/transfer pack that contains a sufficient quantity of ACD or CPD anticoagulant. After five to eight minutes, the collection is complete. The residual blood in the tubing is

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“stripped” into the collection bag, which is then transported to a processing site. In centers in which an ex utero method is used, the placenta is handed to a technician at the time of its delivery and brought to a “clean” room for immediate processing. The placenta is suspended, and the umbilical vein is cannulated with a needle attached to sterile tubing and anticoagulantcontaining collection bag, as for the in utero collection process. The placental blood is collected by gravity drainage. Cord blood units with volumes less than 50 mL and total nucleated cell counts less than 109 are usually not stored for potential clinical transplantation. At the cord blood processing laboratory, the product is examined for clots, tears in the collection bags, and other abnormalities. Before freezing, samples from each unit that is to be stored in a public cord blood bank are obtained for HLA-typing, nucleated cell count, differential cell count, CD34+ cell counts, in vitro colony-forming unit assays, bacterial cultures, infectiousdisease serological markers, and ABO/Rh typing. In addition, several small aliquots are frozen and stored with the unit; these aliquots can be sent to the transplant center for HLA-typing and other assays, as required. Cryopreservation The method of Rubinstein et al. (42) is commonly used for depletion of red cells from and cryopreservation of cord blood units. Steps in this process are: mixing the cord blood with hetastarch (5:1 ratio); centrifuging the mixture at 90 × g for six minutes; transferring the leukocyte-rich plasma to a second sterile bag; centrifuging the plasma at 450 × g for 10 minutes; and cryopreserving the cell pellet (usually in a final volume of about 20 mL) in 10% dimethylsulfoxide and dextran-40 using a controlled-rate freezer. The final product is stored in a liquid nitrogen container at –135°C. Several studies have suggested that cord blood can be stored with reasonable safety at either 4° or 25°C for at least 24 hours and up to 72 hours. However, units should ideally be processed within 48 hours of collection. This has allowed the possibility of transporting cord blood units from the collection site to the processing/cryopreservation/storage facility by means of commercial overnight carriers. In general, cord blood is shipped in a system that includes an unbreakable, leak-proof outer container, which can withstand trauma or significant changes in pressure and temperature, and an inner plastic container (usually plastic) with materials that absorb the contents of a broken package. Transportation Cryopreserved cord blood units are transported to the transplant centers in dry shippers, which are insulated containers with shells that absorb liquid nitrogen and are able to maintain temperatures below –135°C for several days. Transported cord blood may require transcontinental or international shipping. Specific guidelines and practices have been developed and verified for labeling, shipping, and tracking of the cord blood in transit, and for X-ray screening procedures by airport security (43–46). Because most cord blood units are transported without a chaperone (unlike volunteer-unrelated bone marrow or peripheral blood stem cells), most centers require that the cord blood be received by the transplant center before the patient begins the pretransplant preparative therapy. Once the cord blood unit has arrived at the transplant center, it is transferred to a permanent liquid nitrogen storage tank where it remains until transplantation. Thawing and Infusion The cord blood unit must be thawed and washed before intravenous administration into the recipient. The unit is removed from its storage container and inspected to determine the integrity of the cryopreservation bag. The unit is placed in a sealable sterile bag and placed in a 37° water bag. If the cryopreservation bag is fractured, it is temporarily repaired with a hemostat, and its contents are transferred to a sterile transfer pack. Several variations of the basic wash procedure described by Rubinstein et al. (42) have been developed. Solutions of 10% dextran and 5% albumin are slowly added to the cryopreservation bag and thoroughly mixed with the thawed cord blood cells. The contents of the product

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are transferred to a new bag and centrifuged at 400 × g for 15 minutes at 10°C, and the supernatant is placed in another bag and centrifuged to collect a second cell pellet. The two cell pellets are combined in a single transfer pack and resuspended in dextrose and albumin, with final volumes of 60 to 100 mL. Aliquots are removed for cell counts, culture, and viability testing. The thawed cord blood cells are usually infused through an indwelling central venous catheter over 15 to 30 minutes. Depending on the volume of the unit and the size of the recipient, units are either administered by gravity administration or by slow intravenous infusion. Infusion-related toxicities are rare. SELECTION OF CORD BLOOD UNITS FOR TRANSPLANTATION The process of selecting a cord blood unit for transplantation has evolved over the last decade as more information regarding successful transplantation has accrued. The first series of unrelated cord blood transplants, reported by Kurtzberg et al. in 1996 (47), initially required both a 5/6 serologic match at human leukocyte antigen (HLA)-A, B, and DR loci and a cell dose of at least 10 × 106 nucleated cells per kilogram. Present standards currently attempt to match cord blood units for at least four of the six antigens, using serologic or low-resolution matching at HLA-A and -B loci and high-resolution matching at HLA-DR. Although some studies have suggested a higher success rate in recipients of cord blood units matched at HLA-DR by high-resolution typing, other studies have not confirmed this finding. Currently, four parameters have been studied for their influence on outcome in cord blood transplants: HLA matching, total nucleated cell dose, progenitor colony count, and CD34+ cell count. Human Leukocyte Antigen Matching While HLA matching would seem to be of paramount importance in any type of stem cell transplantation, the actual role it plays continues to be explored. In general, fewer than 10% of patients for whom searches are initiated will have cord blood units completely matched at HLA-A, -B, and -DR; the vast majority of patients will have cord blood units identified that are matched at either five of six or four of six HLA antigens. While the initial study from the New York Blood Center suggested a modest benefit for HLA-matched transplants (48), other studies have not shown such a benefit (49,50). Survival has generally been equivalent for 5/6 and 4/6 HLA-matched cord blood transplants, although a European cooperative study did show improved survival for recipients of either class I (A, B) or class II (DR) mismatches only compared with mismatches at both classes I and II (51). Intuitively, higher degrees of HLA matching would appear to be desirable. However, the fact that nucleated cell dose and CD34+ cell dose are also important often makes it preferable to select a cord blood unit that has a larger cell dose but is less well matched. Cell Dose The requisite nucleated cell dose for successful cord blood transplantation is not known. In the report of Rubinstein et al. (48), cell doses as low as 7 × 106 nucleated cells per kilogram were compatible with neutrophil engraftment, although patients receiving at least 24 × 106 nucleated cells per kilogram had the highest engraftment rates. Some of the benefit of larger cell doses per kilogram may have reflected a younger patient age, which obviously correlates with larger cell dose per kilogram, although an independent effect of cell dose per kilogram has been seen in studies of adult cord blood transplantation (52). Currently, most authors recommend minimal nucleated cell doses of 25 × 106 (and sometimes 35 × 106) cells per kilogram of recipient weight (53). Migliaccio et al. (54) showed that total progenitor colony count correlated more closely with neutrophil engraftment and transplant outcome than nucleated cell dose, but this parameter is not available from all cord blood banks and has not enjoyed widespread use. Wagner et al. (32) showed that CD34+ cell counts correlated more closely with outcome than nucleated cell counts, with the best survival in patients who received at least 0.17 × 106 CD34+ cells per kilogram. Unfortunately, nucleated cell counts of at least 25 × 106 cells per kilogram or 0.17 × 106 CD34+ cells per kilogram correspond to total counts of at least 1.5 × 109 nucleated cells and 10 × 106 CD34+ cells per unit for 60 kg patients. Fewer than 10% of available cord bloods are this

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size, which considerably limits the availability of optimal cord blood units for transplantation in many older (i.e., larger) pediatric and adult patients. As discussed next, the infusion of multiple cord blood units and the ex vivo expansion of cord blood cells are two approaches that may facilitate engraftment and improve outcomes of cord blood cell transplantation. OUTCOMES OF CORD BLOOD TRANSPLANTATION The vast majority of cord blood transplant procedures have been performed in pediatric patients. Three reasons for this are: (i) the longstanding concern that a limited number of cells in cord blood units might be inadequate to provide engraftment in larger patients; (ii) the relative rapidity with which cord blood units can be obtained in comparison with unrelated bone marrow, which allows for earlier transplantation in patients who often have a more urgent need because of more rapidly progressing leukemias; and (iii) the higher percentage of pediatric patients requiring unrelated donors because of smaller family sizes. As discussed next, however, there is a growing application of unrelated cord blood transplantation to adults who lack suitably histocompatible related- or unrelated-bone marrow or peripheral blood stem cell donors. Related Donor Transplantation As noted before, the first successful related-donor cord blood transplant was performed in 1988 for a child with Fanconi anemia, whose mother was pregnant with an unaffected child, whose cord blood served as a stem cell source for transplantation. Since then, several hundred relateddonor cord blood transplants have been reported in the literature. In general, this option is available to patients requiring stem cell transplantation whose parent(s) chose to have cord blood privately stored (currently at $700 to $1500 in initial fees and storage fees of $100 to $200 per year), or when cord blood was stored from a delivery of a sibling born after a diagnosis of a transplantrequiring disease was made in an older child. Because this occurs in the fairly narrow situation of a family that either stored cord blood privately, usually with the help of a public or private bank, or anticipated the potential need for a donor when another child in the family was born, far fewer related cord blood transplants have been performed than unrelated cord blood transplants. If an adequate number of cells can be obtained from the unit, related cord blood transplantation allows the possibility of “painless” donation, as the donor sibling does not need either a bone marrow harvest or placement of an apheresis catheter for peripheral blood stem cell collection. While these procedures are generally considered to be quite safe, the possibility of avoiding them is potentially valuable. Because most children do not have suitable donors, private storage costs may be prohibitive for a large portion of the population, and most families usually cannot anticipate the need for a potential donor, the usefulness of this technique is quite limited. In general, the results of related-donor cord blood transplantation appear comparable with those of related-donor bone marrow or peripheral blood stem cell transplantation. As might be predicted from the immunobiology of cord blood cells described before, the rates of GVHD have been considerably lower (55). One potential variant of the use of related-donor cord blood transplantation has been the decision of parents to conceive a child as a means of “creating” a potential donor for a child requiring stem cell transplantation. This technique is only applicable if the transplant can be delayed until after the birth of the donor child (56), a situation that is applicable in some genetic diseases or in slowly progressing hematological malignancies like chronic myelogenous leukemia, or in instances in which parents anticipate that their child, who has a malignancy in remission, may need a hematopoietic stem cell transplant in the event of relapse. Unrelated Donor Transplantation The first two series of cord blood transplantation for primarily pediatric patients appeared in 1996 and described patients with mostly advanced malignancies who received matched unrelated cord blood transplants because unrelated donor marrows were unavailable (47,51). Since then, several large, multi-institution series have been reported. Over 90% of unrelated cord transplants for pediatric malignancies have been performed in patients with leukemia, and the results of these studies are summarized in Table 2. As summarized in Table 3, children

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TABLE 2 Number of patients (leukemia)

Unrelated Cord Blood Transplantation in Children with Leukemia Percent HLA Myeloid engraftment mismatch GVHD grade 0/1/2/3 2–4 (%) (%)

GVHD grade 3–4 (%)

Chronic GVHD (%)

562 (378)

81

1/39/47/7

45

23

25

550 375 25 102 44 27

74 n/a 92 88 82 89

10/44/40/6 9/57/34/1 4/80/12/4 14/43/41/2 9/48/34/9 10/57/33/0

36 n/a 43 39 44 37

20 12 10 11 23 9

26 12 8 9 28 0

EFS

References

Approximately 40% at one year 34% at three years 35% at three years 48% at one year 47% at two years 43% at four years 52% at one year

(48) (51) (49) (47) (32) (61) (62)

Abbreviations: EFS, event-free survival; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; n/a, not available.

with non-neoplastic conditions, including cellular immunodeficiencies, hematological disorders (e.g., thalassemia, high-risk sickle cell disease) and inborn errors of metabolism (e.g., Krabbe’s disease, Hurler’s syndrome) have also been treated with unrelated cord blood transplants. More recent trials of unrelated cord blood transplantation have demonstrated considerably better outcomes than the initial reports. Possible reasons for improved outcomes include: earlier referral for transplantation because of anticipated improved outcomes; recognition of the importance of nucleated cell and CD34+ cell counts (compared with HLA-match) in selection of cord blood units; a larger selection of available cord blood units, with more than 150,000 units currently available; and the end of the initial restriction that cord blood transplantation could only be considered if no suitable bone marrow donor was available. Results of unrelated cord blood transplantation in adults have demonstrated similar outcomes compared with early reports of these types of transplants in pediatric recipients (29,30). The outcomes of unrelated cord blood transplants in adults with leukemia and with other hematological malignancies or severe aplastic anemia are summarized in Tables 4 and 5, respectively. NEW APPROACHES TO CORD BLOOD TRANSPLANTATION Double Cord Blood Transplants To address the problem of the limited size of individual cord blood units for patients (especially adults) requiring stem cell transplantation, Barker et al. (57) first described the infusion of two partially-matched cord blood units for adult patients who did not have a sufficient cell dose in TABLE 3

Unrelated Cord Blood Transplantation for Nonmalignant Pediatric Disorders

Disease Immunodeficiencies Immunodeficiencies Hurler’s syndrome

Number of patients

GVHD Percent HLA GVHD grade grade 3–4 Chronic mismatch 2–4 (%) (%) GVHD (%) 0/1/2/3

12 8 20

11/1/0/0 0/2/4/2 1/11/6/2

17 12 25

8 12 10

n/a 0 10

25 11 asymptomatic 14 symptomatic

0/6/5/0 1/4/9/0

9 46

0 18

36 8

Beta-thalassemia major

5

0/2/2/1

60

20

n/a

Sickle cell anemia

3

0/0/3/0

100

33

33

Infantile Krabbe’s disease

EFS 83% 75% 85% at 30 months 100% 50% (disease and BMT) 100% at 10 months 67%(third patient had autologous recovery)

References (63) (64) (65) (66)

(67) (68)

Abbreviations: BMT, bone marrow transplantation; EFS, event-free survival; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; n/a, not available.

336 TABLE 4

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Unrelated Cord Blood Transplantation in Adults with Leukemia

Percent HLA Myeloid Number of engraftment mismatch patients 0/1/2/3 (%) (leukemia) 150 (150) 98 (98) 22 (22) 34 (34) 68 (68) 57 (56) 23 (23)

91 75 100 66 88 80 100

0/23/77/0 6/51/39/4 5/59/36/0 3/29/68/0 0/21/54/25 4/14/77/5 9/48/43/0

GVHD grade 2–4 (%)

GVHD grade 3–4 (%)

Chronic GVHD (%)

EFS

References

41 26 80 34 50 41 65

— 13 35 17 7 22 13

51 29 90 21 78 32 23

26% at three years 36% at two years 53% at one year 17% at one year 75% at two years 15% at three years 57% at one year

(29) (30) (69) (70) (71) (72) (57)a

aDouble cord blood units. Abbreviations: EFS, event-free survival; GVHD, graft-versus-host disease; HLA, human leukocyte antigen.

a single unit (at first 2.5 × 107 nucleated cells per kilogram, then 3.5 × 107 nucleated cells per kilogram). Patients receiving double cord blood transplants had to be HLA-matched with both units for at least four of six HLA antigens, using serological methods or low-resolution DNA testing for HLA-A and -B, and using high-resolution DNA testing for HLA-DRB1. Additionally, each unit had to be matched with the other unit for at least four of six HLA antigens. Patients received pretransplant conditioning with total body irradiation and cyclophosphamide, and most also received fludarabine. Prophylaxis of GVHD consisted of cyclosporine and mycophenolate mofetil. Twenty-one of the 23 patients who underwent double cord blood transplants were evaluable for engraftment; five of the 21 had evidence of mixed engraftment at day 21, and 16 had evidence of only one cord blood engrafting at that time. By 100 days after transplantation, all patients had engraftment, but by only one unit. The authors concluded that results of the double unit transplants were considerably better than for single unit transplants in adult patients, with 100% myeloid engraftment at a median of 23 days, compared with 72% with a median of 34 days when infused CD34+ cell doses were lower than 1.7 × 105 per kilogram in previous patients treated with single unit transplants. Disease-free survival was 57% at one year (72% for patients in remission or with chronic myelogenous leukemia (CML), versus 25% for higher-risk patients). The authors could not determine as to why the double transplant contributed to the overall success of the treatment regimen they described. The cord blood unit with the least HLA discrepancy, or the unit with the greater total nucleated cell count or CD34+ cell count, was no more likely to become the dominant unit than the unit with greater degree of HLA mismatch or lower cell doses. It did appear that the cord blood with the larger CD3+ cell dose was more likely to engraft. Why infusion of a second unit, usually unidentifiable three weeks after transplantation, should contribute to successful engraftment remains a mystery. Whether there is a transiently higher cell dose, or some humoral or other factor that the second unit contributes to engraftment, is currently being evaluated. Ex Vivo Expansion of Cord Blood Units Another approach to increase the cell dose from a cord blood unit is the ex vivo expansion of the number of cord blood progenitors. Research on ex vivo expansion of hematopoietic TABLE 5 Unrelated Cord Blood Transplantation in Adults with Other Hematological Malignancies and Severe Aplastic Anemia

Disease Non-Hodgkin’s lymphoma Multiple myeloma Severe aplastic anemia Myelodysplastic syndromes

Number of patients 20 2 9 13

Percent HLA GVHD grade mismatch 2–4 (%) 0/1/2/3 1/0/19/0 n/a 1/6/2/0 0/4/7/2

40 50 — 23

GVHD grade Chronic 3–4 (%) GVHD (%) 35 0 — 15

10 100 22 n/a

EFS

References

50% at 12 months n/a 77% at 32 months 77%

(73) (74) (75) (76)

Abbreviations: EFS, event-free survival; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; n/a, not available.

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progenitors has led to the identification of numerous growth factors with the potential to induce proliferation and/or differentiation into more specific cell types. A recent review discusses the cytokines that are capable of promoting ex vivo expansion of cord blood cells (58). Two clinical studies have reported the results of infusion of cord blood cells that have been expanded ex vivo. Shpall et al. (59) reported on 37 patients who received unrelated cord blood transplants, at least parts of which were expanded ex vivo. The authors described two groups of patients, 25 of whom had either 40% or 60% of their cord bloods infused immediately after preparative therapy; the remaining 60% or 40%, respectively, was thawed and, after CD34+ selection, cultured for 10 days in a 5% CO2 incubator with stem cell factor, granulocyte colony-stimulating factor, and megakaryocyte growth and differentiation factor. The other 12 patients had cord blood frozen at the time of collection in two aliquots and underwent identical expansion of either 40% or 60% of the cord blood starting 10 days before transplantation and infused on the same day as the remainder of the cord blood. Although this method resulted in a substantial increase in CD34+ and total nucleated cells, the patients who received ex vivo expanded cord blood cells did not have any more rapid engraftment than historical controls receiving unexpanded cord blood cells only. Jaroscak et al. (60) described 28 recipients of unrelated cord blood transplantation who first received most of the donor cells (at least 107 nucleated cells per kilogram) immediately after preparative therapy and then, approximately 12 days later, received the remainder of the cord blood cells that had been cultured ex vivo in a bioreactor (the Aastrom Replicell System) in the presence of nutrient medium and several cytokines (PIXY321, erythropoietin, and Flt-3 ligand). Again, despite marked increases in nucleated cells, colonyforming units, and CD34+ cells in the ex vivo expanded product, there was no improvement in engraftment. While ex vivo augmentation of cord blood cells appears to be safe and effective (at least in terms of expansion of numbers of committed hematopoietic progenitors), the clinical benefit is currently unproven. This remains an active area of study, and one in which randomized prospective trials are required. SUMMARY AND CONCLUSION Cord blood transplantation has developed into an effective treatment for patients requiring stem cell transplantation. Related-donor cord blood transplantation has been used as an alternative to bone marrow or peripheral blood stem cell transplantation for families that are able to anticipate the need for a donor within the family, but currently accounts for fewer than 10% of all cord blood transplants performed. Unrelated-donor cord blood transplantation is increasingly used for pediatric and adult transplantation in patients with malignant and nonmalignant diseases, and it is estimated that over 6000 such procedures have now been performed. With a more complete understanding of cord blood unit selection, a rapid increase in the quantity of available cord blood units, and consideration of cord blood transplantation as an acceptable alternative (and not simply a second choice) to unrelated marrow donor transplantation, overall success rates continue to improve. Cord blood appears to be rich in primitive stem cells, suggesting the potential use of cord blood-derived stem cells to repair cardiac and neural tissue injured by vascular occlusion or trauma. Such applications are clearly investigational at this time, but may further expand the role of cord blood transplantation in regenerative medicine.

REFERENCES 1. Osgood EE, Riddle MC, Mathew TJ. Aplastic anemia treated with daily transfusions and intravenous marrow; case report. Ann Intern Med 1939; 13:357. 2. van Rood JJ, van Leeuwen A. Major and minor histocompatibility systems in man and their importance in bone marrow transplantation. In: Dupont B, Good RA, eds. Immunology of Bone Marrow Transplantation. New York: Grune and Stratton, 1976:103–110. 3. Amos DB. The era of the immunogeneticist. J Immunol 1981; 127:1727. 4. McCullough J, Hansen J, Perkins H, Stroncek D, Bartsch G. The National Marrow Donor Program: How it works, accomplishments to date. Oncology (Williston Park) 1989; 3:63–68, 72. 5. Kernan NA, Bartsch G, Ash RC, et al. Analysis of 462 transplantations from unrelated donors facilitated by the national marrow donor program. N Engl J Med 1993; 328:593–602.

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6. Beatty PG, Dahlberg S, Mickelson EM, et al. Probability of finding HLA-matched unrelated marrow donors. Transplantation 1988; 45:714–718. 7. Ende M, Ende N. Hematopoietic transplantation by means of fetal (cord) blood. A new method. Virginia Med Monthly 1972; 99:276–280. 8. Knudtzon S. In vitro growth of granulocytic colonies from circulating cells in human cord blood. Blood 1974; 43:357–361. 9. Nakahata T, Ogawa M. Hemopoietic colony-forming cells in umbilical cord blood with extensive capability to generate mono- and multipotential hemopoietic progenitors. J Clin Invest 1982; 70:1324–1328. 10. Smith S, Broxmeyer HE. The influence of oxygen tension on the long-term growth in vitro of haematopoietic progenitor cells from human cord blood. Br J Haematol 1986; 63:29–34. 11. Broxmeyer HE, Kurtzberg J, Gluckman E, et al. Umbilical cord blood hematopoietic stem and repopulating cells in human clinical transplantation. Blood Cells 1991; 17:313–329. 12. Bodger MP. Isolation of hemopoietic progenitor cells from human umbilical cord blood. Exp Hematol 1987; 15:869–876. 13. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989; 321:1174–1178. 14. Rubinstein P, Taylor PE, Scaradavou A, et al. Unrelated placental blood for bone marrow reconstitution: organization of the placental blood program. Blood Cells 1994; 20:587–596. 15. Broxmeyer HE. Role of cytokines in hematopoiesis. In: Oppenheim JJ, Rossio JL, Gearing AJH, eds. Clinical Aspects of Cytokines: Role in Pathogenesis, Diagnosis and Therapy. New York: Oxford University Press, 1993:201–206. 16. Krause DS, Fackler MJ, Civin CI, May WS. CD34: structure, biology, and clinical utility. Blood 1996; 87:1–13. 17. Hao QL, Shah AJ, Thiemann FT, Smogorzewska EM, Crooks GM. A functional comparison of CD34 + CD38– cells in cord blood and bone marrow. Blood 1995; 86:3745–3753. 18. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 1996; 273:242–245. 19. Broxmeyer HE, Cooper S, Li ZH, et al. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. Int J Hematol 1995; 62:203–215. 20. Cairo MS, Wagner JE. Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. Blood 1997; 90:4665–4678. 21. Traycoff CM, Abboud MR, Laver J, et al. Evaluation of the in vitro behavior of phenotypically defined populations of umbilical cord blood hematopoietic progenitor cells. Exp Hematol 1994; 22:215–222. 22. Steen R, Tjonnfjord GE, Egeland T. Comparison of the phenotype and clonogenicity of normal CD34+ cells from umbilical cord blood, granulocyte colony-stimulating factor-mobilized peripheral blood, and adult human bone marrow. J Hematother 1994; 3:253–262. 23. Kinniburgh D, Russell NH. Comparative study of CD34-positive cells and subpopulations in human umbilical cord blood and bone marrow. Bone Marrow Transplant 1993; 12:489–494. 24. Bender JG, Unverzagt K, Walker DE, et al. Phenotypic analysis and characterization of CD34+ cells from normal human bone marrow, cord blood, peripheral blood, and mobilized peripheral blood from patients undergoing autologous stem cell transplantation. Clin Immunol Immunopathol 1994; 70:10–18. 25. Schibler KR, Li Y, Ohls RK, et al. Possible mechanisms accounting for the growth factor independence of hematopoietic progenitors from umbilical cord blood. Blood 1994; 84:3679–3684. 26. Gorin NC, Piantadosi S, Stull M, Bonte H, Wingard JR, Civin C. Increased risk of lethal graft-versushost disease-like syndrome after transplantation into NOD/SCID mice of human mobilized peripheral blood stem cells, as compared to bone marrow or cord blood. J Hematother Stem Cell Res 2002; 11:277–292. 27. Paiva A, Ferreira T, Freitas A, Couceiro A, Coimbra H, Regateiro FJ. Profile of cytokine production in human cord blood and peripheral blood from healthy donors before and after allogeneic activation: relevance in predicting graft-versus-host disease. Transplant Proc 2000; 32:2626–2630. 28. Harris DT, Schumacher MJ, Locascio J, et al. Phenotypic and functional immaturity of human umbilical cord blood T lymphocytes. Proc Natl Acad Sci USA 1992; 89:10006–10010. 29. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004; 351:2265–2275. 30. Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 2004; 351:2276–2285. 31. Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood 2003; 101:4233–4244. 32. Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated-donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100:1611–1618.

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33. Goodwin VJ, Sato TA, Mitchell MD, Keelan JA. Anti-inflammatory effects of interleukin-4, interleukin-10, and transforming growth factor-beta on human placental cells in vitro. Am J Reprod Immunol 1998; 40:319–325. 34. Boussiotis VA, Chen ZM, Zeller JC, et al. Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated alloreactive T-cells that do not induce graft-versus-host disease. Blood 2001; 97:565–571. 35. Dimitriou H, Matsouka C, Perdikoyanni C, et al. Phenotypic characteristics of cord blood hemopoietic cells. Leuk Res 1998; 22:755–758. 36. D'Arena G, Musto P, Cascavilla N, et al. Flow cytometric characterization of human umbilical cord blood lymphocytes: immunophenotypic features. Haematologica 1998; 83:197–203. 37. Sato K, Nagayama H, Takahashi TA. Aberrant CD3- and CD28-mediated signaling events in cord blood T-cells are associated with dysfunctional regulation of fas ligand-mediated cytotoxicity. J Immunol 1999; 162:4464–4471. 38. Chalmers IM, Janossy G, Contreras M, Navarrete C. Intracellular cytokine profile of cord and adult blood lymphocytes. Blood 1998; 92:11–18. 39. Sato K, Kawasaki H, Nagayama H, et al. Chemokine receptor expressions and responsiveness of cord blood T-cells. J Immunol 2001; 166:1659–1666. 40. Rocha V, Cornish J, Sievers EL, et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 2001; 97:2962–2971. 41. Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE. Survival after transplantation of unrelated-donor umbilical cord blood is comparable to that of human leukocyte antigenmatched unrelated-donor bone marrow: results of a matched-pair analysis. Blood 2001; 97: 2957–2961. 42. Rubinstein P, Dobrila L, Rosenfield RE, et al. Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci USA 1995; 92: 10119–10122. 43. Issitt LA, ed. Standards for Cord Blood Services. 1st ed. Bethesda, MD: American Association of Blood Banks, 2001. 44. IATA Dangerous Goods Regulations Manual. 44th ed. Quebec, Canada: International Air Transport Association, 2003. 45. NETCORD and FACT. International Standards for Cord Blood Collection, Processing, Testing, Banking, Selection and Release. 2nd ed. Omaha, NE: Foundation for the Accreditation of Cellular Therapy, 2001. 46. Petzer AL, Speth HG, Hoflehner E, et al. Breaking the rules? X-ray examination of hematopoietic stem cell grafts at international airports. Blood 2002; 99:4632–4633. 47. Kurtzberg J, Laughlin M, Graham ML, et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 1996; 335:157–201. 48. Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 1998; 339:1565–1577. 49. Isoyama K, Ohnuma K, Kato K, et al. Cord blood transplantation from unrelated donors: a preliminary report from the Japanese cord blood bank network. Leuk Lymphoma 2003; 44:429–438. 50. Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 2001; 344:1815–1822. 51. Gluckman E, Rocha V, Arcese W, et al. Factors associated with outcomes of unrelated cord-blood transplant: guidelines for donor choice. Exp Hematol 2004; 32:397–407. 52. Ballen K, Broxmeyer HE, McCullough J, et al. Current status of cord blood banking and transplantation in the United States and Europe. Biol Blood Marrow Transplant 2001; 7:635–645. 53. Bornstein R, Flores AI, Montalban MA, del Rey MJ, de la Serna J, Gilsanz F. A modified cord-blood collection method achieves sufficient cell levels for transplantation in most adult patients. Stem Cells 2005; 23:324–334. 54. Migliaccio AR, Adamson JW, Stevens CE, Dobrila NL, Carrier CM, Rubinstein P. Cell dose and speed of engraftment in placental/umbilical cord blood transplantation: graft progenitor cell content is a better predictor than nucleated cell quantity. Blood 2000; 96:2717–2722. 55. Rocha V, Wagner JE Jr, Sobocinski KA, et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000; 342:1846–1854. 56. Verlinsky Y, Rechitsky S, Schoolcraft W, Strom C, Kuliev A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 2001; 285:3130–3133. 57. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105: 1343–1347. 58. Smith FO, Srour EF, Broxmeyer HE. Ex-vivo expansion and gene transduction of cord blood stem cells. In: Broxmeyer HE, ed. Cord Blood: Biology, Immunology, Banking and Clinical Transplantation. Bethesda, MD: AABB Press, 2004.

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59. Shpall EJ, Quinones R, Giller R, et al. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 2002; 8:368–376. 60. Jaroscak J, Goltry K, Smith A, et al. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the Aastrom Replicell system. Blood 2003; 101:5061–5067. 61. Yu LC, Wall DA, Sandler E, Chan KW, Grayson G, Kletzel M. Unrelated cord-blood transplant experience by the pediatric blood and marrow transplant consortium. Pediatr Hematol Oncol 2001; 18:235–245. 62. Thomson BG, Robertson KA, Gowan D, et al. Analysis of engraftment, graft-versus-host disease, and immune recovery following unrelated donor cord blood transplantation. Blood 2000; 96:2703–2711. 63. Bhattacharya A, Slatter MA, Chapman CE, et al. Single centre experience of umbilical-cord stem-cell transplantation for primary immunodeficiency. Bone Marrow Transplant 2005; 36:295–299. 64. Knutsen AP, Wall DA. Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience. J Clin Immunol 2000; 20:466–476. 65. Staba SL, Escolar ML, Poe M, et al. Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med 2004; 350:1960–1969. 66. Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Engl J Med 2005; 352:2069–2081. 67. Jaing TH, Hung IJ, Yang CP, Chen SH, Sun CF, Chow R. Rapid and complete donor chimerism after unrelated mismatched cord blood transplantation in five children with beta-thalassemia major. Biol Blood Marrow Transplant 2005; 11:349–353. 68. Adamkiewicz TV, Mehta PS, Boyer MW, et al. Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease. Bone Marrow Transplant 2004; 34:405–411. 69. Sanz GF, Saavedra S, Planelles D, et al. Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies. Blood 2001; 98:2332–2338. 70. Cornetta K, Laughlin M, Carter S, et al. Umbilical cord blood transplantation in adults: results of the prospective cord blood transplantation (COBLT). Biol Blood Marrow Transplant 2005; 11:149–160. 71. Takahashi S, Iseki T, Ooi J, et al. Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood 2004; 104:3813–3820. 72. Koh LP, Chao NJ. Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens. Biol Blood Marrow Transplant 2004; 10:1–22. 73. Yuji K, Miyakoshi S, Kato D, et al. Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma. Biol Blood Marrow Transplant 2005; 11:314–318. 74. Yamada T, Tomonari A, Takahashi S, et al. Unrelated cord blood transplantation with a reduced-intensity conditioning regimen following autologous transplantation for multiple myeloma. Int J Hematol 2004; 80:377–380. 75. Mao P, Zhu Z, Wang H, et al. Sustained and stable hematopoietic donor-recipient mixed chimerism after unrelated cord blood transplantation for adult patients with severe aplastic anemia. Eur J Haematol 2005; 75:430–435. 76. Ooi J, Iseki T, Takahashi S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 2003; 101:4711–4713.

Part IX

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SPECIAL TOPICS IN LIVING-DONOR TRANSPLANTATION

Anesthesia for Living-Donor Transplantation Raymond M. Planinsic Department of Anesthesiology, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Increasing demand for organ transplantation has led to the search for alternative sources of organ donation other than deceased-donor donation. The number of available deceased-donor organs for transplantation has not increased to meet the need of patients suffering from end-stage organ failure. Organs from live donors increase the available donor pool and offer new hope to many patients who might otherwise not receive a life-saving transplant. Ethical issues surrounding organ donation for living donor transplantation are mainly concerned with the appropriateness of and risk of morbidity and mortality in the donor. Although primarily for kidney and liver transplantation with excellent results, living-donor lung, pancreas, and intestine transplantation is also evolving to provide alternatives for patients requiring these organs. Once patients are considered possible candidates for organ donation, they must undergo a complete medical, surgical, psychological, and financial evaluation at the transplant center, where the patient will be followed. The transplant anesthesiologist’s role in the evaluation process is extremely important. As with other preoperative evaluations, individual organ systems are addressed. In this chapter, concerns regarding specific organ transplants are discussed, as are the unique aspects of the live donor patient. Surgery on live donors for organ donation present special challenges, as it is performed on healthy individuals. Morbidity and mortality must be kept at a minimum so as to render no harm to the donor providing the gift of life. In addition, the anesthesiologist’s role in maintaining optimal donor organ function, and contributing to the overall success of both the donor and recipient procedures, cannot be understated. LIVE-DONOR RENAL TRANSPLANTATION Patients with end-stage renal disease (ESRD) often wait for years to receive deceased-donor renal transplants. Live-donor renal transplantation (LDRT) offers an alternative to years of dialysis and the complications of long-standing ESRD. Since kidneys are paired organs, and healthy individuals live normal lives after a single nephrectomy, kidneys became the first organ to be considered for live-donor organ transplantation. Currently, over 50% of kidney donors in the United States are living donors. MANAGEMENT OF THE LIVE RENAL DONOR Although the management of live renal donors does not require complex anesthetic techniques, it does require a thorough understanding of anesthestic and fluid management. Special considerations for the donor include protection for the remaining kidney, optimal perfusion and oxygen delivery to the donor kidney, positioning of the patient, and pain control postoperatively for the traditionally open or laparoscopic nephrectomy. Laparoscopic nephrectomy is associated with a significant decrease in postoperative pain, earlier mobilization, and a shorter hospital stay and convalescence time than open donor nephrectomy (1,2).

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When patients are considered for kidney donation, a complete preoperative anesthesiology evaluation must be undertaken. Kidney donor patients should be relatively healthy (ASA PS 1 or 2); however, mild to moderate systemic disease does not necessarily preclude kidney donation. A complete history and physical examination by an anesthesiologist prior to surgery are required. Particular attention to the cardiovascular (CV) and pulmonary systems is essential, along with an airway examination. Examination of the thoracic spine should be made if postoperative epidural analgesia is considered for open nephrectomy. Individual unilateral thoracic perivertebral blocks with in-dwelling catheter placement may also be considered. Laparoscopic or mini-laparotomy procedures typically do not require postoperative epidural analgesia. Routine tests ordered should include electrocardiogram (ECG), Chest Xray (CXR), hemoglobin, hematocrit, coagulation studies (PT, PTT, INR, and platelet count), electrolytes, and a creatinine level. In addition to the normal risks associated with patients who receive a general anesthetic for surgery, the anesthesiologist should discuss specific risks associated with donor nephrectomy in healthy patients (Table 1). Minor early complications include pulmonary atelectasis, pneumothorax, minor dysrhythmias, mental status changes, and wound or urinary infections in up to 13.6% of patients (3). Major early complications may include postoperative sepsis, hemorrhage, or pulmonary embolism in up to 1.4% of patients (3). Transient facial and conjunctival edema may occur in some patients postoperatively because of the large volume of crystalloid or colloid administered to kidney donor patients; however, this tends to resolve quickly. Long-term complications are rare and may include persistent wound pain and incisional hernia (4). Perioperative mortality rates have been reported to be about 0.03% (5). The anesthetic technique for the donor nephrectomy should be tailored to allow rapid emergence and tracheal extubation at the end of the procedure. Induction of anesthesia can be achieved with sodium thiopental or propofol. Tracheal intubation may be assisted with succinylcholine and muscle relaxation maintained with non-depolarizing neuromuscular blockade (cis-atricarium, rocuronium). Narcotic analgesia can be provided with fentanyl, hydromorphone, morphine, or remifentanil, amnesia with a benzodiazepine (midazolam), and hypnosis maintained with a potent inhalational agent (isoflurane, sevoflurane, desflorane). An air/ oxygen mixture, avoiding nitrous, is typically used, especially if a laparoscopic procedure is planned. Invasive monitoring with central venous pressure (CVP) or direct arterial blood pressure (BP) is generally not required in healthy donors for nephrectomy. Two moderate-sized (16-gauge) intravenous catheters should be adequate for the procedure unless there is difficulty obtaining peripheral intravenous access. A laparoscopic nephrectomy requires CO2 insufflation into the peritoneal cavity. This potentially decreases blood flow to the kidneys, and may result in a transient decrease in urine output and occasional delayed graft function in the recipient (6). Standard intra-abdominal insufflation pressure used during laparoscopic procedures (10–15 mmHg) has been reported to increase renal dysfunction (7). Hence, techniques to maintain optimal perfusion and oxygen delivery to both the donor and remaining kidney of the live donor are required. The goal of excess intraoperative fluid administration should be to maintain a positive fluid balance and assure high donor urine output (>200 cc/hr). Use of loop diuretics (furosemide) and osmotic diuretics (mannitol) should be considered to help maintain this goal. In addition, mannitol may act as a free radical scavenger, and in theory may help decrease ischemia/preservation injury of the donor kidney. Finally, proper patient positioning is required to prevent nerve and tissue injury. For an open nephrectomy, the patient is often positioned in the lateral decubitus position. A laparoscopic nephrectomy will require the patient to be in a modified supine position, with slight TABLE 1

Specific Risks Associated with Donor Nephrectomy

Minor early complications

Major early complications

Long-term complications

Pulmonary atelectasis Pneumothorax Minor dysrhythmias Mental status changes Wound or urinary infections

Postoperative sepsis Hemorrhage Pulmonary embolism

Persistent wound pain Incisional hernia

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elevation of the operative side provided by a wedge or roll. The patient’s arms are usually positioned over the patient’s chest with padding between the chest wall and arms. The arms are then secured in this position with tape. Care must be taken not to apply excessive pressure to the chest wall, which may make ventilation more difficult. MANAGEMENT OF LIVE RENAL DONOR RECIPIENT From an anesthetic standpoint, patients with ESRD who will be recipients of living donor renal transplantation are managed similarly to those who receive a deceased-donor renal transplant. Patients with ESRD often present to the operating room with numerous comorbidities (Table 2). These patients may be volume-overloaded, anemic, or hyperkalemic, and may have metabolic acidosis, poorly controlled hypertension, diabetes mellitus, coronary artery disease (CAD), or even congestive heart failure. Evaluation of cardiac risk is especially important in this population. A careful history and physical are required to ascertain cardiac risk factors and functional status. An ECG is not sufficient to screen for CAD in these patients, as they may have clinically silent ischemia. Perioperative Holter monitoring has been recommended to improve the value of preoperative ECG (8). Exercise stress testing may not be adequate if the patient is not capable of completing the study. Either dobutamine stress echocardiography (DSE) or an adenosine thallium stress testing is preferable to screen for ischemia and cardiac reserve. A recent study demonstrated that a negative test result with nuclear scintigraphy or DSE was associated with a low risk of myocardial infarction and cardiac death (9). If either test shows signs of ischemia or poor cardiac performance, then coronary angiography is mandatory, and right heart catheterization may be useful to determine the cardiac output (CO) and measure cardiac filling pressures. Autonomic neuropathy associated with diabetes can make intraoperative BP control difficult. In addition, there is a higher incidence of sudden death during the postoperative period in patients with autonomic neuropathy (10). To evaluate autonomic dysfunction, Ewing and Winney (11) developed two tests—the CV responses to the Valsalva maneuver, and to sustained handgrip. In their study, there was a reduction in the beat-to-beat variation in heart rate at rest in those patients who had abnormal Valsalva maneuvers, independent of age or the resting heart rate. In addition to cardiac dysfunction, autonomic neuropathy may cause anesthetic complications, the result of diabetic gastroparesis. There is often an associated alteration in esophageal motility and a decrease in lower esophageal sphincter tone, both of which may lead to delayed gastric emptying and an increase risk of aspiration during induction of anesthesia (10). These patients should be questioned for a history of gastric reflux as well as NPO status. Chronic renal failure is characterized by a low hemoglobin level (6–8 g/dL), which reduces the oxygen-carrying capacity of the blood and is associated with a compensatory high CO. A hemoglobin concentration greater than 8 g/dL is necessary for adequate oxygen delivery to the heart and the transplanted organ. Blood transfusion to relieve anemia-related symptoms was the only treatment prior to the availability of erythropoietin. Patients receiving erythropoietin can achieve relatively normal hemoglobin levels, although they may be at increased risk for vascular access site thrombosis (12). In patients with ESRD receiving hemodialysis (HD) or peritoneal dialysis, it is important to evaluate their acid–base, electrolyte, and volume status. In patients on dialysis, fluid and electrolyte imbalances can be optimized prior to surgery to a normal or near-normal state. Coagulation defects caused by abnormal platelet function can also be partially reversed by

TABLE 2

Comorbidities Associated with End-Stage Renal Disease

Renal/metabolic

CV

Other

Volume overload Anemia Hyperkalemia Metabolic acidosis

Hypertension CAD Congestive heart failure

Diabetes mellitus Autonomic neuropathy Gastroparesis

Abbreviations: CAD, coronary artery disease; CV, cardiovascular.

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dialysis (13). Patients who have not received dialysis for several days may be volume-overloaded, in addition to having acid–base and electrolyte disturbances. All patients about to undergo LDRT should have CVP monitoring capabilities and good peripheral intravenous access. The internal jugular vein is usually cannulated with a double or triple lumen catheter to allow CVP monitoring, blood sampling, and (if necessary) vasopressor drug use. If the patient has significant cardiac disease and careful measurement of pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, and CO are required; then, a pulmonary artery catheter introducer should be inserted. Direct arterial catheterization of the radial or other artery is routinely performed, as it will allow for direct BP assessment and serial electrolyte, glucose, and hematocrit measurements, both intraoperatively and during the early postoperative period. The technique of induction of anesthesia is not as important as the maintenance of hemodynamic stability. Avoidance of hypertension, hypotension, and tachycardia are important in this patient population who may suffer from CAD. An attenuated hemodynamic and somatic response to laryngoscopy and orotracheal intubation can be obtained using esmolol (0.5–1 mg/kg) before induction (14). Induction can be achieved safely with reduced dose of sodium thiopental (2–3 mg/kg), etomidate (0.1 mg/kg), or propofol (1.5–2 mg/kg), and these can be combined with narcotics (1–2 μg/kg fentanyl) and/or benzodiazepines (2–5 μg/kg midazolam). The choice of muscle relaxant adequate for endotracheal intubation will depend on the potassium level. If potassium is not a concern, then the use of a depolarizing agent (succinylcholine 1–1.5 mg/kg) is safe; otherwise, the administration of an intubating dose of a non-depolarizing agent such as cisatracurium (0.1 mg/kg) or mivacurium (0.15–0.2 mg/kg) is preferable since these will not be affected by renal dysfunction (15). If diabetic gastroparesis is a concern, then use of a non-particulate antacid (sodium citrate and citric acid oral solution 30 mL) immediately prior to the induction of anesthesia will decrease the acid content of the stomach. Use of metoclopramide (30 mg PO) may increase gastric emptying and lower esophageal sphincter tone. If time allows, the use of an H2 blocker six to 12 hours prior to induction will decrease gastric acid production (16). Diabetic neuropathy affects peripheral sensory and motor nerves. The risk of nerve compression related to improper patient positioning and padding of pressure points is increased during anesthesia (16). Pre-existing asymptomatic neuropathy may present postoperatively, and for this reason it is preferable to avoid plexus and truncal blocks in patients with preexisting motor or sensory abnormalities (16). The use of an epidural catheter should be considered for postoperative pain as well as intraoperative anesthetic management. Continuous infusions of low-dose local anesthetics and narcotics (bupivacaine 0.125% and hydromorphone 0.01 mg/mL) can be administered if there are no contraindications, and can decrease intraoperative systemic narcotic use as well as inhalational anesthetic concentrations. This will allow for a more rapid emergence from anesthesia and a more comfortable patient postoperatively. Maintenance of anesthesia can be achieved with a combination of inhalational agents, narcotics, benzodiazepines, and muscle relaxants. During maintenance, a reduction in the narcotic and benzodiazepine doses should be considered to avoid excessive respiratory depression and sedation, which may delay recovery of adequate spontaneous ventilation at the end of surgery (17). Muscle-relaxant drugs such as cisatracurium (0.025 mg/kg) or mivacurium (0.05–0.1 mg/kg) are required for adequate surgical conditions, with close monitoring of the neuromuscular blockade. Use of a bispectral monitor (BIS or PSA) is advocated to maintain an adequate depth of anesthesia. Beta-adrenergic blockers and antihypertensive drugs, as well as vasopressors, should be readily available for administration during the perioperative period. Careful management of intraoperative fluid, electrolytes, and glucose is required in the living-donor kidney transplant recipient. Intravenous fluids should be administered to maintain a CVP of 10 to 12 cmH2O. Prior to reperfusion of the donor kidney, to enhance graft function, intravenous furosemide (1 mg/kg) and mannitol (1 g/kg) are often administered. An additional dose of intravenous furosemide (1 mg/kg) may also be given over 30 minutes after reperfusion of the kidney. Finally, maintenance of good systolic pressure (120–140 mmHg) may require titration of the anesthetic or the use of vasopressors. Low-dose dopamine (1–5 μg/kg/min) is used because of its ability to enhance renal blood flow by stimulating the dopamine-1 renal receptor.

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Dopamine-2 renal, alpha, and beta-adrenergic receptors, however, are also stimulated by lowdose dopamine. A selective dopamine-1 agonist, fenoldopam, is also available (18). At low doses, it exhibits many desirable renal effects, including decreases in renal vascular resistance accompanied by increases in renal blood flow and glomerular filtration rate, and increases in sodium excretion and urine volume. Even at high doses of fenoldopam, dopamine2 renal, alpha- or beta-adrenergic receptors are not stimulated, and undesirable side effects such as arrhythmias can be avoided (18). All of these maneuvers are aimed at having the newly grafted kidney produce urine immediately. Reperfusion of the living-donor kidney graft may be associated with hypotension. This can be related to bleeding or to a reduction in the preload as a consequence of unclamping the iliac artery. This may be treated with intravenous fluids or colloids, and may also require low-dose vasopressors. If hyperkalemia results from ischemia/preservation injury of the donor graft or residual preservation solution, tall-peaked T-waves on the ECG and ventricular arrhythmias may be observed. This can be treated with CaCl2 (0.5–1 g) intravenously; hyperkalemia related to metabolic acidosis can also be (and should initially be) treated with intravenous sodium bicarbonate; insulin and glucose can be administered as well. After the procedure is completed, the patient should be extubated and taken to the postanesthesia care unit prior to transfer to a hospital bed, usually not requiring the intensive care unit. As with induction of anesthesia, hemodynamic stability is essential during emergence. Hypertension can lead to increased myocardial oxygen demand, and in the patient with coexisting CAD may lead to myocardial ischemia. In addition, vascular anastomoses are susceptible to disruption and leakage under the stress of hypertension. Short acting anti-hypertensive drugs such as nitroglycerin, nicardipine, or esmolol may be considered. Finally, as stated above, the use of an epidural catheter for postoperative pain and intraoperative anesthetic management, while by no means mandatory, may allow for a hemodynamically stable emergence from anesthesia. LIVE-DONOR LIVER TRANSPLANTATION Patients with ESLD should be considered for possible LDLT. Over the past few years, LDLT has achieved acceptance as an alternative to deceased-donor liver transplantation (19,20), and has increased to over 6% of liver transplantations performed in the United States (21). For adult-toadult LDLT, up to 70% of hepatic mass may be removed in the donor during the partial (right) hepatectomy. Advantages of LDLT include the fact that the procedure is elective, and the condition of both the donor and recipient may be optimized. In addition, cold ischemia time and thus ischemia/preservation injury to the donor lobe are minimized. MANAGEMENT OF THE LIVE LIVER DONOR Live liver donors are patients willing to undergo a partial hepatectomy in order to provide a segment or lobe of liver tissue to a patient with ESLD. For adult-to-adult LDLT, the right lobe is typically removed, while for adult-to-child the left lateral segment is removed. Initial evaluation of potential live liver donor includes blood type, body size, overall medical condition, and psychological motivation for donation. Several imaging studies are ordered subsequent to assess liver size, and the vascular and biliary tract anatomy. Finally, invasive procedures such as liver biopsy, hepatic angiography, or ERCP may be necessary (22). An adequate mass of hepatic tissue must be resected for implantation into the recipient in order to avoid small-for-size liver syndrome (23). A graft-to-recipient body weight ratio of >0.8% (0.8 g of donor liver tissue per kg of recipient body weight) is recommended to achieve this and maximize patient survival (24). Small-for-size liver syndrome is manifested by signs of poor liver function, including cholestasis, coagulopathy, portal hypertension, elevated liver enzymes, or ascites occurring within the first week of transplantation. Once a potential donor meets the surgical criteria and compatibility for LDLT, the anesthesiologist will review the medical records, and perform a complete history and physical examination of the patient. Routine tests such as an ECG, CXR, serum electrolytes, BUN, creatinine, liver function tests, coagulation studies (PT, PTT, INR platelet count), and hemoglobin/hematocrit

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are required for all patients. In addition, pulmonary function tests (PFTs) and a two-dimensional trans-thoracic echocardiogram are ordered. Finally, when the potential risk for vascular thrombosis exists (Table 3), then a hypercoagulable work-up is pursued. This includes screening the donor for protein C, protein S, and anti-thrombin III deficiencies, factor V Leiden gene mutations, antiphospholipid/cardiolipin antibodies, and elevation of factor VIII. Patients who are found to be hypercoagulable will most likely be excluded from live liver donation for fear of potential thrombotic complications. This is generally true for all live donation. In most cases, on the day of surgery, the live liver donor is brought to the operating suite several hours before the recipient. Exceptions may include the need to explore the recipient to assure there are no contraindications to proceeding, such as metastatic disease. Otherwise, surgery commences first on the donor so as to minimize cold ischemia time of the donor lobe/ segment of hepatic tissue. Separate attending anesthesiologists should staff the donor and recipient operating rooms so as to assure immediate availability to either patient at critical times that often overlap between the two procedures. Furthermore, excellent communication must be kept between both donor and recipient surgical and anesthesiology teams. In most live-liver-donor procedures, the donor will agree and consent to thoracic epidural catheter placement for postoperative analgesia. It is important to confirm adequate function of epidural analgesia prior to induction of general anesthesia. If the epidural analgesia is inadequate postoperatively, then patient-controlled intravenous analgesia with narcotics should be started in the donor. It is not recommended to insert a new epidural catheter postoperatively in liver donor patients. Concerns regarding positioning of the patient adequately for epidural catheter insertion may increase the risk of hemorrhage or injury to the remaining segment of native liver, and this risk outweighs the benefits of this pain control modality. In addition, numerous reports regarding the development of coagulopathy peaking two to four days postoperatively have led to recommendations regarding the optimal timing of removal of epidural catheters to avoid potential epidural hematoma formation (26,27). After the thoracic epidural catheter has been placed and verified to be in a good position and to function well, general anesthesia may be induced. Typically, a combination of local anesthetic (ropivacaine 0.2%) and narcotic (hydromorphone 0.01 mg/mL) are infused, starting at 5 to 6 mL/hr via the epidural catheter throughout the donor procedure. In addition, a loading dose of narcotic (hydromorphone 0.01 mg/mL) can be administered via the epidural catheter once the epidural catheter is verified to be in good position. By using this recommended approach, most patients require minimal intravenous narcotics throughout the operative TABLE 3

Factors Associated with Increased Thrombotic Risk

Platelet

Coagulation factors

Humoral factors

Clinical factors

Source: From Ref. 25.

Thrombocytosis ↑ Platelet concentration of 5-HT ↑ Platelet glycoprotein IIb-IIIa ↑ Fibrinogen ↑ Von Willebrand factor Mutant factor V (Leiden-G1691A, Cambridge, Hong Kong) Mutant prothrombin (G20210A) ↓ Antithrombin III ↓ Protein C ↓ Protein S ↑ Plasmin activator inhibitor Lupus anti-coagulant Anti-cardiolipin antibodies Hyperhomocysteinemia Polycythemia Nephrotic syndrome Smoking Diabetes mellitus Obesity Oral contraceptives Dyslipidemias

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procedure other than a small dose of intravenous narcotics (fentanyl 50–250 μg) with induction of general anesthesia to blunt the patient’s response to laryngoscopy. The local/narcotic epidural infusion is continued postoperatively and may be augmented by the patient self-administering small boluses (3 mL every 20 minutes as needed) of the local/narcotic mixture via a patientcontrolled epidural analgesia (PCEA) pump. In addition to standard monitoring as recommended by the ASA, patients should have central venous pressure and direct arterial pressure monitoring. Two peripheral intravenous catheters (16-gauge each) are also recommended in the rare event of surgical hemorrhage. Induction of general anesthesia may be achieved by routine methods. When a combined general/epidural technique is planned, minimal systemic narcotics are required. This technique should allow for rapid emergence and tracheal extubation in most patients. The patient is then brought to the PACU immediately after tracheal extubation and transferred to the intensive care unit overnight. Use of intraoperative cell salvaging is recommended. If time permits, autologous donation of blood by the donor can be performed. Significant blood loss is rare, and in most cases hemodilution techniques are not necessary. Average blood loss reported for a right hepatic lobectomy for live donor surgery has been reported to be <1 L, with a range from 150 to 2600 mL (19,28). It is generally recommended to maintain a low CVP (<5 mmHg) during live liver donor surgery with judicious use of intravenous fluids. However, improvements in donor and recipient patient outcome have not been verified by this technique in live liver donor surgery. The rationale for its use is to minimize potential hepatic congestion and blood loss during the lobectomy, and thus improve donor hepatic graft function in the recipient and decrease the need for blood transfusion in the live liver donor. When this technique is used, potential for tachycardia, hypotension, and decrease in kidney perfusion (and hence urine output) may exist for the live liver donor. As with any surgical procedure, perfusion and protection of end organs may require modifications of this goal. Hemodynamic changes associated with right hepatic lobectomy for live-liver-donor surgery were documented in a study using indocyanine green (ICG) to measure CO, hepatic function, and blood volume (29). In this study, CO was significantly higher and systemic vascular resistance (SVR) was significantly lower immediately after removal of the right hepatic lobe. In addition, heart rate also increased significantly after removal of the right hepatic lobe, but mean arterial pressure and CVP were not significantly different. Finally, elimination of ICG was significantly reduced (50%) immediately after removal of the right hepatic lobe, and remained decreased five days after surgery. Morbidity and mortality associated with live-liver-donor surgery have been reported. Risks of serious complications are generally higher with right hepatic lobe donation than with the left lateral segment. Cases of bile leaks, bleeding, infection, reoperations, need for liver transplantation in the donor, and death have all been reported (30,31). MANAGEMENT OF LIVE LIVER DONOR RECIPIENT One of the most significant changes in the field of liver transplantation in the United States has been the increase in LDLR. The volume of adult-to-adult live liver transplantation surgery has increased because of organ demand and the success of adult-to-child live liver transplantation surgery. The advantages of live liver transplantation surgery for the recipient include the ability to electively schedule the procedure, and thus optimize the patient’s medical condition, and decrease cold ischemia time and hence ischemia/preservation injury to the donor liver graft. The disadvantages include surgical technical issues related to anastomosis of a partial liver graft, potential for small-for-size liver syndrome, and possible increased postoperative complications such as bile leaks, hemorrhage, or need for retransplantation. Patients who will receive a partial liver segment or lobe from a live liver donor require the same complete preoperative evaluation as candidates for deceased-donor liver transplantation. The initial evaluation performed by the transplant anesthesiologist focuses on the extrahepatic manifestations of ESLD on the various organ systems. An organized and thorough approach to these patients is essential to ensure that the patients are appropriate candidates for the procedure, and that the associated perioperative morbidity and mortality will be minimized.

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During the transplantation procedure, advanced monitoring, vigilance, and frequent laboratory testing are required to assure the best possible outcome. Aggressive management of the patient’s physiology is necessary, and minor abnormalities should be corrected when possible. Unlike other less complex surgical procedures in patients without evidence of ESLD, minor abnormalities may quickly progress to more serious problems that then become increasingly difficult to correct. Patients with ESLD have a hyperdynamic CV system. This is a result of peripheral vasodilatation, the etiology of which may be related to mediators not cleared by the diseased liver, and arteriovenous shunting. This is manifested by an elevated cardiac index (CI), often greater than 3.5 L/min/m2, hyperkinetic left ventricular (LV) function, and low SVR (32). In fact, if a patient with cirrhosis is evaluated and found to have a normal CI, then that patient should be suspect for possible underlying CV disease. The incidence of CAD was once thought to be lower in patients with ESLD; however, this belief that ESLD is protective against CAD is no longer valid, as evidenced by recent advances in the CV evaluation of this patient population (33). Currently, DSE is the study of choice for evaluating myocardial function and assessing for underlying CAD (34). Other tests available include two-dimensional echocardiography (2-D ECHO), adenosine-stress-thallium, multiple-gated (MUGA) blood pool scan with or without thallium, and cardiac catheterization (right heart catheterization and coronary artery angiography) (34). For patients who have significant CAD, options include coronary artery angioplasty with or without stent placement (35). If coronary artery bypass graft (CABG) is considered necessary, then one must consider the option of simultaneous CABG and OLT, with the CABG procedure immediately preceding the OLT (35). Arterial hypoxemia may exist in patients with ESLD. The etiology of this hypoxemia may be due to intrinsic pulmonary disease such as asthma or COPD, or may be a result of restrictive lung disease, often the result of pleural effusions or ascites. Other considerations include interstitial fibrosis, cystic fibrosis, or alpha-1-antitrypsin deficiency that may be associated with ESLD. Hepatopulmonary syndrome (HPS) is the finding of arterial hypoxemia (usually less than 55 mmHg on room air) in the setting of liver disease because of intrapulmonary vascular dilatation (Fig. 1) (36). These abnormally dilated intrapulmonary vessels result in the rapid transit of blood from the right to left heart (intrapulmonary shunting, Fig. 2). Patients with HPS experience improvement of hypoxemia when changing position from upright to supine (orthodeoxia) and report improvement in symptoms of shortness of breath when rising from the recumbent position (platypnea). Other associated signs include digital clubbing, cyanosis, and skin telangiectasias. Chest radiography and PFTs are usually normal, but patients may exhibit a reduced diffusion capacity of carbon monoxide (DLCO) (37). Other studies that may help to confirm HPS include transesophageal echocardiography (TEE) with an agitated saline bubble study, technecium 99 macroaggregated albumin scans, multiple inert gas elimination technique (MIGET), or pulmonary angiography. Portopulmonary hypertension (PPH) associated with ESLD carries a significant risk for intraoperative mortality. Careful evaluation of candidates is required to manage this risk, and includes right and left heart catherization to evaluate PAP and CO, and 2-D ECHO to evaluate right ventricular function (RVF) (36). Administration of a vasodilatator such as intravenous

FIGURE 1 Intrapulmonary vascular dilatations in hepatopulmonary syndrome (HPS). Source: From Ref. 36.

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FIGURE 2 Intrapulmonary shunting in endstage liver disease. Source: From Ref. 36.

epoprostenol, adenosine, or inhaled nitric oxide to determine the reversibility of PPH can be completed at the time of catheterization (38). It is generally agreed that a fall in the mean PAP (mPAP) by more than 10 mmHg with either no change or an increase in CO suggests a significant degree of reversibility. For patients with a positive response during the vasodilatator trial, chronic oral vasodilatator therapy with calcium channel blockers (diltiazem or nifedipine) can be initiated (39). For patients who do not respond during the vasodilator trial, chronic epoprostenol therapy is considered (40). In addition to correction of PPH, preoperative assessment of the ability of the right ventricle to respond to rapid changes in volume is recommended because patients with resting mild PPH may develop an acute rise in mPAP at time of reperfusion (41). Prognostic guidelines are based on mPAP and include mild (≤25 to 35 mmHg), moderate (35–50 mmHg), and severe (≥50 mmHg) PPH. In addition, pulmonary vascular resistance (PVR) may also be measured and used as a prognostic tool. Patients with CO <8 L/min, PVR ≥300 dynes s/cm5 and moderate mPAP are considered at increased rate for mortality (up to 50%) (42). Patients with severe PPH should not undergo OLT given the enormous mortality reported in the literature. To be considered for possible future OLT, these patients must have normal RVF as demonstrated by TEE, have a CI ≥3.5 L/min/m2, show no evidence of thromboembolic disease, and respond to one or more pulmonary vasodilators (e.g., epoprostenol) (43). Renal dysfunction is not an uncommon complication of ESLD. Patients often exhibit prerenal azotemia related to diuretic use, paracentesis, or hypovolemia. Nephrotoxic drugs such as intravenous contrast dyes used in radiographic studies, immunosuppressive agents such as cyclosporine and tacrolimus, or antibiotics such as aminoglycosides may also lead to acute tubular necrosis (ATN). In addition, chronic diseases such as diabetes mellitus and hypertension can cause renal insufficiency. Renal insufficiency in patients with ESLD that is not associated with other causes may be associated with the hepatorenal syndrome (HRS). Renal failure is a result of renal vasoconstriction that develops in response to marked splanchnic and systemic vasodilation (Fig. 3) (44). Administration of terlipressin, a splanchnic and systemic vasoconstrictor, may improve renal function (45). A decrease in urine output, very low urinary sodium levels (<5–10 mEq/dL), and a high urine/plasma creatinine ratio are characteristic of HRS (44). In addition, HRS patients usually do not respond to volume challenges with an increase in urine output. There are two clinical types of HRS, type 1 and 2. Patients with type 1 HRS are in poor condition and are characterized by a doubling of the initial serum creatinine to levels above 130 μmol/L or a 50% decrease in the initial 24-hour creatinine clearance to below 20 mL/min in less than two weeks (44). Type 2 HRS is characterized by moderate and stable renal failure in patients who are in better condition clinically than those with type 1 HRS (44). Renal insufficiency associated with HRS has been shown to be reversible with OLT. Hepatic encephalopathy is a potentially reversible neuropsychiatric syndrome that occurs in patients with significant liver dysfunction and is characterized by an altered sleep–wake cycle, varying degrees of confusion and disorientation, asterixis, hyper-reflexia, and slowing of the dominant rhythm on electroencephalography (46). On the day of the scheduled LDLR, the transplant anesthesiologist re-evaluates the patient immediately prior to surgery. Records and pertinent examinations are reviewed. The patient is

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Overactivated eNOS/NO pathway in splanchnic arteries

Splanchnic and systemic vasodilation

Decreased effective arterial blood volume

Neurohumoral activation

Renal vasoconstriction

FIGURE 3 Mechanism of hepatorenal syndrome. Source: From Ref. 43.

interviewed and examined to ensure that no significant change has occurred since his or her prior evaluation, which might preclude them from undergoing OLT. The equipment (Table 4) and medications required to anesthetize safely and monitor the patient during OLT should include the most sophisticated and advanced tools available, in addition to pharmacological agents. The operating room table should be padded with a silastic gel pad. Arm boards, which are well-padded to support the patient, as well as a footrest to assure dorsiflexion of the foot to prevent peroneal nerve injury, are required. Upper and lower extremity warming devices help to prevent hypothermia. In addition to large-bore intravenous catheters (9 and 8.5 French) for volume and blood transfusion, the transplant anesthesiologist often places a percutaneous veno-venous bypass (PVVB) return cannula (18 French), preferably in the right internal jugular vein, and a left femoral vein (8.5 French) cannula for veno-venous bypass drainage. A device for rapid and large volume fluid and blood product transfusion is indispensable. The FMS 2000 is a new device that can safely be used in the transplant procedure. It warms fluids and blood to body temperature as it is being administered to a patient. It allows a rapid rate of infusion (up to 500 mL/min) of fluids and blood safely into the patient with the use of air detectors. It is compact and quiet, and if blood loss is extremely rapid, two devices can be utilized simultaneously in parallel to allow an infusion rate of up to 1000 mL/min. TEE, in addition to use of an oximetric pulmonary artery catheter, provides maximal safety and early detection of cardiac dysfunction, volume status, or embolic events, which might contribute to hemodynamic instability. Some centers monitor the coagulation system by thromboelastography (TEG) (Fig. 4) (47). This device allows for whole blood to be tested in immediate proximity to the operating room, measuring the quality of the coagulation cascade and clot formation. It provides information on the interactions of platelets, clotting factors, and the thrombolytic systems. The patient’s whole blood may also be evaluated by the addition of protamine sulphate or epsilon-amino caproic

TABLE 4

Equipment Required for Live-Donor Liver Transplantation

Routine equipment Anesthesia machine with volume and pressure controlled ventilator Capnography Mass spectroscopy ECG Blood pressure cuff Pulse oximeter

Specialized equipment TEE TEG Rapid infusion device Blood salvaging device Pulmonary artery catheter and monitor Direct arterial blood pressure monitors Upper and lower body warming devices

Abbreviations: ECG, electrocardiogram; TEE, transesophageal echocardiogram; TEG, thromboelastogram.

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FIGURE 4

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Thromboelastograph tracing.

acid and aprotinin to detect if there is a significant heparin effect or fibrinolysis contributing to coagulopathy during the procedure. Measurement of traditional clotting studies such as prothrombin time (PT), partial thromboplastin time (PTT), International Normalized Ratio (INR), platelet count, fibrinogen level, or fibrin degradation products may also aid in the treatment of coagulopathy; however, the results are often delayed in contributing to the immediate treatment of the patient. The advantage of the TEG, however, is that the results are immediately available in the operating room, and within 10 to 15 minutes, a determination of the type of coagulation defect may determined. Protamine, epsilon-amino caproic acid, aprotinin, and tranexemic acid should be available to treat coagulopathies. Induction agents, muscle relaxants, amnestics, narcotics, and volatile anesthetic agents may be used to maintain anesthesia for the procedure. Caution should be exercised with the use of the newer volatile anesthetic agents, such as sevoflurane and desflurane, given the potential for the production of compound A as well as the reported incidence of renal dysfunction, given the length of the surgical procedure (48). In addition, medications such as epinephrine, dopamine, calcium chloride, and other inotropes should be available in the operating room, in addition to the routine medications available for all anesthetics. A cardiac defibrillator with external and internal paddles should be immediately available. A blood bank service that is well-prepared for each transplant procedure should be intimately involved in all transplant procedures. The need for the availability of up to 50 units of packed red blood cells or whole blood, fresh frozen plasma, cryoprecipitate, and platelets should be discussed with the blood bank prior to commencing with each procedure. The transplantation procedure itself is divided into three stages. Stage I, preanhepatic or dissection stage; stage II, anhepatic stage; and stage III neohepatic stage. Stage I extends from abdominal incision to vascular isolation and removal of the native liver. Stage II begins when the native liver is effectively removed from the patient’s circulation and ends with reperfusion of the donor graft. Stage III begins with reperfusion of the donor graft and ends with closure. Patients with ESLD are often intravascularly volume-depleted, so that, despite a hyperdynamic circulation, hypotension may be a problem immediately after induction of general anesthesia. This may be related to decreased oncotic pressure from low albumin levels, diuretic use, and third-space losses from ascites or pleural effusions. In addition, the sympathetic nervous system may be activated in an attempt to compensate for peripheral vasodilatation. After the patient is brought into the operating room, routine monitors are placed and a peripheral 16-gauge intravenous (IV) catheter is started, preferentially in the antecubital space to allow for exchange to a larger (8 French) catheter after induction. Additionally a 20-gauge radial artery catheter is placed prior to induction of anesthesia. Induction and intubation of the

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trachea should then proceed in rapid-sequence fashion, as these patients are at increased risk of gastric regurgitation and aspiration. Sodium thiopental (3–5 mg/kg) is typically administered after a defasciculating-priming dose of a non-depolarizing muscle relaxant (NDMR) is given. Other agents, such as etomidate (0.2–0.3 mg/kg) or ketamine (1–2 mg/kg), may be used depending upon the patients underlying medical condition. Muscle relaxation sufficient to allow tracheal intubation is achieved with the administration of succinylcholine (1–1.5 mg/kg) or other rapid-acting neuromuscular blocking agents. In addition, a benzodiazepine (lorazapem 1–4 mg) and a potent narcotic (fentanyl 3–5 μg/kg) may be considered, but used carefully. Maintenance of anesthesia is typically achieved with a combination of an inhalational agent, preferably isoflurane, which is minimally metabolized by the liver, fentanyl, lorazapem, and a NDMR. Nitrous oxide is not recommended, as it distends the bowel in addition to the potential risks for air embolism with many vascular anastomoses. After induction of anesthesia is achieved, the airway is secured with an endotracheal tube with a dorsal lumen for intermittent drainage of subglottic secretions (Hi-Lo Evac; Mallinckrodt; Athlone, Ireland), which is associated with a statistically lower incidence of ventilator-associated pneumonia (49). Additional IV access and monitors are placed. Two large-bore (9 and 8.5 French) catheters are placed to allow rapid administration of blood products and fluids if required. Via the Seldinger technique, an 8.5 French catheter may replace the 16-gauge antecubital IV catheter if placed for induction; otherwise, it should be placed in one of the internal jugular (IJ) veins. A 9 French catheter is placed to left IJ in addition to the pulmonary artery catheter. PVVB is used in many centers. The right IJ approach for 18 French PVVB cannula is not without risk and can be complicated by carotid artery injury, pneumothorax, right atrial perforation, or even ventricular perforation. In order to avoid these complications and ensure proper placement of the PVVB cannula, several methods have been developed. These include confirmation of proper positioning of the cannula by CXR or fluoroscopic assistance for cannula placement (50). Planinsic et al. at the University of Pittsburgh Medical Center found the most reliable and rapid method for placement of the PVVB cannula is with the assistance of TEE (51). TEE may be used not only to properly position the PVVB cannula, but it may be useful in detecting complications arising during cannula placement. Figure 5 shows an 18 French PVVB cannula, 18 French × 15 cm, and dilators, which are typically inserted into the IJ vein via the Seldinger technique. It is important that the catheter should be placed between the juncture of the superior vena cava (SVC) and the right atrium (RA) and as far as the fosa ovalis (FO) (52). The TEE probe should be placed in the long axis bicaval view available from the midesophageal position. The SVC is generally best seen at the omniplane angle of 90° to 120°, while the IVC is best seen at the omniplane angle of 40° to 80°. In order to obtain these views, the fourchamber view of the heart is obtained, and the RA is centered. The TEE probe is then translated and rotated until the long axis bicaval view is obtained (51). Next, the IJ vein is cannulated, and a guide wire (GW) is inserted into the vein. Proper placement of the GW can be confirmed by visualization of the GW passing from the SVC into the RA from the TEE image (Fig. 6) (51). The PVVB cannula is then inserted into the IJ vein after sequential dilatation of the vein, and positioned confirmed by TEE (Fig. 7). This technique can easily be performed by one anesthesiologist with the assistance of an anesthesiology technologist and accomplished, in most cases, in less than five minutes (51).

FIGURE 5 Percutaneous bypass cannula and dilatators. Source: From Ref. 51.

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FIGURE 6 Transesophageal echocardiographic bicaval view: guide wire passing from the SVC into the RA. Source: From Ref. 51.

Finally, a femoral artery catheter is placed for additional BP monitoring, as it best reflects central aortic perfusion pressures of the organ, especially postgraft reperfusion. The radial artery catheters allow for arterial blood samples to be taken without disruption of the arterial BP monitoring. This catheter is placed in the femoral artery contralateral to femoral vein to be cannulated for veno-venous bypass. If veno-venous bypass is to be used, the surgeon will rewire the 8.5 French femoral vein catheter placed by the anesthesiologist to pass the 24 French veno-venous bypass drainage cannula. CV monitoring is provided by electrocardiogram, PA catheter, and TEE. The PA oxymetric catheter allows for continuous monitoring of mixed venous oxygen saturation (SvO2), CO, right end diastolic volume (REDV), and right ventricular ejection fraction (RVEF). The TEE provides additional information and is indispensable for differentiating the various causes of hypotension, and aids in the diagnosis of thrombotic pulmonary embolism or intracardiac thrombosis (53). Appropriate positioning of the patient on the operating room table is required to minimize risk of nerve and skin injury. Pressure points must be properly padded. A footrest should be used to maintain dorsiflexion of the foot to minimize peroneal nerve injury. Arms are placed on padded arm boards and abducted to less than 90° so as not to stretch the brachial plexus. In addition, if a surgical retractor used for abdominal exposure is attached to the operating table, above the arm boards, additional padding should be placed between the patients’ shoulders and the retractor bar, so as to decrease the risk of shoulder and brachial plexus injury. Finally, prior to skin preparation and surgical draping, upper and lower extremity forced air-warming devices should be placed to aid in maintaining normal body temperature.

FIGURE 7 Transesophageal echocardiographic bicaval view: PVVB cannula properly positioned. Source: From Ref. 51.

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As stated above, patients with cirrhotic ESLD usually demonstrate a hyperdynamic circulatory state. If the indication for OLT does not involve cirrhosis, but is rather a tumor, metabolic synthetic deficiency, or fulminant hepatic failure, then a normal CV state should be present. Monitoring of the CV system includes ECG, direct arterial BP, PA catheterization, and TEE. In stage I, patients physiologically are vasodilated and occasionally hypovolemic. After incision, with release of potential ascites, hypotension may result. The goal during stage I is to correct volume deficits, and maintain euvolemia and stable hemodynamics. Surgical dissection with associated blood loss and vascular compression can lead to hemodynamic instability. The use of inotropes may be necessary, and options include low-dose dopamine or even an epinephrine infusion. Maintenance of normal acid–base balance and electrolyte composition is required to maximize cardiac function. Stage II may have a profound effect on the patient’s CV system depending upon the surgical technique used. In stage I, the diseased liver is typically removed for LDLR by preserving the intrahepatic vena cava (piggy back dissection). The technique may be performed with or without VVBP. In all approaches, the portal vein, hepatic artery, and common bile duct must be transected. The piggyback technique requires partial occlusion of the intrahepatic vena cava at the level of hepatic venous inflow. The degree of caval occlusion necessary to isolate the hepatic veins and anastomose the donor graft to a recipient hepatic vein often contributes to hemodynamic instability (54,55). Venous return to the heart may decrease by over 50% depending on the degree of caval occlusion. This may lead to hypotension, tachycardia, and the need for volume administration and inotropic support. Vascular engorgement with increased venous pressure in the splanchnic bed and kidneys may lead to intestinal edema and contribute to the development of renal insufficiency. When VVBP is not used, excessive volume loading should be avoided. This is of paramount importance, as with reperfusion of the graft, blood pooled in the lower extremities and splanchnic system will be returned to the systemic circulation acutely, and this may result in acute right heart failure. Use of VVBP, however, is not problem-free (54,55). Poor venous inflow to the bypass system, and hence inadequate bypass flow, may occur because of improper venous drainage cannula (portal and femoral) positioning. It is recommended to maintain bypass flow at approximately 20% to 40% of prebypass CO (54). Although rare, the potential for thrombus formation may occur since patients are not heparinized. If patients are hypercoaguable by TEG prior to commencement of VVBP, small doses of heparin (1000–3000 U) are recommended (53). Air embolization has also been reported with the use of VVBP. Finally, venous return diminishes during partial bypass (femoral to jugular flow) the period during which anastomosis of the portal vein is completed. Bypass flows of less than 1.5 L/min are best avoided as the incidence of venous thrombosis with a marginal blood flow may result in thromboembolism. Flushing the donor graft’s vascular system with 5% albumin and cold lactated ringer solution or normal saline precedes stage III, or reperfusion of the live donor grafted liver. This is done to remove the preservative solution and metabolites, which would be harmful to the recipient. Reperfusion, or stage III, commences with removal of the vascular clamps at the portal and hepatic vein anastomotic sites. When the hepatic vein clamp is removed, blood containing metabolic products of ischemia/preservation injury, which occurs during the cold and warm donor graft ischemia period, are returned to the recipient’s circulation, and significant hemodynamic changes may be seen. Initially, one may observe a transient slowing of the heart rate because of the cold, acidotic, potentially hyperkalemic effluent blood from the liver returning to the heart. Electrocardiographic changes inclusive of ST-segment elevation and T-wave peaking may be seen because of a transient increase in potassium, which, in severe cases, may lead to a sinusoidal ECG rhythm and asystole. If these changes are significant, they are usually temporary, but can lead to cardiac arrest. The patient may require temporary cardiac support and rescue with chest compressions and small intravenous boluses of epinephrine (10–100 μg) or calcium chloride (500 mg to 1 g), if there is evidence of ionized hypocalcemia. Finally, some centers administer methlyene blue (1.5 mg/kg) prior to reperfusion to decrease the hemodynamic changes associated with ischemia/reperfusion injury (56). Hypotension occurring within the first five minutes of reperfusion and lasting more than one minute may occur in up to 30% of patients and is classically referred to as the post-reperfusion

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syndrome (PRS) (57). Treatment is mainly supportive if PRS occurs, but optimizing the patient’s condition with respect to acid–base balance, hyperventilation, volume, and electrolyte status prior to reperfusion may decrease the adverse effects of PRS. In LDLR surgery, Planinsic et al. have shown that PRS occurs at a significantly lower rate than in deceased-donor transplantation (58). The goal of intraoperative management of the pulmonary system should be to maintain adequate ventilation and prevent injury to the lungs. Positive pressure ventilation with a 50% FiO2 and physiological positive end expiratory pressure (PEEP ~5 cmH2O) should be used on patients with normal oxygenation. In patients with HPS, a higher FiO2 may be required to assure adequate tissue oxygenation. If ventilation is difficult, requiring high inspiratory pressures, the possibility of pleural effusions, not uncommon in patients with ESLD, should be considered. Preoperative CXR should be performed to determine if there are effusions or other pulmonary parenchymal disease. Effusions, however, are easily diagnosed with TEE intraoperatively, and may require placement of a chest tube. Arterial hypoxemia that develops intraoperatively should be investigated aggressively. After excluding for the usual causes of hypoxemia, atelectasis, airway obstruction due to secretions, pneumothorax, adult respiratory distress syndrome (ARDS), transfusion-related acute lung injury (TRALI), and cardiogenic pulmonary edema should be considered (59–61). Pulmonary embolization can also contribute to hypoxemia, inadequate ventilation, hypotension, and right ventricular failure (62). Treatment of ARDS may require increases in FiO2 and PEEP. TRALI will require hemodynamic and pulmonary support. Pulmonary edema may be treated with diuretic, inotropes, phlebotomy, and on rare occasions extracorporal membrane oxygenation (ECMO). Treatment of pulmonary embolization requires hemodynamic support as well as the consideration of use of thrombolytic agents, and rarely pulmonary artery thrombectomy or ECMO (63). Activation of the renin–angiotensin–aldosterone (RAA) system leads to the release of antidiuretic hormone (ADH) and free water retention. This may result in hyponatremia. The common use of diuretics in patients with ESLD may contribute to hyponatremia, hypokalemia, and other electrolyte disturbances. In patients with significant hyponatremia, it is important not to raise sodium levels rapidly, as this may result in the development of central pontine myelinolysis (CPM) (64). This rapid correction of hyponatremia may be avoided by treating metabolic acidosis with a combination of tris-(hydroxymethyl)-aminomethane (THAM) and sodium bicarbonate, and using plasmalyte or normosol rather than normal saline to decrease the sodium load. Hyperkalemia should be avoided, and if possible, potassium levels should be kept below 4 mEq/L. This is important particularly as one approaches reperfusion of the liver graft, where there is often a significant transient rise in the serum potassium. Use of older blood units and renal failure may contribute to hyperkalemia. Avoidance of IV solutions like Ringer’s lactate, which contain potassium, should also be avoided in these situations. The use of IV insulin and glucose solutions has been successful in lowering serum potassium levels even during the anhepatic stage of the surgery (65). Uses of a blood-salvaging system to wash RBCs, or intraoperative HD in order to lower potassium, have also been used successfully. Hypocalcemia and hypomagnesemia may occur, especially when large volumes of blood products are transfused (66). This is a result of citrate toxicity because of the inability of the liver to metabolize citrate contained in the administered blood products, particularly during the anhepatic stage of the surgery. In situations where massive transfusion of blood products is necessary, frequent measurement of these electrolytes are required to avoid significant hypocalcemia and hypomagnesemia, which can have a deleterious effect on cardiac function (67). Ionized hypocalcaemia at levels less than 0.56 mmol/L result in hemodynamic dysfunction (68). In massive transfusion situations, it is recommended to administer 500 mg of calcium chloride or gluconate for each 1 L of blood products administered with the use of rapid infusion pumps. Metabolic acidosis becomes progressively worse during the procedure because of the inability of the liver to metabolize molecules such as lactate and other products of metabolism. Sodium bicarbonate and THAM may be used to treat metabolic acidosis (69). However, a mixed acid–base disturbance may be evident due diuretic use and/or nasogastric suctioning. Arterial blood gas samples are required at least hourly to monitor and guide treatment of these metabolic derangements that occur in all liver transplant patients.

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Intraoperative preservation of renal function with prophylactic use of dopamine, mannitol, and lasix has shown mixed results (70,71). Certainly, events such as hypotension and hypovolemia will affect renal function intraoperatively and postoperatively. Pre-existing renal dysfunction, renal failure, or HRS will impact on the postoperative renal state. Patients with ESLD manifest derangements in hemostasis. An imbalance between the clotting and lytic systems exists. Hypersplenism, immunologically mediated platelet destruction, and decreased platelet production can all lead to thrombocytopenia (72). Decreased synthesis of vitamin K-dependent clotting factors (factors II, VII, IX, and X) related to malabsorption of vitamin K in cholestatic disease will lead to coagulopathy. Primary fibrinolysis may occur because of an inability to clear tissue plasminogen activator (tPA), especially during stage II of the surgery (72). The presence of coagulation defects such as antithrombin III deficiency and proteins C and S, factor V Leiden or factor XI mutations, antiphospholipid syndrome, and the MTHFR gene mutation must all be considered, especially in the patient with known portal vein thrombosis (73). Overall, the imbalance in the hemostatic mechanisms usually results in bleeding, although it is a known that patients with primary liver tumors, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC) tend to be hypercoagulable. This can be seen on the TEG: a short r (<10 mm) and an increased α angle (>67°) as shown in Figure 8 (53,74). Administration of a small dose of heparin (2000–3000 U) during stage II, and stage I when there is a proved hypercoagulable status can be an option to prevent thromboembolic complications (75). In stage I, the predominant factors influencing the hemostatic system include the preexisting coagulopathy, dilution of clotting factors, and thrombocytopenia. During stage II, there is increased fibrinolysis because of an inability of the liver to clear tPA as well as decreased levels of plasminogen activator inhibitor (72). The onset of stage III is marked by the development of explosive fibrinolysis noted in approximately 80% of all transplant patients, but frank fibrinolysis with evidence of diffuse bleeding occurs in about 20% of the cases, and this must be treated (76). Possible contributors include washout of tPA from the engrafted liver and splanchnic bed, progressive thrombocytopenia, effects of the preservative solution (UW solution), and hypothermia. In addition, a release of heparin-type substances, from the grafted liver and the heparin contained in the UW solution, may compound the coagulopathy (77). Treatment of coagulopathy requires careful monitoring of the clotting system by TEG or traditional clotting studies at specific intervals during the procedure. Use of fresh frozen plasma (FFP) to replace clotting-factor deficiencies is usually indicated and should be administered throughout stages II and I when necessary. If significant hemorrhage occurs during the

FIGURE 8 Hypercoagulable thromphoelastograph (TEG) (A) compared with a normal TEG (B).

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procedure, then replacement of blood products with a rapid blood-infusion system will be necessary. Typically two units of packed red blood cells (RBC), two units of FFP, and 500 mL of normal saline are combined in the transfusion device reservoir to provide the patient with satisfactory levels of clotting factors (>30%) and hematocrit (26–28%). If fibrinolysis is detected, then careful consideration of small doses of antifibrinolytics, such as tranexamic acid, aminocaproic acid, or aprotinin must be entertained (76,78–80). If fibrinolysis is significant, and fibrinogen levels have been depleted, then the use of cryoprecipitate may be required. Occasionally, protamine sulfate may be required in stage III if the TEG detects a significant heparin effect. This heparin effect is usually self-limiting and often resolves by 30 minutes after graft reperfusion with a well-functioning graft (77). The optimal regime for aprotinin administration during OLT is a point that is still debated. The prophylactic use of aprotinin in a larger dose (1,000,000–2,000,000 KIU initial dose and 500,000 KIU/hr infusion), small dose (initial dose 500,000 KIU followed by 150,000 KIU/hr), or even a lower dose (200,000 KIU/hr continuous infusion from the beginning of the case, without a loading dose) has been recommended by certain centers in order to control fibrinolysis and to reduce the need for transfusion of blood products (81,82). The European Multicenter Study on the Use of Aprotinin in Liver transplantation (EMSALT) showed significant reductions in blood loss and transfusion requirement of 50% and 30%, respectively (83). Its blood-sparing effect appears to be the overall result of a strong antifibrinolytic and a weaker dose-dependent anticoagulant effect (84). Aprotinin is a non-specific serine protease inhibitor with antifibrinolytic activity. At low doses, it is also an inhibitor of plasmin, while at higher doses, it will inhibit the effects of kallikrein and leukocyte derived proteases such as elastase. Recombinant factor VIIa has been investigated for its hemostatic effect in liver transplantation (85–87), while other pharmacological agents such as desmopressin (DDAVP), conjugated estrogen, and antithrombin III have been used, although their efficacy is not well established (78,88). LIVE DONOR LUNG TRANSPLANTATION Lung transplantation presents unique challenges to the anesthesiologist. The scarcity of acceptable deceased donor lungs remains the limiting factor in lung transplantation. It has been estimated that only 10% to 15% of heart donors have lungs acceptable for transplantation (89). Indications for live donor lung transplantation include cystic fibrosis, pulmonary fibrosis, bronchopulmonary dysplasia, bronchiolitis obliterans, and pulmonary hypertension. MANAGEMENT OF THE LIVE LUNG DONOR The use of live donors for lung transplantation implicitly presumes that a pulmonary lobe can be removed with little or no limitations on the long-term pulmonary function of the donor and with extremely low perioperative morbidity and mortality (90). Complications have been reported to be 15% to 61% and include persistent air leaks, pulmonary artery thrombus, postpericardiotomy syndrome, bleeding, sterile empyema, phrenic nerve paralysis, bronchial stricture, persistent cough, and prolonged hospital stay (91,92). Criteria for live lung donor candidates are listed in Table 5 (93). From an anesthetic standpoint, donors of partial lung lobes are managed in a similar manner to patients undergoing partial pulmonary lobectomy procedures. Arterial catheterization is required, and at least one large-bore intravenous catheter should be placed since surgery will occur in the mediastinum. Thoracic epidural analgesia is recommended for postoperative pain control associated with a thoracotomy. Central venous catheterization is optional. After induction of anesthesia, the surgeon examines the bronchial anatomy through a single-lumen endotrachial tube via fiberoptic bronchoscopy. A double-lumen endotrachial tube is then placed to allow lung isolation. A minimal amount of intravenous fluid is required to maintain adequate hemodynamics and thus minimize donor lobe edema. Since the donors are in excellent health, most anesthetic techniques and agents may be given safely. Prostaglandin E1 should be available for administration to dilate the pulmonary vessels.

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Criteria for Live Lung Donor

Age < 55 years Otherwise healthy and without recent viral infection Normal ECG and echocardiogram; normal chest radiograph PaO2 > 80 mmHg while breathing room air FEV1 and FVC > 85% of predicted No pulmonary pathology on chest computed tomography No previous thoracic surgery on donor side Abbreviations: ECG, electrocardiogram; FEV1, forced expiratory volume in one sec; FVC, forced vital capacity. Source: From Ref. 90.

MANAGEMENT OF THE LIVE LUNG DONOR RECIPIENT Recipients of partial lung lobes for transplantation suffer from terminal respiratory failure. Hence, the risk of respiratory depression should be seriously considered in these patients who are chronically hypoxic and/or hypercarbic when narcotics and benzodiazepines are administered. Two large-bore intravenous catheters should be placed. If bilateral lobar transplantation is planned, then a clamshell thoracosternotomy will require intravenous catheters placed above the antecubital fossae or in the internal or external jugular veins. Arterial catheterization is required to monitor blood pressure and obtain arterial blood samples. A ventilator with adjustable inspiratory:expiratory time ratio, positive end expiratory pressure, and low internal compliance is essential. Finally, monitoring with TEE is recommended (90). The main concerns during induction of anesthesia include airway protection, avoidance of myocardial depression and increases in right ventricular afterload in patients with right ventricular dysfunction, and avoidance and recognition of lung hyperinflation in patients with increased lung compliance and expiratory airflow obstruction (90). Anesthesia may be maintained with moderate doses of narcotics (fentanyl 5–15 μg/kg) combined with low doses of potent inhalational anesthetics. The anesthetic should be titrated to allow for possible early postoperative extubation. Problems similar to those encountered intraoperatively during deceased donor lung transplantation may occur during live donor lung transplantation. When two donated lobes are to be transplanted into the live donor lung transplant recipient, the procedure should be performed with the assistance of cardiopulmonary bypass (CPB) so as to avoid reperfusion-induced pulmonary edema. If CPB is not used, then when the first transplanted lobe is perfused, it will receive the entire CO. As a result, congestion and edema will likely occur. Patients with obstructive lung disease and lung hyperinflation who have received a single lobe transplant will likely require differential lung ventilation after transplantation (94). LIVE-DONOR PANCREAS AND SMALL BOWEL TRANSPLANTATION Live-donor pancreas and small bowel transplantation currently make up less than 1% each of the total pancreas and small bowel transplants performed (21). The indication for live donor pancreas transplantation is diabetes. In addition, combined live donor kidney-pancreas transplants have been performed. The indication for live-donor small bowel transplantation is irreversible intestinal failure. Approximately half of the donor pancreas is removed for live-donor pancreas transplantation, and up to 250 cm of jejunem-ileum or ileum is removed for live-donor small bowel transplantation. There are approximately 16 centers worldwide performing live donor intestinal transplants. As of March 2005, a total of 41 live-donor intestinal transplants have been performed, with 21 survivors. The causes of death have been sepsis (12 patients), liver failure or rejection (two patients each), renal failure, cerebral, cardiac, or technical issues (one patient each) (95). Anesthetic management for pancreas and isolated small bowel transplantation has been well-described (96,97). Management of live donors for pancreatic and small bowel transplantation is not significantly different than that for patients undergoing partial pancreatectomy or small bowel resection. The indications and need for such procedures are discussed in Chapter 21 for live-donor pancreas transplantation, and Chapters 25 and 26 for live-donor small bowel transplantation.

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J Hepatology 1997; 26(3):554–559. 75. DeWolf AM, Ramsey G, Teruya J, et al. Hypercoagulability and pulmonary thromboembolism (PE) during liver transplantation (LTX): what is the role of heparin administration? ILTS ELTA LICAGE Abstract Program Berlin 2001; C-5:18. 76. Kang Y, Lewis JH, Navalgund A, et al. Epsilon-aminocaproic acid for treatment of fibrinolysis during liver transplantation. Anesthesiology 1987; 66:766–773. 77. Kettner SC, Gonano C, Seebach F, et al. Endogenous heparin-like substances significantly impair coagulation in patients undergoing orthotopic liver transplantation. Anesth Analg 1998; 86(4):691–695. 78. Mannucci PM. Drug therapy: hemaostatic drugs. N Eng J Med 2001; 339(4):245–253. 79. Molennar IQ, Legnani D, Groenland THN, et al. Aprotinin in orthotopic liver transplantation: evidence for a prohemostatic, but not a prothrombotic effect. Liver Transpl 2001; 7:896–903. 80. Boylan JF, Klinck JR, Sandler AN, et al. Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 1996; 85(5):1043–1048. 81. Soilleux H, Gillon MC, Mirand A, et al. Comparative effect of small and large aprotinin doses on bleeding during orthotopic liver transplantation. Anesth Analg 1995; 80(2):349–352. 82. Marcel R, Stegall W, Suit CT, et al. Continuous small-dose aprotinin controls fibrinolysis during orthotopic liver transplantation. Anesth Analg 1996; 82(6):1122–1125. 83. Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirement in orthotopic liver transplantation: a multicentre randomized double-blind study. Lancet 2000; 355(9212):1303–1309. 84. DeHart SG, Farooqi NU, Delrue GL, et al. Dose-dependent effect of aprotinin on rate of clot formation. Eur J Anaesth 1996; 13(5):463–467. 85. Planinsic RM, van der Meer J, Testa G, et al. Saftey and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl 2005; 11(8):895–900. 86. Lodge JPA, Jonas S, Jones RM, et al. Efficacy and safety of repeated perioperative doses of recombinant factor VIIA in liver transplantation. Liver Transpl 2005; 11(8):973–979. 87. Porte RJ, Caldwell SH. The role of recombinant factor VIIa in liver transplantation. Liver Transpl 2005; 11(8):872–874. 88. Kohler M. Antithrombin (AT) substitution: sense or nonsense? Anesthesia 1998; 53 (suppl 2):52–54. 89. Harjula A, Baldwin JC, Starnes VA, et al. Proper donor selection for heart-lung transplantation. J Thorac Cardiovasc Surg 1987; 94:874–880. 90. Quinlan JJ, Gasior T, Firestone S, et al. Anesthesia for living-related (lobar) lung transplantation. J Cardiothoracic Vasc Anesth 1998; 10(3):391–396. 91. Aigner C, Seebacher G, Klepetko W. Donor Selection. Chest Surg Clin N Am 2003; 13:429–442. 92. 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Management of Infections in Living-Donor Transplant Recipients Fernanda P. Silveira and David L. Paterson Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Infection is a particularly prominent cause of morbidity and mortality in all transplant recipients, including those who have received an organ from a living donor. This chapter covers the risk factors for infection post-transplantation, a general approach to the investigation and diagnosis of infections post-transplantation, and a review of the common infections occurring in the transplant recipient. RISK FACTORS FOR INFECTION POST-TRANSPLANTATION The risk of infection post-transplantation appears to be correlated with six factors: (i) patient status at the time of transplantation, (ii) operative and immediate postoperative factors, (iii) genetic susceptibility to infection, (iv) the net state of immunosuppression, (v) environmental exposures, and (vi) the use of antimicrobial prophylaxis. These risk factors are summarized in Table 1. Patient Status at the Time of Transplantation The clinical status of the patient at the time of transplantation is linked to outcome postoperatively. For example, patients with advanced liver disease who have severe malnutrition and are in the intensive care unit (ICU) with acute renal failure may be more likely to develop infectious complications postoperatively than patients who come from home in better general condition. Contributors to this heightened risk of infection include use of intravenous lines and other indwelling devices, prolonged use of antibiotics, and colonization with bacteria resistant to multiple antibiotics. A potential advantage, therefore, with a living donor, is that transplantation can be scheduled at a time when the patient’s clinical status is optimized. Operative and Immediate Postoperative Factors Solid-organ transplant recipients are uniquely susceptible to infection. They undergo a significant operation, thereby breaching the defenses provided by the skin. They may remain in the ICUs for prolonged periods of time, requiring intravenous access and mechanical ventilation. Thus, pulmonary barriers to infection are also breached. In the early post-transplant period, transplant recipients are susceptible to hospital-acquired bacterial infections, such as pneumonia and central-line associated bloodstream infections associated with routine ICU management. Additionally, wound infections and intra-abdominal infections may be associated with the surgical procedure. Opportunistic infections may be acquired from the organ graft—cytomegalovirus (CMV) is the most pertinent example, but a wide variety of infections such as histoplasmosis or West Nile virus infection have been acquired from the graft (1,2). Solid-organ transplant recipients, by virtue of their being immunosuppressed, are also susceptible to reactivation of latent infections (such as CMV infection, tuberculosis, or histoplasmosis) or to infections acquired through the hospital environment (such as aspergillosis, legionellosis, or tuberculosis), but these infections typically do not appear in the immediate postoperative period. Genetic Susceptibility to Infection It is likely that some patients develop severe infections post-transplant because of a unique genetic susceptibility to infection. The genetic polymorphisms that determine this increased

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Risk Factors for Infection in the Recipient of an Organ from a Living Donor

Patient status at the time of transplantation Colonization with resistant organisms Nutritional status Renal function Operative and immediate postoperative factors Technical issues and time of surgery Donor infection status Genetic susceptibility to infection Net state of immunosuppression Prior use of T-cell depleting agents Current immunosuppression Environmental exposures Exposure to other patients Exposure to organisms in the hospital environment Exposure to organisms outside of hospital Use of antimicrobial prophylaxis Perioperative prophylaxis Prevention of pneumocystis, CMV, and fungi Abbreviation: CMV, cytomegalovirus.

risk of infection have not been well-characterized (3). An example of a potentially relevant genetic polymorphism includes mutation of the gene coding for the mannose-binding protein that is associated with chronic hepatitis B viral infection (4). Net State of Immunosuppression In solid-organ transplant recipients, the “net state of immunosuppression” (i.e., the cumulative burden of immunosuppression with a special weighting toward recent T-cell ablative therapy) influences the risk of infection. For example, a renal transplant recipient who is receiving tacrolimus monotherapy twice per week will likely be less susceptible to opportunistic infection than a patient with a recent acute cellular rejection treated with multiple doses of anti-lymphocyte globulin. There have been recent attempts to quantify immune function in solid-organ transplant recipients (5), although it has not yet been definitively proven that such tests are predictive of infection risk. Environmental Exposures Specific environmental exposures may be potentially important for transplant recipients. For example, a travel history to the southwestern states of the United States may increase the likelihood that an immunocompromised patient has coccidiomycosis. In contrast, histoplasmosis is endemic in the Ohio River Valley. There may even be environmental risks within the ICU. Outbreaks of invasive pulmonary aspergillosis have been linked to construction activity within the hospital (6). Outbreaks of legionellosis may be waterborne. It is likely that many fungal and bacterial infections may actually be waterborne as well (7,8). Tuberculosis transmission has been well-described in units caring for transplant recipients (9). Thus, the “net state of immunosuppression” must be considered in the context of recent environmental exposures and other risk factors mentioned in this chapter. Use of Antimicrobial Prophylaxis The use of agents such as trimethoprim/sulfamethoxazole for Pneumocystis jirovecii (formerly Pneumocystis carinii) prophylaxis is likely to reduce the risk of infections post-transplant. The use of antifungal or antiviral agents as prophylaxis may also have a role in infection prevention, and is discussed further below. GENERAL DIAGNOSTIC APPROACH TO THE TRANSPLANT RECIPIENT WITH A SEVERE INFECTION Although elements of history-taking and physical examination may narrow the differential diagnosis of the causative agent of infection in transplant recipients, it must be remembered

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that some of the “rules” applied to diagnosis in immunocompetent patients do not necessarily apply in this patient population. Caution must be exercised in use of the diagnostic principle that follows “Ockham’s razor” (“entities are not to be multiplied without necessity”). In the immunocompetent patient, given all the patient’s symptoms, signs and noninvasive laboratory test results, one unifying diagnosis usually explains all. However, transplant recipients may have more than one infection simultaneously. For example, a transplant recipient may have bacterial pneumonia and invasive pulmonary aspergillosis simultaneously, or P. jirovecii pneumonia and CMV simultaneously. The potential for multiple diagnoses underscores the need for early invasive testing in transplant recipients with severe infection. For example, patients with unexplained severe community-acquired pneumonia may be best managed by early bronchoalveolar lavage prior to the initiation of antimicrobial therapy aimed at numerous pathogens. Bronchoalveolar lavage can be sent for Gram stain, Ziehl Neelsen stain, modified acid-fast stain, calcofluor stain, direct fluorescent antibody tests, and cytologic analysis to enable rapid diagnosis of infection with bacteria, mycobacteria, Nocardia, fungi, Legionella, viruses, or P. jirovecii. The bronchoalveolar lavage should be inoculated onto solid media and appropriate cell lines to enable culture of pathogens cultivable by such techniques. Molecular diagnostic testing may be appropriate in some instances. Bronchoscopic biopsy or other invasive tests enabling a tissue diagnosis may also be required. An outline of the diagnostic approach in transplant recipients from living donors is given in Table 2. MAJOR MANIFESTATIONS OF INFECTION IN THE TRANSPLANT RECIPIENT Three major sites of infection in the transplant recipient are discussed—pulmonary infection, central nervous system (CNS) infection, and gastrointestinal tract infection. A large variety of organisms can cause infections at these sites. In the majority of circumstances, the differential diagnosis is too broad for definitive clinical diagnosis. This underscores the need for an aggressive diagnostic work-up in transplant recipients. Pulmonary Infection Pneumonia is a significant cause of morbidity and mortality in transplant recipients, including living-donor recipients. Unlike in the normal host, the impaired responsiveness of the immune system means that the disease presents in unusual ways, which may lead to challenges in establishing a diagnosis. Infectious microorganisms usually gain access to the respiratory tract through inhalation, although hematogenous spread, direct inoculation, or pathogenic transformation of normal airway flora may sometimes occur. Mechanical defenses remove the bulk of potentially harmful agents from the lungs. Inhaled particles above 10 μm in diameter usually get trapped in the upper airways or are removed by coughing or mucociliary clearance. Most bacteria range from 0.5 to 2 μm in size and are able to reach the terminal airways/alveoli and potentially cause infection. In the alveoli, the alveolar macrophages are the first line of defense. Subsequently, an inflammatory response comprising polymorphonuclear neutrophils is important. Finally, specific T-and B-cell immune responses are essential for successful defense against many pathogens. Most transplant recipients have an assortment of deficiencies in host defense working together. For example, an organ transplant recipient who is on immunosuppressive medication may also be intubated, diabetic, and on corticosteroids and tacrolimus. All these factors will contribute to the overall degree of immunity, each paving the way for its peculiar array of susceptibilities to pulmonary infection. In solid-organ transplant recipients, specific etiologies of pulmonary infection are most frequent at certain times post-transplantation (Table 3). A normal chest radiograph does not necessarily rule out pulmonary infection in transplant recipients. Additionally, while some diseases have very suggestive radiologic findings (e.g., apical cavitations in tuberculosis), most radiographic findings need to be interpreted in the light of all other data available. Computerized tomography may be required, for example, in the evaluation of pulmonary nodules. Pulmonary nodules have a broad differential diagnosis in the transplant recipient, including infections related to fungi (especially Cryptococcus neoformans,

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The Diagnostic Approach for Severe Infections in Transplant Recipients

History-taking and review of prior records Likely degree of immunocompromise Time since transplantation Recent acute cellular rejection or graft versus host disease, and treatment thereof Current or recent receipt of immunosuppressive medications Prophylaxis against opportunistic infections Receipt of antimicrobial prophylaxis against P. jirovecii, HSV, or CMV Vaccination status (pneumococcus, influenza, N. meningitidis) Family history Personal or family history of tuberculosis or chicken pox Potential environmental exposures Travel history to southwestern United States Exposure to hospital construction activity (aspergillosis) Exposure to hospital water supply (legionellosis, aspergillosis) Exposure to patients with tuberculosis or chicken pox Donor and recipient serostatus for CMV or Toxoplasma gondii Physical examination Skin Presence of cutaneous nodules consistent with cryptococcosis, nocardiosis, etc. Presence of cutaneous manifestations of graft versus host disease Kaposi’s sarcoma Line insertion site erythema or pus Peripheral embolic phenomena Scars consistent with prior surgery Mouth and other mucous membranes Presence of candidiasis Respiratory system Presence of signs of focal versus multilobar pneumonia Cardiovascular system Murmurs, prosthetic heart sounds Abdominal examination Signs of peritonitis Hepatomegaly or splenomegaly Tenderness of renal allograft Neurologic examination Nuchal rigidity Cranial nerve signs Non-invasive laboratory tests White blood cell count and differential Blood and urine cultures Serum cryptococcal antigen Serum galactomannan antigen (aspergillosis) Serum and urine histoplasma antigen Urinary Legionella antigen Invasive laboratory tests Bronchoalveolar lavage Pleural fluid aspiration Upper gastrointestinal endoscopy Colonoscopy Biopsy of liver, kidney, bone marrow Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus.

Coccidioides immitis, Aspergillus fumigatus), Nocardia, mycobacteria, Rhodococcus equi, and Bartonella. In addition, carcinomas and post-transplant lymphoproliferative disorder may present with pulmonary nodules (10). The differential diagnosis of cavitary lesions includes mycobacteria, invasive pulmonary aspergillosis, legionellosis (especially that due to Legionella micdadei), and infection with R. equi. The broad differential diagnosis of pulmonary infection in transplant recipients mandates early and aggressive diagnostic strategies, such as bronchoscopy with bronchoalveolar lavage, sent for a comprehensive battery of microbiologic investigations.

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TABLE 3 Occurrence of Pulmonary Infection After Solid-Organ Transplantation Stratified by Time from Transplantation Time after transplant <1 month

1–6 months

>6 months

Organism Methicillin resistant Staphylococcus aureus Gram-negative bacilli Legionella Aspergillus CMV Aspergillus Legionella Gram-negative bacilli (if still mechanically ventilated) Nocardia Mycobacteria Cryptococcus Coccidiodes immitis

Abbreviation: CMV, cytomegalovirus.

CENTRAL NERVOUS SYSTEM INFECTIONS Most infectious agents reach the CNS via hematogenous dissemination from an extraneural site. Exceptions include retrograde propagation of infected thrombi within emissary veins, spread along olfactory nerves, and spread from a contiguous focus of infection. The blood–brain barrier presents a natural and efficient barrier to hematogenous infection. The function of the blood–brain barrier in transplant recipients has not been well-studied. However, it is wellknown that once CNS infection is established, immune defenses (even in immunologically competent hosts) are inadequate to control the infection. Local opsonization is deficient within the brain. In animal models of bacterial brain abscess, corticosteroid administration leads to a reduction in macrophage and glial response, with an increased number of viable bacteria in the brain abscess (11). Bacterial meningitis from Neisseria meningitidis or Streptococcus pneumoniae is relatively uncommon in transplant recipients. Meningitis due to Listeria monocytogenes is classically associated with the immunocompromised host (Table 4), and may be seen in transplant recipients, reflecting the need for adequate T-cell function and interferon-gamma production to kill this intracellular pathogen (12). In addition to meningitis, Listeria infection may be associated with brain abscess, particularly in the brain stem (13,14). Enteric bacteria (e.g., Escherichia coli) are rare causes of bacterial meningitis in transplant recipients. However, a classical association exists between meningitis with such organisms and disseminated infection with Strongyloides stercoralis (15,16). In the presence of immunosuppression (such as large doses of corticosteroids),

TABLE 4

Central Nervous System Infections in Transplant Recipients

Etiologic agent Meningitis L. monocytogenes Enteric bacteria (e.g., E. coli ) C. neoformans MTB Meningoencephalitis HSV Human herpes virus-6 Varicella-zoster virus West Nile virus Space-occupying lesions Nocardia Fungi

Special considerations Predilection for brain stem Associated with disseminated Strongyloides infection Rapid diagnosis by cryptococcal antigen or India ink stain Consider PCR for rapid diagnosis Surprisingly rare in immunocompromised patients May be associated with lack of CSF pleocytosis Skin lesions yield diagnosis Transmitted via transplanted organ or blood Pulmonary lesions usually also present Pulmonary lesions usually also present

Abbreviations: CSF, cerebrospinal fluid; HSV, herpes simplex virus; MTB, Mycobacterium tuberculosis; PCR, polymerase chain reaction.

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Strongyloides can migrate from the gastrointestinal tract to the CNS, carrying enteric bacterial flora with it. Mortality is high without prompt recognition and treatment. Nocardia and mycobacteria also need to be considered in the differential diagnosis of CNS infections in immunocompromised patients, and diagnostic samples should be sent for inoculation onto appropriate media for the isolation of these organisms. Fungal infection of the CNS may cause meningitis or space-occupying lesions. Cryptococcal meningitis is associated with transplantation (17). The presentation is usually subacute, although dangerous elevations in intracranial pressure are sometimes observed. Unfortunately, spaceoccupying lesions in the brain may occur with disseminated mold infections. Such infections usually arise in the lung, but dissemination to the brain is part of multi-organ spread. Thus, mortality is extremely high. Any of the pathogenic molds such as Aspergillus (10), Zygomycetes (18), Scedosporium (19), or Fusarium (20,21) can disseminate to the brain. The dimorphic fungi (e.g., histoplasmosis, coccidiomycosis) may also disseminate from the lung, causing infection of the CNS. The zygomycetes may also be associated with frequently fatal infection arising within the nose or sinuses (rhinocerebral mucormycosis) (22). Of protozoa, Toxoplasma gondii and amebic encephalitis have been occasionally reported in transplant recipients, but are exceedingly rare. A variety of viruses can cause CNS infections in transplant recipients. Perhaps as a result of the widespread use of acyclovir, ganciclovir, or valganciclovir prophylaxis in transplant recipients, herpes simplex virus (HSV) encephalitis is quite rare (23). Some of the newer herpes viruses, such as HHV-6, have been associated with neurologic infection in transplant recipients (10,24). Lack of diagnostic capabilities for these viruses may partially explain their apparent infrequency. CMV meningoencephalitis has occasionally been reported in transplant recipients (25). Disseminated infection with varicella zoster virus (VZV) in transplant recipients may also result in CNS infection. West Nile virus may be acquired from transplanted organs or blood transfusions and is associated with a significant meningoencephalitis in transplant recipients (26,27). Given the wide variety of organisms that can cause CNS infection, there is a need for a broadly SIET based diagnostic work-up prior to starting empiric therapy. If cerebrospinal fluid is collected, it should be sent for Gram stain and Ziehl Neelsen stain for the rapid diagnosis of bacterial and mycobacterial infections. Polymerase chain reaction (PCR) can be applied to the diagnosis of some viral infections such as HSV, CMV, and VZV. Cryptococcal antigens can be rapidly detected in cerebrospinal fluid, enabling a rapid diagnosis of this form of meningitis. Cerebrospinal fluid may not be able to be collected in patients with space-occupying lesions of the brain. Fine needle aspiration may be performed in some circumstances. However, it is important to stress that before invasive diagnostic testing of the brain is performed, the patient’s skin should be examined for lesions (such as may occur with cryptococcosis or nocardiosis) and the lung carefully reviewed by computed tomographic imaging. Since most CNS lesions have disseminated from other parts of the body, a diagnosis is often easier made by microbiologic sampling of these body sites. Gastrointestinal Infections Gastrointestinal infections in transplant recipients may come to attention because of dehydration or, rarely, visceral perforation. As with respiratory and CNS infections, the differential diagnosis is usually broad, and a precise diagnosis can rarely be made based on clinical suspicion only. Transplant recipients have an increased predisposition to gastrointestinal infections depending on both their type and degree of immunocompromise and their exposure to certain pathogens. The most commonly involved organisms in the etiology of infective esophagitis or gastritis are Candida, CMV, and HSV, though a variety of other organisms (e.g., mycobacteria, zygomycetes) are occasionally implicated. A study of renal transplant patients in the United States showed that esophageal candidiasis was the most common fungal infection, and accounted for 22% of all fungal infections (28). Upper gastrointestinal endoscopy with biopsy is the gold standard for making the diagnosis. Diarrhea is a common problem in transplant recipients and has many etiologies. In a transplant recipient, it is important to differentiate diarrhea caused by opportunistic infections

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from that caused by drugs and other therapeutic agents. The prolonged use of multiple antibiotics in high doses predisposes patients to infection with Clostridium difficile and the development of pseudomembranous colitis (29,30). Antibiotic prophylaxis to prevent P. jirovecii pneumonia or spontaneous bacterial peritonitis has also been associated with C. difficile. In addition to the classical antibiotic risk factors of clindamycin or cephalosporin use, recent studies suggest that fluoroquinolones may be an increasingly common risk factor for C. difficile (31). Enteric bacterial pathogens such as Salmonella occur at increased frequency in transplant recipients, although compared with C. difficile, they are substantially less common. An exception to this statement would be living-donor transplant recipients in India and other areas where non-typhoidal Salmonella infections are particularly prevalent. Severe Salmonella infections may be associated with intestinal perforation. Infections with Shigella, Campylobacter jejuni, E. coli (enterotoxigenic, enteroadherent, and enteroaggregative), and Yersinia spp. are other bacterial causes of diarrhea, although individually quite uncommon in transplant recipients. Finally, mycobacterial infections, such as tuberculosis, can occasionally be associated with colitis (32). Protozoal infections, such as Cryptosporidium and Microsporidium, are occasionally observed in transplant recipients (33–35). It is important to note that these pathogens will not be detected on routine microscopic examination for ova, cysts, and parasites. Special stains and microbiologic techniques are needed. Routine examination will usually detect Giardia lamblia, Entamoeba histolytica, and other more common pathogenic protozoa. CMV can cause significant colitis in all immunocompromised populations. CMV colitis may occur in the absence of systemic evidence of infection (i.e., the CMV PP65 antigen may be negative). Thus, intestinal biopsy may be required to make the diagnosis. CMV intestinal infection may present with diarrhea, but may have more profound presentations such as with intestinal perforation (37–39). THERAPEUTIC DIFFICULTIES IN THE IMMUNOCOMPROMISED PATIENT Empiric Therapy The choice of empiric antimicrobial therapy is often difficult in the transplant recipient because of the broad differential diagnosis involved. The management of infection in the transplant recipient can be simplified by narrowing the differential diagnosis by thorough history-taking, review of prior medical records, and careful physical examination. Aggressive early diagnostic maneuvers, prior to starting empiric antimicrobial therapy, can enable a definitive diagnosis to be made. Failure to collect cultures prior to commencing empiric therapy can lead to prolonged, expensive, and unnecessary therapy. Empiric antibiotic therapy in suspected bacterial infections should be tailored to the individual patient in order to maximize the chance that empiric therapy is microbiologically adequate. There is a clear link between microbiologically adequate empiric therapy and the successful treatment of infections in the ICU (40). In settings such as severe, life-threatening pneumonia in the transplant recipient, empiric regimens comprising vancomycin, ciprofloxacin, meropenem, amphotericin, ganciclovir, and trimethoprim/sulfamethoxazole may be necessary to cover potentially lethal infections with methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Legionella, fungi, CMV, and P. jirovecii. Obviously, a regimen as broad as the one described above should always be preceded by bronchoscopy and collection of appropriate respiratory tract specimens, and should be streamlined to a narrower regimen as soon as possible. The decision to start empiric mycobacterial therapy in a transplant recipient is never an easy one. In general, we advise against it, unless there is a clear risk factor for tuberculosis. Empiric therapy for disseminated Strongyloides infection may have a place in transplant recipients, coming from an endemic area and with the classic presentation of disseminated infection. Transplant recipients presenting with acute meningitis should receive treatment, which will cover both S. pneumoniae and L. monocytogenes. The combination of vancomycin, ampicillin, and ceftriaxone may be necessary (vancomycin and ceftriaxone for multidrug-resistant S. pneumoniae and ampicillin for Listeria). The combination of an amphotericin preparation and 5-flucytosine is recommended empirically for meningitis, in which India ink stain of cerebrospinal fluid reveals encapsulated fungi, consistent with C. neoformans. Transplant recipients with

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space-occupying lesions of the brain could be treated empirically with an antifungal drug (amphotericin or voriconazole) if suspicion of disseminated fungal infection is high, although nocardiosis, toxoplasmosis, or mycobacterial infection would obviously not be covered without specific therapy. Again, the importance of specimen collection prior to initiation of empiric therapy is emphasized. For transplant recipients with severe diarrhea requiring ICU admission, empiric treatment with metronidazole (for C. difficile) and ganciclovir (for CMV) may be started after fecal samples have been collected and colonic biopsy performed. For immunocompromised patients with intestinal perforation, antibiotic coverage against gut flora (i.e., treatment of peritonitis) plus treatment of the most likely causes of perforation (e.g., ganciclovir for CMV) may be initiated. Pathogen-Directed Therapy—General Principles The importance of appropriate specimen collection is that empiric therapy can be streamlined if cultures or other diagnostic tests are positive. Unfortunately, in transplant recipients, antimicrobial therapy is often complicated by drug interactions or adverse drug reactions. Transplant recipients taking calcineurin inhibitors (e.g., cyclosporine or tacrolimus) are most at risk because these drugs are metabolized by the cytochrome P450 system. Therefore, significant interactions may occur between rifampin, macrolide antibiotics, or azole antifungal drugs, and the calcineurin inhibitors (10). Aggressive treatment of infections in transplant recipients (e.g., with amphotericin, pentamidine, or foscarnet) may be associated with renal dysfunction, compounding the nephrotoxic effects of the calcineurin inhibitors. Antimicrobial agents such as linezolid or ganciclovir may frequently cause neutropenia, potentially adding further host defense defects. SPECIFIC PATHOGENS OF IMPORTANCE IN TRANSPLANTATION Cytomegalovirus CMV is highly distributed in the population. Seroprevalence rates in adults are reported to be 80% to 90%. After a primary infection that usually occurs in the first two decades of life, CMV establishes latency and reactivates intermittently (41). CMV infection usually occurs in the first three months following transplantation, when immunosuppression is most intense; however, it may be delayed when patients are receiving prophylaxis. The risk of CMV infection is higher when the donor is seropositive and the recipient is seronegative for CMV (D+/R−). This recipient lacks CMV-specific immunity and rapid replication of the virus occurs, leading to severe CMV disease. Other risk factors for the development of CMV disease include the recipient’s net state of immunosuppression, use of anti-lymphocyte and monoclonal antibodies, coinfection with other viruses such as HHV-6 and HHV-7, and the type of allograft. In the absence of prophylaxis, the risk is highest in lung, small bowel, and pancreas recipients, and lowest in kidney recipients. The risk is lowest when both the donor and the recipient are seronegative, as long as the recipient only receives CMV-negative blood products (41,42). CMV infection is characterized by evidence of CMV replication without associated symptoms. CMV disease occurs when symptoms attributable to CMV are present. CMV disease can be further classified as CMV syndrome, characterized by fever and malaise, with or without leukopenia and thrombocytopenia, or tissue-invasive disease (pneumonitis, hepatitis, gastrointestinal disease, etc.). CMV has a predilection to invade the allograft (41,43), although this can be difficult to demonstrate. Serology (CMV IgG and IgM) is useful only to determine the patient’s risk at transplantation, not to aid the diagnosis. The diagnosis is currently based on detection of pp65 antigen, which has much higher sensitivity and specificity than culture-based methods (43). CMV PCR, which can be qualitative and quantitative, is also available. Occasionally, patients with tissue-invasive disease, especially with gastrointestinal disease, will have a negative pp65 antigenemia (36). In this setting, the diagnosis needs to be confirmed by histopathologic examination of the affected tissue. There are two prophylactic strategies available: universal and pre-emptive therapy. In the first, antiviral therapy is given to all patients at risk, beginning immediately post-transplantation,

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for a predetermined amount of time. In the latter, patients are monitored routinely for evidence of CMV replication prior to the onset of symptoms, and antiviral therapy is commenced whenever replication is detected. Both therapies have advantages and disadvantages. Resistant CMV has been observed with both therapies (2,12,44). To date, there have been no head-to-head comparisons between the two strategies. Drugs that have been used as universal prophylaxis include acyclovir, ganciclovir, valacyclovir, and valganciclovir. Acyclovir is less efficacious than ganciclovir, and should not be used in high-risk CMV D+/R− patients. Ganciclovir is available for both oral and intravenous administration. Valganciclovir is a prodrug of ganciclovir with improved bioavailability. It can be dosed once daily when used for prophylaxis. Intravenous ganciclovir is the therapy of choice for the treatment of CMV disease. A dose of 5 mg/kg every 12 hours should be used, with adjustment for renal dysfunction. Therapy should not be given for less than two weeks, and should be maintained until the viremia is resolved. BK Virus BK is a polyomavirus found worldwide. Primary infection usually occurs in childhood and is asymptomatic. Ninety percent of children have antibodies to BK virus by the age of 12. Seroprevalence rates are as high as 60% to 80% among adults (45,46). Persistent infection is established in the kidneys, peripheral blood, and brain. BK virus infection is reported to occur in 10% to 60% of kidney transplant recipients (47–49). Infections in recipients of other solid organ grafts are only occasional. The risk of disease is higher following intensification of immunosuppression. Viruria may occur early, in the first four to six weeks following transplantation, but the onset of BK disease is late, with a median time of nine to 14 months following transplantation. Tubulointerstitial nephritis is the most common manifestation of BK disease in renal recipients. The typical presentation is elevation in creatinine, often mistaken for rejection. Hematuria, lymphoceles, and obstructive uropathy can also occur. A rate of graft loss of 50% or more has been reported by several authors, although an old study, before the advent of modern immunosuppressive agents, failed to demonstrate an association between BK virus infection and loss of graft function (50). The definitive diagnosis is obtained by kidney biopsy. Quantitative BK virus PCR in the plasma has been shown to have a high sensitivity and moderate specificity for BK virus disease (44,51). Use of BK virus PCR in the urine is associated with better specificity and equivalent sensitivity when compared with the plasma (6,52). Treatment consists of reduction in immunosuppression while monitoring for the development of rejection. If rejection occurs, low-dose cidofovir has been used with success, although the experience is limited. The potential pitfall of cidofovir is its associated nephrotoxicity, which may limit its use. Leflunomide has also been reported to be effective. Prospective monitoring with appropriate reduction in immunosuppression may be the most effective way of preventing this complication. Aspergillus fumigatus and Other Aspergillus spp. Aspergillus is a ubiquitous mold found in soil, water, and plant debris. The most common species causing infection is A. fumigatus, but other common species include A. flavus, A. terreus, A. niger, and A. nidulans. The incidence of invasive aspergillosis varies according to the organ transplanted. The highest incidence of Aspergillus infections is observed in lung transplant recipients, and ranges from 6% to 16% (53). Liver recipients have a moderate risk of infection, ranging from 1% to 8% (24). The lowest incidence is observed in kidney transplantation, where it is not higher than 5% (24,54), and usually much less common. The net state of immunosuppression is the major risk factor for the acquisition of Aspergillus infection. Patients who have received high doses of corticosteroids and/or antilymphocytic therapy for the treatment of acute rejection, and those who have had a viral infection, particularly CMV infection, are at higher risk. Other risk factors have been identified in liver transplant recipients and include renal insufficiency, post-transplantation dialysis, retransplantation, prolonged intubation, and high bilirubin levels (10,36,55).

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Invasive pulmonary aspergillosis is the most common disease manifestation. It usually manifests with a dry cough and dyspnea. Hemoptysis and fever may also occur. In contrast to what is observed in neutropenic patients, a characteristic radiographic pattern is often lacking, and lung nodules (with or without cavitation) and areas of patchy consolidation or infiltrates are the findings most commonly encountered. Disseminated disease is not uncommon, occurring in at least 10% of patients. Almost any organ may be involved, but the fungus has a predilection for the CNS. This infection progresses rapidly, and prompt recognition is necessary. Diagnosis may be difficult, and often it is necessary to combine clinical suspicion, radiographic findings, culture, and histopathologic results. The cornerstone of diagnosis is the demonstration of tissue invasion by the organism, coupled with a positive culture of the same tissue. Serologic tests for the diagnosis of invasive aspergillosis, including galactomannan and (1→3)-β-d-glucan have performed poorly among solidorgan transplant recipients (56–58). The successful management of invasive aspergillosis depends on the prompt recognition and initiation of adequate antifungal therapy. Voriconazole is currently the drug of choice for the treatment of invasive aspergillosis (59). It is available for both oral and intravenous administration, and has good penetration into the CNS. It inhibits cytochrome P450 and significantly interacts with tacrolimus, cyclosporine, and sirolimus. Coadministration with the latter may be contraindicated and require drastic reduction of sirolimus in the order of 75% to 88%. Levels of the immunosuppressive drugs should be monitored closely and adjusted accordingly. Amphotericin B was the gold standard of therapy for several years. Its use was limited by the occurrence of infusion-related side effects and nephrotoxicity. The newer lipid formulations are generally better tolerated, but without clear documentation of improved efficacy. Caspofungin, an echinocandin, is well-tolerated and is associated with few side effects and drug interactions. It does not penetrate into the CNS in high concentration. Caspofungin levels may be increased by cyclosporine. Its different mechanism of action, blocking the synthesis of the fungal cell wall, has generated great interest in its use in combination with other antifungal agents. However, while the use of combination antifungal therapy seems promising, at the moment there is no concrete evidence to support its use. Therapy should be given for at least 12 weeks. Longer courses may be given depending on resolution of clinical and radiographic findings. Cryptococcus Cryptococcus is a ubiquitous encapsulated yeast. The incidence of cryptococcal infection in organ transplant recipients ranges from 1% to 5% (60,61), with an overall mortality rate of 42% (62). CNS infection is the most common form of disease, seen in more than half of the cases, followed by cryptococcal pneumonia, skin and osteoarticular infection. Disseminated disease may also occur. Infection usually occurs late, more than three months following transplantation. CNS infection presents as sub-acute meningitis. Headache, fever, nausea, vomiting, confusion, and lethargy are the most common presenting symptoms. Meningismus is rare. Patients with pulmonary cryptococcosis usually present with cough, fever, and dyspnea. Diagnosis can be made by direct microscopic examination of cerebral spinal fluid (CSF), bronchoalveolar lavage or tissue, and culture or detection of polysaccharide antigen in body fluids or serum. Cryptococcal infection can be present despite a negative serum cryptococcal polysaccharide antigen, and this test should not be used alone to exclude infection (60,63). The radiographic findings in cryptococcal meningitis are nonspecific, ranging from normal to spaceoccupying lesions. Cryptococcal pneumonia most often presents as infiltrates, which are often nodular. The treatment of choice for patients with cryptococcal meningitis is the combination of amphotericin B and 5-flucytosine. The lipid formulations of amphotericin B can be used instead of the deoxycholate formulation. Combination therapy should be given for at least two weeks and can be followed by fluconazole, for at least another 10 weeks of therapy. In the case of isolated pulmonary infection, fluconazole can be used as the initial therapy. Repeated therapeutic lumbar punctures may be necessary in those patients who present with elevated opening pressures; that is, >20 cmH2O.

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Nocardia Nocardia is an aerobic, gram-positive, branching bacteria found in soil, organic matter, and water worldwide. The species most commonly associated with infection in transplant recipients are Nocardia asteroides complex (includes N. asteroides sensu strictu, N. farcinica, and N. nova), N. brasiliensis, N. otitidiscaviarum, and N. transvalensis (64). The incidence of nocardiosis in solid-organ transplant recipients varies from 0.13% to 5%, with most studies reporting an incidence of 0.7% to 3% (65–72). Infections occur mostly in heart, kidney, and liver transplant recipients (64,68,72). Nocardia infection usually occurs late after transplantation. It is very unusual to observe infection in the first month following transplantation. The median time of onset has ranged from six weeks to 48 months, with most infections occurring more than three months after transplantation (66–68,72). Pulmonary infection is the most frequent manifestation of nocardiosis, occurring in approximately 88% of cases (68). The presentation is usually nonspecific and includes fever, cough, pleuritic chest pain, dyspnea, and weight loss. Radiological presentation is variable. Nodules or nodular infiltrates with or without cavitary changes are the most common abnormality seen, but alveolar infiltrates, pleural effusion, lobar consolidation, and mass lesions can be seen. Computed tomography of the chest is the best imaging technique available to visualize the abnormalities produced by pulmonary nocardiosis. Involvement of the CNS occurs in approximately 20% (68,73) of cases. The presentation is usually with single or multiple abscesses, with symptoms of a space-occupying lesion, such as seizures and focal deficits. However, it is not infrequent to observe asymptomatic metastatic dissemination to the CNS. Therefore, it is imperative to obtain an MRI of the brain, looking for abscesses whenever pulmonary nocardiosis is diagnosed. Nocardial infections may also present with subcutaneous nodules. This is the second most common site of dissemination after the CNS, and is reported in 9% to 15% of cases (68). When present, cutaneous involvement may facilitate early recognition and diagnosis of nocardiosis. Other sites of dissemination include endophthalmitis and septic arthritis (74,75). There is no effective prophylaxis for nocardiosis. The use of trimethoprim-sulfamethoxazole (TMP-SMX) for P. jirovecii prophylaxis reduces the rates of Nocardia infections; however, there are reports of breakthrough infections (72,76). Making the diagnosis of nocardiosis often involves performing invasive procedures to obtain specimens from the affected sites. Nocardia usually stains with a modified acid-fast stain (Kinyoun), appearing as delicately branching gram-positive beaded rods. The definitive diagnosis requires growth of the organism on culture from a suspected site. Growth may occur in 48 hours, but typically takes five days to three weeks (68). There are currently no serological tests available to aid in the diagnosis of nocardiosis. The initial choice of antibiotic therapy for the treatment of Nocardia should take into account the site and severity of disease, and the Nocardia spp., if available. Susceptibility testing is recommended, but is available only in a few reference laboratories, and results are not promptly available. Furthermore, it is not known how well in vitro and in vivo susceptibilities correlate. N. farcinica, N. nova, and N. otitidiscaviarum may be resistant to the sulfonamides; N. farcinica, N. transvalensis, and N. otitidiscaviarum are resistant to the cephalosporins. Thus, the preferred regimen in a transplant patient with nocardiosis, especially if the patient is severely ill, is one that uses combination therapy. The sulfonamides are the mainstay of therapy. Among all the sulfonamides, TMP-SMX is the preferred agent to treat nocardiosis. Imipenem coadministered with amikacin is an alternative regimen accepted for the treatment of pulmonary and cerebral infections. The third-generation cephalosporins, ceftriaxone, and cefotaxime are a good alternative for cerebral infections. They are usually safe and have very good penetration through the blood–brain barrier. The only concern is the resistance to third-generation cephalosporins observed among N. farcinica, N. transvalensis, and N. otitidiscaviarum strains. Linezolid has become a commonly used drug in the management of nocardiosis. It has activity against all the Nocardia species, including N. farcinica. It can be administered orally or intravenously, has excellent bioavailability, and penetrates the blood–brain barrier. Minocycline is an alternative to TMP-SMX. It can be administered orally and intravenously, and penetrates well in the CNS.

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Surgical drainage, in conjunction with antibiotic therapy, may be necessary if medical therapy alone is failing. The usual indications for surgical drainage would be large cerebral abscesses or soft tissue collections. For any transplant recipient with nocardiosis, an important component of the therapy is reduction or complete cessation of immunosuppression (64). The duration of therapy will depend on the sites involved, response observed, and resolution of disease. It should be at least six months for pulmonary and soft tissue infections and at least nine to 12 months in the case of cerebral infection. Overall mortality is 25%, but varies according to the site of disease, from 3% among those with isolated soft tissue infection to as high as 44% when the CNS is involved (68). Mycobacterium tuberculosis Organ transplant recipients are at a significant risk of developing Mycobacterium tuberculosis (MTB) infection when compared with the general population. Although the rates of infection are extremely low in the United States and Western Europe, where the prevalence of MTB in the population is low, this represents a major threat in developing countries and to recipients of organs from donors originally from these areas. The majority of cases of tuberculosis following transplantation, about two–thirds, occur in the first year (77). In most cases, infection is related to reactivation of latent tuberculosis. Patients with evidence of old tuberculosis on chest radiograph or a positive tuberculin skin test prior to transplantation, and those who have lived or live in an endemic area for tuberculosis, are at higher risk. Transmission of MTB from the donated organ has been documented (78). Nosocomial acquisition has also been documented, but this is a rare event (79). Tuberculosis may present in atypical ways after transplantation, and a high index of suspicion is necessary in order to make the diagnosis. About half of the cases may have disseminated or extrapulmonary disease. Organ transplant candidates should be carefully evaluated for evidence of latent tuberculosis. A tuberculin skin test should be performed in all candidates, and a chest radiograph should be obtained searching for evidence of healed tuberculosis. The tuberculin skin test should be considered positive if it has an area of induration of ≥5 mm at 48 to 72 hours. The medical history should be carefully reviewed, focusing on a history of previous seroconversion of tuberculin skin testing and treatment administered, or a history of previous active tuberculosis infection and treatment. For the latter, it is important to review the medical records pertaining to therapy, noting the adequacy of drugs, and to duration chosen. The living donor should undergo the same evaluation as the recipient. Candidates with latent tuberculosis should undergo therapy with isoniazid 300 mg a day for nine months. They should also receive pyridoxine 25 to 50 mg a day to prevent the development of neuropathy. Isoniazid can be hepatotoxic, and patients should be monitored carefully. Elevations of transaminases to two to four times normal are common with isoniazid and may not require immediate discontinuation of the drug. However, it should prompt more careful monitoring of the liver enzymes. For recipients of organs from living donors, treatment of latent tuberculosis can be started after transplantation, when the patient is clinically more stable. The only exception is if the candidate has just recently converted his tuberculin skin test, in which case the chances of active infection are higher, and treatment should not be delayed. The patients who cannot tolerate isoniazid therapy should be carefully clinically monitored, with special attention given to respiratory symptoms and protracted fever (80). The standard treatment of active tuberculosis includes initial therapy with four drugs: rifampin, isoniazid, pyrazinamide, and ethambutol. Once it is known that the MTB is susceptible to isoniazid, ethambutol can be discontinued. Therapy with rifampin, isoniazid and pyrazinamide should be continued for a total of two months. After that, pyrazinamide is discontinued, and rifampin and isoniazid are continued for an additional four months, in the case of pulmonary disease. A longer duration, of at least 12 months, is recommended in cases of disseminated or extrapulmonary disease. Rifampin interacts strongly with the calcineurin inhibitors, and is frequently substituted with rifabutin, associated with less interaction but with similar anti-MTB activity. If patients are intolerant of therapy, second-line regimens that frequently include a fluoroquinolone can be used; however, therapy will have to be prolonged to much longer than 12 months (80,81).

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PREVENTION OF INFECTIONS Perioperative Antibiotic Prophylaxis Intravenous antibiotics should be commenced within 60 minutes prior to skin incision. In general, we would recommend cefazolin as prophylaxis for renal transplantation, since the main organisms to be covered are skin staphylococci and streptococci. In patients with a history of MRSA colonization, vancomycin may be substituted. In general, ampicillin/sulbactam is appropriate as prophylaxis in liver transplantation. This antibiotic will cover staphylococci and streptococci, as well as enterococci and enteric gram-negative bacilli. There is no proven benefit of continuing antibiotic prophylaxis for more than 48 hours postoperatively, and we do not recommend this practice. Postoperative Prophylaxis Prevention of infection in the transplant recipient should take primary importance. Pneumonia can be readily prevented by a number of strategies. Firstly, ventilator-associated pneumonia may be prevented by semi-recumbent posturing and use of sucralfate (rather than H2 blockers) for stress ulcer prophylaxis (82). The role of aspiration of subglottic secretions and selective digestive tract decontamination are still controversial. Opportunistic pneumonia with P. jirovecii can be prevented by use of prophylaxis with trimethoprim/sulfamethoxazole, dapsone, or nebulized pentamidine. We prefer lifelong prophylaxis. Environmental exposure to Legionella, Aspergillus, and MTB can be prevented by ensuring water purification techniques (e.g., copper–silver ionization) and by preventing exposure of patients to construction activity or infected patients. A number of extrapulmonary infections can be prevented. CMV infection can be prevented by ganciclovir or valganciclovir prophylaxis, although some centers prefer a pre-emptive approach using serial monitoring of peripheral blood (6). A similar pre-emptive approach in preventing aspergillosis by monitoring peripheral blood for the galactomannan antigen has been proposed (59,83), but we have not found this to be useful in solid-organ transplant recipients. C. difficile infection is difficult to prevent since there is a clear need for antibiotic therapy for transplant recipients with infection. It is suggested that prophylactic metronidazole may play a role in this regard (84). Finally, attention to classic infection control practices such as hand hygiene and contact isolation is of paramount importance in immunocompromised patients. CONCLUSION Infection is likely to be the most significant problem a transplant recipient will face. Good surgical technique and avoidance of over-immunosuppression play an important role in infection prevention. Unfortunately, antibiotic resistance is likely to outstrip the ability of pharmaceutical manufacturers to develop new antimicrobial agents—antibiotics, antiviral agents, and antifungal drugs should be looked upon as a finite resource that should be used cautiously for fear of losing access to these agents, which have made transplantation a safe endeavor. REFERENCES 1. Iwamoto M, Jernigan DB, Guasch A, et al. Transmission of West Nile virus from an organ donor to four transplant recipients. N Engl J Med 2003; 348:2196–3203. 2. Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 2000; 356:645–649. 3. Zaas AK, Schwartz DA. Innate immunity and the lung: defense at the interface between host and environment. Trends Cardiovasc Med 2005; 15:195–202. 4. Thomas HC, Foster GR, Sumiya M, et al. Mutation of gene of mannose-binding protein associated with chronic hepatitis B viral infection. Lancet 1996; 348:1417–1419. 5. Kowalski R, Post D, Schneider MC, et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant 2003;17:77–88. 6. Vats A, Shapiro R, Singh Randhawa P, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children and adults. Transplantation 2003; 75:105–112.

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67. Kalender B, Apaydin S, Altiparmak MR, et al. Opportunistic pulmonary infection after renal transplantation. Transplant Proc 2000; 32:563–565. 68. Wilson JP, Turner HR, Kirchner KA, Chapman SW. Nocardial infections in renal transplant recipients. Medicine (Baltimore) 1989; 68:38–57. 69. Kursat S, Ok E, Zeytinoglu A, Tokat Y, et al. Nocardiosis in renal transplant patients. Nephron 1997; 75:370–371. 70. Leaker B, Hellyar A, Neild GH, Rudge C, Mansell M, Thompson FD. Nocardia infection in a renal transplant unit. Transplant Proc 1989; 21:2103–2104. 71. Gutierrez H, Salgado O, Garcia R, Henriquez C, Herrera J, Rodriguez-Iturbe B. Nocardiosis in renal transplant patients. Transplant Proc 1994; 26:341–342. 72. Husain S, McCurry K, Dauber J, Singh N, Kusne S. Nocardia infection in lung transplant recipients. J Heart Lung Transplant 2002; 21:354–359. 73. Hellyar AG. Experience with Nocardia asteroides in renal transplant recipients. J Hosp Infect 1988; 12:13–18. 74. Lerner PI. Nocardiosis. Clin Infect Dis 1996; 22:891–903; quiz 904–905. 75. Tan SY, Tan LH, Teo SM, Thiruventhiran T, Kamarulzaman A, Hoh HB. Disseminated nocardiosis with bilateral intraocular involvement in a renal allograft patient. Transplant Proc 2000; 32:1965–1966. 76. Munoz P, Munoz RM, Palomo J, Rodriguez-Creixems M, Munoz R, Bouza E. Pneumocystis carinii infection in heart transplant recipients. Efficacy of a weekend prophylaxis schedule. Medicine (Baltimore) 1997; 76(6):415–422. 77. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998; 27:1266–1277. 78. Peters TG, Reiter CG, Boswell RL. Transmission of tuberculosis by kidney transplantation. Transplantation 1984; 38:514–516. 79. Sundberg R, Shapiro R, Darras F, et al. A tuberculosis outbreak in a renal transplant program. Transplant Proc 1991; 23:3091–3092. 80. Mycobacterium tuberculosis. Am J Transplant 2004; 4 (suppl 10):37–41. 81. Rubin RH. Management of tuberculosis in the transplant recipient. Am J Transplant 2005; 5:2599–2600. 82. Collard HR, Saint S, Matthay MA. Prevention of ventilator-associated pneumonia: an evidence-based systematic review. Ann Intern Med 2003; 138:494–501. 83. Bretagne S, Costa JM, Bart-Delabesse E, Dhedin N, Rieux C, Cordonnier C. Comparison of serum galactomannan antigen detection and competitive polymerase chain reaction for diagnosing invasive aspergillosis. Clin Infect Dis 1998; 26:1407–1412. 84. Keven K, Basu A, Re L, et al. Clostridium difficile colitis in patients after kidney and pancreas-kidney transplantation. Transpl Infect Dis 2004; 6:10–14.

32

Pregnancy After Living-Donor Transplantation Vincent T. Armenti Department of Surgery, Abdominal Organ Transplant Program, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Michael J. Moritz Department of Surgery, Lehigh Valley Hospital, Allentown, Pennsylvania, U.S.A.

John M. Davison Department of Obstetrics and Gynecology, University of Newcastle Medical School of Surgical and Reproductive Sciences, Newcastle Upon Tyne, U.K.

INTRODUCTION Successful pregnancy outcomes have been reported after all types of solid organ transplantation (1–7). As immunosuppressive agents and medications for other comorbidities (i.e., hypertension, diabetes, etc.) are required in transplant recipients, concerns for pregnancy in this population include the effects of these medications on the developing fetus. Additional concerns relate to the effect of pregnancy on the well-being of the mother and the transplanted organ. Although there are real risks to the mother, the transplanted organ, and the fetus, successful pregnancies are likely in transplant recipients in the presence of stable graft function and with adequate control of comorbidities (8). Thus far, there does not appear to be an increase in the type or incidence of congenital malformations. Most pregnancies proceed without evidence of graft dysfunction and/or irreversible deterioration in graft function. Efforts to improve immunosuppression, with new agents and new combinations of agents, aim to decrease acute and/or chronic rejection and/or improve the overall safety profile. The introduction of each new immunosuppressive agent brings complex issues to this area including: (i) limited reproductive safety data; (ii) the potential for new combinations of agents to pose an increased risk of teratogenicity; and (iii) new complexity of the equations that balance optimal transplant organ function against fetal risk. An additional element of risk to the mother is the occasional unpredictable occurrence of graft deterioration and graft loss accompanying the pregnancy, even in the setting of stable graft function. Given the potential for an adverse event, another issue for the recipient contemplating pregnancy is the source of the transplanted organ, i.e., living or deceased donor. As a livingdonor organ is a precious commodity, the consequences of graft loss pose an additional area of concern to the recipient as well as the impact on the donor. A balance of good maternal and graft outcome with the lowest risk of fetal toxicity are the goals of managing pregnancy after transplantation. This chapter reviews background information on pregnancy in the transplant population, as well as the commonly used immunosuppressive agents and concepts of teratology as they relate to these agents. Pregnancy outcomes will be reported, followed by a discussion of management options based on published literature and consensus opinions. While there have been many successful pregnancies reported in the literature, to date there has not been a large-scale or detailed analysis separating pregnancy and graft outcomes for living-donor recipients compared with deceased-donor recipients. TERATOLOGY CONCEPTS AND COMMONLY USED IMMUNOSUPPRESSIVE AGENTS From the early 1960s until the early 1980s, immunosuppressive regimens were based on azathioprine (AZA) and prednisone. Certain facts are apparent from the literature and reviews

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of this era. Approximately 35% of conceptions did not continue beyond the first trimester (9). Pregnancies continuing beyond the first trimester experienced an overall complication rate of 49%. If complications occurred prior to 28 weeks of gestation, a successful obstetric outcome occurred in 70%, compared with 93% success if the pregnancy was trouble-free prior to 28 weeks. Problems were reported in 12% of women after delivery, but when the pregnancy was complicated prior to 28 weeks, problems occurred in 25%. Preterm delivery was common, 45% to 60%, and small for gestational age infants were delivered in about 20% of cases; usually, the two problems occurred together (9). Over 50% of liveborn had no neonatal problems. Problems that were reported in these newborns included: thymic atrophy, transient leukopenia, CMV and hepatitis B infection, bone marrow hypoplasia, reduced blood levels of IgG and IgM, septicemia, transient chromosome aberrations in lymphocytes, hypoglycemia, hypocalcemia, and adrenocortical insufficiency (10). No frequent or predominant structural malformations were reported. Cyclosporine (CsA) became the mainstay of immunosuppressive therapy in combination with AZA and prednisone in the 1980s. Early reports raised concern that CsA might be associated with a greater degree of intrauterine growth restriction (11); however, these early reports were not borne out in later studies and were likely related to initial early experiences, including higher dosing. Approximately a decade later, tacrolimus (Prograf®, tacro) was introduced. Successes in the literature were observed not only in renal recipients but also in liver, heart, lung, and pancreas-kidney recipients (12). In the mid-1990s, mycophenolate mofetil (CellCept®, MMF) was introduced, and in 1999 sirolimus (Rapamune®) was approved by the FDA. With these two agents, new concerns of a risk of teratogenicity were raised (13,14). Congenital Anomalies Approximately 3% to 5% of children born in the United States manifest some structural birth defect. A minority of defects can be attributed to a variety of causes, but the majority are classified as having unknown etiology. It is estimated that only approximately 2% to 3% of these defects are classified as teratogen-induced malformations or malformations as the result of environmental or drug exposures during pregnancy (15). In addition to the exposure risk, the susceptibility to teratogenesis depends upon the genotype of the conceptus, and the manner in which the interaction occurs between the conceptus and the environmental exposure. The transplant population is not only exposed to immunosuppressive agents, but is also a population with known comorbidities and other multiple medication exposures, and individual susceptibility as well. Despite all of these potential risks, to date case reports and registries have not observed specific patterns of malformations or an increase in the incidence of malformations in the offspring of female transplant recipients, but data are only now accruing in extra-renal allograft recipients, as well as with the newer agents where there is greater concern (12,16,17). The US Food and Drug Administration (FDA) categories for pregnancy safety are noted in Table 1 with the immunosuppressive agents listed. A review of the literature that analyzed 468 steroid-exposed non-transplant pregnancies noted an overall malformation rate of 3.5%, which was not greater than that reported in the general population (18). In animal studies, corticosteroids, especially in mice, reproducibly have been shown to cause cleft palate (19). In human pregnancies, corticosteroids have been implicated in increasing the risk of premature rupture of membranes, as well as adrenal insufficiency in newborns (20). They are classified as category B agents and are thus considered to be at low teratogenic risk (21). Possible Immunosuppressive Associated Congenital Anomalies AZA is an inhibitor of purine metabolism and is converted rapidly after absorption into a number of metabolites, including the active metabolite 6-mercaptopurine, which has been found in cord blood. A suggestion in the literature is that the embryo would be protected against the effects of AZA, because the fetus lacks the enzyme inosinate pyrophosphorylase, the enzyme which converts 6-mercaptopurine to the agents that act on DNA and dividing cells (22,23). While teratogenicity of AZA was noted in animal studies with embryonic resorptions and/or fetal anomalies, the clinical data have not supported these concerns over the years (2,24,25).

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TABLE 1 FDA Pregnancy Categories for Commonly Used Transplant Immunosuppressive Drugs in Transplantation Drug Corticosteroids (prednisone, methylprednisolone, others) AZA (Imuran®) CsA (Sandimmune®, Neoral®, others) Tacrolimus, FK506 (Prograf®) Antithymocyte globulin (Atgam®, ATG, Thymoglobulin®) Orthoclone (OKT®3) Mycophenolate mofetil (CellCept®) Mycophenolic acid (Myfortic®) Basiliximab (Simulect®) Daclizumab (Zenapax®) Sirolimus (Rapamune®)

Animal reproductive data

Pregnancy category

Y Y Y Y N N Y Y Y N Y

B D C C C C C C B C C

Abbreviations: AZA, azathioprine; B, no fetal risk, no controlled studies; C, fetal risk cannot be ruled out; CsA, cyclosporine; D, evidence of fetal risk. Source: From Ref. 8.

AZA use has decreased markedly with the availability of newer agents. Despite its category D rating, it has remained an option for use during pregnancy. In some cases, recipients on MMF have been switched to AZA as a time-tested alternative. For the calcineurin-inhibitors CsA and tacro, reproductive studies revealed fetal toxicities, fetal resorptions, and abnormalities at dosages higher than those used clinically (26,27). In addition to registry data, there have been two extensive analyses of the two primary immunosuppressives, CsA and tacro. In a meta-analysis of CsA from the MotherRisk program in Toronto, Canada, the overall prevalence of malformations was 4.1% (41 of 339 births). This was not felt to be greater than that in the general population (16). In another study, 84 women treated with tacro (83 transplant recipients and one autoimmune disease patient) were analyzed (12). There were 71 pregnancies that went on to delivery, with 68 of these resulting in liveborn. In this group, four of the 71 (5.6%) had evidence of structural malformation, but no specific pattern was evident. Both studies concluded that these agents were not associated with an increased incidence of malformations. MMF and sirolimus, while also listed as category C, have other concerns. With MMF, rats and rabbits exhibited developmental toxicities, malformations, intrauterine deaths, or intrauterine growth restriction at doses that appear to be comparable to the recommended clinical doses in humans, based on dosing by body surface area (13). Therefore, interpretations of these reproductive studies in animals indicate that there may be the possibility of risk in humans, as there is no safety margin (i.e., therapeutic dose and dose with toxicity overlap). The MMF package insert states that pregnancy avoidance practices be utilized while on this agent. The European Best Practice Guidelines (EBPG) also supported this statement in a recent publication (28). Sirolimus, a macrolide antibiotic, has no effect on calcineurin activity, but inhibits cytokine-driven T-cell proliferation (14). As an antiproliferative agent, concern exists about the potential for teratogenicity. In animal reproductive studies, decreased fetal weights and delayed ossification of skeletal structures were reported. When combined with CsA, there was increased embryo/feto mortality in rats compared with sirolimus alone. Again, pregnancy avoidance is recommended in the package insert and by the EBPG (28). Other agents that can be used transiently for the treatment of rejection or for induction have a minor role with regard to pregnancy, although there may be exposures. OKT3, used for induction or rejection, has no available reproductive studies. Limited numbers of clinical cases have been noted in the registry, with no clear-cut reproductive toxicity. This is also the case with antithymocyte globulin, basiliximab, and daclizumab, the latter two produced by recombinant DNA technology and used only as induction agents. Basiliximab is a category B agent with no maternal toxicity, embryo toxicity, or teratogenicity noted in monkeys in the organogenesis period. Daclizumab is a category C agent, without reproductive information available (see Table 1).

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NATIONAL TRANSPLANTATION PREGNANCY REGISTRY Background In the 1980s, with the advent of CsA, new issues arose concerning pregnancy safety in the transplant population. The National Transplantation Pregnancy Registry (NTPR) was established in 1991 to study the safety of pregnancy in the transplant recipient population, including the assessment of pregnancy outcomes in female transplant recipients, as well as those pregnancies fathered by male transplant recipients. Table 2 lists the total number of female recipients in the NTPR. With the accumulation of CsA data, initial analyses compared CsA-treated recipients with AZA-treated recipients (29). Of note, there was a higher incidence of hypertension among the CsA-treated recipients associated with lower mean birthweights and lower mean gestational ages in the newborns. Similar to AZA-exposed offspring, there was no predominant pattern of structural malformations. Hypertension, shorter transplant-to-conception intervals, and higher prepregnancy recipient creatinine levels were noted among the factors in kidney recipients in those pregnancies associated with lower birthweights. From this multivariate analysis, hypertension was the most significant comorbidity (29). In the intervening years, there have been a number of case and center studies as well as continued registry data analyses. Table 3 compiles pregnancy reports from the NTPR and large organ-specific literature reports. Overall Outcomes from the NTPR Regarding overall NTPR data (8), among the female recipients, there is a higher incidence of prematurity and low birthweight compared with the general population. The maternal conditions evaluated include: transplant-to-conception interval, hypertension, pre-eclampsia, diabetes, rejection, and graft loss within two years of delivery. Many pregnancies are complicated by hypertension and/or pre-eclampsia, and a small number are complicated by rejection and/or peripartum graft function deterioration. Although hypertension is greater than in the general population, the range of drug-treated hypertension varies from recipient group to recipient group, and is lowest in the liver recipients and highest in pancreas–kidney (PK) recipients. Similarly, pre-eclampsia ranges from a low of 10% in heart recipients to 34% in PK recipients. Diabetes has a low incidence and it has been noted that the PK recipient is able to tolerate pregnancy with euglycemic control. Diabetes is highest among the lung recipients, likely influenced by the higher incidence of rejection and the use of steroids during pregnancy. Similarly, rejection rates vary among recipient groups. The highest is among the heart and lung recipients, but in the heart recipients many of these were not treated, as they were diagnosed on protocol biopsy and were low-grade. In lung recipients these appear to be of significant consequence, as there is a higher incidence of graft function deterioration. Fortunately, graft loss among recipient groups is low, except for the 21% incidence among lung recipients. No heart recipients have had graft loss within two years of delivery. While overall prematurity and low birthweight are common, heart and liver recipients have reported deliveries on average closer to term and higher birthweight, compared with other recipient groups. TABLE 2 National Transplantation Pregnancy Registry—Total Reported Pregnancies in Female Transplant Recipients Organ Kidney Liver Liver-kidney Pancreas-kidney Pancreas alone Heart Heart-lung Lung Totals a Includes twins and triplets. Source : From Ref. 8.

Recipients

Pregnancies

Outcomesa

764 126 4 41 1 36 3 15 990

1180 211 6 66 2 60 3 19 1547

1216 215 7 68 2 60 3 21 1592

383 NR 25 0

Tacro-based Tacro-based Neoral based

CsA-based CsA-based

CsA-based n = 5 Tacro-based n = 1

21/27 15/21 14/18

17/19 18/23

6/6

c

b

4 5 24

CsA-based

20

25 21

24

f

Pre-eclampsia (%)

35/47

115/154 146/238

CsA-based 52% AZA-based 38% Tacro-based 0.5% Not reported-10% CsA-based AZA-based 92% Steroid only 8%

Immunosuppression

Newborn malformations. Graft loss within two yrs of delivery. International review including NTPR data. d Not available, only live births reported. e Neonatal deaths excluded from analysis. f NR-not reported. g One kidney and one pancreas loss in two different recipients. h One kidney and one pancreas/kidney loss in two different recipients. Abbreviations: BW, birthweight; GA, gestational age. Source: From Ref. 31.

a

Heart Branch et al.c Liver Jain et al. NTPR NTPR Pancreas-kidney Barrou et al. (30) NTPR Lung NTPR

NTPR

189/194

Recipients/ pregnancies

d

50

N/A 87

N/A 76 72

74

69 83

82

Liveborn (%)

e

32.8

35 34.8

36.6 37.4 36.9

37

35.6 36.2

35.7

Mean GA (wks)

2202

2150 2041

e

2638 3069 2565

2543

2407 2684

2360

Mean BW (gms)

67

11 35

11 38 23

20

22 30

a

3

0

0 0

7 0 0

0

0.9 2.4

1.4

33

0 8.7

11 14 6

24

15 6

19

17

b

g

12 h 11

10 b 0 b 6

26

8 b 4

b

13

Graft dysfunction/ Graft loss Neonatal Newborn (%) complications (%) deaths (%) rejection during (%)

Comparison of Pregnancy Data Reports in the Literature with Those from the National Transplantation Pregnancy Registry

Kidney Toma et al.

TABLE 3

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Is it reasonable to expect that a pregnancy can be well-tolerated in the transplant population, considering the multiple comorbid conditions and immunosuppressive exposures? Series in the literature in the 1970s and 1980s have attested to the thousands of successful post-transplant pregnancies (2,32). The crucial issues that need to be considered include: does pregnancy in and of itself adversely affect graft function, is immunosuppression necessary in pregnancy, and what are the requirements during pregnancy to maintain stable graft function? Pregnancy and Long-Term Graft Prognosis Case-controlled studies comparing transplant recipients with pregnancies to recipients who did not become pregnant suggest that pregnancy in and of itself does not cause deterioration in graft function (33–37). There might be a minor deleterious effect, as shown by an update of one of these studies (35). This is supported by NTPR data where graft loss within two years of delivery has been infrequent, except for lung recipients. NTPR data further suggest that there may be minor deleterious effects on kidney function in some recipients, as there is a slightly higher mean post-partum serum creatinine when compared with prepregnancy. Pregnancy may unpredictably have a deleterious affect on graft function. This appears more likely in the setting of prepregnancy graft dysfunction. An NTPR analysis showed that CsA-treated renal recipients with serum creatinine levels prepregnancy ≥2.5 mg/dL were three times more likely to experience graft loss post-partum than recipients with a mean serum creatinine level ≤1.5 mg/dL (38). Similar outcomes were noted among the recipients studied in the U.K. National Register, where it was identified that lower prepregnancy serum creatinine levels were a favorable predictor for pregnancy outcome (39). Another study illustrated the presence of chronic rejection as a prepregnancy risk for pregnancy-related graft deterioration (40). Serum creatinine alone, however, may not be a sufficient predictor. A more recent analysis of outcomes of six Neoral or tacrolimus-based female kidney recipients with biopsy-proven acute rejection episodes during pregnancy noted a range in prepregnancy creatinine from 1.0 mg/dL to 3.0 mg/dL (summarized in Table 4). Each case had biopsy-proven acute rejection, some with nonviable outcomes and with significantly lower birthweights in the liveborn, illustrating the association of rejection with poorer outcomes. Prepregnancy serum creatinine alone did not predict adverse pregnancy events. Assessment of the risk of pregnancy on graft function has largely come from analyses of renal transplant recipient pregnancies, where thousands have been reported. While the numbers of pregnancies in non-renal recipients do not allow the same detailed evaluation, some conclusions can be drawn. In an NTPR study, outcomes of pregnancies in female liver recipients with biopsy-proven rejection were compared with pregnancies with no rejection episodes. From TABLE 4 NTPR Outcomes of Six Neoral® or Tacrolimus-Based Female Kidney Recipients with Biopsy-Proven Acute Rejection Episodes During Pregnancy

Case

Regimen

Pre-pregnancy creatinine (mg/dL)

Rejection treatment

Graft loss < 2 yrs post partum

Outcome

Gestational age (wks)

Birth weight (gms)

1.3

OKT3® and radiation

Y

SA

6

N/A

2 3 4 5

Neoral® switched a to tacro during pregnancy a Tacro Neoral® Neoral® Neoral®

2.8 1.2 3.0 2.6

N N N N

SA L L L

7 32 29 32

N/A 1378 1247 1417

6

Tacro

1.0

OKT3® and MP MP MP Restart immunob suppression Thymoglobulin® and sirolimus

Y

L

32

1531

1

Cases 1 and 6 from deceased-donor kidney; cases 2–5 from living-donor kidney. a Both recipients stopped their medications during pregnancy. b Recipient was being treated for cancer. Abbreviations: L, live birth; MP, methylprednisolone; NTPR, National Transplantation Pregnancy Registry; SA, spontaneous abortion; Tacro, tacrolimus. Source: From Ref.8

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119 pregnancies in 72 female liver recipients with 91 live births, biopsy-proven rejection occurred in 10 recipients with 11 pregnancies; these rejection episodes were treated with methylprednisolone, OKT3, antilymphocyte serum, or an increase in maintenance immunosuppression (41). Birthweights were lower in the newborns in the rejection group compared with the no-rejection group, 1946 g versus 2107 g (p= 0.006). Also of note was the fact that biopsy-proven rejection occurred within the three months post-partum in 11 female recipients, 45% of whom had had a rejection during pregnancy, illustrating both poor newborn outcomes as well as poor maternal outcomes in the setting of rejection. Registry data also appear to support the concept that liver recipients with recurrent hepatitis C appear to be at risk for peripartum graft dysfunction with subsequent pregnancies (42). An analysis from the registry of PK recipients compared those with and without postpartum graft loss (43). Significant differences between the groups were found in mean serum creatinine levels both during pregnancy and post-partum, and with a higher incidence of rejection during pregnancy in those recipients who lost graft function within two years of pregnancy compared with those who did not have graft loss. While the incidence is fortunately low, rejection during pregnancy can occur and is associated with poor outcomes for both the mother and the newborn. This underscores the need for maintenance immunosuppression during pregnancy. It also raises the question of what to do with the newer immunosuppressive agents, where there is less known about reproductive safety. Outcomes of pregnancies with exposure to MMF and sirolimus are summarized in Table 5. Birth defects occurred in four of 18 liveborn. If this trend continues with a larger experience, an entirely different approach to pregnancy in patients on these agents will be needed. SOME LESSONS FROM THE LITERATURE Although there are many publications about pregnancy after transplantation, no study has specifically compared pregnancy outcome by living or deceased donor source. An analysis of the effect of graft gender on gestational renal adaptation in kidney transplant recipients revealed no significant differences (44). End-stage organ failure often leads to infertility in women. Fertility usually returns with successful transplantation. As fertility can return rapidly, female recipients of child-bearing age need to be educated regarding their contraceptive choices. Ideally, the recipient and her healthcare provider need to discuss which contraception is appropriate, impressing upon the recipient the potential for pregnancy if she is sexually active. This counseling should start at the time of the transplant evaluation and continue during the hospitalization for transplant and at follow-up clinic visits (45,46). Pregnancy After Deceased- and Living-Donor Kidney Transplant The concerns of recipients with living-donor grafts, in addition to the issues already discussed, may include loss of the kidney and/or graft dysfunction. Are the potential risks of pregnancy justified when an organ has been received from a living donor? This section summarizes the outcomes of pregnancies from recipients who received a living-donor organ. As national data show that recipients of living-donor kidneys have, on average, longer graft survival and are generally considered to have lower serum creatinine levels and better function than recipients of deceased-donor kidneys, one might expect that female recipients of living-donor kidneys would have better pregnancy outcomes as well. Outcomes of pregnancy after both types of kidney transplantation appear in Table 6. The similarities between the groups are striking. Of note are the smaller number of reported pregnancy outcomes in tacrolimus-treated recipients. While the incidence of drug-treated hypertension varies among the groups, the incidence of pre-eclampsia in these recipients is similar and approximately three times higher than that in the general population (47). The majority of infections reported during pregnancy are urinary tract infections, which are of course generally minor, and routinely responsive to the appropriate antibiotics. Other infections include vaginal yeast infections and upper respiratory infections. There have been rare reports of other more serious infections, including CMV. Interesting differences for

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TABLE 5 NTPR-Reported Pregnancy Outcomes of Female Recipients with MMF Exposure During Pregnancy Reported to the NTPR Organ

Regimen

1 2 3 4 5

Kidney Kidney Kidney Kidney Kidney

MMF, tacro, prednisone MMF, tacro, prednisone MMF, tacro, prednisone MMF, tacro, prednisone MMF, Neoral®, prednisone

6

Kidney

MMF, Neoral®, prednisone

7 8 9

Kidney Kidney Kidney

MMF, tacro, prednisone, sirolimus MMF, Neoral®, prednisone MMF, tacro, prednisone

10 11

Kidney Kidney

MMF, tacro, prednisone MMF, tacro

12 13

Kidney Kidney

MMF, tacro MMF, Gengraf®, prednisone

14 15 16 17 18 1 1 2 3 1 2

Kidney Kidney Kidney Kidney Kidney P/K Liver Liver Liver Heart Heart

MMF, tacro, prednisone MMF, tacro, prednisone MMF, tacro MMF, Neoral®, prednisone MMF, tacro, prednisone MMF MMF, tacro, prednisone MMF, tacro MMF, tacro MMF, tacro MMF, tacro

Outcome a

L SA L L L SA SA L SA L b L L SA L SA SA SA L SA SA SA c L d L L L L SA L L SA SA SA L

Birth weight (gms) 2240 N/A 822 1701 2495 N/A N/A 2977 N/A 2240 1531 3118 N/A 2211 N/A N/A N/A 3118 N/A N/A N/A 2155 2886 3487 2807 2523 N/A 2466 2608 N/A N/A N/A 1758

Gestational age (wks) 34 7 31 35 36 7 6 36 8 35 31 39 4 33 5 4 5 38 9 6 7 36 39 37 37 34 6 39 37 18 3 6 34

a

Hypoplastic nails, shortened fifth fingers. Cleft lip and palate, microtia. Multiple malformations, neonatal death at age one day. d Microtia. Abbreviations: L, livebirth; MMF, mycophenolate mofetil; SA, spontaneous abortion; Tacro, tacrolimus. Source: From Ref. 8. b c

tacro-treated recipients include a higher incidence of diabetes, and live births that were slightly more premature with proportionately lower birthweights. A comparison of outcomes of pregnancy after living-donor kidney versus deceased donor transplant in CsA-treated is shown in Table 7. The incidence of drug-treated hypertension during pregnancy in recipients who have had a kidney from a deceased donor is higher than the incidence of those who received a living-donor kidney, 69% versus 52%, respectively. Otherwise, the two groups had similar maternal factors. The living-donor recipients reported a higher percentage of live births (81% compared with 73%), fewer premature births, and a longer gestational age in the newborn, a higher mean birthweight, and no neonatal deaths. Graft function as assessed by mean serum creatinine was the same before, during, and after the pregnancy between the two groups. As hypertension alone in women without a transplant can be associated with low birthweight and preterm delivery, this could influence the higher rate of preterm and low-birthweight infants among the deceased-donor kidney recipients. Graft loss within two years of pregnancy, although slightly lower among the living-donor recipients when compared with the deceased-donor recipients (8% versus 11% respectively), has been reported. Careful monitoring of recipient graft function is recommended in the postpartum period.

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TABLE 6

NTPR—All Female Kidney Transplant Recipient Pregnancy Outcomes Reported CsA

Maternal factors Transplant to conception interval (mean) Hypertension during pregnancy Diabetes during pregnancy Infection during pregnancy a Rejection episode during pregnancy Preeclampsia Mean serum creatinine (mg/dL) Before pregnancy During pregnancy After pregnancy Graft loss within 2 years of delivery b Outcomes (n) Therapeutic abortions Spontaneous abortions Ectopic Stillborn Live births Live births (n) Mean gestational age Mean birth weight Premature (<37 wks) Low birth weight (<2500 gms) Cesarean section Newborn complications Neonatal deaths n (%) (within 30 days of birth)

Neoral®

Tacrolimus

3.4 yrs 62% 12% 23% 2% 29%

5.4 yrs 69% 5% 22% 2% 29%

3.5 yrs 57% 8% 30% 4% 29%

1.4 1.4 1.6 9% (508) 8% 12% 1% 3% 76% (387) 36 wks 2492 gms 52% 46% 52% 41% 4 (1%)

1.3 1.4 1.5 5% (173) 1% 19% 0% 1% 79% (136) 36 wks 2501 gms 50% 47% 45% 45% 0%

1.2 1.4 1.4 11% (91) 1% 22% 0% 2% 74% (67) 35 wks 2434 gms 55% 45% 59% 54% 2 (3%)

Note: CsA - Sandimmune® brand CsA (327 recipients, 496 pregnancies). Neoral® brand CsA (119 recipients, 165 pregnancies). Tacrolimus (66 recipients, 89 pregnancies). a Biopsy proven acute rejection only. b Includes twins, triplets. Source: From Ref. 8.

PREGNANCY AFTER LIVING-DONOR TRANSPLANTATION Living-Donor Kidney and/or Living-Donor Pancreas Transplant There are four recipients with six pregnancies and seven outcomes (one ectopic twin pregnancy) where the recipient had a living-donor kidney and a living-donor segmental or deceased-donor pancreas transplant. Important lessons can be learned from this small group of women, so that each case is described below. The first recipient received a living-donor kidney and then a deceased-donor pancreas about a year and a half after the kidney transplant. She conceived using in vitro fertilization four years post-transplantation while taking CsA, AZA, and prednisone. She reported drugtreated hypertension and a urinary tract infection during pregnancy; no diabetes or rejection was reported. She was induced at 33.7 weeks because of intrauterine growth restriction and delivered a 1219 g healthy infant. At last follow-up, at age 9, the child is reported healthy, although being treated for attention deficit disorder. The recipient had a pancreas retransplant six years and a kidney retransplant nine years post-pregnancy. The second recipient as well as the two that follow received a simultaneous livingdonor kidney and segmental pancreas transplant. The second recipient had two pregnancies post-transplantation while on CsA, AZA, and prednisone. The first occurred 3.8 years posttransplant and resulted in a spontaneous abortion at 10 weeks. She conceived twins seven years later. On early ultrasound, one twin was found to be ectopic and was surgically removed at eight and one-half weeks. She reported drug-treated hypertension during pregnancy and preeclampsia requiring bed rest. No rejection, infection, or use of insulin was reported during pregnancy. The remaining twin was delivered at 33 weeks, weighing 1956 g. The infant was

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TABLE 7 NTPR—Living-Donor Versus Deceased-Donor Pregnancy Outcomes in Female Kidney Transplant Recipients CsA living donor Maternal factors Transplant-to-conception interval (mean) Hypertension during pregnancy Diabetes during pregnancy Infection during pregnancy Rejection episode during pregnancy Preeclampsia Graft loss within 2 years of delivery Mean serum creatinine (mg/dL) Before pregnancy During pregnancy After pregnancy Outcomes (n)a Therapeutic abortions Spontaneous abortions Ectopic Stillborn Live births Live births (n) Mean gestational age Mean birthweight Premature (<37 wks) Low birthweight (<2500 gms) Cesarean section Newborn complications Neonatal deaths n (%) (within 30 days of birth)

CsA deceased donor

3.7 yrs 52% 12% 24% 3% 31% 8%

3.2 yrs 69% 11% 21% 5% 28% 11%

1.3 1.4 1.6 (201) 8% 5% 0.5% 5% 81% (163) 37 wks 2684 gms 41% 34% 52% 39% 0

1.4 1.5 1.6 (284) 9% 16% 1% 2% 73% (206) 36 wks 2351 gms 59% 54% 54% 42% 3 (2%)

Living Donor: 127 recipients, 201 pregnancies, 201 pregnancy outcomes. Deceased Donor: 186 recipients, 274 pregnancies, 284 pregnancy outcomes. a Includes twins, triplets; CsA - Sandimmune® brand CsA.

reported to have apnea of prematurity. Current child and maternal status are unknown as they are lost to follow-up. The third recipient had two pregnancies post-transplantation while on tacrolimus, AZA and prednisone. The recipient was switched from MMF to AZA in preparation for pregnancy. She conceived 1.2 years post-transplant. She reported no infections, rejection, or use of insulin during pregnancy. Labor was induced at 35 weeks because of an increase in laboratory values and increased blood pressure. A 2551 g healthy infant was delivered; the infant required phototherapy for jaundice post-delivery. MMF was restarted post-partum and again switched to AZA in preparation for a second pregnancy, which occurred 1.7 years later. She reported no infections, rejection or use of insulin during pregnancy. Bed rest was recommended for two months as her blood pressure was labile. At 37 weeks, she delivered a healthy 2892 g infant. At last follow-up, both children are reported healthy and developing well at ages 5½ and 3½. The mother reported normal pancreas and kidney function. The fourth recipient had one pregnancy post-transplantation while on tacrolimus and AZA. The recipient had been switched from MMF to AZA in preparation for pregnancy. The recipient conceived 4.4 years post-transplant. She reported acute kidney rejection during pregnancy, treated with Thymoglobulin. There was suspected pancreas rejection, and the recipient required insulin after the 30th week of pregnancy. She reported a urinary tract infection during the third trimester, treated with the appropriate antibiotics. The recipient required a Cesarean section following fetal decelerations during her hospitalization for rejection. At 35 weeks, a 2681 g infant was delivered. The infant required hospitalization for six weeks, but at 11 months was healthy and developing well. The mother reported insulin resumption and further kidney

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rejection immediately post-partum, treated with OKT3. The recipient is listed for a deceaseddonor pancreas and is in the process of being evaluated for a living-unrelated kidney transplant. Living-Donor Liver Transplant There has been one case reported to the NTPR of pregnancy post-living donor liver transplant. The recipient, having primary sclerosing cholangitis, received a living-donor liver lobe from a friend. She conceived one year post-transplant while on tacrolimus and prednisone. The recipient required a dilatation and curettage for a non-viable pregnancy in the first trimester. The recipient reported adequate graft function at last follow-up. Living-Donor Liver and Kidney Transplant One recipient transplanted for oxalosis received a living-unrelated donor liver and then eight months later a kidney from a different living unrelated donor. She was maintained on tacrolimus and prednisone, and conceived five years post-transplant. At 37 weeks, she delivered a healthy infant weighing 2792 g. The recipient chose to breastfeed her baby with no reported problems related to breastfeeding. At last follow-up, mother and infant were doing well 11 months post-partum. Living-Donor Lung Transplant Two recipients reported a pregnancy after receiving a living-donor lung transplant. The first had cystic fibrosis and received lobes from two of her relatives, a sister and a cousin. She conceived 1.1 years post-transplant while on CsA and prednisone. The pregnancy was complicated by pneumocystis carnii pneumonia, aspergillus, and pulmonary hypertension. She reported no hypertension, pre-eclampsia, or rejection. Labor occurred spontaneously at 31 weeks and a 2665 g infant was delivered. At last follow-up, she had adequate lung function, and the child (six years old) was reported healthy and developing well. In the second case, a recipient with cystic fibrosis received the lung lobes of two relatives, one from her brother and one from her sister. She conceived 6.5 years post-transplant while maintained on tacrolimus and AZA. She reported drug-treated hypertension during pregnancy, although no pre-eclampsia, infections, or rejections. Because of an increase in blood pressure and proteinuria, labor was induced at 35 weeks, and she delivered an 1899 g healthy infant. The mother reported that she breast-fed for 10 weeks, with no neonatal complications related to breastfeeding. The mother reported adequate graft function at last follow-up, and the baby was reported healthy and developing well at 18 months of age. MANAGEMENT OF TRANSPLANT RECIPIENTS DURING PREGNANCY A conference, sponsored by the American Society of Transplantation (AST), was convened in March 2003 to develop a consensus for pregnancy-related issues (46). Discussion topics included preconception counseling, comorbid factors that may impact pregnancy outcome, the basis on which to determine the timing of pregnancy, and obstetrical management. Recipients must be advised about appropriate birth control as transplantation restores fertility. For all organ recipients, there should be some time interval from transplant to conception in order to allow for the establishment of stable graft function, immunosuppression at maintenance levels, and a reduced risk of post-transplant infections (i.e., CMV). The duration that the recipient has been rejection-free as well as the stability of graft function are also important. Pregnancies are highrisk in this patient population, and require close collaboration among transplant surgeons, physicians, and obstetricians. While there is no specific combination of immunosuppressive agents (at therapeutic doses) known to be teratogenic, there has been recent concern about both MMF and sirolimus because of animal toxicity studies and early clinical reports of MMF exposures and the mechanism of action for sirolimus. The data are limited, and as yet there are no definitive recommendations for switching a recipient from one regimen to another regimen prior to attempting pregnancy.

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Hypertension and Pre-eclampsia In the general population, hypertension complicates approximately 10% of all pregnancies, and is a major cause of morbidity and mortality for mother and newborn (47). In a prospective study, the incidences of preterm as well as full-term small for gestational age infants were twice as high for those mothers with hypertension than for the infants born to mothers that were not hypertensive (48). As hypertension complicates a greater percentage of transplant recipient pregnancies, more female transplant recipients will be receiving one or more antihypertensive medications. The angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists are contraindicated during pregnancy. Their adverse effects occur from mid-pregnancy onward, so that early exposures are not associated with adverse outcomes. It can be argued that they can be continued until conception if needed (28,49). Pre-eclampsia may be difficult to assess in transplant recipients as serum uric acid levels and 24-hour urine protein excretion may be above physiologic limits at baseline without adverse implications and/or effects. Methyldopa has been reported as the first choice of treatment for pregnancy-induced hypertension in non-transplant patients, and parenteral hydralazine has been used in hypertensive emergencies (50). Graft Dysfunction When graft dysfunction occurs during pregnancy, rejection, although not common, must be considered and the cause of graft dysfunction evaluated. Special consideration must be given for each recipient group. As most of the data come from kidney recipients, the usual pattern seen in pregnancy is for serum creatinine levels to slightly decrease in early pregnancy and return to baseline post-partum. Therefore, increases in serum creatinine during pregnancy and post-partum should be evaluated. In PK recipients, good glucose control has been the norm. Additional comorbid factors may present problems, especially with regard to cardiovascular disease. In liver recipients, recurrent liver disease, especially viral hepatitis, appears to be a greater risk to mother and newborn. Overall, the lung recipient group has appeared to have higher risks of peripartum, problems both with regard to graft function and patient survival. Deterioration or changes in graft function should be assessed when possible by biopsy. If a diagnosis of acute rejection is made, it should be treated appropriately. Rejection during pregnancy is associated with poorer outcomes for both mother and newborn. More frequent monitoring is warranted from mid-pregnancy (approximately 20 weeks) onward, including blood pressure measurements, the assessment of graft function, and measurement of medication levels, given the risk of pre-eclampsia as pregnancy proceeds (51). Also included in any work-up for an increase in serum creatinine level during the peripartum period would be an ultrasound to exclude urinary obstruction. Infections Infectious complications during pregnancy have most often been reported in the urinary tract. Therefore, regular urine cultures should be performed during pregnancy. Occasionally, more serious infections, including yeast infections, pneumonia, sepsis, or unspecified viral infections may complicate pregnancy. CMV is usually asymptomatic and most will go unrecognized without antigenemia or PCR viral monitoring (52). In the general population, the incidence of congenital CMV infection ranges from 0.2% to 2.2% of liveborn. Fewer than 10% of congenitally infected infants have clinical manifestations at birth, which include thrombocytopenia and growth retardation. Those newborns with no symptoms may subsequently manifest problems such as hearing loss (53). In non-immunosuppressed women when primary CMV is detected because of maternal symptoms, there is a 30% chance that the child will be infected, with at most a 6% to 7% chance that the child would have damage caused by CMV infection. In about half of the cases, the damage will be evident at birth (54). The effect of anti-CMV treatment of the mother’s infection and preventing or ameliorating the effects on the fetus are uncertain. The rate of hepatitis B transmission in the general population from mother to child is as high as 90% (55). Although there are no reports of transmission rates in the transplant

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population, recipients with hepatitis B infection may transmit it to their offspring and administration of hepatitis B immune globulin and hepatitis B virus vaccine to the newborn within a few hours of birth usually prevents transmission. If infants do not receive prophylaxis, then a high proportion will become chronic carriers. Infection with herpes simplex virus (HSV) before 20 weeks of gestation is associated with an increased risk rate of abortion and, if there is active cervical infection, Cesarean section should be performed. Estimates of the incidence of acute infection with toxoplasmosis are 0.2% to 1%. Most cases diagnosed are asymptomatic. However, toxoplasmosis can have severe consequences. The diagnosis is dependent on culture, direct antigen detection, or serologic tests (56). A single positive titer result does not establish an acute infection, which requires a rise in antibody titer in serial specimens, preferably obtained at least three weeks apart. Other pregnancy complications reported include HELLP Syndrome (hemolysis, elevated liver function tests, low platelets), ureteral obstruction, and complications of Cesarean delivery. Immunosuppression It is best to maintain baseline immunosuppressive dosing during pregnancy; however, issues with the newer immunosuppressive agents remain unresolved. For those immunosuppressants where levels are checked, blood concentrations are likely to decrease during pregnancy, given the increased maternal volume of distribution as well as fetal metabolism of these agents (10). Additionally, some recipients may be non-compliant, choosing to stop taking medications during the pregnancy because of concerns of toxicity to the fetus. With regard to levels, reports to the registry have shown that most centers appear to try to maintain the same levels by dose adjustment. It is very important to follow medication blood levels post-partum, as levels may fluctuate and the risk of rejection may rise with reconstitution of immunologic responsiveness. A dilemma for caretakers and recipients is the current complexity of immunosuppressive agents for which there are limited reproductive data available. It is unlikely for a clinician today to start CsA, and/or AZA, even though many successful pregnancy outcomes have been reported on these agents. Newer agents have limited reproductive clinical pregnancy outcome data available, so there is an unknown potential for teratogenicity. Given this limited information, in some situations centers have chosen to switch patients from MMF to AZA and/or reduce MMF dosages because of the concerns of MMF exposure during pregnancy. The risk of rejection must be weighed against the potential teratogenicity, and rejection must be avoided, as it is associated with poorer outcomes for mother and child. Prednisone at low doses has not been problematic in pregnancies, and new clinical regimens are now being directed toward avoidance or withdrawal of steroids. This will necessarily expose recipients to other agents (MMF or sirolimus) for which there is less pregnancy information. No one regimen has yet been identified as being superior for use during pregnancy; however, the potential exists that a combination of newer agents may pose a higher risk of teratogenicity. Sporadic cases of rejection, graft dysfunction, and/or deterioration with poor pregnancy outcome have been reported with any of the regimens. Delivery and Puerperium While it is generally stated that Cesarean section deliveries are performed for obstetric indications only, a high incidence of Cesarean section delivery has been reported in all organ recipient groups. Immunosuppressive agents should continue during labor and delivery. Generally, immunosuppressive agents can be continued shortly after Cesarean section delivery, but if oral intake cannot be resumed, then intravenous formulations are available for most of the immunosuppressive agents. Surveillance for post-partum depression is essential, as medication non-compliance can be insidious, subtle, and have tragic consequences. Therefore, close monitoring of the mother should continue post-partum. A few recipients have chosen to breastfeed, although breastfeeding remains controversial. The potential exposure of the newborn to immunosuppressive agents must be weighed against

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the known benefits of breastfeeding. A newly emerging view is to consider that the benefits of breastfeeding outweigh the minimal risks. Studies have demonstrated that immunosuppressive delivery to the newborn may be inconsequential (57,58). Potential effects of immunosuppressive exposure as well as long-term outcomes in the offspring require further study. CONCLUSION Successful pregnancies have been reported in recipients of living-donor organs. Analyzing pregnancy outcomes of CsA-treated recipients, pregnancy after living-donor kidney transplantation appears to have slightly better newborn outcomes, with lower incidences of preterm delivery and low-birthweight newborns compared with those mothers who received a deceaseddonor kidney transplant. There may also be slightly better maternal outcomes with regard to graft function and graft survival in the living-donor group. More definitive and long-term comparative studies are needed, as well as analyses of newer regimens. Efforts must continue to ensure reporting all pregnancies, both from living- and deceaseddonor sources, so that more information can be accrued, and because individually investigated cases with adverse outcomes will allow better identification of risk factors. ACKNOWLEDGMENTS The NTPR is supported by grants from Novartis Pharmaceuticals Corp., Astellas Pharma US, Inc., Roche Laboratories Inc., and Wyeth Pharmaceuticals, Inc. The authors would like to thank Lisa A. Coscia, RN, BSN, CCTC for her assistance with the preparation of this manuscript. REFERENCES 1. Murray JE, Reid DE, Harrison JH, et al. Successful pregnancies after human renal transplantation. N Engl J Med 1963; 269:341–343. 2. Penn I, Makowski EL, Harris P. Parenthood following renal and hepatic transplantation. Transplantation 1980; 30:397–400. 3. Toma H, Kazunari T, Tokumoto T, et al. Pregnancy in women receiving renal dialysis or transplantation in Japan: a nationwide survey. Nephrol Dial Transplant 1999; 14:1511–1516. 4. Jain AB, Shapiro R, Scantlebury VP, et al. Pregnancy after kidney and kidney-pancreas transplantation under tacrolimus: a single center’s experience. Transplantation 2004; 77(6):897–902. 5. Molmenti EP, Jain AB, Marino N, et al. Liver transplantation and pregnancy. Clin Liver Dis 1999; 3(1):163–1174. 6. Branch KR, Wagoner LE, McGrory CH, et al. Risks of subsequent pregnancies on mother and newborn in female heart transplant recipients. J Heart Lung Transpl 1998; 17:698–702. 7. Gertner G, Coscia L, McGrory C, et al. Pregnancy in lung transplant recipients. Progress in Transplantation 2000; 10(2):109–112. 8. Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of Pregnancy after Transplantation. In: Cecka JM, Terasaki PI, eds. Clinical Transplants 2005. UCLA Los Angeles, CA: Immunogenetics Center, 2006:69–83. 9. Davison JM. Pregnancy in renal allograft recipients: problems, prognosis and practicalities. In: Lindheimer MD, Davison JM, eds. Balliere’s Clin Obstet Gynaecol: Renal Disease in Pregnancy. London (UK): Bailliere Tindall, 1994:501–525. 10. Armenti VT, Moritz MJ, Cardonick EH, Davison JM. Immunosuppression in pregnancy: choices for infant and maternal health. Drugs 2002; 62(16):2361. 11. Pickrell MD, Sawers R, Michael J. Pregnancy after renal transplantation: Severe intra-uterine growth retardation during treatment with cyclosporin A. BMJ.1988; 296:825. 12. Kainz A, Harabacz I, Cowlrick IS, Gadgil SD, Hagiwara D. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000; 70(12):1718–1721. 13. Roche Laboratories. Mycophenolate mofetil package insert. Nutley, NJ: Roche Laboratories, 2000. 14. Wyeth-Ayerst Pharmaceuticals. Sirolimus package insert. Philadelphia, PA: Wyeth Laboratories, 2001. 15. Finnell RH. Teratology: General considerations and principles. J Allergy Clin Immunol 1999; 103: S337–S342. 16. Oz BB, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001; 71(8):1051–1055.

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17. Armenti VT, Radomski JS, Moritz MJ, et al. National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, eds. Clinical Transplants 2001. Los Angeles CA: UCLA Immunogenetics Center, 2002:97–105. 18. Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology 1995; 51:45–46. 19. Fraser FC, Fainstat TD. The production of congenital defects in the offspring of pregnant mice treated with cortisone: a progress report. Pediatrics 1951; 8:527–533. 20. Hou S. Pregnancy in transplant recipients. Med Clin North Am 1989; 73:667–683. 21. Friedman JM, Polifka JE. The effects of drugs on the fetus and nursing infant: a handbook for healthcare professionals. Baltimore: John Hopkins University Press, 1996. 22. Yeast JD. Immunosuppressives in pregnant transplant patients—what risks? Pharmacology 1987; 30:117–124. 23. Saarikoski S, Seppala M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from mother to the fetus. Am J Obstet Gynecol 1973; 115:1100–1106. 24. Davison JM. Dialysis, transplantation, and pregnancy. Am J Kidney Dis 1991; 17:127–132. 25. Registration Committee of the European Dialysis and Transplant Association. Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynaecol 1980; 87:839–845. 26. Mason RJ, Thomson AW, Whiting PH, et al. Cyclosporine-induced feto-toxicity in the rat. Transplantation 1985; 39:9–12. 27. Fein A, Vechoropoulos M, Nebel L. Cyclosporin-induced embryotoxicity in mice. Biol Neonate 1989; 56:165–173. 28. EBPG Expert group on renal transplantation. Neph Dial Transpl 2002; 17(4):50–55. 29. Armenti VT, Ahlswede KM, Ahlswede BA, et al. National Transplantation Pregnancy Registry— outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 1994; 57:502–506. 30. Barrou BM, Gruessner AC, Sutherland DER, et al. Pregnancy after pancreas transplantation in the cyclosporine era. Transplantation 1998; 65:524–527. 31. Armenti VT, Moritz MJ, Radomski JS, et al. Pregnancy and Transplantation. Graft 2000: 3(2):59–63. 32. Davison JM, Lind T, Uldall PR. Planned pregnancy in a renal transplant recipient. Br J Obstet and Gynaecol 1976; 83:518–527. 33. First MR, Combs CA, Weiskittel P, et al. Lack of effect of pregnancy on renal allograft survival or function. Transplantation 1995; 59: 472–476. 34. Sturgiss SN, Davison JM. Effect of pregnancy on the long-term function of renal allografts: an update. Am J Kidney Dis 1995; 26:54–56. 35. Fischer T, Neumayer HH, Fischer R, et al. Effect of pregnancy on long-term kidney function in renal transplant recipients treated with cyclosporine and with azathioprine. Am J Transpl 2005; 5(11):2732–2739. 36. Pour-Reza-Gholi F, Nafar M, Farrokhi F, et al. Pregnancy in kidney transplant recipients. Transpl Proceed 2005; 37(7):3090–3092. 37. Rahamimov R, Ben-Haroush A, Wittenberg C, et al. Pregnancy in renal transplant recipients: long-term effect on patient and graft survival. A single-center experience. Transplantation 2006; 81(5):660–664. 38. Armenti VT, McGrory CH, Cater JS, et al. Pregnancy outcomes in female renal transplant recipients. Transplant Proc 1998; 30:1732–1734. 39. Davison JM. Renal disorders in pregnancy. Cur Opin Obst Gynecol 2001; 13(2):109. 40. Kozlowska-Boszko B, Lao M, Gaciong Z, et al. Chronic rejection as a risk factor for deterioration of renal allograft function following pregnancy. Transplant Proc 1997; 29:1522–1523. 41. Armenti VT, Wilson GA, Radomski JS, Moritz JM, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, eds. Clinical Transplants 1999, 15. Los Angeles (CA): UCLA Tissue Typing Laboratory, 2000:111. 42. Armenti VT, Herrine SK, Radomski JS, et al. Pregnancy after liver transplantation. Liver Transpl 2000; 6(6):671–685. 43. Wilson GA, Coscia LA, McGrory CH, et al. National Transplantation Pregnancy Registry: postpregnancy graft loss among female pancreas-kidney recipients. Trans Proc 2001; 33:1667–1669. 44. Smith MC, Ward MK, Sturgiss SN, et al. Sex and the pregnant kidney: does renal allograft gender influence gestational renal adaptation in renal transplant recipients? Transplant Proc 2004; 36:2639. 45. Cundy TF, O’Grady JG, Williams R. Recovery of menstruation and pregnancy after liver transplantation. Gut 1990; 31:337–338. 46. McKay DB, Josephson MA, Armenti VT, et al. Women’s Health Committee of the American Society of Transplantation. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transpl 2005; 5(7):1592. 47. Barron WM. Hypertension. In: Barron WM, Lindheimer MD, eds. Medical Disorders During Pregnancy. St. Louis, MO: Mosby, 2000:1–38.

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48. Bumgardner GL, Matas AJ. Transplantation and pregnancy. Transplant Rev 1992; 6:139. 49. Hanssens M, Keirse MJNC, Vankelecom F, Van Assche FA. Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obst Gynecol 1991; 78(1):128. 50. Lindheimer MD. Hypertension in pregnancy. Hypertension 1993; 22:127. 51. Armenti VT, Moritz MJ, Davison JM. Pregnancy following transplantation. In: James DK, Steer PJ, Weiner CP, Gonik B, Eds. High Risk Pregnancy: Management Options. 3rd ed. Philadelphia, PA: Elsevier Science, 2006:1174–1186. 52. Puliyanda DP, Silverman NS, Lehman D, et al. Successful use of oral ganciclovir for the treatment of intrauterine cytomegalovirus infection in a renal allograft recipient. Transpl Infec Dis 2005; 7(2):71. 53. Peckham CS. Cytomegalovirus in the neonate. J Antimicrobial Chemother 1989; 23(suppl E):17. 54. Sison AV, Sever JL. Cytomegalovirus infections in pregnancy and neonate. In: Queenan JT, ed. Management of High-Risk Pregnancy. 3rd ed.. Boston, MA: Blackwell Scientific, 1994:315. 55. Lee C, Gong Y, Brok J, et al. Effect of hepatitis B immunization in newborn infants of mothers positive for hepatitis B surface antigen. BMJ 2006; 332:328. 56. Wong SY, Remington JS. Toxoplasmosis in pregnancy. Clinical Infectious Diseases 1994; 18:853. 57. French AE, Soldin SJ, Soldin OP, Koren G. Milk transfer and neonatal safety of tacrolimus. Ann Pharmacother 2003; 37:815. 58. Nyberg G, Haljamäe U, Frisenette-Fich C, et al. Breastfeeding during treatment with cyclosporine. Transplantation 1998; 65:253.

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Financial Impact of Living-Donor Organ Transplantation Liise K. Kayler and Abigail E. Martin Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Solid-organ transplantations are some of the most costly surgical procedures performed today (1–3). Although solid-organ transplantation has received increased public and private insurance coverage over time, the health-care system in the United States continues to change and to focus on endpoints such as efficacy, cost-containment, equitable allocation of resources, and health-care satisfaction (4). Many payers adopt cost-containment strategies that place transplant programs under financial pressure to improve economic outcomes and maintain profitability; these include limiting outlier protection for high-risk patients and establishing fixed global rates with the intent to shift greater financial risk to the transplant team (1,5). These financial pressures require constant re-evaluation on the part of transplant centers to identify the most cost-effective approaches. Meanwhile, the continually expanding number of candidates for transplantation and relatively unchanged deceased donor (DD) pool has led to the increased use of live donors. The success of living-donor (LD) kidney transplantation opened the way for the possibility of LD transplantation for other organs including the liver, lung, pancreas, and small intestine. The advantages of LD transplantation include expansion of the donor pool, elimination of waiting time, decreased cold ischemia injury, improved immunologic matching, and for some organs improved overall graft survival. Financially, living donation provides the opportunity both to increase the number of patients who can undergo transplantation and also to perform the procedure in an elective manner. The latter may have the advantage of allowing the transplantation of patients who are in optimal condition, can thus potentially reduce the cost of transplantation, and the cost of managing complications of end-stage organ disease in the pretransplant period. The cost-effectiveness of kidney transplantation with LDs compared with DDs has been wellestablished. LD liver transplantation, however, has not been shown to be more cost-effective than DD liver transplantation, and no studies have evaluated cost-effectiveness for LD versus DD lung, pancreas, or intestinal transplantation. The focus of this chapter is on the financial aspects of living donation, predominately of the kidney and liver, with comparisons between LD and DD organ transplantation. Financial perspectives will be viewed from the perspective of the third-party payer, the donor, and society. FINANCES: COST VERSUS CHARGES When assessing resource utilization, it is important to differentiate between costs and charges; these terms should not be used interchangeably. Charges are the amount that an institution or individual provider chooses to request for a service or good. The charge is the price that appears on the patient’s bill. Charges are invariably inflated from actual costs to include a margin for revenue and may incorporate factors such as payer mix, bad debt, or regional competition for particular services. In contrast to charges, costs are defined as the magnitude of resources consumed in producing goods or services. Costs include an economic value for all resources consumed, but do not include a mark-up for revenue. The distinction between costs and charges is imperative when evaluating the literature (6).

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The complete cost of a therapy or disease includes both direct and indirect costs. Direct costs in transplantation include the cost of waiting-list maintenance, organ procurement, workup of acceptable and unacceptable LDs, and the transplant and LD procedures and postoperative care (including professional fees, hospital fees, procedural fees, pharmacy costs, and the cost of treating complications). These direct costs are usually reimbursable. Other direct costs, which are generally not reimbursable, include expenses for travel to the transplant center, lodging, long-distance phone calls, parking, and meals. Indirect health-care costs are “time costs” and are associated with the time involvement of the patients, their families, or others involved in the care process, lost or impaired ability to work or to enjoy leisure activities as the result of morbidity, and lost economic productivity because of death. THIRD-PARTY PERSPECTIVE Kidney Transplantation End-stage renal disease (ESRD) continues to be a costly disease that results in approximately $17.9 billion per year in medical costs (7). In the United States, much of this cost is covered by Medicare. In addition, the number of ESRD patients continues to grow by approximately 7% per year (7). For most patients, renal transplantation offers improved life expectancy and improved quality of life when compared with continued hemodialysis. Despite the fact that renal transplantation is a more cost-effective treatment than chronic hemodialysis, less than half of ESRD patients either receive a transplant or are placed on a waiting list each year. According to the Organ Procurement and Transplantation Network data as of October 1, 2005, there are currently greater than 63,000 patients on waiting lists for a kidney transplant. The median waiting time for adult patients listed between 2001 and 2002 was greater than 1500 days (8). One of the purported advantages of LD renal transplant is shorter time to transplantation. However, most renal transplants in the United States are not from LDs. In 2004, the most recent year for which statistics are available, 6647 (41.5%) of the 16,004 renal transplants performed in the United States were from LDs (8). It has been well-established that renal transplantation offers a cost savings over maintenance hemodialysis in ESRD patients (9–11). Maintenance hemodialysis is estimated to cost $52,000–$57,000 per year (3), whereas kidney transplantation costs on average $84,000 (12) initially followed by approximately $12,000–$28,000 annually (13,14). Studies comparing the two treatment modalities show that the high initial cost of transplantation, which includes the cost of organ acquisition in addition to hospitalization costs, is eventually recouped because of the high ongoing cost of maintenance hemodialysis. Medical costs after transplantation is much less than with maintenance hemodialysis, assuming the patient has a functioning graft. Earlier studies (9,10) showed that the initial outlay is recovered in approximately four years for DD renal transplant patients, and that after that “break-even point” the cost savings of maintaining a renal transplant recipient outweigh the costs of continued dialysis. A more recent study by Mullins and colleagues (11) shows even faster recovery of costs, reporting that DD transplant recipients will recoup costs by 18 months. The faster time to recovery of initial costs has been attributed to improved immunosuppressive regimens, technological advances, and a trend towards shorter hospital stays at the time of initial operation. These studies looked only at institutional and physician costs, and none take into account costs such as the effect on employment or disability status. LD renal transplantation offers several advantages over DD renal transplantation, including better graft function due to shorter ischemia times and higher quality of donated kidneys, which in turn leads to advantages in graft and recipient survival. These advantages are best appreciated in living-related renal transplant recipients, but are still demonstrable when comparing living-unrelated renal transplant recipients with DD renal transplant recipients (15,16). A retrospective study by Gjertson and Cecka showed that (five-year) graft survival rates for spouse and other living unrelated transplants were 75% and 72%, respectively (16). Although this was worse than for HLA-identical siblings (86% five-year graft survival rate), this was comparable to the five-year graft survival from non-HLA identical sibling and parental donors (75% and 74%, respectively), and better than for DD (62%). Numerous studies have shown a relationship between graft survival and length of time on hemodialysis prior to transplantation (17,18). One study has even demonstrated a graft survival advantage of LD

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transplantation versus DD transplantation even when controlling for length of time on hemodialysis (18). Since one of the purported advantages of LD renal transplantation is the decrease in waiting time to receiving an organ, improved outcomes would add cost savings in addition to the money saved by less time and money spent on maintenance hemodialysis. These functional advantages do produce financial advantages over DD renal transplants. Smith and coworkers (19) compared Medicare charges and payments for 42,868 DD renal transplant recipients and 13,754 LD renal transplant recipients during the first year after transplantation. Average total payments for DD recipients were $39,534, compared to $24,652 for LD recipients. This difference was attributed to decreased inpatient hospital charges since the LD recipients had a significantly lower average number of hospitalizations, 2.28 compared to 2.51 for DD recipients (19). These cost savings are also seen when comparing the time to recovery of transplant costs with continued dialysis. In the study by Mullins and colleagues (11), LD recipients reached the break-even point at only 10 months after transplantation, compared with 18 months for DD recipients. Laparoscopic live-donor nephrectomy has increased the LD pool significantly since its introduction in 1995, with some centers having reported a greater than 100% increase in LD renal transplants (20,21). Part of the laparoscopic procedure’s popularity lies in the decreased postoperative pain and time to recovery, which in turn leads to shorter hospital stays. However, this decrease in hospital length-of-stay is offset by increased costs at the time of operation due to utilization of laparoscopic instruments and increased operating room time (22–24). Novotny and colleagues (25) compared 30 open-donor nephrectomy patients with 26 laparoscopic-donor nephrectomy patients and found that the length of stay was only 2.7 days in the laparoscopic group compared with 3.8 days in the open group. However, because of increased operating room charges, the total hospital cost was not significantly different, with the open group averaging $9335 + 2291 and the laparoscopic group averaging $10,273 + 3090. Similarly, Wolf and colleagues (26) found 73% higher operative costs that resulted in 23% higher mean hospital costs for laparoscopic donors compared with open donors. Mullins and colleagues also looked at laparoscopic-donor nephrectomy versus open-donor nephrectomy and deceased donors (11). Because the cost of care of the donor is included in the medical costs of the recipient, patients who had received a kidney via a laparoscopic donor nephrectomy had a break-even point of 14 months as opposed to 10 months for those patients whose donor underwent an open-donor nephrectomy. However, this was still significantly better than the breakeven point of 18 months for the patients who received a DD kidney. It should be noted that in this study there were many fewer laparoscopic donors than open donors and DDs (181 versus 11,466 and 32,416, respectively). As the laparoscopic procedure becomes more widespread, additional data will be needed to determine its true cost-effectiveness, although current data support the idea that it is still a cost-effective alternative to DD renal transplantation. Liver Transplantation Studies report that average costs and charges for orthotopic liver transplantation (OLT) range from $150,000 to $300,000 (27–31); however, costs will be higher at centers that perform transplantations for patients with more advanced liver disease (32). Severity of illness at time of transplantation affects the cost of transplantation, even after adjustment for length of surgery, amount of blood products consumed, graft ischemia time, age of donor, donor cause of death, choice of immunosuppression and/or induction, and development of diabetes, hypertension, or rejection (32). Other factors associated with the increased cost of liver transplantation include the intensive care unit stay, renal failure, cytomegalovirus infection, bacterial or fungal infection, hospital length of stay, and MELD score ≥20 (31–38). Living-donor liver transplantation (LDLT) could potentially result in significant cost savings relative to deceased-donor liver transplantation (DDLT). LDLT offers the possibility of elective liver transplantation with consequent shorter waiting times and decreased resource utilization; transplantation earlier in the disease course may result in less debilitation and shorter post transplant lengths of stay. Cost-effectiveness analyses, however, have not shown economic benefits with LDLT compared with DDLT. Several reasons have been noted for the higher or equivalent costs of LDLT, including more wait-list decompensations among LDLT recipients, the higher costs of LD work-up compared with DD acquisition, and greater post-operative biliary complications, lengths of

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stay, and retransplantations among LDLT recipients (38–41). One study in pediatric liver transplant recipients found the direct costs of LDLT in the first year after transplantation to be higher than DDLT (38). This study matched 16 LDLT recipients with two DDLT recipients (the first match had received a whole-organ graft and the second a technical variant graft). The mean cost for the initial transplantation hospital stay was 38% higher for LDLT than DDLT (p = 0.21) and the mean cost of care in the first year was 60% higher for LDLT than DDLT (p = 0.01). Following transplantation, biliary complications were more predominant in the LDLT group, which increased the requirements for more interventions and prolonged follow-up care. Multivariate analysis identified biliary complications and insurance type as the predictors of cost, accounting for 57% of the variance in the cost of hospitalization for initial transplantation. This analysis was limited in scope; it only addressed direct costs from the day of transplantation, while the cost of care on the waiting list was not included. Costs while on the waiting list are important because the difference in the cost for LDLT may become negligible if the patients who receive DDLT spend a long period on the waiting list and consume more resources. Two decision analysis models have been performed to address the impact of waiting time on the cost of liver transplantation (39, 40). Sarasin and colleagues (39) compared costs of LDLT versus DDLT for patients with hepatocellular carcinoma. LDLT was more cost-effective (less than $50,000 per quality-adjusted life year saved) when waiting list time exceeded seven months. The gain in life expectancy and the cost-effectiveness of LDLT were mostly dependent on the probability of developing contraindications to transplantation and the survival after transplantation. A second model by Sagmeister and colleagues (40) showed that there was comparable cost-effectiveness of programs offering both LD and DD liver transplantation and programs offering only DD liver transplantation. The deficiency of these analytic studies is the lack of real economic data. Models incorporate assumptions and estimated inputs that result in theoretical conclusions. A more recent analysis, the most comprehensive to date, includes both real economic data and outcome data including 90-day pretransplant costs and one-year follow-up. The expression of cost in this study was as cost units (CUs), which had a value between $500 and $1500. This study of 24 LDLT and 43 DDLT adult recipients noted overall transplant costs to be higher for LDLT compared with DDLT recipients (162.7 CU versus 134.5 CU, respectively); however, the difference was not significant (41). Pretransplant costs were 21% higher for LDLT (11.1 CU) compared with DDLT (6.1 CU) recipients because of more frequent decompensations, admissions, and procedures. The costs for the transplant admission, which included donor evaluation and care, were 24% greater for LDLT (118.6 CU) than DDLT recipients (92.9 CU) mostly because of a longer mean length of stay and greater proportion of “early” retransplants (retransplantation within the initial transplant admission) among LDLT compared with DDLT recipients. The one-year post transplant costs were 4% lower for LDLT (33 CU) than DDLT (34.5 CU) recipients, and this was attributed to the greater proportion of readmissions and “late” retransplantations (retransplantation performed after discharge from initial transplant admission) among DDLTs (41). This study also addressed the cost burden of workingup both acceptable and unacceptable donors. While the majority of LD costs were related to the hepatectomy and postoperative care (81%), evaluation of successful donors accounted for 13% of the total donor costs, and the cost of evaluating donors rejected during the donor evaluation added 6% to the total donor costs. Compared with DD organ acquisition, the mean cost of the LD evaluation and procedure (including evaluation, hepatectomy, medical care 365 days after donation, and cost of evaluating rejected donors) was only 1% more than the mean organ acquisition cost (41). Currently, the overall cost of DDLT versus LDLT appears to be comparable. It has been noted in liver transplantation that as the number of procedures performed at a center increases, improved outcome and reduced costs are observed (41,43). As experience with LDLT increases, donor selection and technical advances should improve, and this would lower complications rates, reduce hospital length of stay, and ultimately reduce the costs of LDLT. PERSPECTIVE OF THE DONOR Kidney and liver donors experience financial stress related to both the direct and indirect costs of donation. Among kidney donors, financial hardship has been reported by 9% to 23% (44–47). Among living liver donors, 27% have experienced financial difficulties (48) and mean

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out-of-pocket expenses for the live liver donor have been reported to be $3660 (49). Most transplant programs have established medical billing practices so that direct costs relating to medical care of donors, including the preoperative evaluation, in-hospital costs, and provider fees are billed to the recipient’s insurance (Medicare, Medicaid, or commercial payer) under an “acquisition fee.” The acquisition fee is established by the transplant center and is not specific to any one donor but rather an average of all the program’s donors. The government also requires that post-donation complications be covered by the acquisition fee. There are some indirect financial burdens that donors must face, most notably loss of income from time away from work and potential disability as a result of complications. Several surveys of living renal donors have attempted to quantify the financial burden to donors. A survey by Wolters and colleagues found that 91% of donors reported no financial expenses as a result of donating a kidney (47). Isotani and colleagues found that 16% of their donor population reported a financial burden (46). The largest such survey was by Smith and colleagues, who reported that 23% of donors experienced financial hardship, but this survey was completed before the advent of laparoscopic donor nephrectomy, and may reflect longer recovery times and absence from work (45). Although many respondents among these surveys described loss of income as a burden, no respondent reported losing his or her job as a result of donation. The most common method of reducing donor-incurred expenses is sick-leave benefits provided by employers (50). Other methods of defraying costs include family member donations, personal savings, vacation days, recipient donations, community donations, and borrowed money (51). The advent of laparoscopic live-donor nephrectomy has increased the potential LD renal pool substantially. Factors thought to encourage more LDs include less post operative pain, shorter hospital stays, and decreased time until patients can return to normal activities (20,46). Based on retrospective studies comparing laparoscopic-donor nephrectomy with open donor nephrectomy, there is a decrease in the time before patients return to work. Four studies have specifically looked at this issue; all report a statistically significant decrease in the time off prior to return to work, from 5.3 to 7.4 weeks in the open-donor nephrectomy cohort to 2.3 to 4.4 weeks in the laparoscopic-donor nephrectomy cohort (22,23,52,53). One study was able to quantify the loss of income as 11% less in the laparoscopic donors compared with the open donors (26). At least one prospective study has shown that a formal education program for ESRD patients and their families, which included a discussion of loss of time from work and financial impact on the donor has significantly increased interest by family members in the procedure (20). Other types of living organ donors, such as liver, lung, intestine and pancreas, need more time to recover than kidney donors because of the type of surgery required. The length of hospital stay, the recovery time, complication rates, and the number of required clinic visits also vary by type of organ donated. Right hepatectomy donors can anticipate not returning to work for at least two to three months, which can result in significant income loss depending on the leave policy of the donor’s employer. Complications may occur in up to 15% to 30% of donors, which may further prolong the period away from work (49). Despite use of sick-leave benefits, many donors have inadequate income during the convalescence periods. Wage and other reimbursements for donors are becoming more common with increased efforts by employers and local, state, and federal agencies to help defray the costs of donation. Individuals who work for large employers (more than 50 employees) for at least 12 months may be eligible for the Family Medical Leave Act and may be able to be away from work for up to 90 days when donating an organ (54). Currently, several states within the United States offer financial incentives to LDs. At the time of this publication, Arkansas, Georgia, Iowa, Minnesota, Missouri, New Mexico, North Dakota, Utah, and Wisconsin all offer a $10,000 Organ Donation Tax Deduction to LDs for incurred costs such as travel to a transplant center and lost wages. Ohio, Oklahoma, Virginia, and Wisconsin also offer state employees various amounts of paid leave of absence for LDs (55). This list is by no means inclusive, and many other state legislatures are considering adopting similar legislation at the time of this publication. The American Society of Transplantation is campaigning, with some success, for hospitals with transplant centers to replicate the federal organ donor leave act by providing paid medical leave for employees who donate (56). At the federal level, the U.S. Congress has enacted the Organ Donation and Recovery Improvement Act (H.R. 3926/ S. 1949), which is intended to

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establish a federal grant program for states or organ procurement organizations to provide financial assistance to LDs for any incidental expenses they might incur, such as travel expenses (57). The Department of Defense allows active members to become LDs while still remaining active, and civilian federal employees may take up to thirty days of paid leave in order to become LD under the Organ Donor Leave Act (58). In addition, many of the charitable organizations that assist transplant recipient patients will also often offer assistance to LDs. For a complete list of organizations and contact information, please refer to the UNOS Web site (www.transplantliving.org). The ability of donors to obtain or maintain health, life, or disability insurance at existing rates is occasionally of concern. In isolated incidents, some companies have attempted to raise premiums after kidney donation, or the donor has had difficulty obtaining new insurance coverage (44,59). In most cases, however, higher rates for life and health insurance have not been reported for kidney donors (60–62). Spital and Kokmen (60) surveyed 99 health insurance companies in 1996 and found that most did not consider healthy kidney donors to be at increased risk for medical problems. Only 2% would raise premiums. Santiago and colleagues (63) reported in 1972 that 97% of 75 U.S. life insurance companies surveyed would insure donors after nephrectomy with proof of normal kidney function. Spital (64) in 1988 and Jacobs (65) in 2001 surveyed U.S. life insurance companies (54 and 70 companies, respectively) and found that, overall, companies suggested that they are still willing to insure healthy kidney donors at standard rates. Similar studies that examine insurance practices for LDs of other organs have not been done; however, some reports indicate that following partial donor hepatectomy, costs of late complications, such as incisional hernia, may not be covered by the recipient’s and potential donor’s health insurance (49). In some cases donors may be responsible for costs that are not covered by the recipient’s insurance, even if the problem is related to a complication (49). Additionally, no national insurance benefits are routinely offered in the event of donor disability, complications, or catastrophic death. Individual coverage for donors with measurable loss of function following donation depend on the insurer and the employer’s willingness to provide a higher cost policy; coverage may only be available through high-cost, government-sponsored, high-risk pools (67) or donor foundations (68). The South-Eastern Organ Procurement Foundation offers, life, disability, and medical coverage for complications arising from kidney donation (68). Transplant centers must pay a fee per donor to qualify donors for any benefits. Although this benefit seems appropriate to offer donors, most transplant centers cannot absorb the additional cost. More studies are needed that include responses from direct contact with all donor types regarding their personal experience with insurance companies. SOCIETAL PERSPECTIVE As a society, we have accepted transplantation as the method of choice for treating end-stage organ failure from both a medical and an economic perspective. Living donation, however, may have both financial benefits and disadvantages from a societal perspective. The lost time from work for the donor as well as that of any caregivers who change their schedules to take care of the donor or to fulfill the donor’s obligations must be weighed against the increased productivity that may occur when treatment of the recipient’s end-stage organ disease allows these individuals to return to work. Unfortunately, no data currently exist regarding the impact of transplantation on donor caregivers. The costs of evaluating potential LDs, their postoperative care including potential complications, and time lost from work for the donor may cost more than procurement of a DD organ. Although economic information about time lost from work is rarely investigated, it is clear that patients with ESRD lose substantial employment time. Approximately 17% of patients who start hemodialysis are employed at the time (7), and it is also true that the longer patients are out of work, the less likely they are to return to work. In the renal transplant population, no data have shown that transplantation increases the likelihood of employment; rather, employment rates of ESRD patients on hemodialysis are similar to employment rates of renal transplant recipients (69,70). Fear of rejection episodes, lack of desire to give up disability claims and health insurance benefits, and advancing age of transplant recipients have all been cited as possible factors in these patients’ failure to return to work (70,71). As part of an investigation by

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Papalois and colleagues (72), 1074 LD renal transplant recipients and 775 DD transplant recipients were questioned about their employment status five years after transplantation. Each group was subdivided into those patients who received their transplant pre-emptively before initiation of hemodialysis versus those who received their transplant while on hemodialysis. Employment rates at five years post-transplant were similar across the groups, ranging from 80% to 89%, with no statistical difference found. Thus, early renal transplantation from a LD may not substantially change the rate of employment, and its main economic benefit to society may be from the overall savings in medical costs post-transplant as compared with maintenance hemodialysis. No study to date has compared employment post-transplant in DD versus LD liver transplantation, although most studies of DD liver recipients report similar employment rates in transplant patients pre- and post-transplant (73). However, of those patients who were not employed, up to 50% answered that they would like to work, and 33% stated that they are looking for jobs (74). Most employed liver transplant recipients held jobs that did not require heavy labor, whereas patients who had previously held physically demanding jobs pretransplant were often collecting disability post-transplant. This suggests that educational programs with the goal of finding jobs with fewer physical demands may benefit this group of patients. CONCLUSION Whereas LD kidney transplantation has consistently been demonstrated to be more costeffective than DD kidney transplantation, the jury is still out on the overall financial impact of LD liver transplantation compared with DD liver transplantation. The magnitude of the cost advantage for LD over DD transplantation depends greatly on factors such as graft survival and postoperative complications. Because living donation allows the opportunity for recipients to be less debilitated at the time of LD transplantation, improved LD liver transplant outcomes will likely come with refinements in the procedure. LDs are faced with a variety of financial concerns. Most studies are related to kidney donor outcomes; more studies are needed in the extrarenal population to learn about the financial impact for these donor groups. The 2000 report from the U.S. Consensus Statement on Live Organ Donors states that “living organ donors should not personally bear any costs associated with donation” (75); however, although many efforts have been made at the local, state, and federal levels, that goal has not yet been achieved. In addition to the burden of lost wages, the cost of life, health, and disability insurance should be ascertained. If insurance rates are higher following donation, these costs should be incorporated into economic analyses and may partially offset any potential cost savings of LD transplantation. Calculating costs from a societal perspective is a difficult undertaking because indirect costs are difficult to ascertain. Indirect costs could be substantial and would be worth evaluating because transplantation has an impact on the income generated by donors and close family members in addition to recipients. REFERENCES 1. Morrisey M, Rustand L. Financial considerations in liver transplantation. In: Busuttil RW, Klintmalm GB, eds. Transplantation of the liver. Philadelphia: WB Saunders Co, 1996:861. 2. Ramsey SD, Patrick DL, Albert RK, Larson EB, Wood DE, Raghu G. The cost-effectiveness of lung transplantation. A pilot study. University of Washington Medical Center Lung Transplant Study Group. Chest 1995; 108:1594–1601. 3. Friedman EA. End-stage renal disease therapy: an American success story. JAMA 1996; 275:1118–1122. 4. Inglehart JK. Health care reform: the labyrinth of Congress. N Engl J Med 1993; 329:1593–1596. 5. Lockridge RS Jr. The direction of end-stage renal disease reimbursement in the United States. Semin Dial 2004; 17:125–130. 6. Steinman TI. Economics of transplantation. In: Norman DJ, Turka LA, eds. Primer on Transplantation. New Jersey: American Society of Transplantation, 2001:192. 7. United States Renal data System 2001 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, 2001. 8. http://www.optn.org/latestData/step2.asp (accessed October 2005). 9. Tousignant P, Guttmann RD, Hollomby DJ. Transplantation and home hemodialysis: their cost-effectiveness. J Chronic Dis 1985; 38:589–601.

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10. Eggers PW. Comparison of treatment costs between dialysis and transplantation. Semin Nephrol 1992; 12:284–289. 11. Mullins CD, Thomas SK, Pradel FG, et al. The economic impact of laparoscopic LD nephrectomy on kidney transplantation. Transplantation 2003; 75:1505–1512. 12. Evans RW, Kitzmann DJ. An economic analysis of kidney transplantation. Surg Clin North Am 1998; 78:150–174. 13. Chisholm MA, Vollenweider LJ, Mulloy LL, Wynn JJ, Wade WE, Dipiro JT. Cost-benefit analysis of a clinical pharmacist-managed medication assistance program in a renal transplant clinic. Clin Transplant 2000; 14:304–307. 14. Jassal SV, Krahn MD, Naglie G, et al. Kidney transplantation in the elderly: a decision analysis. J Am Soc Nephrol 2003; 14:187–196. 15. Terasaki PI, Cecka J, Gjertson DW, et al. High survival rates of kidney transplants from spousal and living-unrelated donors. NEJM 1995; 333:333–336. 16. Gjertson DW, Cecka JM. Living-unrelated donor kidney transplantation. Kidney Int 2000; 58:491–499. 17. Mange KC, Joffe MM, Feldman HI. Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. NEJM 2001; 344:726–731. 18. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes. Transplantation 2002; 74:1377–1381. 19. Smith CR, Wookward RS, Cohen DS, et al. DD versus LD kidney transplantation: a Medicare payment analysis. Transplantation 2000; 69:311–314. 20. Scwheitzer EJ, Wilson J, Jacobs S, et al. Increased rates of donation with laparoscopic donor nephrectomy. Ann Surg 2000; 232:392–400. 21. Ratner LE, Montgomery RA, Kavoussi LR. Laparoscopic live-donor nephrectomy: the four-year Johns Hopkins University experience. Nephrol Dial Tranpslant 1999; 14:2090–2093. 22. Flowers JL, Jacobs S, Cho E, et al. Comparison of open and laparoscopic live-donor nephrectomy. Ann Surg 1997; 226:483–490. 23. Odland MD, Ney AL, Jacobs DM, et al. Initial experience with laparoscopic live-donor nephrectomy. Surgery 1999; 126:603–606. 24. Ratner LE, Kavoussi LR, Sroka M, et al. Laparoscopic assisted live-donor nephrectomy—a comparison with the open approach. Transplantation 1997; 63:229–233. 25. Novotny MJ. Laparoscopic live-donor nephrectomy. Urol Clin North Am 2001; 28:127–135. 26. Wolf JS, Tchetgen MB, Merion RM. Hand-assisted laparoscopic live-donor nephrectomy. Urology 1998; 52:885–887. 27. Gilbert JR, Pascual M, Shoenfeld DA, Rubin RH, Delmonico FL, Cosimi AB. Evolving trends in liver transplantation: an outcome and charge analysis. Transplantation 1999; 67:246–253. 28. Evans RW, Manninen DL, Dong FB. An economic analysis of liver transplantation. Costs, insurance coverage, and reimbursement. Gastroenterol Clin North Am 1993; 22:451–473. 29. Best JH, Veenstra DL, Geppert J. Trends in expenditures for Medicare liver transplant recipients. Liver Transpl 2001; 7:858–862. 30. Russo MW, Sandler RS, Mandelkehr L, Fair JH, Johnson MW, Brown RS Jr. Payer status, not race, affects the cost of liver transplantation. Liver Transpl Surg 1998; 4:370–377. 31. Brown RS Jr, Lake Jr, Ascher NL, Emond JC, Roberts JP. Predictors of the cost of liver transplantation. Liver Transpl Surg 1998; 4:170–176. 32. Taylor MC, Greig PD, Detsky AS, McLeod RS, Abdoh A, Krahn MD. Factors associated with the high cost of liver transplantation adults. Can J Surg 2002; 45:425–434. 33. Whitting JF, Martin J, Zavala E, Hanto D. The influence of clinical variables on hospital costs after orthotopic liver transplantation. Surgery 1999; 125:217–222. 34. Rufat P, Fourquet F, Conti F, Le Gales C, Houssin D, Coste J. Costs and outcomes of liver transplantation in adults: a prospective, one-year, follow-up study. Transplantation 1999; 68:76–83. 35. Markmann JF, Markmann JW, Markmann DA, et al. Preoperative factors associated with outcome and their impact on resource use in 1148 consecutive primary liver transplants. Transplantation 2001; 72:1113–1122. 36. Freeman R, Tsunoda S, Supran S, et al. Direct costs for one year of liver-transplant care are directly associated with disease severity at transplant. Transplant Proc 2001; 33:1436–1437. 37. Zapata R, Innocenti F, Sanhueza E. Predictive models in cirrhosis: correlation with the final results and costs of liver transplantation in Chile. Transplant Proc 2004; 36:1671–1672. 38. Cole CR, Bucuvalas JC, Hornung R, et al. Outcome after pediatric liver transplantation impact of living-donor transplantation on cost. J Pediatrics 2004; 144:729–735. 39. Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, Hadengue A. LD liver transplantation for early hepatocellular carcinoma: a life-expectancy and cost-effectiveness perspective. Hepatology 2001; 33:1073–1079. 40. Sagmeister M, Mullhaupt B, Kadry Z, Kullak-Ublick GA, Clavien PA, Renner EL. Cost-effectiveness of DD and LD liver transplantation. Transplantation 2002; 73:616–622.

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41. Trotter JF, Mackenzie S, Wachs M, et al. Comprehensive cost comparison of adult–adult right hepatic lobe LD liver transplantation with DD transplantation. Transplantation 2003; 75:473–476. 42. Brown RS JR, Ascher NL, Lake JR, et al. The impact of surgical complications after liver transplantation on resource utilization. Arch Surg 1997; 132:1098–2003. 43. Chen CL, Fan ST, Lee SG, Makuuchi M, Tanaka K. LD liver transplantation: 12 years of experience in Asia. Transplantation 2003; 75:S6–S11. 44. Shover L, Streem S, Boparai N, Duriak K, Novick A. The psychosocial impact of donating a kidney: long-term follow-up from a urology based center. J Urol 1997; 157:1596–1601. 45. Smith M, Kappell D, Province M, et al. Living-related kidney donors: a multi-center study of donor education, socioeconomic adjustment, and rehabilitation. Am J Kidney Dis 1986; 8:223–233. 46. Isotani S, Fujisawa Ichikawa Y, et al. Quality of life of living kidney donors: the short-form 36-item health questionnaire survey. Urology 2002; 60(4):588–592. 47. Wolters HH, Heidenreich S, Senninger N. LD kidney transplantation: chance for the recipient—financial risk for the donor? Transplant Proc 2003; 35:2091–2092. 48. Sterneck MR, Fischer L, Nischwitz U, et al. Selection of the living liver donor. Transplantation 1995; 60:667–671. 49. Trotter JF, Talamantes M, McClure M, et al. Right hepatic lobe donation for living-donor liver transplantation: impact on donor quality of life. Liver Transpl 2001; 7:485–493. 50. Smith MD, Kappell DF, Province MA, et al. Living-related kidney donors: a multicenter study of donor education, socioeconomic adjustment, and rehabilitation. Am J Kidney Dis 1986; 8:223–233. 51. Jacobs C, Johnson E, Anderson K, Gillingham K, Matas A. Kidney transplants from LDs: how donation affects family dynamics. Adv Ren Replace Ther 1998; 5:89–87. 52. Ratner LE, Kavoussi LR, Schulam PG, et al. Comparison of laparoscopic live-donor nephrectomy versus the standard open approach. Transplant Proc 1997; 29:138–139. 53. Ratner LE, Kavoussi LR, Sroka M, et al. Laparoscopic assisted live-donor nephrectomy—a comparison with the open approach. Transplantation 1997; 63(2):229–233. 54. Family and medical Leave Act of 1993. Available at: http://www.dol.gov/dol/asp/public/programs/handbook/fmla.htm. Accessed June 2002 55. http://www.transplantliving.org/livingdonation/financialaspects/statetax.aspx (accessed October 2005). 56. Delmonico F, Arnold R, Scheper-Hughes N, Simonoff L, Kahn J, Youngner S. Ethical incentives—not payment—for organ donation. N Engl J Med 2002; 346:2002–2005. 57. http://www.organdonor.gov/congressional_summary.htm#S.%201949 (accessed October 2005). 58. http://www.opm.gov/oca/compmemo/1999/Att_wjc.htm (accessed October 2005). 59. Spital A. More on life insurance for kidney donors. Transplantation 1990; 49:664. 60. Spital A, Kokmen T. Health insurance for kidney donors: how easy is it to obtain? Transplantation 1996; 62:1356–1358. 61. Spital A, Jacobs C. Life insurance for kidney donors: another update. Transplantation 2002; 74:972–973. 62. Jacobs C, Thomas C. Financial considerations in living organ donation. Progress Transpl 2003; 13:130–136. 63. Santiago EA, Simmons R, Kjellestrand C, Buselmeir T, Najarian J. Life insurance perspectives for the living kidney donor. Transplantation 1972; 14:131–133. 64. Spital A. Life insurance for kidney donors—an update. Transplantation 1988; 45:819–820. 65. Jacobs C. Expanding organ donor options and financial resources. Graft 2001; 4:410–411. 66. Gorman KJ, Fein AJ, Shield CF. Relationship between clinical outcome, inpatient length of stay, and cost of renal transplantation at four US transplant centers. Transplant Proc 1993; 25(1):1690–1691. 67. Perin DM. Economic point of view and insurance of donors. Transplanatation Proc 2003; 35:972–973. 68. South-Eastern Organ Procurement Foundation. Available at: http://www.seopf.org. (accessed October 2005.) 69. Overbeck I, Baretls M, Decker O, et al. Changes in quality of life after renal transplantation. Transplantation Proc 2005; 37:1618–1621. 70. Markell MS, DiBenedetto A, Maursky V, et al. Unemployment in inner-city renal transplant recipients: predictive and sociodemographic factors. Am J Kidney Dis 1998; 29:881–887. 71. Raiz L. The transplant trap: the impact of health policy on employment status following renal transplantation. J Health Soc Policy 1997; 8:67–87. 72. Papalois VE, Moss A, Gillingham KJ, et al. Pre-emptive transplants for patients with renal failure. Transplantation 2000; 70:625–631. 73. Bravata DM, Olkin I, Barnato AE, et al. Employment and alcohol use after liver transplantation for alcoholic and nonalcoholic liver disease: a systematic review. Liver Transplantation 2001; 7:191–203. 74. Rongey C, Banbha K, Vaness D, et al. 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Transplantation Tolerance Fadi G. Lakkis Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION Long-term survival of organ allografts is readily attainable in patients maintained on continuous immunosuppressive therapy, particularly those who receive organs from living donors (1). Long-term allograft survival without ongoing immunosuppression, however, remains an elusive goal. Research efforts over the past 50 years have focused on immunologic tolerance as the means of achieving this goal. Despite relative success in rodents, tolerance to organ transplants, defined as donor-specific unresponsiveness, has been seldom attained in larger animals or in humans (2). In this chapter, I review the mechanisms of immunological tolerance and the barriers to its induction. DEFINING TOLERANCE Transplantation tolerance is traditionally defined as donor-specific unresponsiveness (3). Implicit in this definition is that tolerant recipients are unresponsive to donor antigens, but maintain reactivity to other (third-party) antigens. For example, a tolerant patient is someone who is capable of mounting an effective immune response against vaccines or pathogens, but is incapable of rejecting the transplanted organ after withdrawing immunosuppression. Donor-specific unresponsiveness, however, is rarely observed in the clinic, and patients with long-term functioning allografts off immunosuppressive medications often retain normal immunological reactivity against their donors. These observations have led to alternate definitions of transplantation tolerance such as “allograft acceptance in recipients on minimal or no immunosuppression,” and have spurred terminologies such as “operational” and prope tolerance. In this chapter, I put forth the thesis that the classical definition of tolerance, antigen-specific unresponsiveness, does not apply to clinical transplantation tolerance because the acquisition of absolute unresponsiveness to donor alloantigens may not be feasible. To provide support for this argument, I first review examples of immunological tolerance that occur spontaneously in nature. Second, I examine the mechanisms of immunological tolerance and their limitations. Third, I summarize the biological barriers that prevent donor-specific unresponsiveness. Fourth, I describe the concept of immunological ignorance and how, in combination with a state of reduced host reactivity to donor antigens, it may lead to tolerance. Finally, I review the current status of transplantation tolerance in the clinic and will propose a modified definition of transplantation tolerance that is more commensurate with reality than the long-sought state of absolute donor-specific unresponsiveness. NATURAL EXAMPLES OF TRANSPLANTATION TOLERANCE The classical example of naturally occurring transplantation tolerance is the chimeric animal. Dizygotic twin embryos that exchange blood through vascular anastomoses in the placenta develop permanent mixed hematopoietic chimerism and, as adults, are fully tolerant of grafts of each other’s skin. This phenomenon was reported in freemartin cattle by Owen in 1945 and later by Medawar and colleagues in 1951 and 1952 (4–6). Subsequent work by Billingham, Brent, and Medawar duplicated chimerism and tolerance in the laboratory by demonstrating that fetal mice inoculated with live cells from a genetically disparate strain would, as adults, accept skin grafts from that strain (7). The state of mixed hematopoietic chimerism and

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acquired tolerance could be achieved only if donor cells were injected prenatally or in the early neonatal period, but not if injected later in life. The latter observation underscored the formidable barriers to realizing donor-specific unresponsiveness in the clinic. It also implied that the immunological mechanisms that operate during ontogeny are not fully functional in the mature animal. Therefore, mixed hematopoietic chimerism results in donor-specific unresponsiveness if it is established prenatally, but is less likely to do so once the immune system has matured. Are there, then, situations in nature whereby the mature immune system tolerates nonself, and if so, can tolerance be equated with antigen-specific unresponsiveness? The answer to the first part of the question is that “natural” tolerance does exist, including situations in which non-self is a potentially lethal microbe; for example, tolerance to the gut flora (8). The average adult human harbors billions of bacteria in the gut, yet humans co-exist peacefully with their microbial symbionts. Another conspicuous example is maternal tolerance of the allogeneic fetus despite abundant expression of paternal antigens on fetal cells (9). The answer to the second part of the question is that tolerance in either situation is not dependent on antigen-specific unresponsiveness. Gut microbes are largely ignored by host lymphocytes because they are sequestered behind the gut mucosal barrier, and immuno-regulatory mechanisms dampen unwanted reactions to the occasional bacterium that penetrates the gut barrier. Likewise, tolerance to the fetus results from a combination of mechanisms that include immunological ignorance, regulation, and antigen-non-specific hypo-responsiveness in the mother. Therefore, examples of immunological tolerance in adult animals do occur in nature, but do not support the contention that tolerance is equivalent to donor-specific unresponsiveness. MECHANISMS OF TRANSPLANTATION TOLERANCE The immunologic mechanisms that lead to tolerance are traditionally divided into central and peripheral (3). Central tolerance occurs in the thymus, where immature, antigen-specific lymphocytes are eliminated through a process known as negative selection. Peripheral tolerance, on the other hand, occurs extrathymically and may be crucial for silencing mature T-cell populations in the adult animal whose thymus has become less active. Mechanisms proposed to mediate peripheral tolerance include deletion, anergy, suppression, and immune deviation of alloantigen-specific, mature T-lymphocytes. The clonal deletion (or exhaustion) hypothesis presumes that tolerance results from apoptosis of the antigen-specific T-cell population. Alternatively, a tolerance-inducing strategy could inactivate T-lymphocytes without causing their death (anergy), generate regulatory cells which block T-lymphocyte activation and function (suppression), or induce the differentiation of antigen-specific T-lymphocytes into a non-harmful phenotype (immune deviation). The mechanisms described above are not mutually exclusive. Their relative contribution to tolerance depends on the organ being transplanted, the tolerance-inducing regimen used, and the degree of donor-recipient histo-incompatibility. Although the mechanisms of transplantation (non-self) tolerance overlap with those that maintain tolerance to self-antigens, there are important differences that distinguish the two. The principal mechanism responsible for self-tolerance is thymic deletion of self-reactive T-cells. During ontogeny, self-antigens are abundantly expressed in the thymus through the action of the transcriptional factor AIRE or via the migration of dendritic cells from the periphery (10). Maturing thymocytes that have high avidity to self-antigens are deleted in the thymus while those with intermediate affinity are believed to give rise to regulatory T-cells (11). The peripheral tolerance mechanisms described in the previous paragraph become necessary only if the rare self-reactive T-cell escapes thymic deletion. Therefore, the robustness of central (thymic) deletion ensures that animals with adaptive immune systems are largely unresponsive to their self-antigens. Unlike self-antigens, the foreign antigens of a transplanted organ reach the thymus only in small quantities. Moreover, the thymus of transplant recipient, whether children or adults, are less active than the fetal thymus. Therefore, tolerance to non-self antigens, such as those of transplanted organs, relies more heavily on the less robust tolerance mechanisms that operate in the periphery.

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LIMITATIONS OF TOLERANCE MECHANISMS Central (Thymic) Deletion As alluded to in the previous paragraph, thymic deletion of antigen-specific T-cells is the most robust mechanism of immunological tolerance and is responsible for purging the T-cell repertoire of self-reactive lymphocytes in the fetus. Although there are examples of transplantation tolerance mediated by central deletion of alloreactive T-cells in adult animals (mainly rodents and inbred miniature swine) (12,13), it is not clear whether central deletion can be consistently achieved in adult primates and humans in whom the thymus involutes over time. Moreover, the majority of these studies point to the importance of antigen persistence in sustaining tolerance (14–16). Specifically, unresponsiveness to donor antigens is dependent on establishing hematopoeitic macrochimerism by infusing allogeneic bone marrow into recipients conditioned with a short course of cytotoxic and/or immunosuppressive therapy. The obvious disadvantages of this approach are the toxicities of the conditioning regimens and the risk of graft versus host disease once immunosuppression is stopped. It is also unclear whether deletion of alloreactive T-cells in outbred primates and humans, among whom antigenic differences are more diverse than inbred experimental animals, will put the recipient at risk for serious infections and malignancies by creating a large hole in the T-cell repertoire. Peripheral Deletion Several studies have shown that the apoptosis of mature alloreactive T-cells, mainly via a mechanism referred to as activation-induced cell death (AICD), is a prerequisite for achieving transplantation tolerance (17,18). AICD, however, is not unique to immune responses that result in immunologic unresponsiveness, but is a universal property of all vigorous immune responses. This is best illustrated by Murali-Krishna et al., who demonstrated that a typical antiviral immune response consists of three phases: massive clonal T-cell expansion, massive T-cell apoptosis (the “crash”), and finally immunologic memory and not tolerance (19). These findings suggest the existence of potent factors that rescue activated T-cells from apoptosis and favor T-cell memory generation. Therefore, AICD is necessary but not sufficient for the induction of peripheral transplantation tolerance. Factors that rescue activated T-cells from apoptosis could present an important hurdle to achieve donor-specific unresponsiveness. Despite its shortcomings, peripheral deletion could under certain circumstances cause the elimination of most if not all antigen-specific T-cells. The circumstances that favor peripheral T-cell deletion are determined by the location, dose, and persistence of antigen (20). A foreign antigen that reaches secondary lymphoid tissues in large quantities, or one that persists in the host and continues to have access to secondary lymphoid organs tends to cause exhaustion/ deletion of antigen-specific T-cell clones. The principal of exhaustion/deletion has been demonstrated in experimental animals exposed to nominal antigens, viruses, tumors, and allogeneic cells (14,15). In the latter case, the migration of allogeneic cells of hematopoietic origin to the host’s lymphoid tissues is responsible for peripheral T-cell deletion—thus, the clinical interest in mixed hematopoietic chimerism as a means to achieve transplantation tolerance. As discussed later in the chapter, the relatively large repertoire of alloreactive T-cells present in a given recipient makes the deletion of all donor-reactive T-cells an unrealistic goal. Anergy Although anergy has been defined in vitro in the context of the two signal hypothesis for T-cell activation, anergy remains poorly defined in vivo. In vitro studies indicate that T-cells stimulated via the TCR (signal 1) in the absence of adequate costimulation (signal 2) are rendered anergic (21). In vivo studies, however, do not support this finding and, instead, provide evidence that T-cell anergy is the consequence of full T-cell activation (22,23). Specifically, anergic T-cells are detected among previously activated T-cells that escaped apoptosis following the primary immune response. Therefore, it is unlikely that agents that block T-cell costimulation will lead to tolerance by inducing T-cell anergy as predicted by in vitro models. Another significant limitation of anergy is its reversibility. It has been

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repeatedly shown that viral or bacterial infection can restore antigen-specific immunologic responsiveness in anergic animals (24,25). Regulation Regulatory T-cell phenomena have been described in animal models of transplantation and autoimmunity (26,27). However, peripheral tolerance to transplanted organs in adult animals could be attributed to immune regulation in select circumstances where antigenic differences between the donor and recipient are restricted to minor or incomplete MHC mismatches (28). These studies suggest that regulatory T-cells alone are not sufficient for maintaining tolerance to organs transplanted across greater histocompatibility barriers. Furthermore, the regulatory T-cell phenotype may be an unstable one. Lanzavecchia and Sallusto have proposed that regulatory T-cells are intermediate and not terminally differentiated lymphocytes (29). These intermediates can differentiate to effector cells upon restimulation or in vitro culture. Thus, regulatory T-cells alone are unlikely to bring about stable transplantation tolerance. In summary, tolerance induction in transplant recipients is bound to rely more on peripheral than central mechanisms of T-cell deletion and regulation. These peripheral mechanisms, although effective in moderating immune responses and subduing the rare self-reactive T-cell that escapes thymic deletion, are unlikely to guarantee absolute and specific unresponsiveness to transplanted organs. BIOLOGICAL BARRIERS TO TRANSPLANTATION TOLERANCE In addition to the inherent limitations of tolerance mechanisms, other important barriers to transplantation tolerance exist. Here, I highlight three: (i) the nature of alloreactivity; (ii) the presence of alloreactive memory T-cells; and (iii) the innate immune system. The Nature of Alloreactivity The immune response to a nominal antigen is initiated when antigen-specific T-cells recognize foreign peptides presented in the context of self-MHC molecules. T-cells specific to peptides derived from a nominal antigen constitute a very small fraction (<0.1%) of the total T-cell repertoire. In contrast, a much higher frequency (up to 10%) of T-cells react to a transplanted organ (30). The presumed reason for this vigorous response is the presence of two pathways for allorecognition (31). In the indirect pathway, foreign donor antigens (e.g., those derived from donor major or minor histocompatibility molecules) are presented to recipient T-cells by recipient APC in the context of self-MHC. This pathway is identical to that employed during the immune response to a nominal antigen and, therefore, activates only a small number of alloreactive T-cells. In the direct pathway, a much higher frequency of recipient T-cells respond to donor APC expressing foreign MHC complexed to donor peptides. Donor peptides could be either foreign to the recipient (e.g., those derived from donor major and minor histocompatibility molecules) or, in the majority of cases, are self-peptides (e.g., cellular proteins common to both the donor and recipient) that are recognized as foreign because they are presented in the context of non-self-MHC. It is the latter phenomenon that is thought to account for the high frequency of T-cells stimulated via the direct pathway because of the large number of peptide-non-self-MHC combinations that could be recognized as foreign by the recipient (32). This brings up the possibility that alloreactive T-cells exist because they recognize potentially harmful foreign antigens presented in the context of self-MHC (e.g., microbial and tumor peptides), but happen to cross-react with foreign MHC complexed to self-peptides. In other words, the foreign antigen-specific and the allospecific T-cell repertoires overlap. This conclusion is supported by numerous examples of foreign peptide-specific T-cells that also exhibit strong alloreactivity (30,33,34). Since deletion or inactivation of the majority of alloreactive T-cells is necessary for inducing transplantation tolerance, it is possible that tolerance strategies will create a “hole” in the immunological repertoire of the adult recipient that could lead to intolerable immunodeficiency. This undesirable side effect has already been observed in mixed macrochimerism studies in primates in which the majority of animals developed lethal CMV infection (C. P. Larsen, public presentation).

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The Presence of Alloreactive Memory T-Cells It is widely argued that the immune response to a transplanted organ, particularly in humans, results from the stimulation of both naive and memory alloreactive T-cells (35–37). Since currently available tolerance induction strategies are based on agents that modulate the naive T-cell response, it is not known whether or how these agents affect the memory response. Memory T-cells exist at much higher frequency differ significantly from their naive counterparts in their survival and activation requirements (38,39). Memory T-cells survive even in the presence of minimal antigens, and are maintained by factors distinct from those required for naive lymphocytes. Moreover, memory T-cell activation is independent of costimulatory molecules essential for naive T-cell activation. Although naive and activated T-cells are susceptible to apoptosis, it is suspected that memory T-cells are resistant to apoptosis. Thus, it may be quite difficult to delete or inactivate alloreactive memory T-cells using currently available tolerance strategies. This could present an important hurdle to achieving transplantation tolerance in humans. Innate Immunity The innate immune system is the first line of defense against foreign antigens (40). The soluble components of the innate immune system include complement and clotting factors. The cellular components include neutrophils, macrophages, natural killer (NK) cells, and antigenpresenting cells (APC). Many of these cells express innate receptors that recognize molecular motifs on microbes or injured cells. The best known of these receptors are the Toll-like receptor (TLR) family (41,42). Ligation of TLRs by their microbial ligands leads to APC activation, maturation, and migration to secondary lymphoid tissues where they initiate adaptive (T-and B-cell) immune responses. That the innate immune system plays a role in allograft rejection has been demonstrated in experimental models of transplantation (43). C3-deficient kidneys are rejected at a much slower tempo than their wild-type counterparts (44). Likewise, the rejection of minor histo-incompatible skin grafts is completely abrogated if both the donor and recipient lack Myd88 (45), an intracellular adaptor molecule required for TLR signaling. Moreover, innate immune activation prevents tolerance induction (46) (D. R. Goldstein, public presentation). Mice that lack Myd88 signaling can be rendered tolerant to fully allogeneic skin grafts much more readily than wild-type mice, and, conversely, the introduction of TLR ligands at the time of transplantation prevents the acceptance of skin and cardiac allografts. TLR stimulation interferes with tolerance induction by preventing the apoptosis (deletion) of alloreactive T-cells. Therefore, innate immune activation caused by ischemic, microbial, or other injury to the graft or host constitutes an important barrier to the induction of transplantation tolerance. In summary, the limitations of traditional tolerance mechanisms (deletion, anergy, and regulation) and the biological barriers to tolerance (alloreactivity, memory T-cells, and innate immunity) account for the failure of experimental tolerance strategies to induce donor-specific unresponsiveness reliably in outbred experimental animals and humans. In the next section, I discuss the concept of immunological ignorance and provide evidence that ignorance could contribute to allograft acceptance. IMMUNOLOGIC IGNORANCE OF SELF AND FOREIGN ANTIGENS Secondary lymphoid organs (the spleen, lymph nodes, and mucosal lymphoid tissues) provide the optimal environment for APC to interact with and activate naive T-and B-lymphocytes (47). An antigen that is processed and transported by APC to secondary lymphoid organs results in T-cell and B-cell activation, while an antigen that remains outside the secondary lymphoid organs is ignored by the immune system (20). Immunologic ignorance, therefore, is failure to respond to an antigen despite the presence of immunocompetent antigen-specific T-cell clones. Immunologic ignorance is an important extrathymic mechanism by which self-tolerance is maintained. This conclusion is supported by several landmark experiments. For example, transgenic mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein on the surface of β islet cells of the pancreas do not develop diabetes when cross-bred with TCRtransgenic mice that carry a large number of T-lymphocytes that recognize the LCMV

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glycoprotein. In these double-transgenic mice, clonal deletion, clonal anergy, and TCR downregulation did not account for tolerance to the viral (“self”) antigen expressed on islet cells. Instead, these mice developed diabetes upon infection with LCMV virus, suggesting that naive self-reactive cytotoxic T-cells ignore islet antigens unless activated by an external stimulus that is capable of reaching the secondary lymphoid tissues (48). Similar observations were made in transgenic mice that express ovalbumin or an allogeneic MHC molecule on β islet cells (49,50), and in transgenic mice that express LCMV glycoprotein in the liver (51). In all of these models, the extrathymic mechanism that prevented autoimmunity was immunologic ignorance and not peripheral deletion, anergy, or regulation. Immunologic ignorance can also explain why certain tumors and viruses evade immune surveillance. Peripheral solid tumors such as sarcomas and carcinomas are ignored by the immune system because they remain outside secondary lymphoid organs; however, these tumors are promptly rejected if tumor cell suspensions are injected into the animal such that tumor cells reach the secondary lymphoid tissues (52). Similarly, viruses can evade immune responses if viral antigens do not reach secondary lymphoid organs. This has been demonstrated in mice that lack secondary lymphoid organs and in models of persistent viral infection (53). Ignorance is also an important mechanism by which the gut microbial flora and the fetus are protected from immune rejection (see previous section). Therefore, naturally occurring examples of tolerance, whether physiological or pathological, are often a reflection of immunological ignorance rather than antigen-specific unresponsiveness. IMMUNOLOGIC IGNORANCE OF TRANSPLANTED ORGANS AND TISSUES The prevailing view has been that immune responses to primarily vascularized organ transplants such as hearts and kidneys do not require the presence of secondary lymphoid tissue. The assumption has been that the immune response to such organs is initiated in the graft itself when recipient lymphocytes encounter foreign histocompatibility antigens presented by the graft’s endothelial cells (54), implying that immunologic ignorance of vascularized organ transplants is not possible. This hypothesis has been challenged recently (55). Using two models, alymphoplastic (aly/aly) or Homeobox 11 gene-knockout (Hox11-/-) mice, which lack lymph nodes or the spleen, respectively, it was shown that fully allogeneic, vascularized heart transplants are rejected in both models (56). If, however, the aly/aly mice were splenectomized before transplantation, heart grafts were accepted indefinitely (56). These recipients failed to generate anti-donor alloantibodies and the graft histology remained normal even when examined six months after transplantation. Thus, the complete absence of secondary lymphoid tissues prevented rejection of fully vascularized transplants. Using adoptive transfer experiments, the authors proved that immunological ignorance—that is, absence of rejection despite the presence of alloreactive T-cell clones—was responsible for indefinite allograft acceptance. This implies that chance encounter between recipient alloreactive T-cells and donor antigens outside secondary lymphoid organs does not lead to clonal deletion, anergy, or regulation but, instead, the recipient’s T-cells simply ignore the transplanted organ as if it were self. Relative ignorance of vascularized organ allografts has also been achieved in experimental animals by first ridding the allograft of passenger leukocytes. This has been best demonstrated in the renal allograft parking experiments performed by Lechler and Batchelor in rats in 1982 (57). Despite long-term allograft acceptance without immunosuppression in these experiments, the transplanted kidneys eventually developed chronic rejection. It has since become apparent that eliminating donor APCs from vascularized organ grafts is quite difficult and, even if it were to be accomplished, does not guarantee ignorance because of the ability of host APCs to present donor antigens to host lymphocytes (so-called indirect antigen presentation). Unlike vascularized organs, non-vascularized, or neo-vascularized allografts such as pancreatic islets may provide a unique opportunity for exploiting immunological ignorance (58). First, APCs that contaminate pancreatic islet preparations can be reduced or eliminated by culturing the islets prior to transplantation. Second, islets could be shielded from the immune system by either encapsulating them or transplanting them into privileged anatomical sites that minimizes the migration of donor antigens to the recipient’s secondary lymphoid tissues.

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Despite success in rodents, the clinical feasibility of either approach remains to be tested carefully in larger animals or humans. IS IMMUNOLOGIC IGNORANCE FEASIBLE CLINICALLY? Strober and colleagues reported on a deceased-donor renal transplant recipient who received pretransplant total lymphoid irradiation (59). Despite MHC mismatches at all HLA-A, -B, and -DR loci, the patient maintained very good graft function 12 years after withdrawing all immunosuppression. Surprisingly, the recipient’s peripheral blood mononuclear cells exhibited vigorous donor-reactivity as measured by the mixed leukocyte reaction, suggesting that neither clonal deletion nor anergy of alloreactive T-cells accounted for allograft acceptance. This anecdotal clinical case suggests that immunologic ignorance could exist in humans following an extended period of immunosuppression. It is possible that during the immediate post-transplant period immunologic ignorance can be achieved only if the function of secondary lymphoid tissues is paralyzed (e.g., by irradiation) or if APC and lymphocyte homing to secondary lymphoid tissues is blocked (potentially by antagonizing chemokine receptors). However, once a transplanted organ is established in the recipient, APC trafficking between the organ and secondary lymphoid tissues may dwindle to a point where alloimmunity cannot be initiated despite discontinuing immunosuppression. As with tolerance induction, many hurdles stand in the way of immunologic ignorance. Total lymphoid irradiation or non-specific blockade of APC and lymphocyte homing to secondary lymphoid organs is bound to increase the incidence of opportunistic infections. Furthermore, it is not known whether inflammation or innate immune activation in an established transplant could break immunologic ignorance by enhancing APC trafficking between the graft and secondary lymphoid tissues. Mouse experiments have shown that although transplanted organs become resistant to acute rejection after they heal, they remain susceptible to chronic rejection. These obstacles serve as a reminder that indefinite allograft acceptance in the absence of immunosuppression, if achieved in humans, will most likely be the consequence of multiple immunological mechanisms. In this context, it is possible that ignorance may serve as an adjunct to traditional tolerance mechanisms. TRANSPLANTATION TOLERANCE IN THE CLINIC Spontaneous tolerance of organ allografts after a brief period of immunosuppression was first reported by Starzl and colleagues in 1963 (60). Additional tolerant recipients have been reported since and some have enjoyed excellent allograft function in the absence of immunosuppression for more than 30 years (61). Spontaneously tolerant patients, however, represent a very small minority of all transplant recipients, and many do not conform to the classical definition of tolerance (donor-specific unresponsiveness). More recently, deliberate induction of tolerance has been attempted by infusing hematopoietic stem cells to conditioned recipients who received low-dose total body irradiation (plus myelo- and lympho-depletion) with the goal of creating mixed hematopoietic macrochimerism (62). Although only a handful of renal transplant recipients have participated in this experimental protocol, allograft acceptance in the absence of immunosuppression was achieved in most but, paradoxically, neither macrochimerism nor absolute donor-specific unresponsiveness was observed. These clinical observations raise three important questions: (i) What are the mechanisms of spontaneous transplantation tolerance in humans? (ii) Why is spontaneous transplantation tolerance rare? (iii) Can tolerance be reliably and safely induced in organ transplant recipients? Here, I attempt to answer the first two questions. The third question is addressed in the concluding section of this chapter. What Are the Mechanisms of Spontaneous Transplantation Tolerance in Humans? A unified answer to this question is lacking largely due to our inability to measure the human alloimmune response reliably. Although a variety of tolerance mechanisms have been implicated (deletion, regulation, and ignorance), it is likely that multiple mechanisms cooperate in the same host to maintain allograft acceptance. A compelling account of spontaneous

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transplantation tolerance in humans, however, is based on the exhaustion/deletion of alloreactive T-cells by migratory donor cells that emanate from the graft and persist in the host (63). The initial wave of migration causes T-cell activation followed by deletion, and the continued migration of donor cells to host secondary lymphoid tissues results in recurrent activation/deletion cycles that eventually minimize or exhaust the alloreactive T-cell repertoire. The state in which a small number of migratory donor cells persist in the recipients’ tissues after transplantation is known as microchimerism. Microchimerism is associated with spontaneous transplantation tolerance in animals and humans (63), and the cause–effect relationship between microchimerism and deletion of antigen-specific T-cells has been elegantly established in a mouse model of minor antigen-mismatched transplantation (64). Although microchimerism is an important mechanism of allograft tolerance in humans, it occurs spontaneously in only a small fraction of patients, and it may not lead to absolute donor-specific unresponsiveness across HLA barriers. Why Is Spontaneous Transplantation Tolerance Rare? The simple immunological answer to this question is that the location, dose, and timing of antigen exposure in most cases of organ transplantation favor immunity rather than tolerance. The transplanted organ can be thought of as a vaccine with both antigenic and adjuvant properties. Tipping the balance toward tolerance requires that the graft’s adjuvanticity and antigenicity are kept minimal to ensure ignorance by the host’s immune system or, conversely, that adjuvanticity and antigenicity remain maximal in order to effect clonal exhaustion/deletion of host T-cells. Unfortunately, neither situation is common, and tolerance mechanisms that lie on the spectrum between absolute ignorance and absolute deletion are unstable. Reducing immunogenicity by transplanting well-matched organs from living donors increases the chance that immunosuppressive drugs could be withdrawn from a given recipient, but does not guarantee tolerance. Likewise, transplanting an APC-rich organ such as the liver promotes T-cell exhaustion/deletion but does not ensure that tolerance will occur uniformly. Most importantly, the common practice of administering large doses of immunosuppressive drugs in the early post-transplantation period inhibits T-cell activation and prevents the beneficial apoptosis of donor-reactive T-cells. Thus, the early window of opportunity for inducing tolerance via T-cell deletion is practically closed shut in patients on conventional immunosuppressive regimens. CONCLUDING REMARKS: CAN TOLERANCE BE RELIABLY AND SAFELY ACHIEVED IN ORGAN TRANSPLANT RECIPIENTS? Based on the arguments provided throughout this chapter, transplantation tolerance, defined in absolute terms as donor-specific unresponsiveness, is neither feasible nor safe. Even if donorspecific unresponsiveness were to be achieved, its toll on the host would be unacceptable. Tolerance, however, need not be equated with antigen-specific unresponsiveness as inferred from natural examples of tolerance to foreign antigens and from numerous cases of spontaneous allograft acceptance in humans. Therefore, I propose here that transplantation tolerance be redefined as coexistence of graft and host at minimal cost to either. This definition is consistent with how living organisms interact with the most ubiquitous of all foreign antigens, those of the microbial world. Throughout evolution, both plants and animals have largely opted to cohabitate with microbes in symbiotic, neutral, or parasitic relationships (65). An all-or-none outcome where either the host or the microbe ”wins” is uncommon and is beneficial to neither. A host obsessed with clearing microbial pathogens risks dying of immunopathology, and a microbe intent on killing its host curtails its chances of survival by spreading to other hosts. Transplantation tolerance can be perceived through the same evolutionary lens. Donor-specific unresponsiveness assumes that the organ has been declared the ”winner,” a situation that could be very costly to the host because of the enormity of the alloreactive T-cell pool and its extensive overlap with the anti-microbial repertoire. Even if one were to postulate regulation rather than T-cell deletion as a safer mechanism of donor-specific unresponsiveness, the number of regulatory T-cells, the complexity of the regulatory networks, and the amount of energy a host has to expend to suppress every alloreactive T-cells seems unnatural. Perhaps the most important and pragmatic reason why “coexistence of graft and host

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at minimal cost to either” is a useful definition is that it allows for all mechanisms of tolerance, including ignorance, to participate in mediating allograft acceptance. Such a definition, in my opinion, makes transplantation tolerance a clinically attainable goal. So what, then, are the most promising clinical strategies for achieving transplantation tolerance? Based on natural and clinical observations, the induction of mixed hematopoietic chimerism is the most likely candidate strategy. Several caveats, however, apply: (i) that microchimerism is sufficient to induce transplantation tolerance, as macrochimerism may be disadvantageous to the host both in terms of graft versus host disease and increased susceptibility to infection; (ii) that heavy immunosuppression with conventional agents that block T-cell activation is avoided around the time of transplantation as T-cell activation is a pre-requisite for T-cell deletion and regulation; (iii) that alternate strategies are utilized to avoid irreversible acute rejection episodes in the early post-transplantation period as long as these strategies do not interfere with the establishment of chimerism; and (iv) the understanding that deleting or suppressing all donor-reactive T-cells is simply unrealistic—ultimately allograft acceptance has to rely on adjunctive tolerance mechanisms such as immunological ignorance. In closing, transplantation tolerance may indeed become a reality if we can successfully maintain a safe and stable level of mixed hematopoietic chimerism in the recipient. If achieved, mixed hematopoietic chimerism that leads to organ allograft tolerance would constitute a state of balanced coexistence between graft and host. To realize this goal, however, we first have to revisit the most fundamental question—what prevents stable micro- or macrochimerism? Like most biological questions, the answer to this question most likely lies in the realm of evolutionary science, specifically in the understanding the origins of individuality (66). REFERENCES 1. Hariharan S, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000; 342:605–612. 2. Salama A, et al. Challenges to achieving clinical transplantation tolerance. J Clin Invest 2001; 108:943–948. 3. Charlton B, Hugh Auchincloss J, Fathman CG. Mechanisms of transplantation tolerance. Annu Rev Immunol 1994; 12:707–734. 4. Owen RD. Immunogenetic consequences of vascular anastomeses between bovine twins. Science 1945; 102:400–401. 5. Anderson D, et al. The use of skin grafting to distinguish between homozygotic and dizygotic twins in cattle. Heredity 1951; 5:379–397. 6. Billingham R, et al. Tolerance to homografts, twin diagnosis, and the freemartin condition in cattle. Heredity 1952; 6:201–212. 7. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 1953; 172:603–606. 8. MacDonald T, Monteleone G. Immunity, Inflammation, and Allergy in the Gut. Science 2005; 307:1920–1925. 9. Trowsdale J, Betz A. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nature Imm 2006; 7:241–246. 10. Venanzi ES, Benoist C, Mathis D. Good riddance: thymocyte clonal deletion prevents autoimmunity. Curr Opin Immunol 2004; 16(2):197–202. 11. Kronenberg M, Rudensky A. Regulation of immunity by self-reactive T-cells. Nature 2005; 435(7042):598–604. 12. Fuchimoto Y, et al. Mixed chimerism and tolerance without whole-body irradiation in a large animal model. J Clin Invest 2000; 195:1779–1789. 13. Huang CA, et al. Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large animal model. J Clin Invest 2000; 105:173–181. 14. Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. N Engl J Med 1998; 339:1905–1913. 15. Starzl TE, Zinkernagel RM. Transplantation tolerance from a historical perspective. Nat Rev Immunol 2001; 1(3):233–239. 16. Waldmann H. Transplantation tolerance—where do we stand? Nat Med 1999; 5:1245–1248. 17. Dai Z, Lakkis FG. The role of cytokines, CTLA-4, and costimulation in transplant tolerance and rejection. Curr Opin Immunol 1999; 11:504–508. 18. Li XC, et al. T-cell death and transplantation tolerance. Immunity 2001; 14:407–416. 19. Murali-Krishna K, et al. Counting antigen-specific CD8 T-cells: a re-evaluation of bystander activation during viral infections. Immunity 1998; 8:177–187.

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20. Zinkernagel RM, et al. Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity. Immunol Rev 1997; 156:199–209. 21. Schwartz RH. Models of T-cell anergy: Is there a common molecular mechanism? J Exp Med 1996; 184:1–8. 22. Rocha B, Grandien A, Freitas A. Anergy and exhaustion are independent mechanisms of peripheral T-cell tolerance. J Exp Med 1995; 181:993–1003. 23. Pape KA, et al. Direct evidence that functionally-impaired CD4+ T-cells persist in vivo following induction of peripheral tolerance. J Immunol 1998; 160:4719–4729. 24. Rocken M, Urban JF, Shevach EM. Infection breaks T-cell tolerance. Nature 1992; 359:79–82. 25. Ehl S et al. Viral and bacterial infections interfere with peripheral tolerance induction and activate CD8+ T-cells to cause immunopathology. J Exp Med 1998; 187:763–774. 26. Shevach EM. Regulatory T-cells in autoimmunity. Annu Rev Immunol 2000; 18:423–449. 27. Fontenot JD, Rudensky AY. A well-adapted regulatory contrivance: regulatory T-cell development and the forkhead family transcription factor Foxp3. Nat Immunol 2005; 6(4):331–337. 28. Waldmann H, Cobbold S. How do monoclonal antibodies induce tolerance? A role for infectious tolerance? Annu Rev Immunol 1998; 16:619–644. 29. Lanzavecchia A, Sallusto F. Dynamics of T-lymphocyte responses: intermediates, effectors, and memory cells. Science 2000; 290:92–97. 30. Sherman LA, Chattopadhyay S. The molecular basis of allorecognition. Annu Rev Immunol 1993; 11:385–402. 31. Gould DS, Auchincloss H, Jr. Direct and indirect recognition: the role of MHC antigens. Immunol Today 1999; 20:77–82. 32. Rotzschke O, et al. On the nature of peptides involved in T-cell alloreactivity. J Exp Med 1991; 174:1059–1071. 33. Pantenburg B, et al. T-cells primed by leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol 2002; 169:3686–3693. 34. Adams A, et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003; 111:1887–1895. 35. Lombardi G, et al. Are primary alloresponses truly primary? Int Immunol 1990; 2(1):9–13. 36. Pober JS, et al. Can graft endothelial cells initiate a host anti-graft immune response? Transplantation 1996; 61:343–349. 37. Heeger PS, et al. Pretransplant frequency of donor-specific, IFN-g-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol 1999; 163:2267–2275. 38. Lakkis FG, Sayegh MH. Memory T-cells: a hurdle to immunologic tolerance. J Am Soc Nephrol 2003; 14(9):2402–2410. 39. Valujskikh A, Lakkis F. In remembrance of things past: memory T-cells and transplant rejection. Imm Rev 2003; 196:65–74. 40. Medzhitov R, Janeway CJ. Decoding the patterns of self and nonself by the innate immune system. Science 2002; 296:298–300. 41. Medzhitov R. Toll-like receptors and innate immunity. Nature Rev Immunol 2001; 1:135–145. 42. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004; 5(10):987–995. 43. Obhrai J, Goldstein DR. The role of toll-like receptors in solid organ transplantation. Transplantation 2006; 81(4):497–502. 44. Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nature Med 2002; 8:582–587. 45. Goldstein D, et al. Critical role of the Toll-like receptor signal adaptor protein Myd88 in acute allograft rejection. J Clin Invest 2003; 111:1571–1578. 46. Thornley TB, et al. TLR agonists abrogate costimulation blockade-induced prolongation of skin allografts. J Immunol, 2006; 176(3):1561–1570. 47. Goodnow CC. Chance encounters and organized rendezvous. Immunol Rev 1997; 156:5–10. 48. Ohashi P, et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 1991; 65:305–317. 49. Heath W, et al. Autoimmunity caused by ignorant CD8+ T-cells is transient and depends on avidity. JI 1995; 155(5):2339–2349. 50. Kurts C, et al. CD8 T-cell ignorance or tolerance to islet antigens depends on antigen dose. Proc Natl Acad Sci 1999; 96:12703–12707. 51. Voehringer D, et al. Break of T-cell ignorance to a viral antigen in the liver induces hepatitis. JI 2000; 165:2415–2422. 52. Ochsenbein AF, et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci 1999; 96:2233–2238. 53. Karrer U, et al. On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11-/-) mutant mice. J Exp Med 1997; 185:2157–2170. 54. Brent L, Medawar PB. Cellular immunity and the homograft reaction. Brit Med Bull 1967; 23:55–60.

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55. Lakkis F. Where is the alloimmune response initiated? Am J Transplant 2003; 3:241–242. 56. Lakkis FG, et al. Immunologic “ignorance” of vascularized organ transplants in the absence of secondary lymphoid tissue. Nature Med 2000; 6:686–688. 57. Lechler R, Batchelor J. Restoration of immunogenicity to passenger cell depleted kidney allografts by the addition of donor strain dendritic cells. J Exp Med 1982; 155:31–41. 58. Pericin M, et al. Allogeneic beta-islet cells correct diabetes and resist immune rejection. Proc Natl Acad Sci USA 2002; 99(12):8203–8206. 59. Strober S, et al. Clinical transplantation tolerance twelve years after prospective withdrawal of immunosuppressive drugs: studies of chimerism and anti-donor reactivity. Transplantation 2000; 69:1549–1554. 60. Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 1963; 117:385–395. 61. Starzl TE, Lakkis FG. The unfinished legacy of liver transplantation: emphasis on immunology. Hepatology 2006; 43(2 suppl 1):S151–S163. 62. Buhler LH, et al. Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation 2002; 74(10):1405–1409. 63. Starzl T. Chimerism and tolerance in transplantation. Proc Natl Acad Sci 2004; Early Edition (August 19):online publication. 64. Bonilla WV, et al. Microchimerism maintains deletion of the donor cell-specific CD8+ T-cell repertoire. J Clin Invest 2006; 116(1):156–162. 65. Hedrick SM. The acquired immune system: a vantage from beneath. Immunity 2004; 21(5):607–615. 66. Buss L. The evolution of individuality. Princeton: Princeton University Press, 1987.

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Ethics of Paid Living-Unrelated Donation: The Case for a Regulated System of Kidney Sales Arthur J. Matas Department of Surgery, University of Minnesota, Minneapolis, Minnesota, U.S.A.

INTRODUCTION Discussion of kidney sales raises passionate emotions. The debate is unending. Why is this? The arguments for and against sales are relatively straightforward. Proponents argue that sales will increase the number of successful transplants and save lives, without any excess harm to the paid donors, hereafter called vendors (versus altruistic donors). Opponents argue that donation and the total number of kidneys may decrease, that vendors will suffer some (undefined) damage (either physical or emotional), and that the doctor-patient relationship will be negatively affected (1). Both sides can present only limited data. Proponents note the success of a regulated system of sales in Iran [currently, there is no prolonged wait for deceased donor (DD) transplants] (2–4). Opponents note the often poor donor outcomes in Iran and in areas of the world with unregulated trafficking (5–7). However, the situation in those places is not applicable to the United States and Canada, or to much of the Western world. In the United States and Canada (and much of the Western world), transplants are done in specialized centers that are already highly regulated. In the United States, center-specific donor and recipient information is available to the general public (via the Internet). Most other Western countries (or geographic areas) have publicly available registries. Standards for donor evaluation and care of living donors (LDs) have been developed (8–10). Countries with universal health-care (sorely lacking in the United States) can provide long-term care and follow-up for vendors. If a regulated system of sales were integrated into these already highly-regulated transplant programs, vendor interests could be protected. In this chapter, I present the argument for a regulated system of sales. I then note the many flaws in the arguments given for not setting up such a system. In Chapter 36, Arthur Caplan will argue against sales (having had the advantage of first reading my manuscript). But I caution the reader—until we try this, the debate will continue to be unending. Until we try this, we will not know whether or not implementing a system of sales will increase the number of available kidneys. Until we try this, we will not know whether sales can be done in a way that protects the health and dignity of the vendor in the same way that we currently protect the health and dignity of unpaid LDs. My perspective on the issue of sales is that of a physician whose major clinical and academic focus is kidney transplantation. More detailed bioethical arguments can be found in the writings of Radcliffe-Richards (11,12), Gill and Sade (13), Harris and Erin (14), Hippen (15), Taylor (16), and Cherry (17). A REGULATED SYSTEM By “regulated,” I mean a system in which a fixed price is paid to the vendor (by the government or a government-approved agency); the kidney is allocated by a predefined algorithm similar to that used for DDs (thus, everyone on the waiting list has an opportunity to receive a vendor kidney); criteria are defined for vendor evaluation, acceptance, and follow-up; and safeguards are adequate for vendor protection. In addition, as noted by Harris and Erin, the payment should not affect taxes and welfare benefits (14). Such a system would differ from the “unregulated” markets that have developed elsewhere, in which the kidney may go to the

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highest bidder, payment is directly from the recipient, most of the payment goes to a broker, and standards for donor care are few (7,18,19). Still another, parallel, approach would be to implement a system for payment for DD organs (because the arguments for and against this approach differ somewhat from the arguments regarding living vendors, I do not further consider this approach). Arguments for and against sales may be different for different geographic and socioeconomic areas of the world. I will limit the discussion to issues concerning a regulated system in the industrialized Western world (preferably with universal health care). Other authors have elucidated reasons to consider sales in other areas (20,21). It is crucial to recognize that, at least in the United States, a substantial payment (≈$100,000) could be made to a vendor and still be cost-neutral to the health care system (because of the savings of a transplant over ongoing dialysis) (22). ARGUMENTS FOR SALES The major argument for sales is that they would likely increase the number of available kidneys, shorten waiting time for a transplant, decrease the number of patients with end-stage renal disease (ESRD) who die on the waiting list, and improve patient and graft survival rates. It has long been recognized that a successful transplant provides significantly better quality of life than does maintenance dialysis (23). Recently, considerable evidence has emerged showing a successful transplant significantly prolongs patient survival, compared with dialysis (24,25), and that survival is better with a pre-emptive transplant (versus a transplant after initiation of dialysis) (26,27). As a consequence, more patients with ESRD are opting for a transplant rather than dialysis; waiting lists for DD transplants have grown; and the average wait for a DD kidney is now over five years. A major parallel development has been the recognition that outcome after living-unrelated donor (LURD) kidney transplants is the same as after (non-HLA-identical) living-related kidney transplants (28). The significant increase in waiting time for DD transplant candidates has already had dire negative consequences. In the United States, over 6% of waiting candidates die annually (24,29). And, it is important to remember, these are patients who were declared to be suitable transplant candidates when they were listed. We recently studied patient deaths on the waiting list at the University of Minnesota (unpublished data). We noted that, on average, 6.7% of patients on the list died each year. The mean age (± SD) was 54 ± 11 years. Of the deaths, 11% occurred in patients less than 40 years old, 33% in those less than 50 years old, and 73% in those less than 60 years old. At the time of death, the mean waiting time was 1078 ± 847 days; 70% of the patients who died were waiting for a first transplant, and 70% had a panel-reactive antibody (PRA) level <10%. Because the number of waiting candidates is growing steadily, and because the number of DDs has increased very little in the last decade (in North America), the waiting list and waiting times are projected to continue to increase (29,30). Thus, even more candidates will die while waiting. In fact, this issue alone (i.e., death on the waiting list) led Radcliffe-Richards to suggest lifting the ban on sales, unless those who oppose sales can provide any reasonable arguments justifying the ban’s continuation (11). After all, currently everyone but the donor already benefits financially from the transplant (physicians, coordinators, hospitals, recipients). Moreover, ample legal precedent already exists for sales of body parts (e.g., sperm, eggs) and for payments to surrogate mothers. Gill and Sade argue a prima facie case for kidney sales based on two claims: “good donor claim” and “sale of tissue claim” (13). The good donor claim stems from the fact that it is already legal for a living person to donate a kidney, that is, to transfer a kidney to someone else. It then follows that kidney sales should be allowed: “If donating a kidney ought to be legal, and if the only difference between donating a kidney and selling one is the motive of monetary self-interest, and if the motive of monetary self-interest does not on its own warrant legal prohibition…,” then donating for money should be legal. The sale of tissue claim stems from the fact that “it is legal (and ought to be legal) for living persons to sell parts of their bodies (blood, sperm, eggs).” Thus, again, “monetary self-interest does not on its own warrant legal prohibition.” In subsequent discussions, Gill and Sade point out that if we oppose kidney sales (versus the sale of sperm or eggs) because donor nephrectomy is more dangerous, then we should also

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oppose kidney donation; if we oppose kidney sales because people should not sell body parts, then we should also oppose the sale of sperm or eggs (13). Another argument in favor of sales relates to current Western philosophical principles, in particular, the emphasis on autonomy (31). The ban on sales is paternalistic and ignores the need to respect individual autonomy. In general, with “few constraints, people make personal decisions on what they wish to buy and sell based on their own values” (13), and should be allowed to do so. In discussing the prohibition of sales, Radcliffe-Richards notes that “in a surprising contravention of our usual ideas about individual liberty, we prevent adults from entering freely into contracts from which both sides expect to benefit, and with no obvious harm to anyone else” (2). Finally, although most countries have laws against organ sales, a growing unregulated market for sales already exists—a market in which donors are often poorly evaluated and cared for, and a market in which most of the payment goes to a broker (7,18,19). Eliminating the legislative ban on sales and establishing a regulated system may well eliminate or minimize the ongoing unregulated markets (32,33), thereby leaving people who actually do sell a kidney in a better position—better paid and better cared for. As conceded by the International Congress on Ethics in Organ Transplantation (Munich, Germany, December 2002): “The well-established position of transplantation societies against commerce in organs has not been effective in stopping the rapid growth of such transplants around the world. Individual countries will need to study alternative, locally relevant models, considered ethical in their societies, which would increase the number of transplants, protect and respect the donor, and reduce the likelihood of rampant, unregulated commerce” (34). Of note, much of the recent discussion about sales has occurred in the bioethics and general medicine literature, with limited participation by transplant-related personnel. Two exceptions have been the Bellagio Task Force Report on Transplantation, Body Integrity, and the International Traffic in Organs (convened under the auspices of the Center for the Study of Society and Medicine of the College of Physicians and Surgeons of Columbia University), which found no ethical principle that would justify a ban on sales under all circumstances (35), and the report of the International Forum for Transplant Ethics, which concluded that the discussion of organ sales needs to be reopened (12). Clearly, if sales are to become a reality, we in the transplant community must be participants in the process—at a minimum, we must be involved in each vendor’s evaluation, surgery, and care. For that reason, it is imperative that we also must more actively join in the discussion about sales (and in the formulation of any policy). We must be knowledgeable about the arguments for and against sales and about the practical concerns that would need to be addressed before any system of sales could be established. ARGUMENTS AGAINST SALES (AND SOME COUNTERPOINTS) Numerous arguments—ethical, political (public policy), and practical—have been made against sales (Table 1). Yet, it is noteworthy that the debate about sales is occurring in an environment

TABLE 1

Arguments Used to Justify the Ban on Sales

“Artificial crisis” Previous contamination of the blood supply “Exploitation” of the poor Society’s role in protecting the marginalized “Commodification” of the body (and violation of body integrity) Harm to vendors Lack of genuine consent Difficulty in changing the law Objections of organized religions Desire for altruistic donation Erosion of trust in the government or doctors Fears of abuse of the system

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in which we accept living donation. Any effective argument against sales must be able to justify the ban on sales while simultaneously permitting donation (11). An “Artificial” Crisis One argument is that “a medically invented, artificial scarcity in human organs for transplantation has generated a kind of panic and a desperate international search for them…” (36). No doubt, the field of transplantation is “medically invented.” But it is the patients who are requesting transplants. Patients with ESRD have the choice of long-term dialysis or a transplant (at least in the industrialized world). Because a successful transplant provides a longer life and a better quality of life than dialysis, many patients opt for a transplant. Previous Contamination of the Blood Supply Some argue that sale of blood resulted in contamination of the blood supply and in transmission of disease (specifically hepatitis C and HIV). There is no doubt that this is true. But it occurred when screening tests were not available for these viruses. Currently, LDs are screened for both hepatitis C and HIV; vendors would be similarly screened. As an extra cautionary step, vendors could be screened twice, with a six-month interval between screening tests. In fact, Hippen notes that it was not altruistic donation but improved screening that made the blood supply safer (15). “Exploitation” of the Poor The core of this argument is that risks are involved with nephrectomy, the poor are more likely to sell a kidney than the rich, and the financial offer will override their better judgment. In a broader context, the concern is that the citizens of developing countries will become vendors for citizens of industrialized countries. The fact that uninephrectomy has risks plays an important role in this argument. For example, it was never seriously suggested that commercialization of the blood supply exploited the poor. Nevertheless, the risk of uninephrectomy, alone, cannot justify the ban on sales. As discussed above, if surgical risk is deemed sufficient to justify a ban on sales, then surgical risk should also be sufficient to justify a ban on donation. Moreover, our society allows the less wealthy to take many high-risk jobs that the rich are unlikely to apply for (e.g., police officers, deep sea divers, firefighters, military “volunteers,” North Sea oil rig workers, coal miners). In addition, we allow both the rich and the poor to engage in recreational activities that have considerably greater risk than does uninephrectomy (e.g., smoking, mountain climbing, skydiving, bungee jumping). Serious objections have never been raised about permitting financial incentives to encourage middle-class and upper-class people to be vendors (11,37). One possible solution to the possibility of “exploitation” is to establish a minimum income for one to become a vendor. However, if it were permissible for the middle or upper classes to sell a kidney, why should it not be permissible for the lower classes? Thus, in a regulated system, the “exploitation” argument against kidney sales becomes, in part, the argument that the poor are more likely to be vendors than the rich. Clearly, the “exploitation” argument is not about equality. As noted by Gill and Sade, “if paying for kidneys is legalized, the ratio of poor people with only one kidney to rich people with only one kidney probably will increase” (13). This result could be seen as not being equal. But, as Gill and Sade emphasize, “the kind of equality that matters to egalitarians, however, concerns not the presence of one kidney versus two but economic and political power. There is no reason to believe that allowing payment for kidneys will worsen the economic or political status of kidney sellers in particular or of poor people in general” (13). In a regulated system as described above, the “exploitation” argument is not about coercion, which is defined as “persuasion (of an unwilling person) to do something by using force or threats” (38). No potential vendor can be coerced by the opportunity to sell an organ. But when the term is (mis)used in this way, many authors argue that a payment is coercive in that it might “manipulate the victim’s preferences, even if it would be rational to accept” (39) or

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in that “the intent of the offer is to elicit behavior that contradicts the individual’s normal operative goals” (40). However, the fact of payment does not necessarily mean that the vendor’s choice was not free and voluntary (11,13,37). Moreover, Harvey suggests that, first, if this “financial pressure” is sufficient to justify a ban on sales, then psychological or emotional pressure that may occur in related donation could justify a ban on donation and, second, a ban on sales also stops potential vendors who are not financially vulnerable (41). Cherry distinguishes between “coercion” and “peaceful manipulation.” Coercion violates the free choice of individuals, whereas peaceful manipulation “grounds the very process of negotiation through which individuals fashion consensual agreements.” Cherry argues that “to be coercive, rather than peaceably manipulative, requires showing that making such an offer places potential vendors into unjustified, disadvantaged circumstances.” Financial offers may be “seductive,” but they “are not subtle threats” (42). Most important, the “exploitation” argument centers on whether a regulated system of organ sales takes wrongful advantage of the calamity of others and on whether the financial offer will override the better judgment of individuals in desperate need. No doubt, a significant financial offer will provide hard choices for people in need. But there is a difference between a “hard choice” and an “involuntary choice.” I do not think we are willing to say that being poor removes the ability to make rational decisions (if we believed that, we would need legal guardians to protect any decision an impoverished person makes). A regulated system is not necessarily exploitive if it pays a significant amount (an amount that has the potential to make a positive impact on the vendor’s life) and if it includes procedural safeguards to ensure that vendors know what they are doing and are acting voluntarily to seek their individual best. In the case of kidney sales, the system would not be seeking the typical exploiter’s “wrongful gain,” but would be established to help patients in need (T. Gutmann, personal communication). Many authors have countered the “exploitation” argument by suggesting that the ban on sales removes one potential option for the poor, and leaves them poor; whereas if they could sell a kidney, it would give them the possibility to better their lives (11,43). There is a difference between having limited options versus being able to choose rationally in one’s best interests among the options available. Clearly, the ideal solution to the problem of the poor being more likely to be vendors would be to end poverty. However, no evidence suggests that poverty will disappear in the near future, and not allowing sales does nothing to eradicate poverty. One prominent bioethicist, Veatch, once suggested that, rather than permit sales, we should prompt social change to end poverty, but he has become pessimistic about the possibility of social change and now favors sales (37). Veatch’s original concern about sales was that the (political) decision-makers could, in effect, force the poor to sell their organs by withholding alternative means of addressing their problems. He has now re-examined the issue 20 years later, concluding that our society has done little to help the poor, and with “shame and bitterness” proposes that it is time to lift the ban on sales: “If we are a society that deliberately and systematically turns its back on the poor, we must confess our indifference to the poor and lift the prohibition on the one means they have to address their problems themselves” (37). A final concern regarding “exploitation” has been that, in a government-controlled singlepayer system, there would be pressure to lower the price paid for each kidney—i.e., there would be institutionalized “exploitation” (as described by Veatch, above). However, the system could be designed with safeguards to prevent such institutionalized exploitation. Society’s Role in Protecting the Marginalized Many argue that a major responsibility of government in our Western industrialized society is to provide a “safety net” to protect the marginalized, and that legalization of sales would abrogate this responsibility. However, governments often have competing priorities, and protecting citizens from unnecessary death (i.e., for those on the waiting list) is certainly a worthy goal. Certainly, continuing the ban on one choice for citizens (i.e., to sell a kidney) does not overtly protect them; rather, it may, in fact, prevent them from financially protecting themselves.

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“Commodification” of the Body and Violation of Body Integrity Some argue that sales would lead to “commodification” of people, of the human body. The concern seems to be that a vendor will, in some way, lose human dignity and be seen as only worthwhile as a provider of spare parts. As Sutton phrased it, “if we allow body parts to enter the marketplace, we depersonalize and devaluate ourselves” (44). In fact, no evidence suggests that sperm or egg donors, or surrogate mothers, have diminished self-dignity or self-worth. And, as noted in a detailed analysis by Wilkinson, “there is no necessary connection between the commodification of bodies or the commodification of persons” (45). As Gill and Sade state, “my kidney is not my humanity” (13); they continue, “humanity—what gives us dignity and intrinsic value—is our ability to make rational decisions, and a person can continue to make rational decisions with only one kidney.” If, in a regulated system, vendors are treated as heroes who receive compensation for their pain (as suggested by Gutmann and Land) (46), and have their rights and interests protected, it would be quite possible to sell a kidney without loss of dignity. Implied in the concern regarding “commodification” is the concept that “body integrity is highly valued” (45). The fear is that vendors would have some longstanding emotional or psychological damage because of the breaks in body integrity. Wigmore et al. argue that “violation of this integrity is not well-compensated for other than by spiritual or philosophical gains such as acting in an altruistic fashion” (47). But, again, little evidence supports this concept of negative violation. Surgical procedures, a direct violation of body integrity, do not usually lead to long-term psychological harm or damage to human dignity. One could argue that surgical procedures are necessary for the cure of disease, and this, in some way, leads to personal justification for the violation of body integrity. But, in fact, plastic surgery done solely for cosmetic purposes requires a break in body integrity. In addition, numerous occupations and recreational activities are associated with risks to body integrity; yet, we have no compunction about limiting people’s involvement in these activities. Furthermore, many cultures and religions throughout the world violate body integrity as part of their beliefs (e.g., piercings, male circumcision). In reality, individuals who value their body integrity over compensation for a kidney could choose not to be vendors. Thus, the “commodification” argument does not justify the ban on sales. Harm to Vendors Currently, the mortality rate associated with living kidney donation is 0.03%. If vendors are screened as thoroughly as LDs, the associated mortality rate would likely remain about 0.03%. So, on a purely rational level, the concern about vendor death does not differentiate kidney sales from donation. But, on an emotional level, death of a vendor “feels” different from death of a donor. When a donor dies because of donation, we might suggest that the death occurred while doing something “noble.” Of course, a vendor might also have a “noble” use for the money. Still, the practice of transplantation requires the goodwill of the public, and it is unclear how the press or public would react to the death of a vendor. Similarly, the surgical and long-term risks for vendors are identical to the risks for LDs. As discussed above, if these risks alone are sufficient to justify the ban on sales, they should also be sufficient to justify a ban on donation. Lack of Genuine Consent Some argue that, because money is involved, a potential vendor cannot ever truly provide genuine informed consent. But this argument rests on a paternalistic attitude that “we” are best able to weigh the risks and benefits for others. As described above, this argument also ignores a fundamental tenet of current medical practice and philosophy: autonomy. Some also argue that some potential vendors may be unable to understand the risks fully; but this worry also applies to LDs, yet we feel capable of screening and educating them. If the fact that some potential vendors may not understand the risks justifies the ban on sales, then the fact that some potential LDs may not understand the risks should justify a ban on living donation.

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Difficulty in Changing the Law Some argue that, because organ sales are currently a contentious issue, politicians (always concerned about re-election) would be reluctant to propose and fight for a change in the law. Whether or not this is true, it is not an argument either for or against sales. Certainly, it was difficult to change the law to allow emancipation of women and blacks. Presumably, if polls find that the public generally supports a regulated system of organ sales, then politicians would be willing to eliminate the ban. Objections of Organized Religions Almost all organized religions currently support organ donation. In Judeo-Christian culture, saving lives takes precedence over other religious laws and customs. Yet, it is unclear whether organized religions would take a formal stand against sales. According to Steinberg, almost all rabbinic authorities who have expressed an opinion have stated that, from a Jewish moral point of view, there is “nothing wrong in receiving reasonable compensation for an act of self-endangerment, whereby one still adequately fulfills the most important commitment—to save life” (48). The Catholic church has taken a somewhat mixed stance. Capaldi (49) argues that it is morally permissible for Catholics to participate in a market in organ sales; he quotes Pope Pius XII as saying, “It would be going too far to declare immoral every acceptance on every demand of payment. The case is similar to blood transfusions. It is commendable for the donor to refuse recompense; it is not necessarily a fault to accept it” (50). In contrast, Pope John Paul II stated, “The body cannot be treated as a merely physical or biologic entity, nor can its organs and tissues ever be used as items for sale or exchange. Such a reductive materialistic conception would lead to a merely instrumental use of the body, and therefore of the person” (51). In a subsequent address to The Transplantation Society, Pope John Paul II stated, “Any procedure which tends to commercialize human organs or to consider them as items of exchange or trade must be considered morally unacceptable” (52). Clearly, individuals with religious objections can choose not to be vendors. But it will require a change in the law to eliminate the ban on sales. In theory, religious belief should not determine law and public policy (14), yet strong opposition from organized religions could have an impact on political discussion and action. Caplan raises the objection of organized religion as a practical concern rather than an ethical argument. Caplan feels that moving forward toward sales will lead organized religion to object to donation, in general, and that the number of transplants will decrease (Arthur Caplan, personal communication). This is a testable hypothesis. Desire for Altruistic Donation Historically, it has been felt that donation should be altruistic. But there is no reason it must be this way. With our current practice of altruistic donation, the waiting list and resultant waiting time are getting longer every year. If there is a market in organs, some fear that altruistic living donation may decrease. But no evidence supports this concern (it is a hypothesis that can be tested). In fact, there are many reasons to believe that altruistic donation will continue. First, some recipients would continue to want to know their donor. As discussed below, there may be concerns about the “quality” of vendor kidneys. Families with these concerns might opt for donation. Second, with a regulated system of sales, waiting time is likely to be reduced but not eliminated. The outcome for kidney transplant recipients is better with a pre-emptive transplant (26,27), so many recipients would still opt for preemptive transplants from altruistic directed donors. Third, potential vendors may be demographically different (e.g., older) from potential altruistic donors, providing another reason for preferring a donor (over a vendor) kidney. Nevertheless, in some situations, a family might rather turn to a government-regulated vendor system than to a family member or altruistic friend. If so, there could be some decrease in altruistic donation (probably related to how long the waiting list is, once a vendor system is implemented). Some of this decrease may be good. First, we do not know how much coercion

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is involved in living-related donation; presumably a vendor system could eliminate this form of family coercion. Second, criteria for acceptance of LDs are being expanded (e.g., single-drug hypertension is allowed in some centers). An expanded-criteria donor is usually accepted only if he or she is the sole available donor for an individual recipient. A large vendor system might eliminate the need to use expanded-criteria donors. Clearly, whether sales will result in a significant decrease in donation needs to be studied. If there is a market, there is also a concern that deceased donation may decrease (again, an untested hypothesis). The great need for livers, hearts, lungs, and pancreases—all of which could never be supplied by vendors—will continue. However, it does need to be recognized that, if we eliminate the ban on organ sales, families of DDs may also lobby for a payment. Erosion of Trust in the Government or Doctors Government If the government (or its appointed agency) is the sole buyer of kidneys (in a regulated system), the government may be seen as preying on the poor, rather than providing a safety net (37). Potentially, one function of the government (providing for the needy) would be in direct conflict with the other (buying kidneys). However, in reality, government agencies often have competing priorities (e.g., consumer advocacy versus environmental protection, development of the economy versus raising the minimum wage, minimizing dependence on foreign oil versus preserving the country’s wilderness). In addition, the goal of purchasing kidneys would be to save lives—certainly an acceptable goal for the government. It is not unreasonable to believe that a regulated system with appropriate screening, good postoperative follow-up, and a substantial payment to the vendor could also be managed with care and dignity so that respect (for either the government or the vendor) would not suffer. Doctor-Patient Relationship Some also argue that allowing organ sales would disrupt the traditional doctor-patient relationship. However, no evidence suggests that sales would have any negative impact either on patient care or on a patient’s (vendor’s) expectations of the physician. No evidence suggests that medical care for surrogate mothers (analogous to vendors) has differed in any way from the current standard of practice. Presumably, in a regulated system, vendors would be given the same care as current LDs (and better care than current vendors in unregulated markets). Fears of Abuse of the System Potential vendors might lie about their health-care status and risks. Alternatively, physicians and transplant centers (who are paid when a transplant is done) might relax acceptance criteria in order to increase the number of transplants. However, such fears do not differentiate sales from altruistic living donation. The possibility of abuse is not used to justify bans on numerous other activities (e.g., paying taxes, driving powerful cars). In practice, a regulated system could be established to minimize such risks (e.g., rigid acceptance criteria, viral screening twice at six-month intervals). SOME PRACTICAL CONSIDERATIONS Many practical considerations are involved in establishing a regulated vendor system (Table 2). Each will require considerable discussion. Not being able to statistically address such considerations could alone justify not setting up a system. Determining Criteria for Vendors Should There Be a Minimum Age? In North America, 18-year-olds can join the military, vote, and be LDs. However, in most states, young adults cannot legally drink until age 21 (in part because a sense of mortality is not developed until at least the mid-20s). Car rental companies, recognizing the typical poor driving record of so many young drivers, have different restrictions and rates for those under age 25.

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Some Practical Considerations

Determining criteria for vendors Minimum age Defined geographic area Providing long-term health care for vendors Following vendors long-term Distributing payment Verifying health status of vendors Handling logistics Designating price Drawing the line at kidneys

Given the many issues associated with being a young adult, it might be reasonable to set a higher minimum age for vendors than currently exists for donors. Should Vendors Be Limited to a Defined Geographic Area? A major concern of opponents of sales is that people from “poor” countries would come to “rich” countries to sell their kidneys. A related concern is that financial compensation would be different between countries. Harris and Erin suggest that one solution would be to confine the marketplace to a geographic area (a country or a group of countries) in which vendors or families of vendors could benefit from a policy of organ sales (14). However, if we accept the concept of sales, is it really wrong to allow vendors to come from poor countries and provide kidneys to those in need (rich and poor) in rich countries? It could be argued that sales would allow a significant redistribution of wealth, and certainly could improve the lifestyle of each vendor. (It would be interesting to know whether opponents of sales check the labels on their clothes to determine where they were produced and whether “sweatshops” were involved.) Another way to limit an influx of potential vendors from poor to rich countries would be to only pay if a kidney is used. Potential vendors would likely incur some expenses in getting to a transplant center. Obviously, if they become actual vendors, the compensation could more than cover those expenses. Thus, on the one hand, it is likely that the expenses of getting to a transplant center (once for the evaluation and then for the uninephrectomy) would minimize the number of potential vendors crossing from one country to another. On the other hand, if a regulated system were established, it might not be surprising to see local “screening” clinics signing up vendors in poor countries; theoretically, vendors could pay the screening clinic after the uninephrectomy. Providing Long-Term Health Care for Vendors Although the risks of uninephrectomy are small, they are not zero. In a regulated system, in a country with a universal (national) health plan, long-term care can be assured. In other countries, the payment to vendors might include payment for health insurance. However, health insurance and long-term care would be difficult to organize if vendors come from different countries. Following Vendors Long Term Clearly, if a vendor system (or a pilot trial) were initiated, it would be important to study longterm outcome. Again, this would be difficult if vendors come from different countries. Distributing Payment Our previous study suggested that, in the United States, a payment of about $100,000 would be potentially cost-effective (some of this could be used to pay for life and health insurance and to fund long-term follow-up) (22). It might be reasonable to pay the $100,000 in a lump sum to U.S. vendors. But what if a regulated system were established that permitted vendors to come

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from other countries? Such vendors may have no experience in managing large sums of money; appropriate local facilities such as banks might not be available. In addition, regulation would have to be developed regarding whether or not payment would affect welfare benefits or taxes. Another issue is whether or not payment would be subject to attachment by other concerned parties (e.g., creditors, ex-spouses). Verifying Health Status of Vendors How to verify the health status of vendors is both an ethical and practical issue. From a practical perspective, potential vendors could be evaluated twice (e.g., viral studies), with a minimum six-month interval between evaluations. Although two evaluations would not guarantee safety, they would minimize the risk. It could be made a federal (U.S.) offense to lie about health risks when undergoing vendor evaluation (but such a statute would have little impact on potential vendors from other countries). Potential recipients could be informed about the limitations of the evaluation process (similarly, some limitations apply to the current LD and DD pool) and sign an appropriately developed informed consent form. Handling Logistics Numerous logistical issues would have to be resolved before a system of sales could be implemented. For example, where would potential vendors go to apply or to be evaluated? Who would do the evaluation? Would only local potential recipients be considered, or would six-antigen matches confer priority? Would vendors have to travel to a recipient’s center? Who would be responsible for long-term follow-up? Designating Price Should there be a fixed price? If we accept sales, why not have the kidney go to the highest bidder? A government-sponsored regulated system with a fixed price paid to vendors has many advantages. The most important is that all potential recipients would have access to vendor kidneys. If some form of bartering or a “to the highest bidder” system were established, the rich would clearly benefit. Other advantages of a government-sponsored regulated system are that it could ensure adequate donor evaluation and mandatory use of informed consent, and could guarantee that payment goes to vendors (rather than brokers). In addition, could there be a lower price for “old” (versus “young”) donor kidneys, or for kidneys that have potentially worse outcome? This complex issue could possibly be resolved by open discussion. Drawing the Line at Kidneys If we establish a regulated system for kidney sales, should we have a system for sales of a liver lobe, a lung lobe, or a partial pancreas? Could vendors return repeatedly to sell more body parts? LD liver, lung, and pancreas transplants have been done successfully. But, for each, the potential donor morbidity is higher than after uninephrectomy. In addition, considerably more information is available on long-term follow-up after donor uninephrectomy (versus after LD liver, lung, or pancreas donation). For those reasons, it could be argued that, at this time, a vendor system should be limited to kidneys. WHAT DOES THE GENERAL PUBLIC THINK? Currently, the debate about sales is taking place in the bioethics and general medicine literature, with limited involvement by transplant-related personnel. Most important, the general public has not been involved. Interestingly, two surveys have suggested that the general public is much more willing than the medical community to accept sales. In 1991, Kittur et al. found that 52% of the general public favored sales (68% of those 18–34 years old; 49% of those 35–54 years old; 31% of those ≥ 55 years old) (53). Subsequently, Guttmann and Guttmann found that 70% of the general public and 51% of medical students, but only 25% of surveyed physicians and nurses, favored sales (54).

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Those survey results obviously suggest that attitudes to sales may differ between the general public and the medical community. This is an important consideration. In discussing bioethics, the opinions of medical personnel are usually included—but as only one of many communities with differing perspectives. Organ sales, however, could not take place without the participation of medical and surgical personnel. A LIMITED CLINICAL TRIAL? As discussed above, careful analysis shows the shortfalls of the ethical arguments against sales. In addition, no evidence supports the argument that a regulated system of sales will have negative consequences. If additional surveys show that the public supports sales, legislators might consider repealing the prohibition. One way to proceed would be to repeal the ban on sales and develop a national system, taking the many practical issues (Table 2) into account. Another way would be to begin a clinical trial limited to a single organ procurement area or geographic area. For the duration of the trial, potential vendors would have to come from that defined area. Standards for vendor evaluation and follow-up could be developed by a panel of physicians, ethicists, and lay personnel. Organ allocation could be by UNOS criteria; payment could include life and/or health insurance. Long-term follow-up, including psychosocial assessment, could be mandatory. Ideally, such a trial could be carried out in a culture of universal health coverage. In addition to assessing the impact on vendors, endpoints could include the impact on the waiting list, on altruistic donation (both from LDs and families of DDs), and on the use of expanded-criteria donors. CONCLUSION The issue of kidney sales is not a hypothetical ethical fine point, but rather affects the lives of people worldwide. While thinking of balancing moral principles (35), any individual must question what his or her personal actions would be, should the need arise. Leon Kass writes, “I suspect that regardless of all my arguments to the contrary, I would probably make every effort and spare no expense to obtain a suitable life-saving kidney for my child—if my own were unusable… . I think I would readily sell one of my own kidneys, were its practice legal, if it were the only way to pay for a life-saving operation for my children or my wife” (55). How should this topic be approached? One option would be to accept that organ sales are illegal, the issues are complex, and the feelings are strong, and to end discussion. But this leaves us with the continually expanding waiting list, the probability of worse outcomes for future patients with ESRD (because of a longer wait for a transplant), and the probability of an increasing number of patients dying while waiting for a transplant. A second option would be to open discussion about the possibility of establishing a regulated vending system. Such a discussion needs to address two (separate but intertwined) questions: (i) could a regulated vending system ever be ethically supported and (ii) if so, under what circumstances? Important practical considerations must be resolved before such a system could be established. Acknowledgments I would like to thank Mary Knatterud for editorial assistance and Stephanie Daily for preparation of the manuscript.

REFERENCES 1. Matas AJ. The case for living kidney sales: rationale, objections, and concerns. Am J Transplant 2004; 4:2007–2017. 2. Ghods AJ. Governed financial incentives as an alternative to altruistic organ donation. Exp Clin Transplant 2004; 2(2):221–228. 3. Ghods AJ. Changing ethics in renal transplantation: presentation of Iran model. Trans Proc 2004; 36:11–13.

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4. Ghods AJ, Nasrollahzadeh D. Transplant tourism and the Iranian model of renal transplantation program: ethical considerations. Exp Clin Transplant 2005; 2:351–354. 5. Zargooshi J. Quality of life of Iranian kidney “donors.“ J Urol 2001; 166(5):1790–1799. 6. Jha V. Paid transplants in India: the grim reality. Nephrol Dial Transplant 2004; 19(3):541–543. 7. Goyal M, Mehta RL, Schneiderman LJ, Sehgal AR. Economic and health consequences of selling a kidney in India. JAMA 2002; 288(13):1589–1593. 8. Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000; 285(11):1440–1441. 9. Adams PL, Cohen DJ, Danovitch GM, et al. The nondirected live-kidney donor: ethical considerations and practice guidelines: A National Conference Report. Transplantation 2002; 74(4):582–589. 10. Davis CL. Evaluation of the living kidney donor: current perspectives. Am J Kidney Dis 2004; 43(3): 508–530. 11. Radcliffe-Richards J. Nefarious goings on: kidney sales and moral arguments. J Med Phil 1996; 21: 375–416. 12. Radcliffe-Richards J, Daar AS, Guttmann RD, et al. The case for allowing kidney sales. The Lancet 1998; 351:1950–1952. 13. Gill MB, Sade RM. Paying for kidneys: The case against prohibition. Kennedy Institute of Ethics J 2002; 12(1):17–45. 14. Harris J, Erin C. An ethically defensible market in organs (Editorial). BMJ 2002; 325:114–115. 15. Hippen BE. In defense of a regulated market in kidneys from living vendors. J Med Philos 2005; 30:593–626. 16. Taylor JS. Stakes and Kidneys: Why Markets in Human Body Parts are Morally Imperative. Hampshire, England: Ashgate Publishing Ltd, 2005. 17. Cherry MJ. Kidney for Sale by Owner: Human Organs, Transplantation, and the Market. Washington, DC: Georgetown University Press, 2005. 18. Scheper-Hughes N. The global traffic in human organs. Curr Anthropol 2000; 41:191–222. 19. Daar AS. Money and organ procurement: narratives from the real world. In: Gutmann T, Daar AS, Sells RA, Land W, eds. Ethical, Legal, and Social Issues in Organ Transplantation. Lengerizh: Pabst Science Publishers, 2004. 20. Reddy KC. Should paid organ donation be banned in India? To buy or let die! Natl Med J India 1993; 6(3):137–139. 21. Ghods AJ, Ossareh S, Khosravani P. Comparison of some socioeconomic characteristics of donors and recipients in a controlled living unrelated donor renal transplantation program. Trans Proc 2001; 33:2626–2627. 22. Matas AJ, Schnitzler M. Payment for living-donor (vendor) kidneys: a cost-effectiveness analysis. Am J Transplant 2004; 4(2):216–221. 23. Evans RW, Manninen DL, Garrison LP, et al. The quality of life of patients with end-stage renal disease. N Engl J Med 1985; 312:553–559. 24. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341:1725–1730. 25. Schnuelle P, Lorenz D, Trede M, Van Der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998; 9:2135–2141. 26. Cosio FG, Alamir A, Yim S, et al. Patient survival after renal transplantation. I. The impact of dialysis pretransplant. Kidney Int 1998; 53:767–772. 27. Meier-Kreische HU, Port FK, Ojo AO, et al. Effect of waiting time on renal transplant outcome. Kidney Int 2000; 58:1311–1317. 28. Gjertson DW, Cecka JM. Living unrelated donor kidney transplantation. Kidney Int 2000; 58(2):491–499. 29. Ojo AO, Hanson JA, Meier-Kreische HU, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant patients. J Am Soc Nephrol 2001; 12:589–597. 30. Xue JL, Ma JZ, Louis TA, Collins AJ. Forecast of the number of patients with end-stage renal disease in the United States to the year 2010. J Am Soc Nephrol 2001; 12:2753–2758. 31. Gillon R. Ethics needs principles—four can encompass the rest—and respect for autonomy should be “first among equals.” J Medical Ethics 2003; 29:307–312. 32. Friedlaender MM. The right to sell or buy a kidney: are we failing our patients? Lancet 2002; 359:971–973. 33. Rapoport J, Kagan A, Friedlaender MM. Legalizing the sale of kidneys for transplantation: suggested guidelines. Isr Med Assoc J 2002; 4(12):1132–1134. 34. Ethical, Legal, and Social Issues in Organ Transplantation. Gutmann T, Daar AS, Sells RA, Land W. Lengerich: Pabst Science Publishers, 2004. 35. Rothman DJ, Rose E, Awaya T, et al. The Bellagio Task Force report on transplantation, bodily integrity, and the international traffic in organs. Transplantation Proceedings 1997; 29:2739–2745.

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36. Scheper-Hughes, N. The Ends of the Body: The Global Commerce in Organs for Transplant Surgery. Berkeley, University of California: Organs Watch, Online Essay, 1998. 37. Veatch RM. Why liberals should accept financial incentives for organ procurement. Kennedy Institute of Ethics Journal 2003; 13(1):19–36. 38. The New Oxford American Dictionary. New York: Oxford University Press, 2001. 39. Zimmerman D. Coercive wage offers. Philosophy and Public Affairs; 10:121–145, 1981. 40. Rudinow J. Manipulation. Ethics; 88:338–347, 1978. 41. Harvey J. Paying organ donors. J Med Ethics 1990; 16:117–119. 42. Cherry MJ. Is a market in human organs necessarily exploitative? Public Affairs Quarterly 2000; 14(4):337–360. 43. Andrews LB. My body, my property. Hastings Center Report 1986; October:28–38. 44. Sutton AM. Commodification of body parts. BMJ 2002; 235:114. 45. Wilkinson S. Commodification arguments for the legal prohibition of organ sale. Health Care Analysis 2000; 8:189–201. 46. Gutmann T, Land W. Ethics in living-donor organ transplantation. Langenbeck’s Archives of Surgery 1999; 384:515–522. 47. Wigmore SJ, Lumsdaine JA, Forsythe JLR. Defending the indefensible? BMJ 2002; 325:114–115. 48. Steinberg A. Compensation for kidney donation: a price worth paying. IMAJ 2002; 4:1139–1140. 49. Capaldi N. A Catholic perspective on organ sales. Christian Bioethics 2000; 6(2):139–151. 50. Pius XII, Pope. Papal teachings: the human body. Monks of Solemes (selected and arranged), the Daughters of Saint Paul, Boston, 1960. 51. John Paul II, Pope. Blood and organ donors, August 2, 1984. The Pope Speaks 1985; 30(1):1–2. 52. John Paul II, Pope. Special Address to the Transplantation Society. Trans Proc 2001; 33:31–32. 53. Kittur DS, Hogan MM, Thukral VK, et al. Incentives for organ donation? The United Network for Organ Sharing Ad Hoc Donations Committee. Lancet 1992; 338:1441–1443. 54. Guttmann A, Guttmann RD. Attitudes of healthcare professionals and the public towards the sale of kidneys for transplantation. J Med Ethics 1993; 19:148–153. 55. Kass LR. Organs for sale? Propriety, property, and the price of progress. Public Interest 1992 (Spring); 107:65–86.

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Do No Harm: The Case Against Organ Sales from Living Persons Arthur L. Caplan Department of Medical Ethics and Center for Bioethics, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION In the face of the lethal gap between supply and demand, some experts (1–4) have concluded that the fastest way to increase the supply of kidneys is to permit living persons to sell one of theirs. This shift toward considering markets has also been reflected in a recent spate of editorials and op-ed pieces by those who see markets as the optimal solution to resolving shortage of organs or any other desirable thing (5–7). Few of those touting markets involving living persons who would sell kidneys and presumably lobes of lung, liver, and segments of pancreas are willing to advocate an open, free market in body parts. Rather, as, for example, Matas argues, they believe in some version of a “regulated vendor system” (4). The government would have to play a role in trying to keep the brokering of organs honest and to protect against fraud and abuse. The drive to find more organs for those on waiting lists has led to an increasing reliance on living donors. This practice raises a number of ethical issues in its own right (8). There are very real ethical concerns about the practice of living donation, including a lack of data concerning the impact of donation on the health and emotional well-being of donors, the lack of donor advocates for those thinking about donation, the lack of agreement about the assessment of competency in allowing individuals to choose to donate, and no agreement on whether and what health conditions ought disqualify a person as a potential living donor (8–10). Does it make sense to try and expand the pool of available organs by encouraging the sale of organs from living persons? What does the evidence about existing commercial markets involving living persons reveal? Importantly, nothing even remotely positive for the proponents of kidney sales can be found. HAVE MARKETS WORKED SO FAR? There is ample evidence that existing markets in nations such as India have failed dismally (11). They have not produced a large number of successful kidney transplants due to the high failure rate associated with bought kidneys (12). There is overwhelming evidence that kidney sales have resulted in diminished health and emotional disappointment among the desperate and often frail sellers of kidneys (11–14). Proponents of markets dismiss this evidence as not applicable or relevant to the developed world. But, would creating markets in body parts from living persons in the United States or the United Kingdom, or Canada really be free of the numerous and serious problems that have plagued the existing markets in human organs in poor parts of the globe? The current flow of illegal immigrants into North America and Europe make it highly unlikely that adequate controls could be put in place to prevent those in the underdeveloped world from selling their organs in the markets of the developed world. And the grinding poverty that exists for many persons who dwell in large cities in America, France, and the United Kingdom, while by no means as horrific as that to be found in Bangladesh, Burundi, or Mali, is still sufficient to presume that many of those who would turn to organ sales would do so not from choice but from desperation—or worse, as the result of coercion from those to whom they owe money, or simply because no other options to make money are made available to them.

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WOULD PEOPLE REALLY CHOOSE TO SELL THEIR PARTS? Defenders of markets try to subject the claim that sellers will be exploited to vigorous criticism (3–5,7). They note with a hint of noblesse oblige that the poor are surely just as capable of rationality as the rich or intellectuals in think tanks. Therefore, when it comes to selling bits of themselves to the more affluent, it is only paternalists who would prohibit the poor from being able to avail themselves of this wondrous opportunity to make some quick cash. The argument that the poor should be free to donate their organs for sale is wanting. The issue is not, as the pro-marketeers try to make it appear, the rational capacity of possible sellers. Of course, poor people can make decisions. But the capacity to decide is only a part of what is required to make a free, voluntary choice. Information is required to weigh the risks both of donation and of sale. But information is sadly lacking about what happens long-term to living donors. So those who sell would do so more in ignorance and motivated by money than by a careful calculus of whether a sum of money is worth risking a life with one kidney or a diminished lung. Those who are in need of money might rationally decide to sell their children, but the sale of babies is not permitted. Why? Because this is seen as a gross exploitation of the poor if they have no options but to resort to child sales. If you have no other alternative but to sell your kidney to try and feed your family or to pay back your loan, it may be “rational” to do so, but that does not make it a matter of free, rational choice. Watching your child go hungry while you lack a job and a wealthy person waves a wad of bills in your face is not exactly a scenario that inspires confidence in the rational choice of the sellers involved in meat-market transactions in the real world of organ sales. Talk of individual rights and autonomy is hollow if those with no options must “choose” to donate their kidney in order to purchase life’s necessities or dig their way out of debt. Proponents of markets continue to insist that those who object to sale do so because they doubt the poor can think ill about it. The sale of organs is immoral because too often those faced with sale will lack relevant information and not be able to think of anything else but to risk their health by selling their organs when no alternatives exist since—they are poor. It is hard to imagine that there will be numerous persons in wealthy Western nations eager to sell a kidney. In fact, unless compensation is relatively high, few can really be expected to undertake surgery for cash rewards. That has been the experience with markets in egg sales and paid surrogacy in the United States (15,16). So those attracted to sale will in all likelihood be those most in need of money. and it will not take much to make them lie down and await the surgeon’s knife. Relatively small amounts of money can coerce choice. Choice is imperiled by relatively high compensation, not because the sellers are rendered irrational by the prospect of money but because for those in desperate need of money, certain offers, no matter how degrading, are irresistible (16–19). It is precisely for this reason that severe restrictions are in place on what can be paid to subjects who “volunteer” themselves in clinical research or their children for medical experiments and toxicity testing (17). The possibility of making a lot of money relative to one’s means also creates enormous pressure from third parties on the prospective seller to “choose” to sell. Those in severe debt with no alternatives cannot truly be said to choose to become organ vendors if those to whom they are in debt force them into sales. Choice requires information, options, and some degree of freedom, as well as the ability to reason. The debate about whether exploitation is inevitable in markets in rich or poor countries misses two other important ethical reasons why allowing the sale of kidneys and parts of other organs ought not be allowed. Participation in sales, even in a tightly regulated market, violates the ethics of medicine—and markets will prove next to impossible to implement successfully in North America, Europe, and many other places on ethical grounds. HOW COULD THE PROFESSIONS OF MEDICINE AND NURSING BE INVOLVED IN ORGAN MARKETS? Medicine has long held that the core ethical norm of the profession is the principle “Do No Harm”. Taking organs from living persons is in direct violation of this moral norm. The only

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way in which it seems morally defensible to remove an organ from someone is on the grounds that the donor chooses to undergo the harm solely to help another and that there is sufficient medical benefit to the recipient. The creation of a market puts medicine and nursing in the position of removing body parts from persons solely to abet their interest in securing compensation for themselves. Is this a role that the health professions can ethically countenance (26)? What would engaging in damaging surgery for hire do to public trust in physicians? The goal of medicine is the alleviation of illness, disability, and suffering, not finding ways to permit persons to make a profit for themselves by interventions that cause them possible permanent and significant harm. In a market, even a regulated one, doctors still would be using their skills to help people harm themselves for money—solely for the money. The distrust and loss of prestige that would follow is a high price for medicine to pay to gamble that a market may secure more organs for those in need (26). Even if it is possible to get past the facts that there are no data that existing markets in organs have done much to increase the supply, that there is much exploitation associated with such markets, since choice would be mostly an illusion, and that a market using living sources severely compromises the ethics of the medical profession, is there any real chance of shifting public policy toward a market? WHAT HAPPENS WHEN LARGE GROUPS OF AMERICANS DROP OUT OF THE DECEASED-DONOR POOL? What little data exist show that health-care providers are opposed to markets (19). If they are not willing to support markets out of moral reservations, then markets simply will not be effectively implemented. Even more important than a patent lack of enthusiasm for markets among those who would be expected to serve them, major religions and cultural views in the developed world will not countenance a market in living body parts (20–22). Various Popes, for example, have made quite clear the Catholic Church’s aversion to markets in organs. Anglo-American law, ever since the days in which markets in body parts resulted in graveyards being stripped to supply medical schools with teaching materials, has not recognized any property interest in the human body and its organs (22). Alienating religions and cultures which do not view the body as property would have a devastating impact on the supply of organs available. Indeed, some sub-populations in the United States, particularly AfricanAmericans, are as likely to be turned off by the institution of a market in body parts because of their historical experiences with slavery and a keen distrust of medicine, as they are to be motivated to become sellers to the rich (23–26). The argument that increasing the supply of organs through sales will be efficient and costeffective is not persuasive. It will take real and expensive resources to try to regulate and police a market in organs. Since markets, even regulated ones, would shift the supply of organs toward those who can afford to buy them, those who cannot might well withdraw from participation in the deceased-donor organ system, thereby putting in peril any overall increase in the pool of organs available to transplant. The case for kidney sales is not persuasive. Existing experience with markets has been dismal. The notion that free choice supports the creation of markets in human body parts does not square with the reality of what leads people to be likely to want to sell them. The devastating moral cost to medicine of engaging in organ-brokering is far too great a price to pay for the meager benefit in supply that might be had by those in need of transplants. The storm of opposition that markets will trigger in many individuals based on religious or cultural objections may actually produce a decrease rather than an increase in the overall pool of transplantable organs— an outcome that by itself would make calls for the creation of markets dubious. REFERENCES 1. Wight JP. Ethics, commerce and kidneys. BMJ 1991; 303:110. 2. Radcliffe-Richards J, Daar AS, Guttmann RD, et al. The case for allowing kidney sales. Lancet 1998; 351:1950–1952. 3. Harris J, Erin C. An ethically defensible market in organs. BMJ 2002; 325:114–115.

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4. Matas AJ. The case for living kidney sales: rationale, objections and concerns. Am J Transplant 2004; 4:2007–2017. 5. Satel S. The Kindness of Strangers and the Cruelty of Some Medical Ethicists. The Weekly Standard 2006; 11:20. 6. Postrel V. Cash for Kidneys. Los Angeles Times. June 10, 2006. http://www.latimes.com/news/ printedition/opinion/la-oe-postrel10jun10,1,3518623.story?ctrack=1&cset=true 7. Epstein R. Kidney Beancounters. Wall Street Journal. 2006; 15:A15. 8. Zink S, Weinraub R, Sparling T, Caplan AL. Living donation: focus on public concerns. Clin Transplant 2005; 19:581–585. 9. Truog, RD. The ethics of organ donation by living donors. NEJM 2005; 325:444–446. 10. Israni AK, Halpern SD, Zink S, et al. Incentive models to increase living-kidney donation: Encouraging without coercing. Am J Transplant 2005; 5:15–20. 11. Rothman DJ, Rose E, Awaya T, et al. The Bellagio Task Force reports on transplantation, bodily integrity and the international traffic in organs. Transplant Proc 1997; 29:2739–2745. 12. Goyal M, Mehta RL, Schneiderman LJ, Sehgal AR. Economic and health consequences of selling a kidney in India. JAMA 2002; 288:1589–1593. 13. Ram V. International traffic in human organs. Frontline 2002; 19(7):6–10. 14. Wilkinson S. Bodies for sale: ethics and exploitation in the human body trade. London: Routledge, 2003. 15. Harris J, Holm S, eds. The Future of Human Reproduction. Oxford: Oxford University Press, 2000. 16. Macklin R. Is there anything wrong with surrogate motherhood? In: Gostin L. ed. Surrogate Motherhood. Indiana: Indiana University Press, 1990:136–151. 17. Lyons D. Welcome threats and coercive offers. Philosophy 1975; 50:23–32. 18. Macklin R. Due and undue inducements: on paying money to research subjects. IRB 1981; 3:1–6. 19. Jasper JD, Nickerson CAE, Ubel PA, Asch DA. Altruism, incentives and organ donation. Medical Care 2000; 42(4):378–386. 20. Stempsey WE. Organ markets and human dignity: on selling your body and soul. Christian Bioethics 2000; 6(2):195–204. 21. Goodenough P. Pope nixes embryonic cloning, okays organ donation, 2000. Available at: http:// www.christianity.com/partner/Article_Display_Page/0, PTID5339%7CCHID24%7CCIID139361,00. html 22. Meyers DW. The Human Body and the Law. Stanford 1990. 23. Minniefield W, Yang J, Muti P. Differences in attitudes toward organ donation among AfricanAmericans and whites in the United States. J National Med Assoc 2001; 93:372–379. 24. Siminoff LA. Saunders Sturm CM. African-American reluctance to donate: beliefs and attitudes about organ donation and implications for policy. Kennedy Institute of Ethics Journal 2000; 10(1):59–74. 25. Scott R. The Body As Property. New York: Viking, 1981. 26. Fox RC, Swazey JP. Spare Parts: Organ Replacement in American Society. New York: Oxford, 1992.

Part X

37

SAMPLE CONSENT FORMS TO LIVING KIDNEY AND LIVER DONATION

Consent to Living Kidney Donation Henkie P. Tan Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Patient Name:_____________________ Identification Number: ___________

CONSENT TO LIVING KIDNEY DONATION I, ___________________________________________________________, have indicated a desire and am being given (printed name of patient)

the choice to undergo surgery to remove one of my kidneys that could be considered for transplantation into another person. I understand that I have the right to receive enough information about the procedure of kidney donation, its risks and alternatives necessary for me to make an informed decision whether to voluntarily and freely donate one of my kidneys. This information in this consent form in addition to discussions with physicians and other health care providers is intended to provide me with the information I need to make my decision. I have been requested to read all of the information contained in this consent form. I have been told that I should ask questions about anything that I do not understand. By signing this consent form, I will be acknowledging that I have read and understood all of the information given to me and that I voluntarily choose to donate one of my kidneys. I know that I am free to change my mind and withdraw my consent at any time. Evaluation Process. The person who will receive my kidney (“recipient”) and I will be evaluated before surgery to help determine if the recipient could benefit from my kidney and if I can tolerate the surgery and function with only one kidney. As part of the pre-surgical evaluation process, I will need to be available and willing to undergo some or all of the following tests, procedures and evaluations and any others the physicians may believe are necessary: •

Blood and urine tests to help determine if my kidney and other organs are functioning normally and my kidney would be compatible with the recipient’s body.

•

Electrocardiogram (record of the electrical activity of my heart) to help determine if further testing of my heart function is necessary.

•

Echocardiogram (pictures created by sound waves bounced off my heart) that will show how well my heart is beating and how well my heart valves work. My physicians will analyze these pictures to decide if my heart is in good enough condition for the surgery.

•

Pulmonary Function tests (Breathing tests) to help analyze my lung capacity.

•

Ultrasound (pictures created by sound waves) of my kidney and abdomen to help determine the adequacy of the circulation to my kidneys and to determine the presence or absence of kidney stones, unusual fluid or structures within the kidney.

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Patient Name:_____________________ Identification Number: ___________

CONSENT TO LIVING KIDNEY DONATION •

CT Scan (A complex X-ray that shows pictures of my organs every fraction of an inch) to verify the adequacy of the circulation to my kidney. (If I have a CT Scan, a radiologist or his/her representative(s) will give me m ore information about the scan and its risks.)

• Arteriogram (An X-ray with dye) of the arteries going to my kidneys to determine if it is possible to safely remove a kidney and to help determine which kidney may be removed. (If I have an arteriogram, I will receive a separate explanation of the arteriogram and its risks and be asked to sign a separate consent form.) •

Social Service and/or Psychiatric Evaluation (Interview) to assist in determining my ability to cope with the personal, emotional, physical and logistical issues related to kidney donation.

I understand that as I progress through the pre-surgery evaluation process, my physicians could decide at any time that I should not be a kidney donor. If my physicians decide that I should not be a kidney donor, it does not mean that there is anything wrong with my kidney. Surgery. I understand that the following is a general description of the surgery that I will undergo which is called a nephrectomy (the surgical removal of a kidney). This description is general in nature and I understand that my surgery may be somewhat different based on my specific condition. I will be put under general anesthesia, which means that I will be given drugs to put me to sleep, block pain and paralyze parts of my body. (The type of anesthesia and the risks of the anesthesia will be explained to me by a representative of the anesthesia department and I will be asked to sign a separate consent form.) I will have a catheter (tube) placed into my bladder to drain urine and check the amount of urine my kidney is producing during the surgery. I will be positioned on my side so that my head and feet are slightly lower than the rest of my body. The surgeon(s) will locate and remove my kidney either laparoscopically [using an optical instrument (laparoscope) to visualize the kidney through different tubes that are placed in my body and then removing it through a relatively small incision (cut)] or by making a larger incision on my side through which the kidney can be identified and removed (open nephrectomy). In very rare cases, it may be necessary to remove part of my ribs in order to access or remove the kidney. The entire operation should take approximately two (2) to five (5) hours. My physician(s) will decide the manner in which the surgery is performed (with or without the use of a laparoscope) based on my condition, anatomy or other factors. I understand that the physicians usually try to perform the surgery using a laparoscope when reasonable to do so because there is less scarring from a laparoscopic procedure and recovery is normally quicker and less painful. However, I understand that even if my physicians believe they can perform the nephrectomy using a laparoscope, they may later decide to perform or change to an open nephrectomy due to actual conditions observed or encountered prior to or during the surgery. After my surgery is started, a second team of surgeons will begin surgery on the recipient. The evaluation process will not stop when the surgeries begin, but will continue throughout the surgeries. If at any point the surgical team believes that I am at risk or that my kidney is not appropriate for transplantation, the surgery may be stopped. Post-Surgical Care and Recovery. After the surgery, I will be taken to a special recovery unit where I will be closely monitored. When I am recovered from anesthesia and my condition is stable, I will be taken to my assigned hospital room. My length of stay in the hospital will depend on the rate of my recovery. I will remain in the hospital as long as my physician(s) feel hospitalization is necessary. The average range of time in the hospital is two (2) to four (4) days after a laparoscopic nephrectomy and three to six (6) days after an open nephrectomy.

Donor’s Initials_______

437

Consent to Living Kidney Donation

Patient Name:_____________________ Identification Number: ___________

CONSENT TO LIVING KIDNEY DONATION After I leave the hospital, I will still be recovering. I understand it will probably take two (2) to six (6) weeks before my physician(s) allow me to resume normal activity, including driving a car. If I experience any post¬operative complications, my recovery time could be longer. During the recovery period, a team of doctors will follow my progress. I understand and agree that for at least seven (7) to ten (10) days, I will make myself available for examinations and necessary laboratory tests. After that, I will still need to be monitored on a longterm basis by my primary care physician. Medical Risks of Surgery. I understand that there are inherent risks in all surgeries, especially surgeries conducted under general anesthesia. The risk of having some type of complication (problem), minor or major, from this type of kidney donor surgery may be as high as 10%. Most complications are minor and get better on their own. In rare cases, the complications are serious enough to require another surgery or medical procedure. Death from kidney donor surgery is very rare. Removal of one of my kidneys will most likely cause the remaining kidney to get larger. The remaining kidney should compensate for the loss of the donated kidney by increasing the amount of blood it filters. Immediately following the surgery, I will experience pain. Most donors are pain-free several weeks after surgery. Some people continue to have pain for a longer time. In some cases, a portion of the lung may collapse due to contact with the lung or the lining around the lung (atelectasis). This is usually temporary. Occasionally, infection can occur, most often at the site of the surgical incisions (cuts on my body) or in the urinary tract (organs and tubes that help eliminate urine from the body). In rare cases, the following injuries to organs can occur: a.

Pneumothorax (entry of air into the chest cavity causing a portion of the lung to collapse). If the amount of collapsed lung is small, no treatment is needed. In 1% to 5% of the cases of pneumothorax, a tube may be placed into the chest to treat the collapse and help the lung return to normal.

b.

Injury to the spleen. If my physician(s) recognize an injury to the spleen during surgery, they may determine that the spleen needs to be removed. (The spleen helps to prevent bacterial infections, most commonly pneumonia. Getting vaccinated can usually prevent these infections. These infections can also be treated with antibiotics. If the infections are not treated, they can cause death).

c.

Injury to the pancreas. Injury to the pancreas can result in pancreatitis (painful inflammation of the pancreas) that can last for an extended period of time and may require that I be fed through my veins.

d.

Injury to the small or large intestine. These injuries could require additional surgeries resulting in an ileostomy [creating an opening between the abdomen and the small intestine] or a colostomy [creating an opening between the abdomen and the large intestine (colon)] and the need to wear an adhesive bag to collect feces (body waste)]. In most cases, the intestines can eventually be reconnected.

Some studies have shown the risk of developing high blood pressure in kidney donors is about 7%, which is currently the same as the risk for people who have not donated a kidney. Based on current medical knowledge, kidney donors are no more likely than non-donors to develop kidney failure. Other risks associated with the surgery include:

Donor’s Initials_______

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Patient Name:_____________________ Identification Number: ___________

CONSENT TO LIVING KIDNEY DONATION a.

Blood clots. These clots usually develop in the legs and can break free and move through the heart to the lungs. In the lungs, they can cause serious interference with breathing, which can lead to death. Blood clots are treated with blood-thinning drugs that may need to be taken for an extended period of time.

b.

Bleeding, either during surgery or after surgery. In a small percentage of cases, the bleeding may require blood transfusions or blood products. The use of blood or blood products has the following general risks: reactions resulting in itching, rash, fever, headache or shock; respiratory distress (shortness of breath); kidney damage; systemic infection; exposure to bloodborne viruses including hepatitis (an inflammatory disease affecting the liver) and Human Immunodeficiency Virus (HIV, the virus that causes AIDS); and death. The risk of getting hepatitis is very rare. The risk of getting HIV is approximately 1 in 2 million per unit transfused. In rare cases, blood transfusions (usually multiple transfusions) can adversely affect a person’s ability to receive future organ or bone marrow transplants.

c. Injury to internal organs and structures. d.

Damage to nerves from pressure or positioning of the arms, legs or back or by direct contact during surgery. Nerve damage can cause numbness, weakness, paralysis and/or pain. In most cases these symptoms are temporary, but in rare cases they can last for extended periods or even become permanent.

e.

Pressure sores on the skin due to positioning.

f.

Damage to arteries and veins.

g.

Burns caused by use of electrical equipment that may be needed to stop bleeding or by other equipment.

h.

Pneumonia.

i.

Heart attack.

j.

Stroke.

k.

Permanent scarring at the sites of the incisions (cuts in my skin).

Other particular risks, if any _______________________________________________ Risk of Not Helping Recipient. Because there may be unforeseen and unpredictable factors that affect the final determination whether to transplant my kidney into the recipient, there is a small chance that I could have my kidney removed before it is determined that my kidney cannot be transplanted in the recipient. Therefore, I could suffer the loss of my kidney (and any other resulting medical harm - see other risks above) and not bestow any benefit to the recipient. I also understand that even if my kidney is transplanted into the recipient, the kidney may not function in the recipient’s body or may be rejected by the recipient’s immune system. Risks Involving Medical Costs and Insurance. I have been advised that a financial counselor is available to talk to me about the costs associated with my surgery and to answer questions about sources of payment for those costs. If the recipient has medical insurance, the recipient’s medical insurance may pay for all, some or none of my donor surgery and post-surgery treatment. It may be necessary to bill my own insurance company.

Donor’s Initials_______

439

Consent to Living Kidney Donation

Patient Name:_____________________ Identification Number: ___________

CONSENT TO LIVING KIDNEY DONATION to see if they will pay any of my medical expenses before I can submit a bill to the recipient’s insurance company. I understand that after I have my kidney removed, it is possible that insurance companies could try to avoid paying for medical care, treatment or procedures related to my kidney(s), increase my premiums and/or deny me insurance coverage. Benefits. I understand that I will derive NO medical or physical benefit from the surgery. My donation of one of my kidneys may help the recipient. The kidney donated by a live person usually has a better chance of functioning for a longer time than a kidney from a cadaver (dead donor). Alternatives. I have the choice NOT to undergo this surgery. If I choose not to undergo the surgery, there will be no medical consequences to me, and if the recipient so desires, the recipient’s name will continue to remain (or be placed) on the list of patients requesting kidneys from cadavers maintained by the United Network for Organ Sharing (UNOS). I understand that I can request more information about this process. UNOS Donor Registry. If I do become a donor, federal regulations require that some personal health information about me be sent to the UNOS donor registry. Teaching Facility. My physicians are associated with the University of Pittsburgh Medical Center, which includes teaching facilities. I understand and agree that residents, fellows, students and others may assist with or perform all or parts of procedures or other medical acts as deemed appropriate by and under the supervision of my physician(s). For the purpose of advancing medical education, I also consent to the admittance of observers who may not be directly responsible for my care. MY SIGNATURE BELOW ACKNOWLEDGES THAT: a.

I have read (or had read to me), understand and agree to the statements set forth in this consent form.

b. A physician or physician’s representative has explained to me all information referred to in this consent form. I have had an opportunity to ask questions and my questions have been answered to my satisfaction. c. All blanks or statements requiring insertion or completion were filled in before I signed. d.

No guarantees or assurances concerning the results of the surgery or any benefit to the recipient have been made.

e.

I am signing this consent voluntarily. I am not signing due to any threat, coercion, offer of payment or other influence.

f.

I understand that I can withdraw my consent at any time prior to the surgery.

g.

I hereby consent and authorize ____________________________ (“my physician(s)”) and/or those associates, assistants and other health care providers designated by my physician(s)

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Patient Name:_____________________ Identification Number: ___________

CONSENT TO LIVING KIDNEY DONATION to perform the procedure(s) described in this consent form, including the surgical removal of one of my kidneys. I understand that during the course of the surgery, conditions may become apparent that require my physicians or their designees to perform additional procedures that they believe are medically necessary to carry out the purpose of the procedure or for my well-being, including but not limited to, the removal of rib(s), removal of my spleen, an ileostomy or colostomy and the administration of blood or blood products. I authorize and request my physician(s) or their designees to perform any additional procedures that they, in the exercise of their professional judgment, deem reasonable; and I waive any obligation on their part to stop or delay the continuation of my surgery in order to obtain additional consent.

–––––––––––––––––––– Date

–––––––––––––––––––––––––––––––––––––––––––––––––––––– Signature of Patient

–––––––––––––––––––––––––––––––––––––––––––––– Witness ___________________________________________________________________________________________________ I have explained to the prospective kidney donor signing above all of the information contained in this consent form. No guarantee or assurance has been given by me as to the results that may be obtained.

–––––––––––––––––––– Date

–––––––––––––––––––––––––––––––––––––––––––––––––––––– Signature of physician or physician’s representative obtaining consent for kidney donor surgery ___________________________________________________________________________________________________ I, ________________________, am the ________________ (spouse, child, parent, etc.) of_________________________ (“prospective kidney donor”). I have read the information contained in the attached consent form, and I have discussed this information with the prospective kidney donor. I believe the prospective kidney donor understands the information and is voluntarily consenting to be a donor. I have no objection to the prospective kidney donor undergoing the procedures set forth in this consent form.

–––––––––––––––––––– Date

–––––––––––––––––––––––––––––––––––––––––––––––––––––– Signature of spouses or close family member

38

Consent to Living Partial-Liver Donation Henkie P. Tan and Ron Shapiro Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Amadeo Marcos Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine and Medical Center, Pittsburgh, Pennsylvania, U.S.A.

Patient Name:_____________________ Identification Number: ___________

CONSENT TO PARTIAL LIVER DONATION INCLUDING GALLBLADDER REMOVAL I, ____________________________________, have indicated a desire and am being given (printed name of patient)

the choice to undergo surgery to remove one of my liver that could be considered for transplantation into another person. I understand that I am being given information about the procedure of liver donation, its risks and alternatives to help me make an informed decision whether to voluntarily and freely undergo the procedure. The information in this consent form, in addition to discussions with my physicians and other health-care providers and any other written material they may provide, is intended to give me the information I need to make my decision. I have been requested to read all of the information contained in this consent form. I have been told that I should ask questions about anything that I do not understand. By signing this consent form, I will be acknowledging that I have read and understood all of the information given to me and that I voluntarily choose to donate a part of my liver. I know that I am free to change my mind and withdraw my consent at any time prior to the procedure. Evaluation Process. The person who will receive a part of my liver (“recipient”) and I will be evaluated before surgery to help determine if the recipient could benefit from my liver and if I can tolerate the surgery and function well without part of my liver. As part of the pre-surgical evaluation process, I will need to be available and willing to undergo any or all of the following tests and procedures and any other tests or procedures the physicians may believe are necessary: •

Blood tests to help determine the function of my kidney and liver and if my liver would be compatible with the recipient’s body.

•

Electrocardiogram to help determine if further testing of my heart function is necessary.

•

Echocardiogram (pictures created by sound waves bounced off my heart) that will show how well my heart is beating and how well my heart valves work. My physicians will analyze these pictures to decide if my heart is in good enough condition for the surgery.

•

Pulmonary Function tests (Breathing tests) to help analyze my lung capacity.

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Patient Name:_____________________ Identification Number: ___________

CONSENT TO PARTIAL LIVER DONATION INCLUDING GALLBLADDER REMOVAL •

CT Scan (A complex X-ray that shows pictures of my organs every fraction of an inch) to determine the size of the portion of the liver that can be removed and to verify the adequacy of the circulation to my liver. (If I have a CT Scan, the person(s) performing the CT Scan will give me more information about the scan and its risks.)

•

Arteriogram (An X-ray with dye) of the arteries going to my liver to determine if it is possible to safely remove a portion of my liver. (If I have an arteriogram, I will receive a separate explanation of the arteriogram and its risks and be asked to sign a separate consent form.)

•

Social Work Evaluation (an interview with a social worker) to evaluate the plan for my care upon discharge from the hospital including but not limited to housing arrangements, discharge medications, transportation to and from appointments and support for my personal, emotional and physical needs.

•

Psychiatric Evaluation (an interview with a psychiatric professional) to insure that I am psychologically able to deal with the stresses that may result from my donating a potion of my liver and to assess the reasons for my decision to donate.

I understand that as I progress through the pre-surgery evaluation process, the doctors could decide at any time that I should not be a liver donor. If the doctors decide that I should not be a liver donor, it does not mean that there is anything wrong with my liver. Surgery. The surgery that I will have is called a partial hepatectomy (the surgical removal of a part of my liver). This surgery is most often used to treat liver disease. (Partial hepatectomy performed on a person without liver disease has fewer risks than when performed on a person with liver disease.) I will be put under general anesthesia, which means that I will be given drugs to put me to sleep, block pain and paralyze parts of my body. (The type of anesthesia and the risks of the anesthesia will be explained to me by a representative of the anesthesia department and I will be asked to sign a separate consent form.) The surgeon(s) will then make a cut across my abdomen as large as necessary to safely locate and remove my gallbladder and a portion of my liver. It is necessary to remove my gallbladder because it is located under the part of my liver that will be removed. The surgeons will remove 25%-65% of my liver (partial hepatectomy) and will also remove all of my gallbladder. Special mechanical “boots” will be used to keep blood flowing through my legs to try to prevent dangerous blood clots. While I am still in the operating room, drains will be put into my body to allow fluids to be removed and help me to heal. The entire operation should take approximately six (6) to ten (10) hours. After my surgery is started, a second team of surgeons will begin surgery on the recipient. The evaluation process will not stop when the surgeries begin, but will continue throughout the surgeries. If at any point the surgical team believes that I am at risk or that the segment of my liver is not appropriate for transplantation, the surgery will be stopped. This has happened in the United States at least five percent (5%) of the time. Post-Surgical Care and Recovery. After the surgery, I will be taken to a special recovery unit where I will be closely monitored. Depending on my condition, I may be placed on a machine to help me breathe. My length of stay in the hospital will depend on the rate of my recovery. I will remain in the hospital as long as my physician(s) feel hospitalization is necessary. The average time for discharge is around seven (7) to eight (8) days after surgery.

Initials__________

443

Consent to Living Partial-Liver Donation

Patient Name:_____________________ Identification Number: ___________

After I leave the hospital, I will still be recovering. I understand it will probably take four (4) to six (6) weeks before my physician(s) allow me to resume normal activity, including driving a car. If I experience any post¬operative complications, my recovery time could be longer. During the recovery period, a team of doctors will follow my progress. I understand and agree that for approximately six (6) months, I will make myself available for examinations, laboratory tests and scans of my abdomen (if necessary) to see how my liver is doing. After that, I will still need to be monitored on a long-term basis. My primary-care physician will be given information about my progress and the transplantation team will determine when and how much of my long-term care will be taken over by my primary care physician. Medical Risks of Surgery. There are inherent risks in all surgeries, especially surgeries conducted under general anesthesia. The risk of having some type of complication (problem), minor or major, from this type of liver-donor surgery is 15%-30% (about two in seven cases). Most complications are minor and get better on their own. In rare cases, the complications are serious enough to require another surgery or medical procedure. The death rate from liver donor surgery is V£% to 1%. Immediately following the surgery, I will experience pain. Most donors are pain-free three (3) weeks after surgery. Some people continue to have pain for a longer time. The most common liver-related complication is bile leak. Bile is a secretion of the liver that aids in digestion. The incidence of this happening ranges from 5% to 15%. Most bile leaks get better without the need for surgery. Occasionally, tubes need to be placed through the skin to aid in the healing process. In rare cases, surgery is necessary to correct the bile leak. Biliary strictures (narrowing or constrictions of the ducts conveying the bile from the liver) can also occur. Because this is a long-term complication and living-donor surgery is so new, enough data is not yet available to know how often this will occur. Early data suggests that this complication will be rare. Some of the strictures will be able to be fixed by non-surgical means such as the insertion of tubes, but some will require surgical repair. As a result of gallbladder removal, some patients have periods of diarrhea and cramping. In the vast majority of cases, the diarrhea and cramping goes away after two or three months. In rare cases, the spleen may be injured during surgery, even though reasonable care is exercised. If my physician(s) recognize an injury to the spleen during surgery, they may determine that the spleen needs to be removed. (The spleen helps to prevent bacterial infections, most commonly pneumonia. Getting vaccinated can usually prevent these infections. These infections can also be treated with antibiotics. If the infections are not treated, they can cause death.) Removal of a portion of my liver may cause the liver to function abnormally. This period of abnormal liver function is usually short. The part of the liver left behind should begin to grow back within a few weeks and eventually return to normal function. In very rare cases, the liver does not improve and the donor develops liver failure, which is a serious condition that could require a liver transplant. Other risks associated with the surgery include: a.

Blood clots. These clots usually develop in the legs and can break free and move through the heart to the lungs. In the lungs, they can cause serious interference with breathing, which can

Initials__________

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Tan et al.

Patient Name:_____________________ Identification Number: ___________

CONSENT TO PARTIAL LIVER DONATION INCLUDING GALLBLADDER REMOVAL lead to death. Blood clots are treated with blood-thinning drugs that may need to be taken for an extended period of time. b.

Bleeding, either during surgery or after surgery. In a small percentage of cases, the bleeding may require blood transfusions or blood products. The use of blood or blood products has the following general risks: reactions resulting in itching, rash, fever, headache or shock; respiratory distress (shortness of breath); kidney damage; systemic infection; exposure to bloodborne viruses including hepatitis (an inflammatory disease affecting the liver) and Human Immunodeficiency Virus (HIV, the virus that causes AIDS); and death. The risk of getting HIV and/or hepatitis C is approximately 1 in 2 million per unit transfused. The risk of getting hepatitis B is approximately 1 in 200,000 per unit transfused. In rare cases, blood transfusions (usually multiple transfusions) can adversely affect a person’s ability to receive future organ or bone marrow transplants.

c.

Infection, including urinary tract infection,

d.

Injury to structures in the abdomen.

e.

Damage to nerves from pressure or positioning of the arms, legs or back or by direct contact within the abdomen during the surgery. Nerve damage can cause numbness, weakness, paralysis and/or pain. In most cases these symptoms are temporary, but in rare cases they can last for extended periods or even become permanent.

f.

Pressure sores on the skin due to positioning, g.

h.

Burns caused by use of electrical equipment that may be needed to stop bleeding or by other equipment.

i.

Pneumonia.

j.

Heart attack.

k.

Stroke.

1.

Permanent scarring at the site of the abdominal incision.

Damage to the arteries and veins.

Risk of Not Helping Recipient. Because there may be unforeseen and unpredictable factors that affect the final determination whether to transplant my liver into the recipient, there is a small chance that I could have both my gallbladder and part of my liver removed before it is determined that my liver cannot be transplanted into the recipient. Therefore, I could suffer the loss of a part of my liver and all of my gallbladder (and any other resulting medical harm - see other risks above) and not bestow any benefit to the recipient. This occurs in 1 % of cases.

Initials__________

445

Consent to Living Partial-Liver Donation

Patient Name:_____________________ Identification Number: ___________

CONSENT TO PARTIAL LIVER DONATION INCLUDING GALLBLADDER REMOVAL Even if part of my liver is transplanted into the recipient, the liver segment may not function in the recipient’s body or may be rejected by the recipient’s immune system. This occurs 5% to 10% of the time. If for any reason my liver cannot be used, does not function or is rejected, the recipient will have to find another living donor or be placed on the donor list of the United Network for Organ Sharing (UNOS) to wait for a cadaveric liver (liver taken from a person who has been declared brain-dead). The recipient could die while waiting for another liver. Risks Involving Medical Costs and Insurance. If the recipient has medical insurance, the recipient’s medical insurance may pay for all, some or none of my donor surgery or post-operative treatment. It may be necessary to bill my own insurance company to see if they will pay any of my medical expenses before I can submit a bill to the recipient’s insurance company. I have been advised that a financial counselor is available to talk to me about the costs associated with my surgery and to answer questions about sources of payment for those costs. After I have part of my liver and all of my gallbladder removed, health-insurance companies may consider me to have “pre-existing” liver disease or other abdominal-related medical problems and refuse to pay for medical care, treatment or procedures related to those conditions. Because of my condition after the surgery, my health insurance and life insurance premiums could be raised and remain higher and that in the future, insurance companies could refuse to insure me. Benefits. I will derive no medical or physical benefit from the surgery. My donation of a part of my liver could help the recipient recover from his or her underlying condition by decreasing the waiting time before the recipient receives a liver transplant. Alternatives. I have the choice NOT to undergo this surgery. If I choose not to undergo the surgery, there will be no medical consequences to me and the recipient’s name will continue to remain (or be placed) on the UNOS list for cadaveric livers (livers from brain-dead donors). I can request more information about this process. UNOS Donor Registry. If I do become a donor, federal regulations require that some personal health information about me be sent to the UNOS donor registry. Teaching Facility. My physicians are associated with the University of Pittsburgh Medical Center, which includes teaching facilities. Residents, fellows, students and others may assist with or perform all or parts of procedures or other medical acts as deemed appropriate by and under the supervision of my physician(s). For the purpose of advancing medical education, observers who may not be directly responsible for my care may also be involved. MY SIGNATURE BELOW ACKNOWLEDGES THAT: a

I have read (or had read to me), understand and agree to the statements set forth in this form.

Initials__________

446

Tan et al.

Patient Name:_____________________ Identification Number: ___________

CONSENT TO PARTIAL LIVER DONATION INCLUDING GALLBLADDER REMOVAL b. A physician or physician’s representative has explained to me all information referred to in this consent form. I have had an opportunity to ask questions and my questions have been answered to my satisfaction. c. All blanks or statements requiring insertion or completion were filled in before I signed. d.

No guarantees or assurances concerning the results of the surgery or any benefit to the recipient have been made.

e.

I am signing this consent voluntarily. I am not signing due to any threat, coercion, offer of payment or other influence.

f.

I understand that I can withdraw my consent at any time prior to the surgery.

g.

I hereby consent and authorize ____________________________ (“my physician(s)”) and/or those associates, assistants and other health-care providers designated by my physician(s) to perform the procedure(s) described in this consent form, including the surgical removal of a part of my liver and my gallbladder. I understand that during the course of the surgery, conditions may become apparent that require my physicians or their designees to perform additional procedures that they believe are medically necessary for my well-being, including but not limited to, the removal of my spleen and the administration of blood or blood products. I authorize and request my physician(s) or their designees to perform any additional procedures that they, in the exercise of their professional judgment, deem reasonable; and I waive any obligation on their part to stop or delay the continuation of my surgery in order to obtain additional consent.

–––––––––––––––––––– Date

–––––––––––––––––––––––––––––––––––––––––––––––––––––– Signature of Patient

–––––––––––––––––––––––––––––––––––––––––––––– Witness ___________________________________________________________________________________________________ I have explained to the prospective liver donor signing above all of the information contained in this consent form. No guarantee or assurance has been given by me as to the results that may be obtained.

–––––––––––––––––––– Date

–––––––––––––––––––––––––––––––––––––––––––––––––––––– Signature of physician or physician’s representative obtaining consent for liver-donor surgery ___________________________________________________________________________________________________

Initials__________

447

Consent to Living Partial-Liver Donation

Patient Name:_____________________ Identification Number: ___________

CONSENT TO PARTIAL LIVER DONATION INCLUDING GALLBLADDER REMOVAL I, ________________________, am the ________________ (spouse, child, parent, etc.) of_______________________ (“prospective liver donor”). I have read the information contained in the attached consent form, and I have discussed this information with the prospective liver donor. I believe the prospective liver donor understands the information and is voluntarily consenting to be a liver donor. I have no objection to the prospective liver donor undergoing the procedures set forth in this consent form.

–––––––––––––––––––– Date

–––––––––––––––––––––––––––––––––––––––––––––––––––––– Signature of spouses or close family member

Initials__________

Index

Abdominal compartment syndrome, 222–223 ABO-incompatible transplants, 121 ABPM. See Ambulatory BP monitoring (ABPM) Accommodation, 120 AICD. See Activation-induced cell death (AICD) ACR. See Acute cellular rejection (ACR) Acrolimus, 144 Activation-induced cell death (ACID), 407 Acute cellular rejection (ACR), 110, 212 incidence, 211–213 monocyte-predominant, 214 severity, 211–213 UNOS data, 111 Acute lymphoblastic leukemia (ALL), 321 Acute myelogenous leukemia (AML), 321–322 Acute respiratory disease syndrome (ARDS), 277, 355 treatment, 355 Acute tubular necrosis (ATN), 103, 349 ADA. See American Diabetes Association (ADA) ADPKD. See Autosomal dominant polycystic kidney disease (ADPKD) Adult hematopoietic stem cells collection, 309–316 infusion, 309–316 processing, 309–316 sources, 310 Adult hematopoietic stem cell transplants donor evaluation, 310–311 dose requirements, 310 infectious disease screening, 311 types, 309 Adult living donor liver transplantation, 187–188 Aging donors, 30 hypertension, 37 Alemtuzumab, 104, 108, 154, 209 acute cellular rejection, 110 adult recipient outcomes, 207–214 HIV, 108 immunosuppression status, 213 methods, 209 results, 209–214 transplantation, 108 ALG. See Antilymphocytic globulin (ALG) ALL. See Acute lymphoblastic leukemia (ALL) Alloantibody donor-specific detection of, 115–116 immunosuppressive agents, 115 Allogeneic hematopoietic stem cell transplantation applications and outcomes, 319–326 treatment failure, 319 Allograft nephropathy chronic, 154

Alloreactive memory T cells, 409 Altruism theories, 9 Ambulatory BP monitoring (ABPM), 37 American Diabetes Association (ADA), 39 American Society of Transplant Surgeons, 160 Aminoglycosides, 349 AML. See Acute myelogenous leukemia (AML) AMR. See Antibody-mediated rejection (AMR) Amsterdam Forum hypertension, 38 Amyloidosis, 324 Anastomoses placement, 152 Anesthesia thoracic epidural catheter, 346 Anterior retroperitoneal live donor nephrectomy patient positioning, 51 retractor system, 51 Antibody detection test, 115 patient approach, donor specific, 117 Antibody-mediated rejection (AMR) diagnosis, 116 risk factors, 116 treatment, 113, 116–117 Antigen-presenting cells (APC), 409 Antilymphocytic globulin (ALG), 207 Anti-retroviral drugs, 138–139 cyclosporine, 144 infections, 139 transplantation, 140–143 Antiviral prophylaxis, 155 APC. See Antigen-presenting cells (APC) Apheresis, 313 ARDS. See Acute respiratory disease syndrome (ARDS) Arterial anatomy CT-angiogram, 170 Arterial mobilization, 61 Aspergillus fumigatus, 366, 371 ATN. See Acute tubular necrosis (ATN) Autoimmune diseases, 326 Autologous hematopoietic stem cell transplantation applications and outcomes, 319–326 Autosomal dominant polycystic kidney disease (ADPKD), 33 Azathioprine (AZA), 379 Bacterial infections empiric antibiotic therapy, 369–370 Benzodiazepines, 344 Bile duct transection, 177–178 BK virus, 156 Black sheep donors, 20 BMT. See Bone marrow transplants (BMT)

450 Body mass index live intestinal donors, 273 Bone marrow collection postoperative management, 312 risks, 312 technique, 311 donor assessment, 311 processing, 313 Bone marrow transplants (BMT), 319 BOS. See Bronchiolitis obliterans syndrome (BOS) Bovine spongiform encephalopathy (BSE), 310 Bowel donors, 173 Brain death, 1 Bronchial anastomosis, 262 Bronchiolitis, 264 Bronchiolitis obliterans syndrome (BOS), 264 Bronchopulmonary dysplasia, 264 BSE. See Bovine spongiform encephalopathy (BSE) CAD. See Coronary artery disease (CAD) Campylobacter jejuni, 369 CAN. See Chronic allograft nephropathy (CAN) Cardiovascular disease (CVD) mortality, 88 reduced renal function, 88 Cavitron ultrasonic surgical aspirator (CUSA), 210 Cell death activation-induced, 407 Cellular rejection acute, 110 incidence, 211–213 severity, 211–213 UNOS data, 111 Central nervous system (CNS) infections transplant recipients, 367 Cesarean section deliveries, 391 cGMP. See Cyclic guanine monophosphate (cGMP) Children cord blood transplantation, 334 leukemia, 335 intestinal transplantation, 299, 300 intestinal failure, 276 kidney transplantation results, 155 recipients, approach, 157 live donor liver transplantation, 159–160, 186–187 morbidities in left lobectomy, 187 published cases, 187 Cholestasis parenteral nutrition-induced intestinal transplantation, 276 Chronic allograft nephropathy (CAN), 154 Chronic kidney disease (CKD), 91 Chronic lymphocytic leukemia (CLL), 322 Chronic myelogenous leukemia, 322 Chronic myeloid leukemia, 319 Ciprofloxacin, 173 CKD. See Chronic kidney disease (CKD) Clavien classification live donor nephrectomy, 75 CLL. See Chronic lymphocytic leukemia (CLL) Cloacae maximum, 203 Clonal lymphohematopoietic disorders, 324 Clostridium difficile, 369 CMV. See Cytomegalovirus (CMV) CNS. See Central nervous system (CNS)

Index Coccidioides immitis, 366 Congenital immunodeficiency syndromes, 325–326 Congenital nephritic syndrome, 150 Conventional paired donation, 126–128 incompatible blood types, 127 Cord blood cells adult bone marrow, 331 Cord blood transplantation cell dose, 333–334 children, 334 leukemia, 335 double, 335–336 hematological malignancies, 336 leukemia, 336 new approaches, 335–337 nonmalignant pediatric disorders, 335 outcomes, 334–335 related donor transplantation, 334 treatment, 337 unrelated donor transplantation, 334–335 Cord blood units cryopreservation, 332 ex vivo expansion, 337 infusion, 332–333 thawing, 332–333 transplantation, 333–334 transportation, 332 Coronary artery disease (CAD), 343 myocardial function, 348 Creatinine live kidney donors, 81 Cryopreservation cord blood units, 332 hematopoietic cells, 315 Cryptococcal meningitis, 372 Cryptococcus, 372–373 Cryptococcus neoformans, 365 CUSA. See Cavitron ultrasonic surgical aspirator (CUSA) Cushing stitches, 289 CVD. See Cardiovascular disease (CVD) Cyclic guanine monophosphate (cGMP), 252 Cyclosporine, 144, 349, 372 Cystic fibrosis, 264 Cytomegalovirus (CMV), 250, 260 infection, 220 retinitis, 139 Daclizumab, 108 DCCT. See Diabetes Control and Complications Trial (DCCT) DDIT. See Deceased donor intestinal transplantation (DDIT) DDLT. See Deceased donor liver transplantation (DDLT) Deceased donor intestinal transplantation (DDIT) status, 297 worldwide growth, 298 Deceased donor kidney transplantation, 141 financial advantages, 397 pregnancy, 385–386 recipient lymphoid irradiation, 411 Deceased donor liver transplantation (DDLT), 169 financial impact of, 401 graft survival, 217 patient survival, 217

451

Index Deceased donor lobar-lung transplantation, 265 donor outcomes, 265–266 Deceased donors growth rates, 126 organs payment system, 418 recipients, 141 supply, 433 Dennis-Drash syndrome, 150 Desmopressin, 357 Diabetes familial history, 92 therapeutic options, 245–246 Diabetes Control and Complications Trial (DCCT), 245 Diabetic neuropathy, 344 Distal pancreas pancreatic remnant, 239 Distal superior mesenteric vessels, 287 Domino paired donation, 133–134 example, 133 Donor-centric allocation, 132 Donor-specific alloantibody detection of, 115–116 Donor-specific antibody patient approach, 117 Donors. See also Deceased donors; Kidney donors; Live donor aging, 30 bowel preparation, 173 decision-making, 11–12 end stage renal disease, 80 Good Samaritans, 12 independent medical evaluation, 201 liver function tests, 190 living versus deceased female renal transplantation recipients, 388 lobectomy donor consent, 267 health donors, 267 long-term outcomes, 87–95 moralities, 102 nephrectomy anesthesia, 342 kidney sales, 418 laparoscopic, 56–59 risks associated with, 342 outcomes, 185–194 surgeon experience, 189–190 paid regulated system of sales, 418 psychological status, 12–13 pulmonary artery, 261 right lobectomy moralities, 188 morbidities, 188 safety, 165 surgery mortality, 186 uninephrectomy impact of, 90–91 Dopamine, 356 Double cord blood transplants, 335–336 Dual grafts graft volume, 199 EBV. See Epstein-Barr virus (EBV) Edmonton protocol, 246–247

End-stage renal disease (ESRD), 33 arterial hypoxemia, 348 blood transfusions, 114 donors, 80 intrapulmonary shunting, 349 legislation, 2 living donation, 79–81, 129 morbidities associated with, 343 renal function, 36 renal transplantation, 235 risk factors, 93 Endotracheal anesthesia, 173 Entamoeba histolytica, 369 Epstein-Barr virus (EBV), 224, 250, 260 diagnosis, 224 Erythrocyte depletion, 313–314 ESRD. See End-stage renal disease (ESRD) FAL. See Fractional allelic loss (FAL) rate Female kidney transplantation recipients living donor versus deceased, 388 Fenoldopam, 345 Fentanyl, 352 Field strength, 202 Fractional allelic loss (FAL) rate, 230 microsatellites, 230 tumor-free survival, 232 Fungal infections CNS, 368 Furosemide, 50, 54, 57, 64, 153, 154 Gerota’s fascia, 49, 56 ligaments division, 57 GFR. See Glomerular filtration rate (GFR) GIA endovascular stapler, 61 GIA stapler ileum, 287 Giardia lamblia, 369 Glomerular filtration rate (GFR), 33 BSA, 37 lower candidate, 36–37 measurements of, 37 SCr, 74 Good Samaritans donors, 12 Graft mucosa morphologic adaptation, 304 Graft-recipient weight ratio (GRWR), 172–173 Graft venous drainage, 177 Graft-versus-host disease (GVHD), 330 GRWR. See Graft-recipient weight ratio (GRWR) GVHD. See Graft-versus-host disease (GVHD) HALDN. See Hand-assisted laparoscopic donor nephrectomy (HALDN) Hand-assisted distal pancreatectomy, 238 Hand-assisted donor pancreatectomy, 241, 242 Hand-assisted laparoscopic donor nephrectomy (HALDN), 71 live, 62–64 pneumo-sleeve hand, 64 position of hand assist port, 63 Harvesting, 311 HAT. See Hepatic artery thrombosis (HAT) HCC. See Hepatocellular carcinoma (HCC) HDFP. See HTN Detection and Follow-up Program (HDFP)

452 Helsinki debate, 2–3 Hematologic disorders, 324–325 Hematopoiesis, 329–330 Hematopoietic cells cryopreservation, 315 fresh, 315 Hematopoietic colony types identification list, 330 Hematopoietic stem cells (HSC) adult collection, 309–316 infusion, 309–316 processing, 309–316 sources, 310 collection, 311–313 cryopreservation, 314–315 infusion of, 315 post-transplant care, 316 storage, 314–315 Hematopoietic stem cell transplantation (HSCT) adult donor evaluation, 310–311 dose requirements, 310 infectious disease screening, 311 types, 309 allogeneic applications and outcomes, 319–326 treatment failure, 319 autologous applications and outcomes, 319–326 genetic diseases, 320 hematologic diseases, 320 hematologic malignancies, 321–324 immunologic diseases, 320 myeloablative regimens, 320–321 neoplastic diseases, 320 nonmyeloablative regimens, 321 outcomes, 321–326 preparative regimens, 320–321 Hematuria, 40–41 isolated microscopic, 40 Hemoglobinopathies, 325 Heparin intravenous, 52 Hepatectomy. See also Live donor hepatectomies (LDH) liver donors preoperative donor evaluation, 169–172 right lobe donor, 169 Hepatic arterial complications pediatric liver transplantation, 218 Hepatic artery dissection, 175, 176 stenosis, 219 Hepatic artery thrombosis (HAT), 197 risk factors, 218–219 Hepatic duct right transection, 178 Hepatic lobe allograft right, 179 Hepatic vein right transection, 179 Hepatic venous complications, 221–222 Hepatocellular carcinoma (HCC), 161 donor operation safety, 227 fractional allelic loss, 230–233

Index [Hepatocellular carcinoma (HCC)] living donation, 229–230, 233 organ allocation, 227 organ transplantation, 227 outside current UNOS criteria, 229 pretransplant biopsy, 230–233 waiting list, 228 Hepatopulmonary syndrome (HPS), 348 Hepatorenal syndrome (HRS), 349 mechanism, 350 HIV. See Human immunodeficiency virus (HIV) HLA. See Human leukocyte antigen (HLA) Hodgkin’s disease, 319, 323 HPS. See Hepatopulmonary syndrome (HPS) HRS. See Hepatorenal syndrome (HRS) HSC. See Hematopoietic stem cells (HSC) HSCT. See Hematopoietic stem cell transplantation (HSCT) HTN Detection and Follow-up Program (HDFP), 88 Human immunodeficiency virus (HIV), 250 alemtuzumab, 108 end-stage renal disease, 138, 145 mortality, 138 renal transplantation immunosuppression, 144 recipients, 142, 143, 144 Human leukocyte antigen (HLA), 113 donor, 247 matching, 333 recipient, 247 transfusion exposure, 125 Hyper filtration damage, 89 Hypertension, 37–38 aging, 37 Hypocalcemia, 313 Idiopathic pulmonary fibrosis, 264 Ileum, 281–282, 305 GIA stapler, 287 superior mesenteric artery, 282 Illegal immigrants organ sales, 431 Immunologic barriers reduction matching, 128 Immunological incompatible kidney transplantation, 113–121 Immunosuppression, 107–110 mechanisms of, 208 monotherapy, 110 Immunosuppressive drugs, 381 Infections live donor transplantation recipients, 363–375 Intestinal graft mucosa morphologic adaptation, 304 vascular anastomoses, 291 Intestinal transplantation adult intestinal failure, 276 angiography, 275 children, 299, 300 intestinal failure, 276 cost-effectiveness, 305 CT angiography, 275 current outcomes, 297–300 deceased donors advantages, 270 disadvantages, 270 status of, 297 worldwide growth, 298

453

Index [Intestinal transplantation] dehydration, 277 donors evaluation, 272–276 follow-up duration, 274–275 responsibility, 274–275 selection, 272–276 end-stage intestinal failure, 297 factors affecting survival, 299 graft survival, 298 human leukocyte antigen, 269, 297 imaging studies, 274 immunologic benefit, 271 intestinal continuity, 289 line infections, 277 live donors, 269–278 advantages, 270–271 body mass index, 273 disadvantages, 270, 272 mortality rates, 271 rationale, 270 liver failure, 300 MRI, 273 parenteral nutrition-induced cholestasis, 276 preoperative workup, 277–278 post-transplant lymphoproliferative disease, 269, 303 quality of life, 305 radiographic imaging studies, 278 recipients evaluation, 275–276 genetic disorder, 273 operation illustration, 291 selection, 275–276 surgical procedure, 287–288 sepsis, 300 short bowel syndrome, 300 survival, 299 thrombosis, 300 types, 299 UNOS, 275 Intestinal Transplant Registry, 298 Intravenous glucose tolerance test (IVGTT), 251 Intravenous heparin, 52 Ischemic injury, 304–305 Islet-cell transplantation assessment, 253 background, 246–249 donors considerations, 249–252 outcomes, 245–256 recipient evaluation criteria, 250 risks, 252–253 evaluation, 245–256 future directions, 255–256 immunosuppressive therapy, 254–255 metabolic complications, 252–253 procedure, 253 recipients considerations, 253–254 evaluation criteria, 250 risks, 254–255 recipients outcomes, 245–256 selection, 253 success, 247 surgical complications, 252–253, 254–255 technical aspects, 245–256

Isoniazid, 374 IVGTT. See Intravenous glucose tolerance test (IVGTT) Jehovah’s Witness, 67 Jejunum, 281–282, 305 vascular distribution, 283 John Hopkins Kidney Paired Donation Program results, 128–129 KDOQI. See Kidney Disease and Outcome Quality Initiative (KDOQI) Kidney allografts HIV, 140 Kidney disease chronic, 91 Kidney Disease and Outcome Quality Initiative (KDOQI), 39 Kidney donors financial stress, 398 quality of life after, 93–94 survival, 87–88 Sweden, 78 Kidney paired donation (KPD), 126 example, 131, 132 local experience, 128–129 optimized matching algorithm, 130 regional experience, 128–129 Kidneys. See also Live donor kidneys dysfunction, 349 flipping, 61 laparoscopic approach, 104 mass, 78 reduction, 89 paired exchanges, 120–121 perinephric fat, 52 preoperative angiogram, 51 registrations, 79 removal, 238 Kidney sales arguments for sales, 418–419 artificial crisis, 420 changing the law, 423 emotions, 417 lack of consent, 422 paid donations, 417–427 previous blood contamination, 420 transplant failure rate, 431 Kidney transplantation, 1, 101, 113 children results, 155 deceased donor, 141 financial advantages, 397 pregnancy, 385–386 recipient, 411 dialysis, 121 donors evolution of, 117–119 impact sensitization, 114 sensitized patient problem, 113–114 end-stage renal disease, 69, 235 female recipients living donor versus deceased, 388 historical background, 149 HIV, 141 immunosuppression, 144 recipients, 139–143

454 [Kidney transplantation] immunological incompatible, 113–121 immunosuppression, 145 live donors, 341 ABO-incompatible, 119–120 nondirected donation, 125–134 paired donation, 125–134 Monte Carlo decision tree model, 130 pediatric living donors, 149–157 recipients children, 157 pregnancy outcomes, 387 third-party perspective, 396–397 Kidney transplantation recipients HIV characteristics of donors, 144 deceased donors, 142 live donors, 143 pregnancy risk, 384 KPD. See Kidney paired donation (KPD) Kupffer cells, 326 Langerhans cells, 326 Laparoscopic (hand-assisted) distal pancreatectomy, 238 Laparoscopic (hand-assisted) donor pancreatectomy, 241 Laparoscopic live donor nephrectomy (LLDN), 55–62, 60, 71–74, 141 Australian systematic review, 72 complication rate, 103 development, 67 donor outcomes, 101–111 endocatch bag introduction, 56 endovascular GIA stapler, 59 hand-assist port position, 60, 63 hemoclip application, 57 morbidity, 70 multiple renal arteries, 106 obesity, 102, 105–106 patient outcomes, 104–107 patient position, 65 postoperative pain, 101 recipient outcomes, 242 recipients children, 106–107 outcomes, 101–111 renal allografts, 110 vascular injury, 102 Lasix, 57, 356 Lateral segmentectomy, 180–181 LDH. See Live donor hepatectomies (LDH) LDLT. See Live donor liver transplantation (LDLT) Left lateral segment graft, 197–198 Left lobectomy, 180–181 Left lobe graft, 198–199 Lembert stitches, 289 Leukemia acute lymphoblastic, 321 acute myelogenous, 321–322 chronic lymphocytic, 322 chronic myelogenous, 322 chronic myeloid, 319 cord blood transplantation, 335–336 Listeria monocytogenes, 367 Live donations hepatocellular carcinoma, 229–230, 233 long-term risks, 77–84

Index Live donor age, 29–30 associated medical concerns, 82 consequences of donation, 18 cultural-centered issues, 83 deaths, 81 donor-recipient relationship, 22 ethnic-centered issues, 83 evaluation, 30, 163 expanding acceptance criteria, 94 growth rates, 126 health, 28 hepatic vein territories, 202 kidneys, 22, 29 knowledge, 14 literature, 17 liver, 22 long-term risk, 69–76 medical evaluation of, 27–30 medical problems, 28 mental health history, 14 moral objections, 21 moral outcomes, 20 mortality, 81–82 outcomes, 20 pain concerns, 83 perioperative risk, 69–75 physical function scores, 82 physical health, 17 postdonation psychosocial outcomes, 16–19 potential gift-giving relationship, 8–9 potential predictor evidence, 20 programs, 15 psychiatric assessment, 16 psychological function scores, 82 psychological stability, 18 psychosocial evaluation, 13–16 psychosocial information, 15 psychosocial outcomes, 16–19 quality of life, 19, 82–84 outcomes, 19–21 recipients management, 343–345 response rates, 95 studies, 84 transplant centers, 165 value of, 27–28 World War II, 34 Live donor hepatectomies (LDH) back-table procedure, 180 biliary anatomy, 172 cholangiography, 174 cholecystectomy, 174 complications, 185–186 financial aspect, 191–192 graft adequacy, 172 graft removal, 178–180 hepatic artery, 170–171 hepatic venous anatomy, 171–172 hilar dissection, 175 initial exploration, 173–174 intraoperative ultrasound, 174–175 intraparenchymal transection, 176–177 mobilization, 174–175 mortality, 191 perioperative considerations, 172

455

Index [Live donor hepatectomies (LDH)] portal vein, 170 postoperative care, 180–181 quality-of-life after donation, 191 state legislation, 192, 193 surgeon role, 190 technical aspects, 169–181 universal classification system, 185 Live donor intestinal transplantation, 269–278, 300–303 absorption tests, 304 advantages, 270–271 associated liver disease, 278 body mass index, 273 centers, 300–301 historical data, 302 immunosuppression, 302–303 infections, 303 recipient survival, 302 rejection, 302–303 clinical outcomes, 297–306 contraindications, 278 demographics of transplants performed, 300–301 diagnostic procedures, 278 disadvantages, 270, 272 donors, 285–287, 301 inclusion criteria, 276 indications for, 301 mortality rates, 271 postoperative follow-up, 286–287 postoperative orders, 286 preoperative orders, 285 procedure-specific risk, 272 psychosocial assessment, 273 quality of life analysis, 306 rationale, 270 recipient, 287–291 outcomes, 301–302 schematic illustration, 285 surgical procedure, 285–286 surgical technique, 281–295 worldwide growth, 298 Live donor islet transplantation historical context, 248 procedure, 247–249 Live donor kidneys, 34 function, 36 intervention, 35 medical screening, 35 medical testing, 35 pregnancy, 386 Live donor kidney transplantation, 101, 341, 387–389 ABO-incompatible, 119–120 advantages, 150 age, 151 benefits, 69 dialysis access, 152 donors autonomy, 151 demographics, 154 evaluation, 151 risks, 150 ethical considerations, 150–151 evaluation, 33–45 graft survival, 109 HIV positive recipients, 137–145

[Live donor kidney transplantation] immunosuppression, 109, 154–156 nondirected donation, 125–134 operative procedure, 152–153 paired donation, 125–134 postoperative care, 153–154 pregnancy after, 385–387 preoperative considerations, 152 recipients characteristics, 109 demographics, 154 relative benefit, 151 surgery, 151 technical considerations, 151–152 Live donor liver transplantation (LDLT), 4, 345, 389 adults, 187–188, 198 adult-to-adult, 165 adult-to-child, 165 advantages, 160 biliary problems, 202 children, 159–160 published cases, 187 Clavien classification, 186 comparison, 201 disadvantages, 160 donors evaluation, 162–164 minimum age of, 163 technique, 217 drawbacks, 160 Epstein-Barr virus, 224 equipment required, 350 financial impact of, 401 graft survival, 211, 217 hepatocellular carcinoma, 227–233 health care, 5 hepatic vein cuff, 218 imaging technology, 201 lifesaving liver transplants, 181 patient survival, 217 recipients contraindications, 161 exclusions, 164 hepatitis C, 162 outcomes, 197–203 technique, 217–218 standard liver volume, 199 surgeons, 169 surgery tests, 164 Live donor lobectomy perioperative complications, 266 Live donor lung transplantation, 357, 389 Live donor nephrectomy anterior retroperitoneal patient positioning, 51 retractor system, 51 Clavien classification, 75 complication classification scheme, 73–74 donor-incurred expenses, 399 technical aspects, 49–67 Live donor organs pregnancy, 392 Live donor organ transplantation, 1–6 costs versus charge, 395–396 donor perspective, 398–400 financial impact, 395–401 living donors awareness, 266

456 Live donor pancreas transplantation, 235–243, 358–359, 387–389 chest X-ray, 236 donors outcomes, 240–241 postoperative care of the, 239 ECG, 236 enteric drainage, 240 operative techniques, 237–240 preoperative donor evaluation, 235–237 radiologic evaluation, 236 recipients, 239 outcomes, 241–242 technical points, 239 Live donor renal arteries example, 107 Live donor small bowel transplantation, 358–359 Live donor transplantation, 256 anesthesia, 341–359 congenital anomalies, 380 immunosuppressive agents, 379–382 immunosuppressive associated congenital anomalies, 380–381 kidney reperfusion, 345 pregnancy, 379–392 recipients antimicrobial prophylaxis, 364 environmental exposure, 364 immunocompromised patient, 369–370 net state of immunosuppression, 364 operative factors, 363 postoperative factors, 363 postoperative prophylaxis, 375 sever infection approach, 366 time of patient transplantation, 363 infection central nervous system, 367–369 diagnostic approach, 364–365 gastrointestinal, 368–369 genetic susceptibility, 363–364 management of, 363–375 manifestations of, 365–366 prevention of, 375 protozoal, 369 pulmonary, 365–366 risk factors for, 364 teratology concepts, 379–381 Live kidney donation consent form, 435–440 Live kidney donors, 94 age, 104–105 consequences of donation, 17 creatinine, 81 deaths, 81 end-stage renal disease, 80, 95 management, 341–343 recipients cardiac risk, 343 induction of anesthesia, 344 Live liver donors management, 345–347 recipients management, 347–357 surgery hemodynamic changes, 346 Live lobar-lung transplantation, 259–267 allograft implantation, 262–263 allograft preservation, 261–262

Index [Live lobar-lung transplantation] bilateral lobar grafts, 264 donors left lower lobectomy, 261 right lower lobectomy, 260–261 selection, 259–260 operative technique, 260 postoperative management, 263 pulmonary functions, 265 recipients indications, 259–260 outcomes, 264–265 pneumonectomy, 262–263 Live lung donors candidate criteria, 358 criteria, 357–358 management, 357–358 recipients management, 358 Live nondirected donation, 131–132 Live organ donation, 3–5 cadaver donor kidneys, 3 donor’s motives, 10–11 gift relationship, 8 historical barriers, 8 psychosocial aspects, 7–22 psychosocial evaluation, 9–16 Live Organ Donor Consensus Group, 193 Live organ donors recovery time, 399 Live pancreas donation procedure, 251–252 Liver CT images, 171 partial donation consent form, 441–447 regeneration, 191 Liver donations transplant community, 194 Liver donors hepatectomy preoperative donor evaluation, 169–172 psychiatric status, 13 psychosocial status, 13 Liver function tests donor comparisons, 190 postoperative regeneration in donors, 190–191 Liver transplantation. See also Live donor liver transplantation (LDLT) deceased donor, 169 financial impact of, 401 graft survival, 217 patient survival, 217 financial impact, 397–398 orthotopic, 397 pediatric living donors, 217–224 Live tumor study group classification system, 228 Living disorder psychiatric disorders, 18 LLDN. See Laparoscopic live donor nephrectomy (LLDN) Lobar-lung transplantation deceased, 265–266 Lobar recipients antibiotic therapy, 263 immunosuppression, 263 prophylaxis, 263

Index Lobectomy donors donor consent, 267 health donors, 267 left, 180–181 right arterial anatomy, 171 donors, 188 Long-term donor risks, 77 Lorazapem, 352 Lumbodorsal fascia, 53 Lung transplantation live donor, 357 Malignancy, 28–29 Mannitol, 57, 64, 356 MDS. See Myelodysplastic syndrome (MDS) Medical altruism, 8–9 MELD. See Modified end-stage liver disease (MELD) Metabolic acidosis, 355 Methyldopa pregnancy-induced hypertension, 390 Metoclopramide, 344 Middle hepatic vein harvesting morbidities, 189 Middle vein recovery, 188–190 Milan criteria tumor-free survival, 231 Minimal posterior supracostal approach, 55 Modified end-stage liver disease (MELD), 200, 228–229 outflow block, 203 Monocyte-predominant ACR, 214 Monotherapy immunosuppression, 110 Mycobacterium tuberculosis, 374–375 Myelodysplastic syndrome (MDS), 323–324 Myeloproliferative syndromes, 324 National Health and Nutrition Examination Survey, 91 National Kidney Foundation (NKF), 39 National Marrow Donor Program (NMDP), 311 National paired donation program impact, 129–130 National transplantation pregnancy registry, 382–385 Native nephrectomy, 152 NDLD. See Nondirected living donation (NDLD) Neisseria meningitidis, 367 Neoplastic plasma cells multiple myeloma, 324 Nephrectomy. See also Laparoscopic donor nephrectomy; Laparoscopic live donor nephrectomy (LLDN); Live donor nephrectomy; Open donor nephrectomy (ODN) donors anesthesia, 342 kidney sales, 418 risks associated with, 342 hand-assisted laparoscopic donor, 71 pneumo-sleeve hand, 64 position of hand-assist port, 63 impact of long-term survival, 87–88 impact on renal function, 88–89 long-term risk, 34 native, 152 right laparoscopic retroperitoneal live donor, 64–65 robot-assisted laparoscopic donor, 242 robotically hand-assisted laparoscopic donor, 65–67

457 NFK. See National Kidney Foundation (NKF) NMDP. See National Marrow Donor Program (NMDP) Nocardiosis, 373 transplant recipient, 374 Nondirected kidney donation, 126 Nondirected living donation (NDLD), 10 decision making donor, 11–12 moral pattern, 10 motives, 10 psychological reasons, 10–11 social reasons, 10–11 Nondonors uninephrectomy, 90 Non-Hodgkin’s lymphoma, 322–323 Nucleoside analog reverse-transcriptase (NRTI), 138 Nystatin, 155 Ockham’s razor, 365 ODN. See Open donor nephrectomy (ODN) Open donor distal pancreatectomy, 237–238 Open donor nephrectomy (ODN), 49–50, 69–71 areolar tissue, 50, 52 Australian systematic review, 72 dissection retraction, 53 donor position, 52 hilum dissection, 54 minimal incision, 50–51 morbidity, 69 position of patient, 50, 52 retractor incision, 52 position, 52 ureter dissection, 53 Open donor pancreatectomy, 240 recipient outcomes, 241 OPTN. See Organ Procurement and Transplantation Network (OPTN) Organ donations alternative sources, 341 debates, 9 live, 3–5 Organ Procurement and Transplantation Network (OPTN), 79, 185 Organs allograft tolerance, 413 distribution method, 233 donor recipient evaluation, 160–162 markets nurse involvement, 433 professions of medicine, 432–433 medical suitability, 28 reserve, 29 scarcity for transplantation, 27 Organ sales abuse, 424 altruistic donation, 423–424 argument against, 419–420 ban justification, 419 commodification of the body, 422 doctor-patient relationship, 424 exploitation of the poor, 420–421 financial pressure, 421 harm to vendors, 422 illegal immigrants, 431 living persons, 431–433

458 [Organ sales] markets, 431 organized religion, 423 practical considerations, 425 society’s role, 421 trust in doctors, 424 in government, 424 vendor criteria determination, 424–425 geographic area, 425 health care, 425 Western nations wealth, 432 Western philosophical principles, 419 Organ transplantation graft-versus-host, 208 host-versus-graft, 208 live donor, 1–6 donor perspective, 398–400 living donors awareness, 266 societal perspective, 400–401 tuberculosis, 374 Orthotopic liver transplantation, 397 Paid donors regulated system of sales, 418 Paired kidney exchanges, 120–121 PAK. See Pancreas after kidney (PAK) transplants Pancreas dissected inferior margin, 238 distal pancreatic remnant, 239 posterior surface exposure, 238 Pancreas after kidney (PAK) transplants, 235 Pancreas transplantation. See also Live donor pancreas transplantation bladder exocrine drainage, 239–240 segmental pancreas grafts, 239–240 Pancreas transplants (PTA), 235 Pancreatectomy laparoscopic (hand-assisted) distal, 238 laparoscopic (hand-assisted) donor, 241 recipient outcomes, 242 open donor, 240 recipient outcomes, 241 post-laparoscopic distal surgical incisions, 241 Panel of reactive antibodies (PRA), 114 Parenchymal transection liver, 177 Parenteral nutrition-induced cholestasis intestinal transplantation, 276 Paroxysmal nocturnal hemoglobinuria (PNH), 325 Partial liver donation consent form, 441–447 Patient-controlled analgesia postoperative epidural catheter, 173 Pediatric liver transplantation (PLT) biliary structures, 220 complications allograft-specific, 218–219 biliary, 219–220 diagnosis of, 218–222 general operative, 222–223 infectious, 223–224 intestinal, 222–223 management of, 218–222

Index [Pediatric liver transplantation (PLT) complications] portal venous, 221–222 pulmonary, 222 perioperative infections, 223 post-transplant lymphoproliferative disease, 223–224 Peripheral blood stem cells collection, 312–313 risks, 313 technique, 312–313 processing, 313–315 Peripheral solid tumors immune system, 410 Piggyback technique, 354 Planned donor operation recipient disease, 5 Plasmapheresis, 118 determination of extent, 118 PLT. See Pediatric liver transplantation (PLT) Pneumocystis carinii, 138, 263 Pneumoperitoneum, 56 Pneumo-sleeve hand hand-assisted laparoscopic donor nephrectomy, 64 PNH. See Paroxysmal nocturnal hemoglobinuria (PNH) Polycystic liver disease, 210 Polyoma (BK) virus, 156 Portal vein confluence magnetic resonance angiogram, 237 Portal veins right CT showing, 170 Portal vein stenosis (PVS), 221 Portal vein thrombosis, 221–222 Portopulmonary hypertension (PPH), 348 Post-laparoscopic distal pancreatectomy surgical incisions, 241 Postoperative liver function tests regeneration in donors, 190–191 Postoperative patient-controlled analgesia epidural catheter, 173 Post-reperfusion syndrome (PRS), 355 Post-transplant lymphoproliferative disease (PTLD), 155, 213, 303–306 Epstein-Barr virus, 314 graft adaptation, 303 intestinal transplantation, 269, 303 Potential live donor gift-giving relationship, 8–9 PPH. See Portopulmonary hypertension (PPH) PRA. See Panel of reactive antibodies (PRA) Preemptive transplantation, 149–150 Pregnancy deceased donor kidney transplantation, 385–386 graft dysfunction, 390 immunosuppression, 385 immunosuppressive dosing, 390 infections, 390–391 kidney transplantation recipients, 385–387 live donor kidney transplantation, 385–387 live donor organs, 392 live donor transplantation, 379–392 long-term graft prognosis, 384–385 national transplantation registry, 382–385 preeclampsia, 390 tacrolimus, 388 transplant recipients, 389–392 urinary tract infections, 385

459

Index Pretransplant immune modulation, 5–6 Proteinuria, 38–39 kidney disease, 89–90 PRS. See Post-reperfusion syndrome (PRS) Pseudomonas aeruginosa pneumonia, 140 PTA. See Pancreas transplants (PTA) PTLD. See Post-transplant lymphoproliferative disease (PTLD) Pulmonary artery anastomosis, 262 donors, 261 Pulmonary aspergillosis, 372 Pulmonary fibrosis idiopathic, 264 PVS. See Portal vein stenosis (PVS) Pyrazinamide, 374 RAA. See Renin-angiotensin-aldosterone (RAA) Rapamune, 380 Recipient-centric allocation, 132–133 Recipients infectious diseases transmission, 28 Renal arteries division of, 60 live donor example, 107 magnetic resonance angiogram, 236 Renal vein staple placement, 62 Renin-angiotensin-aldosterone (RAA), 355 Reperfusion, 354 Retinitis cytomegalovirus, 139 Rhodococcus equi, 366 Rifampin, 374 Right hepatic duct transection, 178 Right hepatic lobe allograft, 179 Right hepatic vein transection, 179 Right laparoscopic retroperitoneal live donor nephrectomy, 64–65 Right live donor liver transplantation characteristics, 210 Right lobe adult living donor liver transplantation (RLALDT), 208 Right lobe donor hepatectomy (RLDH), 169 Right lobe graft, 199 Right lobe living donor liver transplantation adult graft recipient survivals, 211 Right lobe outcome, 200–203 Right lobectomy arterial anatomy classification for donor, 171 donors mortalities, 188 morbidities, 188 Right portal veins CT showing, 170 dissection, 175 Rituximab, 119 RLALDT. See Right lobe adult living donor liver transplantation (RLALDT) RLDH. See Right lobe donor hepatectomy (RLDH) Robotically hand-assisted laparoscopic donor nephrectomy, 65–67, 242 room set-up, 66

[Robotically hand-assisted laparoscopic donor nephrectomy] surgeon console, 66 ureter, 67 SAA. See Severe aplastic anemia (SAA) Sales. See Kidney sales; Organ sales Scientific Registry of Transplant Recipients (SRTR), 80 Segmental graft optimal length, 282–285 Segmentectomy lateral, 180–181 Sepsis, 277, 303 Severe aplastic anemia (SAA), 324–325 cord blood transplantation, 336 Short bowel syndrome, 289 intestinal transplantation, 300 Sirolimus, 372, 381 HIV, 145 SMA. See Superior mesenteric artery (SMA) Small intestine blood supply, 281 Small intestine transplantation live donors, 358–359 Socio-centric allocation, 131, 133 Solid organ transplantation pulmonary infection, 367 Splenectomy, 120 Splenic arteries magnetic resonance angiogram, 236 Splenic vein confluence magnetic resonance angiogram, 237 Spontaneous allograft acceptance, 412 Spontaneous transplantation tolerance frequency of, 411 mechanisms, 411–412 SRTR. See Scientific Registry of Transplant Recipients (SRTR) Stem cell transplantation cord blood transplantation, 337 morbidity causes, 330 mortality causes, 330 Streptococcus pneumoniae, 367 Strongyloides stercoralis, 367 Superior mesenteric artery (SMA), 271 angiography, 274 ileum, 282, 283 pattern of distribution, 281 terminal branches, 286 vascular supply to small intestine, 282 Superior mesenteric vessels distal, 287 Tacrolimus, 349, 372 female kidney recipients, 384 pregnancy, 388 Tacrolimus monotherapy, 155, 209 adult recipient outcomes, 207–214 immunosuppression status, 214 methods, 209 results, 209–214 Tazobactam, 173 T cells alloreactive memory, 409 depletion, 314 TEG. See Thromphoelastograph (TEG) Thrombocytopenia, 313

460 Thrombotic risk factors associated with, 346 Thromphoelastograph (TEG), 356 Thymoglobulin, 108, 154 Total parenteral nutrition (TPN), 269 Toxoplasma gondii, 368 TPN. See Total parenteral nutrition (TPN) Transesophageal echocardiographic bicaval view, 353 Transplantation tolerance, 405–413 allograft function, 411 anergy, 407–408 biological barriers, 408–409 clinical strategies, 413 definition, 412 immunologic ignorance, 409–410 mechanisms, 406 limitations of, 407–408 natural examples, 405–406 nature of alloreactivity, 408 strategies, 409 Transplanted organs immunologic ignorance, 410–411 peripheral tolerance, 408 Transplanted tissues immunologic ignorance, 410–411 Transplant immunosuppressive drugs, 381 Transplant programs medical billing practices, 399 Transplant recipients BK virus, 371 Cryptococcus, 372–373 cytomegalovirus, 370–371 health insurance benefits, 400 Nocardia, 373–374 pathogen-directed therapy, 370 pathogens, 370–374 pregnancy management, 389–392 Trimethotrim-sulfamethoxazole, 155 Tuberculosis organ transplantation, 374

Index Tumor-free survival FAL, 231 Turner-Warwick approach, 54 Umbilical cord blood cells biology of, 329 collection, 331–333 infusion, 331–333 processing, 331–333 Umbilical cord blood cell transplantation, 329–337 Unconventional paired donation, 128 Uninephrectomy donors impact of, 90–91 United Network for Organ Sharing (UNOS), 36, 90, 200 donor rights, 192 for donors, 166 for recipients, 166 United States Renal Data System (USRDS), 140 UNOS. See United Network for Organ Sharing (UNOS) Ureter division, 58 Urinary tract infections, 40 USRDS. See United States Renal Data System (USRDS) Valganciclovir, 155 Vancomycin, 173 Voiding cystourethrogram (VCUG), 40 Von Willebrand’s disease, 67 Voriconazole, 372 West Nile virus, 310 Wilms’ tumor, 150 Wolf-Parkinson-White syndrome, 265 World War II unilateral nephrectomy, 78