Kidney and Pancreas Transplantation: A Practical Guide

Current Clinical Urology Eric A. Klein, MD, Series Editor Professor of Surgery Cleveland Clinic Lerner College of Medicine Head, Section of Urologic Oncology Glickman Urological and Kidney Institute Cleveland, OH

For other titles published in this series, go to www.springer.com/series/7635

Kidney and Pancreas Transplantation A Practical Guide

Edited by

T.R. Srinivas and

Daniel A. Shoskes

Editors T.R. Srinivas, MD Cleveland Clinic Glickman Urological and Kidney Institute 9500 Euclid Avenue Cleveland, OH 44195 USA [email protected]

Daniel A. Shoskes Cleveland Clinic Glickman Urological and Kidney Institute 9500 Euclid Avenue Cleveland, OH 44195 USA [email protected]

ISBN 978-1-60761-641-2 e-ISBN 978-1-60761-642-9 DOI 10.1007/978-1-60761-642-9 Springer New York Dordrecht Heidelberg London © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or ­dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, ­neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (www.springer.com)

Preface

Kidney transplants are the most frequently performed solid organ transplants. Pancreas transplantation offers unique survival and quality of life benefits to selected diabetics with or without concomitant renal failure. The growing trend in the transplant community is that patients with kidney and pancreas transplants are cared for by a multidisciplinary team led by transplant surgeons and physicians. The complexity of clinical transplantation is further compounded by the competitive and regulatory landscape that transplant programs have to operate in. Given this scenario, the knowledge base that is required of the transplant physicians and surgeon encompasses not only medical aspects of patient care but also a sound grasp of issues related to the administration of programs and monitoring finance and outcomes. We offer a textbook devoted to kidney and pancreas transplantation that is well grounded in scientific principles, quantitative clinical reasoning, clinical pharmacology, tested clinical practices and overall clinical applicability. Also addressed are key aspects in the initiation, maintenance and sustained growth of viable clinical programs in kidney and pancreas transplantation. The intended audience includes medical and surgical fellows who intend to pursue an interest in transplantation and the practicing transplant physician. The editors acknowledge the valuable contributions of the authors and the inspiration provided by their fellows and trainees.

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Contents

The Immune Response to Transplanted Organs...................................................................... William M. Baldwin III, Anna Valujskikh, Peter N. Lalli, and Robert L. Fairchild

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The Histocompatibility Laboratory in Clinical Transplantation........................................... 23 Diane J. Pidwell and Peter N. Lalli Immunosuppressive Therapy in Kidney and Pancreas Transplantation.............................. 49 George Thomas, Saul Nurko, and Titte R. Srinivas Clinical Pharmacologic Principles and Immunosuppression................................................. 87 Patricia West-Thielke and Bruce Kaplan Pathology of Kidney and Pancreas Transplants...................................................................... 111 Lillian Gaber and Byron P. Croker Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ Transplantation............................................................................... 139 Agnes Costello and D. Scott Batty, Jr. Outcomes of Kidney and Pancreas Transplantation............................................................... 155 Titte R. Srinivas, Herwig-Ulf Meier-Kriesche, and Jesse D. Schold Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate................................................................................................................. 183 Richard A. Fatica, Stuart M. Flechner, and Titte R. Srinivas Selection and Preparation of the Pancreas Transplant Recipient.......................................... 201 Ho-Yee Tiong and Venkatesh Krishnamurthi Kidney Transplant Recipient Surgery...................................................................................... 211 Daniel A. Shoskes Issues and Surgical Techniques to Expand the Pool of Kidneys Available for Transplantation................................................................................. 219 Charles S. Modlin III and Charles S. Modlin, Jr.

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Pancreas Transplantation: Surgical Techniques...................................................................... 249 Alvin C. Wee and Venkatesh Krishnamurthi Laparoscopic Living Kidney Donation..................................................................................... 259 Wesley M. White and Jihad H. Kaouk Perioperative and Anesthetic Management in Kidney and Pancreas Transplantation Management.................................................................................................... 273 Jerome F. O’Hara Jr. and Samuel A. Irefin Surgical Complications after Kidney Transplantation........................................................... 281 Stuart M. Flechner Urologic Complications After Kidney Transplantation.......................................................... 299 Islam A. Ghoneim and Daniel A. Shoskes Medical Management of Kidney Transplant Recipients......................................................... 311 Vidya Vootukuru and Brian Stephany Infectious Complications: Prevention and Management........................................................ 333 Robin K. Avery, Michelle Lard, and Titte R Srinivas Living Kidney Donation: Pre-and Postdonation Evaluation and Management................... 357 Jonathan Taliercio and Emilio D. Poggio Psychology, Quality of Life, and Rehabilitation After Kidney and Pancreas Transplantation.................................................................................................. 373 Kathy L. Coffman Kidney Allocation System for Deceased Donor Kidneys in the United States...................................................................................................... 385 Islam A. Ghoneim and David A. Goldfarb Ethics of Transplantation........................................................................................................... 391 David A. Goldfarb and Jerome F. O’Hara, Jr. World-Wide Long-Term (20–40 Years) Renal Transplant Outcomes and Classification of Long-Term Patient and Allograft Survivals......................................................................... 399 William E. Braun, Sankar Navaneethan, and Deborah Protiva Quantitative Aspects of Clinical Reasoning: Measuring Endpoints and Performance......................................................................................................................... 411 Jesse D. Schold The Business of Transplantation............................................................................................... 423 Art Thomson Index............................................................................................................................................. 433

Contributors

Robin K. Avery, M.D. Department of Infections Disease, Medicine Institute, The Cleveland Clinic, USA William M. Baldwin, III Department of Immunology, Cleveland Clinic, Cleveland, OH, USA Donald Scott Batty, Jr. M.D. Genzyme Corporation, Cambridge, MA USA William E. Braun, M.D. Glickman Kidney & Urological Institute, Department of Neurology – Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA Kathy L. Coffman, M.D., FAPM Cleveland Clinic Transplant Center, 9500 Elucid Ave/P-57, Cleveland, OH 44195, USA Agnes Costello, PharmD, MS Transplant Business Unit, Genzyme Corporation, 500 Kendall Street, Cambridge, MA, 02142, USA Byron P. Croker, M.D., Ph.D. Pathology and Laboratory Medicine Service, NF/SG Veterans Health System, Gainesville, FL 32608, USA Robert L. Fairchild Glickman Urological and Kidney Institute and Department of Immunology, Cleveland Clinic, Cleveland, OH, USA Richard A. Fatica, M.D. Cleveland Clinic, Cleveland, OH, USA Stuart M. Flechner, M.D. FACS. Professor of Surgery, Glickman Urologic and Kidney Institute, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Ave/Q10, Cleveland, Ohio 44236 Islam A. Ghoneim, M.D., Ph.D Cleveland Clinic, Glickman Urological & Kidney Institute – Q10, 9500 Euclid Avenue, Cleveland, OH, USA, 44195

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Contributors

David A. Goldfarb, M.D. Cleveland Clinic, Glickman Urological & Kidney Institute – Q10, 9500 Euclid Avenue, Cleveland, OH USA, 44195 Samuel A. Irefin, M.D. Cleveland Clinic, Cleveland, OH, USA Jihad H. Kaouk, M.D. Cleveland Clinic, Glickman Urological & Kidney Institute, Cleveland, OH, USA Bruce Kaplan, M.D University of Arizona, Tucson, AZ, USA Venkatesh Krishnamurthi, M.D. Department of Urology, Glickman Urological and Kidney Institute, 9500 Euclid Avenue Q10, Cleveland, OH, 44195, USA Peter N. Lalli, Ph.D. Allogen Laboratories, Cleveland Clinic, Cleveland, OH, USA Michelle Lard, CNP Cleveland Clinic, Cleveland, OH, USA Herwig-Ulf Meier-Kriesche, M.D. Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA Charles S. Modlin, III Glickman Urological & Kidney Institute, Section of Renal Transplantation, Cleveland Clinic, Cleveland, OH, USA Charles S. Modlin, Jr. Glickman Urological & Kidney Institute, Section of Renal Transplantation, Cleveland Clinic, Cleveland, OH, USA Saul Nurko, M.D Cleveland Clinic, Cleveland, OH, USA Sankar Navaneethan, M.D. Glickman Kidney & Urological Institute, Department of Neurology – Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA Jerome F. O’Hara, Jr. M.D. Department of Anesthesia, Cleveland Clinic, Cleveland, OH, USA Diane J. Pidwell, Ph.D. Allogen Laboratories, Cleveland Clinic, 9500 Euclid Ave. C100, Cleveland, OH, USA Deborah Protiva, B.S.N. Cleveland Clinic Transplant Center, Cleveland, OH, USA Emilio D. Poggio, M.D Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Eluclid Avenue Cleveland, OH 44195, USA Jesse D. Schold, Ph.D. Department of Quantitative Health Sciences, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

Contributors

Daniel A. Shoskes, M.D., MSc., FRCS(C) Cleveland Clinic, Glickman Urological and Kidney Institute, Q10, 9500 Euclid Avenue, Cleveland, OH 44195, USA Titte R. Srinivas, M.D. Cleveland Clinic, Glickman Urological and Kidney Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA Brian Stephany, M.D. Department of Nephrology and Hypertension, 9500 Euclid Ave., Q7 Cleveland, OH 44195, USA Jonathan Taliercio, D.O. Cleveland Clinic, Cleveland, OH, USA George Thomas, M.D Cleveland Clinic, Cleveland, OH, USA Art Thomson, M.A. Cleveland Clinic, General Surgery & Transplant Center, A100, 9500 Euclid Avenue, Cleveland, OH, 44195, USA Anna Valujskikh Glickman Urological and Kidney Institute and Department of Immunology, Cleveland Clinic, Cleveland, OH, USA Srividya Vootukuru, M.D. Department of Nephrology & Hypertension, Mayo Clinic, Rochester, MN, USA Alvin C. Wee, M.D. Cleveland Clinic, Glickman Urological & Kidney Institute, Cleveland, OH, USA Patricia West-Thielke, PharmD, BCPS Clinical Sciences Building, Suite 402, University of Illinois at Chicago, Chicago, IL, 60612, USA Wesley M. White, M.D. Division of Urology, University of Tennessee Medical Center, Knoxville, TN, USA

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Chapter 1

The Immune Response to Transplanted Organs William M. Baldwin III, Anna Valujskikh, Peter N. Lalli, and Robert L. Fairchild

Keywords  T-lymphocytes • B-lymphocytes • Antibody • Complement • Rejection • Chemokines

Introduction The recipient immune response to major histocompatibility complex (MHC)-mismatched organ transplant is one of the most vigorous responses elicited. The response to an allograft is composed of: (1) components of innate immunity that are engaged immediately following reperfusion of the graft through germline-encoded receptors reactive to sets of conserved molecular patterns produced or exposed during inflammatory processes; and (2) adaptive or donor-specific components, T and B lymphocytes that clonally express somatically recombined receptors with specificity for donor allogeneic MHC-encoded molecules as well as non-MHC or minor histocompatibility antigens. Importantly, the innate and donor antigen-specific components intersect during the course of the response to amplify the intensity of the inflammation in the graft that ultimately results in tissue injury and graft failure. Many factors underlie the vigor of this antidonor immune response, including the initial injury imposed on the allograft by ischemia-reperfusion

W.M. Baldwin (*) Department of immunology, Cleveland Clinic, Cleveland, OH, USA e-mail: [email protected]

injury, the high frequency of reactive T cells for allogeneic MHC molecules, and the virtual immediacy of the response to donor MHC molecules by circulating memory T cells expressing reactivity to allogeneic molecules. This chapter covers the initial inflammatory response to transplanted organs followed by the priming and activities of donor-specific T cells in mediating graft tissue injury. We then cover the induction and impact of antibody-mediated injury on grafts. Finally, we discuss immune mediated injury resulting in chronic injury; that is, the development of interstitial fibrosis and occlusive vasculopathy of the graft.

Ischemia-Reperfusion Injury Reperfusion of organs subjected to ischemia induces an intense inflammatory response that directs leukocyte infiltration into the ischemic tissue [1–3]. Ischemia-reperfusion injury continues to be a major clinical problem causing significant morbidity and mortality in transplantation and other surgeries. The imposition of ischemia and reperfusion is an inherent component of solid organ transplantation that has a critical impact on graft outcome. Longer ischemic times correlate with delayed renal graft function, earlier and increased incidences of acute rejection episodes, and more rapid development of graft fibrosis and arteriopathy leading to poorer renal allograft outcome [4–7]. Many molecular and cellular mechanisms contribute to the injury provoked by reperfusion of

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_1, © Springer Science+Business Media, LLC 2011

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ischemic tissues. Oxygen deprivation followed by the stress of blood flow during reperfusion induces the formation of reactive oxygen species (ROS) by the ischemic vasculature that directly mediates injury to the vasculature and the parenchymal tissues of transplanted organs [8]. This initial injury also has downstream, indirect, effects to exacerbate graft tissue injury. For example, these oxygen radicals induce the vascular endothelium to produce acute phase proinflammatory cytokines, including TNFa and IL-1b. These cytokines in turn bind to receptors on the surface of endothelial cells and induce the mobilization of the Weibel-Palade bodies containing P-selectin and von Willebrand factor (vWf) to the luminal surface that facilitate the recruitment of circulating leukocytes and platelets to the endothelium. The ROS, TNFa, and IL-1b, also induce the endothelium and parenchymal cells to produce cytokines with chemoattractant properties (i.e., chemokines), including IL-8, CXCL1/KC, CXCL2/MIP-2, CCL2/MCP-1, and complement cleavage products, including C5a, that further facilitate leukocyte recruitment to the endothelium [9–12]. Neutrophils are typically the first leukocytes to infiltrate inflammatory sites, including ischemic tissues within hours of reperfusion [3, 10, 13, 14]. In addition to directing tissue inflammation, chemokines such as IL-8 and Groa/CXCL1 binding to CXCR1 and CXCR2 activate neutrophils to degranulate, releasing additional ROS, proteolytic enzymes, and proinflammatory cytokines that mediate tissue damage [15, 16]. In animal models, strategies either depleting neutrophils prior to reperfusion or inhibiting their infiltration into ischemic tissues have been extremely effective in attenuating injury of ischemic organs [10, 12, 17–20]. There is also evidence supporting a role of other leukocyte populations in mediating tissue damage during reperfusion of ischemic tissues. The inflammatory mediators produced during reperfusion of ischemic tissues induce production of the macrophage/monocyte chemoattractants CCL2/MCP-1 and CCL3/MIP-1a and the T-cell chemoattractant CXCL10/IP-10. A role for macrophages has been reported in

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ischemia-reperfusion tissue injury, although other studies have raised the possibility that the macrophages may afford some protection during the injury. Infiltrating macrophages clearly have protective functions, in part by producing hemoxygenase-1 (HO-1) and antiinflammatory cytokines such as IL-10 [21–23]. It is also worth noting that a critical function of macrophages infiltrating into tissue sites of inflammation is the phagocytosis and removal of apoptotic cells such as neutrophils [24]. Thus, macrophage infiltration into ischemic tissues during reperfusion is a natural step in the wound healing process and has many beneficial effects. A considerable amount of recent interest has focused on the role of a group of germ-line encoded pattern recognition receptors, Toll-like receptors (TLR), expressed on leukocytes and on tissue parenchymal cells as important sensors of infection and tissue damage [25, 26]. These receptors are a key step in the initial innate immune response to such infections at time points that precede the appearance of T cells primed to microbial antigens. The TLRs include transmembrane receptors as well as intracellular receptors and bind a variety of microbial products including peptidoglycans (TLR2), double-stranded RNA (TLR3), lipopolysaccharide (TLR4), and flagellin (TLR5). The majority of signals transmitted by ligand binding to TLRs are mediated through the MyD88 adaptor pathway to activate NF-kB. This signaling initiates the innate response to inflammation through the production of acute phase cytokines and chemokines, and the expression of adhesion molecules. Reperfusion of ischemic tissues also induces the rapid production and release of stress proteins from injured cells and extracellular matrix components including HMGB1, heat shock proteins, hyaluronan fragments, and heparin sulfate that are endogenous ligands for TLR2 or TLR4 [27– 32]. Recent evidence indicates that these endogenous, or sterile, TLR agonists activate endothelial cells and leukocytes to express inflammatory functions mediating tissue damage in ischemiareperfusion injury [33–38]. These studies have documented the absence or attenuation of injury when ischemia-reperfusion injury to a variety of

1  The Immune Response to Transplanted Organs

organs is imposed in mice with targeted deletions in genes encoding TLR2 or TLR4 when compared to wild-type mice, implicating TLR-mediated inflammation as a critical component of the tissue injury induced by acute ischemic injury. Furthermore, renal grafts from donors with TLR4 gene polymorphisms encoding a nonfunctional receptor have been shown to have decreased inflammation following reperfusion and lower incidence of delayed-graft function when compared to grafts expressing functional TLR4 [39]. Overall it is clear that ischemia-reperfusion is a major cause of direct graft tissue injury and creates an intense inflammatory environment. This environment directs the infiltration and activation of different leukocyte populations into the graft, increasing the intensity of tissue injury. The intensity of this initial tissue injury impacts the incidence of acute rejection and the development of the fibrotic process.

Induction of the Donor-Specific T-Cell Response Inflammation induced by ischemia-reperfusion injury also facilitates the initiation of the adaptive immune response to graft donor MHC and other antigens. Solid organs contain a network of bone marrow-derived cells that are interspersed throughout the tissue as a surveillance mechanism for infection and other types of tissue injury [40]. During the inflammation of transplant surgery, the ischemia-reperfusion induced TNFa and endogenous TLR ligands discussed above activate these interstitial dendritic cells in the graft to alter expression of molecules involved in dendritic cell migration [41, 42]. First, these inflammatory mediators induce the downregulation of E-cadherin expression and other molecules that tether the interstitial dendritic cells within the parenchymal tissue. Second, these mediators upregulate the expression of integrins and chemokine receptors that direct the migration of these dendritic cells out of the graft and into the vasculature where they traffic to the lymphoid tissue draining the graft. Since the transplant

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surgery disrupts lymphatic flow to the organ graft, the spleen is the major secondary lymphoid tissue draining the allograft. The dendritic cells enter the T-cell-rich zones of the spleen and activate donor antigen-reactive T cells. It is important to appreciate that one of the most important characteristics underlying the vigor of the T-cell response to MHC-mismatched allografts is the high frequency of T cells that can be activated to allogeneic class I and II MHC molecules [43]. Normally, the frequency of T cells that would react to a foreign peptide/selfMHC complex, such as that encountered during viral or bacterial infections, is on the order of 1 in every 105–106 cells. This low frequency is in part a result of the process of T cell development in the thymus. In order for thymocytes to be positively selected, mature to T cells, and emigrate from the thymus to join the T-cell repertoire in the peripheral lymphoid tissues the cells must be able to interact with peptide/MHC complexes presented by the thymic epithelium which delivers pro-survival signals during maturation. In contrast, T-cell receptors on developing thymocytes that have high affinity for self-peptide/MHC complexes receive signals from presenting bone marrow-derived cells in the thymic medulla resulting in the deletion of the thymocyte clone. Thus, all positively selected T cells express receptors possessing conserved molecular properties for binding to MHC, including self-MHC, molecules with a threshold affinity, so-called germline affinity [44, 45]. However, T cells that are positively selected by self-peptide/MHC complexes are not negatively selected by allogeneic MHC molecules and their inherent germline affinity for MHC. This results in precursor frequencies of CD4 and CD8 T cells with reactivities for allogeneic class II and class I MHC, respectively, on the order of 1 in every 10–103 cells, an increase in alloreactive T-cell frequency of several orders of magnitude when compared to the frequency of a T cell for a foreign peptide/ self-MHC complex. Recent studies have also indicated the pre­ sence of T cells with two T-cell receptors com­ posed of a single b chain paired with two different a chains (e.g., dual-specificity T cells) [46].

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The expression of two T-cell receptors on a ­single T cell is the result of the manner in which recombination of each of the T-cell receptor chains is regulated during thymocyte development. In mouse models, dual receptor T cells have been shown to play a prominent role in the development of graft-versus-host disease. Such dual receptor T cells are also likely to be present in the peripheral T-cell repertoire of humans, although their impact on the response to solid organ allografts remains to be tested. The high precursor frequency of T cells for allogeneic MHC molecules translates into a more robust response to the allograft interstitial dendritic cells that have migrated to the recipient spleen (Fig. 1.1). The presentation of allogeneic MHC molecules by these donor-derived antigenpresenting cells to reactive T cells is termed the direct pathway [47]. With the high precursor

frequency of recipient T cells for allogeneic MHC molecules, it is through this pathway that the most robust donor-specific T-cell response is generated. Graft antigens may also be processed and presented to T cells by recipient-derived dendritic cells through the indirect pathway [48]. Among the recipient cells infiltrating the graft in response to the inflammation induced by ischemia-reperfusion are monocytes. In this inflammatory environment these graft-infiltrating monocytes receive signals to mature and develop into dendritic cells [49]. During this maturation the recipient-derived dendritic cells acquire graft alloantigens, process them, and present allopeptide/self-MHC complexes to the T-cell repertoire in the spleen and other lymphoid tissues as well as to T cells infiltrating the graft. It is also important to note that it is through the indirect pathway that CD4 T cells interact

Fig.  1.1  Activation of donor-reactive T cells can occur through three different pathways of donor antigen presentation. (a) T cells activated through the direct alloantigen recognition pathway have reactivity directly for donor class I or II major histocompatibility complex (MHC) molecules that are presented by donor-derived antigenpresenting cells, such as dendritic cells that have emigrated from the graft to the recipient spleen; (b) T cells activated

through the indirect pathway have reactivity for donor antigens that are processed by recipient antigen-presenting cells and presented as donor peptide/class I or class II MHC complexes; and (c) T cells activated through the semi-direct alloantigen pathway have reactivity directly for donor class I or class II MHC molecules that have been acquired by recipient antigen-presenting cells from membrane vesicles released by donor cells

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with donor peptide/MHC complexes presented by B cells to provide help for the generation of antidonor antibodies during the initiation of acute humoral rejection [50, 51]. A third mechanism of donor alloantigen presentation is termed the semidirect pathway [52]. The activation of dendritic cells during inflammatory processes results in the release of portions of their membrane as small vesicles called exosomes. Such exosomes include many membrane molecules, such as MHC molecules as well as costimulatory molecules. These exosomes can be acquired by other dendritic cells and incorporated directly into the membrane by a poorly understood process. Recipientderived dendritic cells can acquire such exosomes from allograft-derived dendritic cells and present the intact allogeneic MHC molecules to the reactive T-cell repertoire. Recent studies support the activation of alloreactive T cells through the semidirect pathway, although the magnitude of the response generated and the impact of this response on graft outcome remains unclear [52]. In addition to naïve T-cell receptor engagement of MHC molecules (to provide signal 1), activation of T cells to undergo clonal proliferation and development into effector T cells requires the delivery of additional costimulatory signals (signals 2 and 3) (Fig. 1.2) [53]. Ligand stimulation of TLRs on dendritic cells induces upregulation of class I and II MHC molecules and the expression of costimulatory molecules, particularly B7-1/CD80 and B7-2/CD86. Thus, dendritic cells migrating from allografts into the recipient spleen are equipped not only to present high levels of donor antigen/MHC complexes to the reactive T-cell repertoire, but also the necessary costimulatory signals for the initiation of the T-cell response. The naïve T cells constitutively express CD28 the ligand for both CD80 and CD86 expressed by the presenting dendritic cells. During activation the T cells eventually express another ligand for CD80 and CD86, CTLA-4, which delivers negative signals to begin down-modulation of T-cell activation by transducing signals that inhibit the transcription of growth factors and slows down T-cell progression through the cell cycle [54]. It is worth noting that CTLA-4 has about a 20-fold higher

affinity than CD28 for binding to CD80 and CD86. Another costimulatory pair of molecules required for the activation of naïve CD4 T cells is the T-cell receptor signal mediated induction of CD154 on the T cell and its engagement with the constitutively expressed CD40 on the mature dendritic cell. As T cells become activated they become independent of CD28 delivered costimulatory signaling. However, as they differentiate into effector T cells the expression of those committed functions during peptide/MHC interactions in the periphery require the delivery of so-called “alternative” costimulatory pathway signals [55]. These costimulatory pathways include members of the immunoglobulin superfamily inducible T-cell costimulator (ICOS), and from the tumor necrosis factor receptor superfamily CD134 (OX40), CD27, CD137 (4-1BB), and CD30. In addition to the activation of effector T cells, specific members of these alternative costimulatory molecules are required for the activation and function of various memory T-cell populations. A considerable amount of effort has gone into the development of strategies to inhibit the activation of naïve donor-reactive T cells through the administration of costimulatory blockade such as CTLA-4 Ig or anti-CD154 mAb [56, 57]. The use of anti-CD154 mAb has caused some thromboembolic events and has been discontinued for the time being [58, 59]. Clinical strategies to block the B7-CD28 costimulation pathway are continuing with a new generation CTLA-4-Ig engineered molecule, Belatacept, that has been modified with two amino acid substitutions that increase its binding to CD86 in vivo [60].

The Functional Development of T Cells during Activation During antigen priming CD4+ T cells can develop into: (1) cells producing type 1 cytokines (e.g., Th1 cells); (2) cells producing type 2 cytokines (e.g., Th2 cells); (3) cells producing IL-17 and

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Fig. 1.2  Activation of naïve T cells during T-cell receptor engagement of peptide/major histocompatibility complex (MHC) complexes (signal 1) requires additional

costimulatory signals, including those delivered between receptor–ligand interactions such as CD28/CD80 or CD86 (signal 2) and soluble cytokine signals (signal 3)

IL-21 (Th17 cells); or (4) cells that express regulatory function [61–63]. Type 1 cytokines include IFNg and TNFb (also called lymphotoxin) that are critical components of cell-mediated immune responses, particularly to intracellular parasites and in mediating tissue injury during graft rejection. The prototypic type 1 cytokine IFNg induces a number of proinflammatory events, including stimulating increased class I and II MHC expression, stimulating production of intracellular molecules required for antigen-processing and presentation, and stimulating neutrophil and macrophage proinflammatory activities such as superoxide and nitric oxide (NO) production. Type 2 cytokines include IL-4, IL-5, and IL-13 and are critical components of allergic responses and immune responses to extracellular parasites. These activities include the stimulation of eosinophils and mast cells to release histamine and other molecules involved in allergic responses. IL-4 is also an important stimulus of B-cell growth and antibody class switching. IL-17 and IL-21 are important cytokines amplifying inflammation by inducing the recruitment and activation of innate immune cells, particularly neutrophils. Recent studies have also documented the critical role of IL-17 in the elicitation of autoimmune

disease. The production of IL-17 has been observed in grafts during rejection, although the role in rejection, if any, is poorly understood. Recent studies in lung transplant models and lung transplant patients implicate IL-17 as a component of an autoimmune response to collagen IV that is a sequelae to the initial alloimmune response, and this autoimmune response clearly exacerbates lung graft tissue injury in animal models and human lung transplant patients [64]. It is important to note the appearance of CD4+ T cells producing both IFN-g and IL-17 during the course of many autoimmune responses. The type 1 and 2 cytokines also influence the isotype of antibody produced by B cells during an immune response. In general, the type 1 cytokines direct antibody responses to those fixing complement and participating in cellmediated immune responses. In contrast, type 2 cytokines generally stimulate antibodies involved in allergic reactions. The most important factor influencing the development of CD4+ T cells to a particular functional phenotype is the cytokine environment present during T cell priming by the antigenpresenting cell (Fig. 1.3). This polarization can

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1  The Immune Response to Transplanted Organs Fig. 1.3  Following T-cell activation by cognate recognition of peptide/major histocompatibility complex (MHC) complexes and delivery of sufficient costimulatory signals (signals 2 and 3), differentiation of T cells to distinct functional effector phenotypes is promoted by the cytokines in the activation environment. These cytokines induce the activation of specific transcription factors to drive differentiation to the T cells to produce distinct patterns of cytokines

occur within 48 h of initial priming by dendritic cells within the lymphoid tissue. Production of the cytokine IL-12 by antigen-presenting dendritic cells is a critical factor in guiding CD4+ T-cell development to the type 1 cytokine producing phenotype. IL-12 is a 75  kDa disulfide linked dimer of p35 and p40 subunits produced by macrophages and dendritic cells. Induction of p40 expression and IL-12 heterodimer production by these cells is stimulated by microbial or endogenous stress products binding to TLR and/ or by CD40 ligation during interaction with T cells. The development of CD4 T cells to Th17 cells during antigen priming occurs in the presence of TGFb plus IL-6, IL-1b, or IL-21, cytokines that are present during the priming of donor antigen-reactive T cells in response to an allograft. In addition, the p19/p35 heterodimer, IL-23, stabilizes the phenotype and function of the IL-17/IL-21 producing cells. The presence of TGFb in the absence of IL-6 IL-1b or IL-21 promotes expression of FoxP3, a transcriptional activator required for the development of regulatory T cells. The skewed development of CD4 T cells to a specific functional phenotype occurs through the induced expression of specific transcription factors. IL-12 stimulates T-cell production of the transcription factor T-Bet, which promotes IFNg production during Th1 development, whereas IL-4 stimulates production of the transcription factors c-Maf and GATA-3 which promote IL-4

production. The combination of TGFb and IL-6 leads to the activation of RORgt, the transcription factor required for differentiation to Th17 cells. Other factors may also influence CD4+ T cell development, including the antigen dose and the type of costimulation provided during priming. Antigen priming of CD8+ T cells in vivo usually induces IFN-g producing cells and/or cells expressing cytotoxic function. In contrast to CD4+ T cells, CD8+ T cell development to IFN-g producing cells is not dependent on the presence of IL-12 during priming. It is now clear that many immune responses, including allograft rejection in the absence of IFN-g, involve the priming and activation of CD8 T cells producing IL-17.

T-Cell-Mediated Cytolysis of Target Cells The development of CD8+ T cells with cytolytic function is a critical component of many immune responses to tumors, intracellular parasites, and in graft rejection [65]. There are two major mechanisms utilized by CD8+ T cells to mediate cytolysis of cells expressing the target peptide/class I MHC complex (Fig.  1.4). During priming in the lymphoid tissue, CD8+ T cells may develop into cells containing intracellular granules ­containing perforin and a family of serine esterases, of which granzyme B is the prototype

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Fig. 1.4  T-cell-mediated cytolysis of target cells expressing the specific peptide/major histocompatibility complex (MHC) complex recognized by the T-cell receptor of the

cytolytic T cell. Two different mechanisms of delivering injury to the target cell can be used to kill it: Fas-FasL interactions or through production of perforin and granzyme B

enzyme [66, 67]. Following TCR engagement of the specific peptide/class I MHC complex on a target cell the CD8+ T cell becomes activated to release these granules toward the target cell. The perforin monomers polymerize in the membrane of the target cell forming a pore. Granzyme B then enters the target cell and enzymatically activates intracellular caspases, such as caspase 10, leading to the induction of apoptosis. The second major cytolytic mechanism is mediated through expression of Fas ligand (FasL), a member of the TNF family of proteins [68]. FasL is induced on T cells following TCR recognition of the specific peptide/MHC complex. Engagement of FasL with the Fas receptor expressed by the target cell transduces apoptotic signaling, resulting in target cell death. Although cytolytic function has been primarily attributed to CD8+ T cells during immune responses, there is considerable evidence for CD4+ T cell expression of perforin/granzyme B and FasL mediated lytic function, which may be an important component of immune responses to class II MHC bearing target cells [69, 70]. Expression of mRNA encoding perforin, granzyme B, and FasL is observed in the peripheral

blood and urine sediment during rejection of renal allografts and may be a reliable indicator of an ongoing acute rejection response.

Phenotypic Changes During TCR-Mediated Activation In addition to the development or acquisition of immune function, priming induces many phenotypic changes in T cells. The activation-induced expression of high-affinity receptors for growth factors is necessary for clonal expansion of reactive T cells and for their development to cells with immune effector function. During activation the majority of CD4+ and many CD8+ T cells express high levels of CD25, the a chain of the IL-2 receptor that confers high affinity binding of IL-2 [71]. This is the basis of the strategy to treat transplant recipients with an anti-CD25 monoclonal antibody as induction therapy. Once T cells have been primed to the specific peptide/MHC complex, it is essential that they be able to get to sites in the peripheral tissue where an immune response is needed. Activation

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induces two phenotypic changes that alter the migration pattern of the T cell. First, the expression of the lymph node homing receptor CD62L is down-regulated. This decreases the ability of the T cells to traffic into the lymph nodes and promotes T-cell circulation through the blood vessels [72, 73]. Second, expression of molecules that facilitate localization of antigenprimed T cells to inflammatory tissue sites is stimulated. T cells and other leukocytes travel through the circulation under extremely high shear force. The expression of these adhesion molecules is critical for mediating the arrest of the activated cells on the vascular endothelium under this shear force and facilitates T cell entry into the peripheral tissues [74, 75]. Complementary sets of receptors on leukocytes and endothelial cells help mediate the arrest of activated T cells and other leukocytes at inflammatory foci on the vascular endothelium such as allografts. These molecules include the selectins and their ligands, the addressins, and the integrins and their ligands, which are members of the Ig superfamily. The principal adhesion molecules upregulated during cellular activation of leukocytes are the integrins, a family of noncovalently associated dimers composed of a a chain and a common b chain [75]. Antigen-priming stimulates increased expression of CD11a on T cells and the CD11a then associates with CD18 to form the integrin LFA-1 (leukocyte functional antigen-1) or aLb2. T cell activation also induces expression of the integrin VLA-4 (very late activation antigen-4) or a4b1. In addition to their adhesive functions, integrin engagement may deliver costimulatory signals during T cell interaction with antigenpresenting cells. Integrins also bind to extracellular matrix proteins, and this engagement may augment T cell effector function during the elicitation of an immune response. Activation of ­leukocytes including T cells also upregulates expression of a proteoglycan binding receptor, CD44. Macrophages and neutrophils also express LFA-1 as well as CD11b in association with CD18 (aMb2), commonly called Mac-1. In a symmetric manner, inflammation activates endothelial cells to express ligands for

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integrins and other adhesion molecules. As discussed, proinflammatory cytokines produced during ischemia-reperfusion activate endothelial cells to express P- and E-selectins. During activation, endothelial cell expression of adhesion molecule members of the super Ig family is also upregulated. These molecules include intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. The localization of T cells and other leukocytes in response to inflammation on the vascular endothelium is a highly regulated process [75]. As the leukocytes circulate through the blood vessels, engagement of selectins tether the cells and slow their movement to rolling along the endothelial surface. After cell movement is slowed by selectin-mediated tethering, the binding of integrins to Ig superfamily counter receptors mediates the arrest of the T cells on the vascular endothelium. During this process, leukocyte engagement of cytokines produced by endothelial cells such as IL-8 triggers activation of the integrins and their binding to ligands on the endothelium. Binding of these cytokines through specific G protein-coupled receptors induces a conformational change to a high-affinitybinding molecule and mediates arrest of the leukocytes on the vascular endothelium. As leukocyte movement is arrested there is a considerable amount of “cross-talk” between the leukocyte and the endothelial cell. Antigen-primed T-cell recognition of specific peptide/MHC complexes on the endothelial cell surface stimulates the T  cells to express immune function such as cytokine production. T-cell production of IFN-g stimulates endothelial cells to upregulate expression of MHC molecules and produce chemoattractant cytokines, which amplifies T-cell recruitment and the immune response to localized areas in the endothelium. Following the arrest of the leukocyte on the vascular endothelium, the cell traverses the endothelial barrier into the peripheral tissue, a process termed diapedesis. Platelet/endothelial cell adhesion molecule-1 (PECAM, CD31) is expressed on endothelial cells and is concentrated at the cell junctions in the vessel [76, 77]. This molecule is also expressed on the surface of

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l­eukocytes. A critical property of PECAM-1 is the ability to bind to another PECAM-1 molecule, a process called homophilic adhesion. During diapedesis, PECAM-1 on the leukocyte binds to a PECAM-1 molecule at the endothelial cell junction and the leukocyte. These binding steps guide the leukocyte through the endothelium and the leukocyte enters the peripheral tissue. Cytokines with chemoattractant properties, chemokines, are also critical in mediating localization and trafficking of leukocytes to tissue sites during inflammation such as graft rejection [78]. Chemokines are a superfamily of small (<14 kDa) heparin-binding proteins. More than 50 chemokine proteins have been identified, and are grouped into four families based on a cysteine motif in the amino terminal area of the protein. The C-X-C chemokines, in which these cysteines are separated by a single amino acid, are attractant for neutrophils and include IL-8 and CXCL1. The CXC chemokines also include three members, CXCL9/Mig, CXCL10/IP-10, and CXCL11/ ITAC, which are chemoattractants for activated T cells. The C-C chemokines, in which the two cysteines are adjacent, are chemoattractant for a variety of leukocytes, including monocytes, eosinophils, T lymphocytes, NK cells, and dendritic cells. Representative CC chemokines include CCL2/MCP-1, CCL3/MIP-1a, and CCL5/RANTES. The C-X3-C family contains a single chemokine, fractalkine, which is on a membrane-bound mucin stalk and has adhesive and chemoattractant properties for IL-2 activated NK cells and CD8+ T cells. CX3CR1 also plays a critical role in the migration of monocytes into extravascular spaces and the seeding of peripheral tissues with interstitial dendritic cells. Chemokines play a major role in tissue pathology by directing receptor-bearing leukocytes to tissue sites of inflammation [78, 79]. Under appropriate stimulatory conditions such as inflammation, virtually all cells produce specific chemokines. Chemokine production is primarily regulated by the cytokine environment. TNFa and IL-1b induce many different cell types to produce neutrophil (e.g., IL-8 and CXCL1) and macrophage (e.g., CCL2) chemoattractants. IFNg

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stimulates many different cells to produce the T-cell attractants CXCL9, CXCL10, and CXCL11. The hepta-transmembrane spanning chemokine receptors are linked to G-coupled proteins, which transduce intracellular signals following ligand binding. Since chemokines bind to glycosaminoglycans on cell surfaces and to extracellular matrix proteins, leukocytes expressing the appropriate receptors most likely bind chemokines as solid phase, not as soluble, proteins during infiltration into inflammatory ­tissue sites, and this solid-phase binding may be required or augment intracellular signaling. Chemokine receptors are constitutively expressed by some leukocyte populations, but cellular activation is required for expression of chemokine receptors on other types of cells. The expression of chemokine receptors such as CXCR3, the ligand for CXCL9, CXCL10, and CXCL11, on T cells is induced by antigen priming and/or cytokines. There is considerable experimental and clinical evidence indicating that unique patterns of chemokine receptors are expressed by distinct populations of CD4+ T cells; those producing type 1 (e.g., Th1 cells) cytokines tend to express CXCR3 and CCR5, those producing type 2 (e.g., Th2 cells) cytokines tend to express CCR4, and those producing IL-17 express CCR6. As one would expect, during the elicitation of responses mediated by these different functional subsets of T cells, the respective chemokine ligands for the receptors are produced at the tissue site where the immune response is elicited and promote the trafficking of the antigenprimed T cells to the site. The critical role of chemokines during inflammatory processes has been clearly demonstrated in animal models where neutralization of specific chemokines results in inhibition of leukocyte infiltration and tissue pathology [79]. Chemokines are produced by all renal cell types and promote tubulointerstitial and glomerular pathology [133]. In addition to leukocyte recruitment, many chemokines stimulate other proinflammatory activities that amplify the function of target ­leukocyte populations in vivo and intensify ­tissue inflammation. The most important of these activities include the ability of specific

1  The Immune Response to Transplanted Organs

chemokines to trigger the arrest of monocytes and T lymphocytes rolling on endothelial surfaces under physiologic shear conditions in an adhesion molecule-dependent manner and the activation of integrins. The chemoattractant role of chemokines in directing leukocyte recruitment to inflammatory sites has generated a great deal of interest regarding the role of chemokines in directing donor antigen-primed T cells and other leukocytes into allografts during the rejection process [80, 81]. Reperfusion of ischemic tissues, including vascularized grafts, induces many different chemokines that promote the recruitment of neutrophils and macrophages. As donor-antigen specific T cells are primed in the spleen, the T cells are activated to express CXCR3 and CCR5. Ligands for these receptors, CXCL9 and CXCL10 for CXCR3, and CCL3 and CCL5 for CCR5, are produced in the grafts as T-cell infiltration begins and increases as the intensity of this infiltration increases. These T-cell chemoattractant chemokines are likely to promote the recruitment of these T cells into the graft. Experiments in rodent studies using either recipients with targeted deletions in the gene encoding CXCR3 or CCR5 or the use of chemokine blocking antibodies indicated some beneficial effect of the absence or neutralization of these chemokines or receptors. However, it is fairly well accepted that chemokine/chemokine receptor antagonism is not likely to be a very effective strategy for inhibiting cell infiltration into allografts and acute rejection. Nevertheless, the amplified production of chemokines during acute rejection, particularly CXCL9 and CXCL10, have indicated these chemokine are good biomarkers in blood or urine of ongoing rejection episodes, and several clinical studies are ongoing to validate these as markers of rejection [80, 81].

T-Cell-Mediated Rejection In the absence of immunosuppression the activation of T cells with specificity for donor antigens results in the development to effector T cells, and trafficking of these effector T cells to the

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allograft occurs, as has been detailed above [82–84]. During activation in response to donor- and recipient-derived dendritic cells, the majority of donor antigen-primed CD4+ and CD8+ T cells develop into IFN-g producing T cells expressing CXCR3 and CCR5. The activated CD8 T cells as well as CD4 T cells may also acquire the ability to express perforin/granzyme B-mediated cytolysis. These T cells leave the spleen and are recruited to the allografts, where they interact with and infiltrate the endothelial barrier into the graft parenchyma. Within the graft parenchyma, these T cells are activated to express immune functions, including cytokine production and expression of cytolytic functions resulting in the graft tissue injury that leads to necrosis and apoptosis of parenchymal cells and eventually graft failure. There is considerable redundancy in the effector T-cell arm of the response with regard to both the phenotype of the T cell (i.e., CD4 vs CD8) and the functions that they produce (i.e., cytokine- vs cytolytic-mediated injury). Experiments using rodent allograft models have demonstrated that removal of one type of T cell or effector mechanism from the recipient is typically compensated by the other T cell and mechanism. It is also important to note that the expression of these effector T-cell functions in the graft parenchyma is accompanied by the infiltration of macrophages and neutrophils in the tissue. These innate immune components are activated by cytokines produced by the T cells and cause a great deal of the tissue injury observed. Histopathologic features of this rejection include intense mononuclear cell infiltration throughout the graft tissue with obvious pockets of tissue necrosis and parenchymal cell apoptosis. In renal allografts this includes marked apoptosis of tubular epithelial cells that accompanies the decline in renal graft function. It is also worth noting that a great deal of current work is focused on the detection of inflammatory markers expressed during acute rejection as biomarkers to indicate the presence of an acute rejection episode. There is good evidence that the presence of high levels of mRNA or protein for granzyme B, perforin, FasL, and the IFN-g

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induced chemokine CXCL9 in the urine and/or blood may be good indicators of an ongoing rejection episode [85, 86].

Memory Cells During activation and clonal expansion of specific T cells, a portion of this T-cell pool develops into a population of memory T cells [87–89]. In contrast to the effector T cells developing during the course of a primary immune response, the memory T-cell population is long-lived, surviving after the inciting antigen is no longer present. Whether memory T cells originate from specific precursor cells or from a set of long-lived primary effector T cells is still not clear and is under investigation in many laboratories. Memory T cells have a lower threshold of activation requiring less antigen/MHC complex to become activated. Unlike naïve T cells, memory T cells do not require CD28-mediated costimulatory signals during activation. This has complicated the use of costimulatory blockade strategies to inhibit T-cell-mediated responses in sensitized transplant patients [93, 94]. Following re-encounter with the specific ligand memory T cells expand and develop to effector T cells more quickly than naïve T cells. It is also important to note that during differentiation to memory cells, some memory T cells express chemokine receptors such as CXCR3 and integrins directing their trafficking to peripheral tissues and are termed effector memory T cells so that they are situated for rapid response in the peripheral tissue. In contrast, central memory cells express receptors such as CCR7 and CD62L that promote their presence in secondary lymphoid tissues. Phenotypically, both effector and central memory T cells express a high molecular weight form of CD45, CD45RO, whereas naïve T cells express the low molecular weight form, CD45RA [90]. Similar to T cells, naïve B cell activation results in the development of a memory B cell pool [91]. Subsequent activation of memory B lymphocytes results in more rapid generation of antibody responses than during primary antibody

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responses. In contrast to memory T cells, the antibody produced by memory B cells is of increased affinity that is the result of somatic hypermutation of the V region genes of the memory B cell [92]. Furthermore, the isotypes of antibody produced by memory B cells (e.g., IgG and IgA) are different from those produced during primary B cell responses (e.g., primarily IgM with some IgG). The purpose of vaccination is to induce populations of memory T and B cells so that upon infection with the microbial agent, a protective immune response is quickly mounted and consists of a broader range of protective effector mechanisms. Successful control of T cells activated from naïve precursors upon allotransplantation through immunosuppression has revealed donor-reactive memory cells as a serious threat to transplanted organ [93, 94]. In humans, high frequencies of previously antigen-exposed T cells are present with an effector/memory phenotype that have donor-reactivity prior to transplantation. These memory T cells are resistant to many currently used graft-prolonging strategies, suggesting that an individual’s immune history can influence allograft outcome. Such memory cells can arise through multiple mechanisms. In addition to direct alloantigen exposure that would occur during blood transfusions or a previous transplant, alloreactive T cells may become activated by pathogens and environmental antigens [93–95]. This “heterologous immunity” may arise during infection from molecular resemblance between a microbial antigen/self-MHC complex and an allogeneic MHC molecule. In mice, infections with influenza virus, vesicular stomatitis virus and Leishmania major elicit pathogen-specific T cells with cross-reactivity to various MHC alleles. In mice and humans, CD4 and CD8 T-cell clones generated in response to EBV, HSV, and CMV recognize allogeneic HLA molecules. This cross-reactivity has important implications for several aspects of clinical transplantation. Attempts to induce allograft tolerance during ongoing infection are unsuccessful in recipients that harbor pathogen-induced memory CD8 T cells with donor-reactivity.

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1  The Immune Response to Transplanted Organs

Another source of alloreactive memory T cells is a consequence of T-lymphocyte proliferation that occurs in lymphopenic settings [96]. Several approaches used as induction therapy prior to solid organ transplantation result in partial depletion of recipient lymphocytes. Small numbers of naïve T cells rapidly expand in the lymphopenic host and repopulate peripheral lymphoid compartments. During this process termed homeostatic proliferation, proliferating cells acquire the surface phenotype as well as functional characteristics of memory cells, namely rapid and strong recall responses and decreased requirements for costimulation. A portion of these “memory-like” cells may arise from allospecific precursors and are potentially dangerous for the transplanted organ. Studies in mice have demonstrated that memory T cells induced by homeostatic proliferation interfere with tolerance induction by costimulatory blockade [97]. Compared to their naïve counterparts, memory T cells have decreased sensitivity to the effects of depletion with antibodies or immunotoxins. Studies in mice and non-human primates have demonstrated that memory T cells are not only resistant to antibody-mediated depletion but also undergo accelerated homeostatic proliferation so that the resulting T cell repertoire after such conditioning is skewed toward memory cells [96]. The aftermath of lymphoablative therapies has also been assessed in human transplant patients. As suggested by animal studies, T cells with an effector memory phenotype are prevalent in kidney transplant recipients after aggressive depletion with anti-CD52 Ab (alemtuzumab) or rabbit ATG [98]. It remains unclear whether the increase in memory T-cell numbers after lymphoablation is due to the expansion of nondepleted preexisting memory cells or due to conversion of naïve T cells during the course of homeostatic proliferation. A study performed on a group of lung transplant patients treated with alemtuzumab demonstrated the persistence of CMV-specific memory T cells [99]. Recent studies in rodent models have provided further mechanistic insights into how endogenous donor-reactive memory T cells mediate graft tissue damage. The general notion that

“memory T cells expand after re-exposure to the antigen, migrate into the graft and cause tissue injury” has been reconsidered. The most important function of memory CD4 T cells appears to be providing help for other components of the alloimmune response, including CD8 T lymphocytes and the production of donor-reactive alloantibody by B cells [100]. Memory CD8 T cells infiltrate allografts within hours after transplantation, proliferate, and facilitate allograft inflammation through upregulation of chemokines and adhesion molecules. This early inflammation is a critical step in the recruitment of neutrophils, macrophages, and recently activated effector T cells into the graft.

B Cells and Antibody in Transplant Rejection The understanding of B cells and antibodies in transplants began with hyperacute rejection. In the 15 years after 1954, when the first successful renal transplant was performed in humans between identical twins, hyperacute rejection was a frequent and devastating outcome. Between 1966 and 1969, hyperacute rejection was defined clinically and pathologically [101, 102]. Antibodies were determined to be the cause of hyperacute rejection and a test was devised to detect the antibodies [103]. Hyperacute rejection occurs when a recipient has a high titer of antibodies to the prospective organ donor. Antibodies to antigens encoded by the major histocompatibility complex (MHC antigens) or the major blood group antigens (ABO) are the most common cause of hyperacute rejection. High titers of antibodies to MHC antigens result from previous transplants, transfusions or pregnancies. In contrast, antibodies to blood groups A and B develop over the first year of life in response to crossreactive carbohydrate antigens on natural gut flora [104]. Consequently, these antibodies to blood group antigens are often referred to as “natural” antibodies. Exposure to viral or other pathogens may result in low levels of B cell immunity to MHC antigens; a process referred to

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as heterologous immunity. When an organ is transplanted to a patient with high levels of antibodies to MHC or ABO antigens, which are expressed on the vascular endothelium, rejection ensues within minutes to hours as the result of an escalating series of reactions. Antibody initiates the rejection by binding to endothelial cells and activating complement. Activation of the complement cascade results in recruitment of neutrophils and injury of endothelial cells. Finally, disruption of vascular integrity causes edema, hemorrhage, and activation of the coagulation system. In addition to widespread neutrophil infiltrates and fibrin deposits that are evident on routine histology, antibodies, and complement can be readily demonstrated throughout the vasculature by immunohistology. After the pathological link was established between antibodies and hyperacute rejection, a method was published in 1969 to test for antibodies by incubating serum from the prospective recipient with peripheral blood leukocytes from the donor [103]. The universal institution of this test (called cross-matching) has practically eliminated hyperacute rejection of allografts. Interest in B cells and antibody responses to transplants has gone through phases since the institution of cross-matching. Experimental models that were often too reductionist to be clinically relevant dissuaded the majority of basic immunologists from investigating B cells and antibodies in allografts. Most influential were early experimental models, in which either serum or leukocytes were transferred from sensitized mice to naïve transplant recipients. These models demonstrated that lymphocytes could cause rejection in the absence of antibodies. Appreciation of the potential proinflammatory effects of antibodies in transplants was eroded further by experiments demonstrating that passive transfer of antibodies often prolonged graft survival in rats and mice. Clinically, interest in B cells has been coupled with improvements in techniques to detect antibodies in the serum (see Chap. 2). For many years these data were limited by the lack of support for serological testing after transplantation and the insensitivity of histological assessment

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of diagnostic biopsies. Beginning in 1990, Halloran and colleagues published a series of papers describing a minority of rejections that did not have the normal features of cell-mediated acute rejection [105, 106]. Immunohistology for antibodies and split products of C3, the central complement component, were not diagnostically helpful. However, low levels of donor specific antibodies could be detected in serum samples and eluted from some of the rejected organs. Marginated neutrophils in the peritubular capillaries emerged as a key feature in these cases. Interest in antibody-mediate acute rejection quickly expanded with the recognition of C4d as a pathological marker of complement activation in transplants. C4d is a product of the initial steps of the classical and lectin pathways of complement activation (Fig. 1.5). The term complement cascade is used to describe the series of enzymatic steps in which successive components are cleaved into biologically active split products. As a result, a single C1 molecule bound to a pair of antibodies can cleave many C4 molecules. C4b, the larger split product of C4, has the unusual capacity of forming a covalent bond with nearby proteins or carbohydrates. When C4b binds to endothelial cells, it is quickly cleaved to the smaller biologically inactive C4d. This molecule serves as a very practical marker of complement activation (see Fig. 1.5). C4d is easy to detect because it is deposited in larger quantities than antibody and it has a longer halflife. The use of reagents specific for the cryptic epitopes of C4d that are exposed by the cleavage process increases the specificity of the test by eliminating background staining of unactivated C4. As a result, deposition of C4d in renal or cardiac biopsies has been incorporated into the diagnostic criteria for antibody-mediated acute rejection [107–111]. Supporting data for antibody-mediated rejection include detection of antibodies in the serum with specificity for donor antigens, and infiltrates of cells with receptors for antibody and complement, including neutrophils, monocytes, or macrophages in the transplant biopsy. In addition to activation of complement, antibodies can modulate inflammatory responses in

1  The Immune Response to Transplanted Organs

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Fig. 1.5  Diagram of major antibody initiated processes, including antigen cross-linking, Fc receptor interaction, and complement activation. Antigen cross-linking causes exocytosis of von Willebrand factor (vWf), expression of adhesion molecules (e.g., P-selectin), release of growth factors, upregulation of receptors, and cell proliferation. Leukocytes with Fc receptors (e.g., neutrophils and macrophages) can be stimulated by antibodies bound to antigen. The strength of Fc receptor interactions with IgG is

dependent on the carbohydrate side chains (yellow hexagons) on the antibodies. The carbohydrate side chains on IgG also interact with the first components of the classical and lectin complement pathways. Activation of the complete complement cascade results in assembly of the membrane attack complex (C5b–C9). The many intermediate split products produced in the complement cascade also expand the effects of antibodies in part through complement receptors (CR) on leukocytes

transplants by direct activation of vascular endothelial and smooth muscle cells as a consequence of cross-linking MHC antigens [112, 113] and by activation of neutrophils, macrophages, or natural killer cells through Fc receptors [114, 115]. Undoubtedly, these mechanisms do not occur independently in vivo, but rather interact to modulate inflammation. Extensive studies by Reed and coworkers have demonstrated that even in the absence of leukocytes and complement, binding of antibodies to MHC class I antigens on endothelial cells or smooth muscle cells causes release of growth factors, upregulation of receptors, and cell proliferation [113]. Importantly, these proliferative responses were blocked by the mTOR inhibitor rapamycin. Lowenstein and colleagues have demonstrated that antibody-mediated cross-linking of MHC class I antigens on endothelial cells can also induce exocytosis of von Willebrand factor

(vWf) and P-selectin from Weibel-Palade storage granules [112]. Although most of these experiments were performed on isolated endothelial cells in vitro without complement, purified components of the terminal membrane attack complex (MAC) of complement can induce endothelial cell proliferation [116] and exocytosis of vWf and P-selectin [117]. In vivo, noncomplement activating antibodies induce the exocytosis of vWf and P-selectin followed by adhesion of platelets and neutrophils to capillaries in skin grafts, but complement activating antibodies have a more prolonged effect. Similarly, antibodies alone can cause endothelial cells to produce cytokines such as IL-6 and MCP-1, but increased production of these cytokines occurs when antibodies also activate macrophages through Fc receptors [114]. These cytokine responses are likely enhanced further in transplanted organs by complement because

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macrophages express an array of receptors for complement split products. During immune responses, complement and antibody participate in feedback loops to regulate antibody production by B cells. Complement activation by classical (through C1), lectin (through MBL), or alternative (through C3 itself) pathways all converge on C3 (see Fig.  1.5). Cleavage of C3 results in a final split product, C3d. The receptor for C3d (CR2 or CD21) functions as a coreceptor for the membrane Ig (mIg) antigen receptor on B cells. C3d bound to antigen can increase the antibody response of B cells by lowering the threshold of concentration or affinity for an antigen to cross-link mIg. Antibodies bound to antigens can deliver a counterbalancing signal to B cells through the FcgRIIB for IgG. This receptor delivers an inhibitory signal to B cells and functions as a negative feedback for continued antibody production. Low levels of antibody or repeated cycles of antibody production may contribute to the vascular pathology that is a common manifestation of chronic rejection in all types of organ transplants. This is an attractive concept because antibodies and complement cause vasculocentric pathology. Moreover many of the cells (macrophages, platelets, endothelial cells, smooth muscle cells, and fibroblasts) and growth factors (basic fibroblast growth factor, plateletderived growth factor) associated with vasculopathy in transplants are stimulated by antibodies and complement [118]. However, direct evidence for causation is limited and there are experimental models of graft vasculopathy that develop in the absence of demonstrable antibody responses. At a minimum, antibodies and complement are probably contributory factors in chronic rejection. Knowledge of the mechanisms of anti­­bodymediated immune responses already has begun to provide therapeutic interventions. Monoclonal antibodies to C5, for example, eculizumab, have been used to inhibit antibody-mediated rejection [119]. Preventing the cleavage of C5 into C5a and C5b blocks two proinflammatory links.  C5a chemoattracts neutrophils and ­macrophages. It  also activates endothelial cells as well as

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n­ eutrophils and macrophages. C5b initiates the formation of MAC. Therefore, monoclonal antibodies to C5 can inhibit leukocyte and endothelial cell activation. The finding that MHC cross-linking by antibody involves the mTOR pathway has obvious implications for the use of rapamycin for immunosuppression. Understanding feedback regulation through FcgRIIB on B cells may lead to improvements in formulations of intravenous immunoglobulin (IVIg) to inhibit alloantibody production. Ravetch and colleagues have demonstrated that the affinity of Ig binding to FcgRIIB is dependent on the carbohydrate side chain on the IgG [120]. Therefore, calculated modifications of the carbohydrate side chain may increase the inhibitory effect of IVIg on B cells. Recent therapeutic strategies in clinical transplantation have also directly targeted the B cells themselves. These strategies include antibodies specific for CD20, Rituximab, which effectively deplete B cells and are used in transplant patients with suspected antibody-mediated rejection. It is important to note, however, that antibodyproducing plasma cells that have differentiated from activated B cells do not express CD20 and are not depleted by this antibody. A new generation of antibodies and engineered molecules that neutralize B-cell activating factor (BAFF) and A proliferation inducing ligand (APRIL), factors required for differentiation of B cells into plasma cells and survival of plasma cells and germinal center B cells, is being introduced into clinical transplant studies to treat antibody-mediated rejection [121, 122]. These molecules include an anti-BAFF monoclonal antibody and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)-Fc. Whereas BAFF-R only binds BAFF, TACI-Fc binds both BAFF and APRIL and is likely to be the more effective reagent in transplant patients experience antibody-mediated rejection. Alloantibodies do not always initiate inflammatory responses. At various times, the beneficial effects of alloantibodies have been studied in mouse and rat models of transplantation. These waves of enthusiasm have been initiated by both experimental and clinical observations.

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1  The Immune Response to Transplanted Organs

Over 50 years ago, alloantibodies were found to enhance the growth of allogeneic tumors in mice [123]. This phenomenon of enhancement was translated to experiments in tissue transplants in mice and even stimulated discussions of a clinical trial with F(ab¢)2 antibodies [124]. More recently, interest in beneficial or at least harmless antibodies has reemerged in the context of a phenomenon called accommodation. The term accommodation was introduced to describe the good function and survival of major blood group incompatible renal transplants in patients with circulating antibodies to the donor blood group [125]. These antibodies apparently bind to the target antigen on the vascular endothelium of the graft, as evidenced by the deposition of the complement split product C4d. When circulating antibodies and C4d deposition are not associated with margination of neutrophils or macrophages in the vessels, and there is no evidence of endothelial injury or graft dysfunction, then the graft is described as accommodated. Accommodation has been reported in patients with donor specific antibodies to HLA, but this is much less frequent and less stable than in patients with donor-specific antibodies to blood groups A or B [126]. Several mechanisms for accommodation have been explored, including the increased expression of complement regulatory pathways [127]. It is not yet established whether any aspect of accommodation is associated with improved graft outcomes. Another function of B cells that may benefit transplants is the secretion of cytokines with anti-inflammatory activity. B cells that secrete IL-10 and inhibit autoimmunity have been demonstrated in mice. In analogy to T-cell nomenclature, these cells have been termed B regulatory cells or B regs [128]. The potential role of B regs has not been examined in organ transplantation.

The Problem of Chronic Rejection Currently used immunosuppression strategies have decreased the incidence of acute graft rejection to low levels. One of the major causes of

graft loss in the current era is the development of so-called “chronic rejection” or the development of graft interstitial fibrosis and occlusive ­vasculopathy [129]. This pathology is induced by both donor antigen- independent and antigendependent mechanisms that mediate graft injury. Normally the fibrosis and vasculopathy develop slowly over time posttransplant, but evidence of their initiation may often be detected within weeks to months posttransplant. Many factors contribute to the development of this pathology including longer ischemic times and number of acute cellular- and/or antibodymediated rejection episodes [129–131], It is clear that donor-specific mechanisms are required to mediate the graft injury and initiate the remodeling program that results in the development of interstitial fibrosis and occlusive ­vasculopathy, as this pathology rarely occurs in syngeneic grafts in animal models. However, identification of the immune triggers, as well as the mechanisms, leading to the initiation of fibrosis and of the vasculopathy remain very poorly understood and stand as one of the ­biggest scientific challenges in transplantation biology. Many current studies have identified the production of the profibrogenic factors TGFb and its downstream mediator connective tissue growth factor (CGTF) as mediators of the interstitial fibrosis [132]. The activity of these factors results in the deposition of collagen and other extracellular matrix components in the graft interstitium and the inability of the tissue to remove or replace these remodeling matrices. Similarly, the factors and mechanisms inducing the proliferation of vascular smooth muscle cells to form the neointima that leads to the occlusive vasculopathy remain poorly understood. Currently there is no therapy to retard or stop the progression of this pathology and the only eventual recourse when this injury leads to graft failure is retransplantation.

Summary Allografts are subjected to multiple directions of attack. Although most of this attack is directed

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through the donor-specific arm, multiple innate donor antigen nonspecific mechanisms contribute to graft tissue injury early after graft reperfusion and have an established detrimental effect on graft outcome. In addition, these innate mechanisms function in conjunction with the donorspecific T-cell and antibody-mediated effector functions to impose acute and chronic injury in the graft. The donor-specific arm is rapid and intense and can vary with respect to the multiple effector functions that can mediate tissue injury by distinct populations of T cells and antibodies. A concerted effort continues to design safe strategies to prevent or neutralize these lymphocyte effector functions to improve graft outcome. It is sufficient to note that there have been some recent successes in the development and implementation of some strategies, even going to the point of being able to withdraw recipients completely from immunosuppression in a very limited set of patients. Such results have proved that this goal can be achieved, and the search continues to find appropriate strategies that can be implemented to achieve immunosuppression free transplantation in all patients.

References 1. Bonventre JV, Zuk A. Ischemic renal failure: an inflammatory disease? Kidney Int 2004;66:480–485. 2. De Groot H, Rauen U. Ischemia-reperfusion injury: processes in pathogenetic networks. A review. Transplant Proc 2007;39:481–484. 3. Rabb H, O’Meara YM, Maderna P, Coleman P, Brady HR. Leukocytes, cell adhesion molecules and ischemic acute renal failure. Kidney Int 1997;51:1463–1468. 4. Koo DD, Welsh KI, Roake JA, Morris PJ, Fuggle SV. Ischemia/reperfusion injury in human kidney transplantation: an immunohistochemical analysis of changes after reperfusion. Am J Pathol 1998;153:557–576. 5. Land W, Messmer K. The impact of ischemia/reperfusion injury on specific and non-specific, early and late chronic events after organ transplantation. Transplant Rev 1996;10:236–253. 6. Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 1997;63:968–974. 7. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. NEJM 1995;333:333–336.

W.M. Baldwin et al. 8. Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 2006;17:1503–1520. 9. Linas SL, Whittenburg D, Parsons PE, Repine JE. Ischemia increases neutrophil retention and worsens acute renal failure: role of oxygen metabolites and ICAM-1. Kidney Int 1995;48:1584–1591. 10. Miura M, Fu X, Zhang Q-W, Remick DG, Fairchild RL. Neutralization of Groa and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury. Am J Pathol 2001;159:2137–2145. 11. Raab H, Mendiola CC, Saba SR, et al. Antibodies to ICAM-1 protect kidneys in severe ischemic reperfusion injury. Biochem Biophys Res Commun 1995;211:67–73. 12. Takada M, Nadeau KC, Shaw GD, Marquette KA, Tilney NL. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. J Clin Invest 1997;99:2682–2690. 13. Heinzelmann M, Mercer JM, Passmore JC. Neutrophils and renal failure. Am J Kidney Dis 1999;34:384–399. 14. Welbourn CRB, Goldman G, Paterson IS, Valeri CR, Shepro D, Hechtman HB. Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br J Surg 1991;78:651–655. 15. Baggiolini M, Walz A, Kunkel SL. Neutrophilactivating peptide-1/interleukin-8, a novel cytokine that activates neutrophils. J Clin Invest 1989;84:1045–1049. 16. Jaeschke H, Smith CW. Mechanisms of neutrophil-induced parenchymal cell injury. J Leuk Biol 1997;61:647–653. 17. Colletti LM, Kunkel SL, Walz A, et  al. Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat. The role of epithelial neutrophil activating protein. J Clin Invest 1995;95:134–141. 18. Cugini D, Azzollini N, Gagliardini E, et al. Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion injury. Kidney Int 2005;67:1753–1761. 19. Klausner JM, Paterson IS, Goldman G, et  al. Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol 1989;256:F794–F802. 20. Seekamp A, Mulligan MS, Till GO, Ward PA. Requirements for neutrophil products and L-arginine in ischemia-reperfusion injury. Am J Pathol 1993;142:1217–1226. 21. Day Y-J, Huang L, Ye H, Li L, Linden J, Okusa MD. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-g. J Immunol 2006;176:3108–3114. 22. Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int 2004;66:486–491. 23. Gueler F, Park J-K, Rong S, et al. Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages. Am J Pathol 2007;170:1192–1199. 24. Savill J, Dransfield I, Gregory C, Haaslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2002;2:965–975.

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19 41. Randolph GJ, Ochando J, Partida-Sanchez S. Migration of dendritic cells subsets and their precursors. Annu Rev Immunol 2008;26:293–316. 42. Sozzani S. Dendritic cell trafficking: more than just chemokines. Cytokine Growth Factor Rev 2005;16:581–592. 43. Felix NJ, Allen PM. Specificity of T-cell alloreactivity. Nat Rev Immunol 2007;7:942–953. 44. Felix NJ, Donermeyer DL, Horvath S, et  al. Allreactive T cells respond specifically to multiple distinct peptide-MHC complexes. Nat Immunol 2007;8:388–397. 45. Huseby ES, White J, Crawford F, et al. How the T cell repertoire becomes peptide and MHC specific. Cell 2005;122:247–260. 46. Morris GP, Allen PM. Highly alloreactive dual TCR T cells play a dominant role in graft-versus-host disease. J Immunol 2009;182:6639–6643. 47. Rogers NJ, Lechler RI. Allorecognition. Am J Transplant 2001;1:97–102. 48. Auchincloss H Jr, Lee R, Shea S, Markowitz JS, Grusby MJ, Glimcher LH. The role of “indirect” recognition in initiating rejection of skin grafts from major histocompatibility complex class II-deficient mice. Proc Natl Acad Sci USA 1993;90:3373–3377. 49. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767–811. 50. Sauve D, Baratin M, Leduc C, Bonin K, Daniel C. Alloantibody production is regulated by CD4+ T cells’ alloreactive pathway, rather than precursor frequency or Th1/Th2 differentiation. Am J Transplant 2004;4:1237–1245. 51. Taylor AL, Neugs SL, Negus M, Bolton EM, Bradley JA, Pettigrew GJ. Pathways of helper CD4 T cell allorecognition in generating alloantibody and CD8 T cell alloimmunity. Transplantation 2007;83:931–937. 52. Herrera OB, Golshayan D, Tibbott R, et al. A novel pathway of alloantigen presentation by dendritic cells. J Immunol 2004;173:4828–4837. 53. Sharpe AH, Abbas A. T-cell costimulation-biology, therapeutic potential, and challenges. NEJM 2006;355:973–975. 54. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev 2008;224:141–165. 55. Li XC, Rothstein DM, Sayegh MH. Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 2009;229:271–293. 56. Ford ML, Larsen CP. Translating costimulation blockade to the clinic: lessons learned from three pathways. Immunol Rev 2009;229:294–306. 57. Kishimoto K, Dong VM, Sayegh MH. The role of costimulatory molecules as targets for new immunosuppressives in transplantation. Curr Opin Urol 2000;10:57–62. 58. Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB. Thromoembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000;6:114.

20 59. Weaver TA, Charafeddine AH, Kirk AD. Costimulation blockade: towards clinical application. Front Biosci 2008;13:2120–2139. 60. Emamaullee J, Toso C, Merani S, Shapiro AMJ. Costimulatory blockade with belatacept in clinical and experimental transplantation-a review. Exp Opin Biol Ther 2009;9:787–796. 61. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol 2009;27:485–517. 62. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7:145–173. 63. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4 T cells. Science 2010;327:1098–1102. 64. Burlingham WJ, Love RB, Jankowska-Gan E, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest 2007;117:3498–3506. 65. Williams MA, Bevan MJ. Effector and memory CTL differentiation. Annu Rev Immunol 2007;25:171–192. 66. Shi L, Mai S, Israels S, Browne K, Trapani JA, Greenberg AH. Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and BraB nuclear localization. J Exp Med 1997;185:855–866. 67. Chowdhury D, Lieberman J. Death by a thousand cutes: granzyme pathways of programmed cell death. Annu Rev Immunol 2008;26:389–420. 68. Sabelko-Downes KA, Russell JH. The role of Fas ligand in vivo as a cause and regulator of pathogenesis. Curr Opin Immunol 2000;12:330–335. 69. Ju ST, Cui H, Panka DJ, Ettinger R, MarshakRothstein A. Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells. Proc Natl Acad Sci USA 1994;91:4185–4189. 70. Williams NS, Engelhard VH. Identification of a CD4+ CTL that utilizes a perforin- rather than a Fas ligand-dependent cytotoxic mechanism. J Immunol 1996;156:153–159. 71. Nelson BH, Willerford DM. Biology of the interleukin2 receptor. Adv Immunol 1998;70:1–81. 72. Bradley LM, Watson SR, Swain SL. Entry of naive CD4 T cells into peripheral lymph nodes requires L-selectin. J Exp Med 1994;180:2401–2406. 73. Rosen SD. Ligands for L-selectin: homing, inflammation and beyond. Annu Rev Immunol 2004;22:129–156. 74. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–314. 75. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007;7:678–689. 76. Muller WA, Randolph GJ. Migration of leukocytes across endothelium and beyond: molecules involved

W.M. Baldwin et al. in the transmigration and fate of monocytes. J Leuk Biol 1999;66:698–704. 77. Nourshargh S, Krombach F, Dejana F. The role of JAM-A and PECAM-1 in modulating leukocyte infiltration in inflamed and ischemic tissues. J Leuk Biol 2006;80:714–718. 78. Luster AD. Chemokines-chemotactic cytokines that mediate inflammation. NEJM 1998;338:436–445. 79. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. NEJM 2006;354:610–621. 80. El-Sawy T, Fahmy NM, Fairchild RL. Chemokines: directing leukocyte infiltration into allografts. Curr Opin Immunol 2002;14:562–568. 81. Hancock WW, Wang I, Ye O, Han R, Lee I. Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Curr Opin Immunol 2003;15:479–486. 82. Hall BM, Dorsch SE. Cells mediating allograft rejection. Immunol Rev 1984;77:31–59. 83. Hidalgo LG, Halloran PF. Role of IFN-gamma in allograft rejection. Crit Rev Immunol 2002;22:317–349. 84. Heeger PS. T-cell allorecognition and transplant rejection: a summary and update. Am J Transplant 2003;3:525–533. 85. Li B, Hartono C, DIng R, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. NEJM 2001;344:947–954. 86. Hu H, Swun J, Alzenstein BD, Knechtle SJ. Noninvasive detection of acute and chronic injuries in human renal transplant by elevation of multiple cytokines/chemokines in urine. Transplantation 2009;87:1814–1820. 87. Lefrancois L, Marzo AL. The descent of memory T-cell subsets. Nat Rev Immunol 2006;6:618–623. 88. Lefrancois L. Development, trafficking, and function of memory T-cell subsets. Immunol Rev 2006;11:93–103. 89. Ahmed R, Bevan ML, Reiner SL, Fearon DT. The precursors of memory: models and controversies. Nat Rev Immunol 2009;9:662–668. 90. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation and maintenance. Annu Rev Immunol 2004;22:745–763. 91. McHeyzer-Williams LJ, McHeyzer-Williams MG. Antigen-specific memory B cell development. Annu Rev Immunol 2005;23:487–513. 92. Peled JU, Kuang FL, Iglesias-Ussel MD, et al. The biochemistry of somatic hypermutation. Annu Rev Immunol 2008;26:481–511. 93. Ford ML, Kirk AD, Larsen CP. Donor-reactive T-cell stimulation history and precursor frequency: barriers to tolerance induction. Transplantation 2009;87:569–574. 94. Valujskikh A, Lakkis F. In remembrance of things past: memory T cells and transplant rejection. Immunol Rev 2003;196:65–74.

1  The Immune Response to Transplanted Organs 95. Sellin LK, Brehm MA, Naurov YN, et al. Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity. Immunol Rev 2006;211:164–181. 96. van Leeuwen EM, Sprent J, Surh CD. Generation and maintenance of memory CD4+ T cells. Curr Opin Immunol 2009;21:167–172. 97. Wu Z, Bensinger SJ, Zhang J, et  al. Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med 2003;10:87–92. 98. Pearl JP, Parris J, Hale DA, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 2005;5:465–474. 99. Zeevi A, Husain S, Spichty KJ, et al. Recovery of functional memory T cells in lung transplant recipients following induction therapy with alemtuzumab. Am J Transplant 2007;7:471–475. 100. Chen Y, Heeger PS, Valujskikh A. In vivo helper functions of alloreactive memory CD4+ T cells remain intact despite donor-specific transfusion and anti-CD40 ligand therapy. J Immunol 2004;172:5456–5466. 101. Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts associated with pre-existing humoral antibodies against donor cells. Lancet 1966;2:662. 102. Williams GM, Hume DH, Hudson J, R. P., Morris P, Kano K, Milgrom F. “Hyperacute” renal-homograft rejection in man. NEJM 1968;279:611. 103. Patel R, Terasaki P. Significance of the positive crossmatch test in kidney transplantation. NEJM 1969;280:735–739. 104. Fan X, Ang A, Pollock-Barziv SM, et  al. Donorspecific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med 2004; 10:1227–1233. 105. Halloran PF, Schlaut J, Solez K, Srinivasa NS. The significance of the anti-class I antibody response. II. Clinical and pathologic features of renal transplants with anti-class I-like antibody. Transplantation 1992;53:550–555. 106. Halloran PF, Wadgymer A, Ritchie S, Falk J, Solez K, Srinivasa NS. The significance of the anticlass I antibody response. I. Clinical and pathologic features of anti-class I mediated rejection. Transplantation 1990;49:85–91. 107. Feucht HE, Felber E, Gokel MJ, et  al. Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection. Clin Exp Immunol 1991;86:464–470. 108. Collins AB, Schneeberger EE, Pascual MA, et  al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999;10:2208–2214. 109. Feucht HE, Mihatsch MJ. Diagnostic value of C4d in renal biopsies. Curr Opin Nephrol Hypertens 2005;14:592–598. 110. Racusen LC, Colvin RB, Solez K, et al. Antibodymediated rejection criteria-an addition to the Banff

21 ’97 classification of renal allograft rejection. Am J Transplant 2003;3:708–714. 111. Racusen LC, Haas M. Antibody-mediated rejection in renal allografts: lessons from pathology. Clin J Am Soc Nephrol 2006;1:415–420. 112. Yamakuchi M, Kirkiles-Smith NC, Ferlito M, et al. Antibody to human leukocyte antigen triggers endothelial exocytosis. Proc Natl Acad Sci USA 104;2007:1301–1306. 113. Zhang X, Reed EF. Effect of antibodies on endothelium. Am J Transplant 2009;9:2459–2465. 114. Lee C-Y, Reynolds M, Garyu J, Baldwin WM, III, Wasowska BA. The involvement of FcR mechanisms in antibody-mediated rejection. Transplantation 2007;84:1324–1334. 115. Millington TM, Madsen JC. Innate immunity in heart transplantation. Curr Opin Organ Transplant 2009;14:571–576. 116. Benzaquen LR, Nicholson-Weller A, Halperin JA. Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J Exp Med 1994;179:985–992. 117. Hattori R, Hamilton KK, McEver RP, Sims PJ. Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface. J Biol Chem 1989;264:9053–9060. 118. Wehner J, Morrell CN, Reynolds T, Rodriguez ER, Baldwin WM 3  rd. Antibody and complement in transplant vasculopathy. Circ Res 2007;100:191–203. 119. Locke JE, Magro CM, Singer AL, et al. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am J Transplant 2008;9:231–235. 120. Nimmerjahn R, Anthony RM, Ravetch JV. Agalctosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc Natl Acad Sci USA 2007;104:8433–8437. 121. Benson MJ, Dillon SR, Castigli E, et al. The dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol 2008;180:3655–3659. 122. O’Connor BP, Raman VS, Erickson LD, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 2004;199:91–98. 123. Kaliss N, Sinclair NR, Cantrell JL. Immunological enhancement of a murine tumor allograft by passive alloantibody IgG and F(ab¢)2. Eur. J Immunol 1976;6:38–42. 124. Batchelor JR. The riddle of kidney graft enhancement. Transplantation 1978;26:139–141. 125. Platt JL. C4d and the fate of organ allografts. J Am Soc Nephrol 2002;13:2417–2419. 126. Haas M, Rahman MH, Kraus ES, et al. C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings. Am J Transplant 2006;6:1829–1840.

22 1 27. Brodsky SV, Nadasdy GM, Pelletier R, et  al. Expression of the decay-accelerating factor (CD55) in renal transplants-a possible prediction marker of allograft survival. Transplantation 2009;27:457–464. 128. Fillatreau S, Gray D, Anderton SM. Not always the bad guys: B cells as regulators of autoimmune pathology. Nat Rev Immunol 2008;8:391–397. 129. Chapman JR, O’Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol 2005;16:3015–3026.

W.M. Baldwin et al. 130. Waaga AM, Gasser M, Laskowski I, Tilney NL. Mechanisms of chronic rejection. Curr Opin Immunol 2000;12:517–521. 131. Weiss MJ, Madsen JC, Rosengard BR, Allan JS. Mechanisms of chronic rejection in cardiothoracic transplantation. Front Bioschi 2008;13:1290–2988. 132. Mannon RB. Therapeutic targets in the treatment of allograft fibrosis. Am J Transplant 2006;6:867–875. 133. Segerer, S, Nelson PJ, Schlondorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J Am Soc Nephrol 2000;11:152–176.

Chapter 2

The Histocompatibility Laboratory in Clinical Transplantation Diane J. Pidwell and Peter N. Lalli

Keywords  Human leukocyte antigen (HLA) • Cross-matching • Tissue typing • Alloantibody • Sensitization

Our History Histocompatibility testing in humans began in the 1950s with the discovery by Dausset, Payne, and others of leukoagglutinins in the serum of multiply transfused patients and multiparous women [1]. The science and clinical practice of histocompatibility testing, however, grew and matured in parallel with, and as a direct consequence of, the advent of clinical kidney transplantation. The major technological advances in the histocompatibility laboratory have been developed in a response to the need to better serve the transplant community, which for the first 25+ years was synonymous with serving renal transplantation. The histocompatibility laboratory is in a very interesting position, situated midway between the basic science laboratory and the clinic, and laboratories have been able to make significant contributions in both arenas from this enviable position.

D.J. Pidwell (*) Allogen Laboratories, Cleveland Clinic, 9500 Euclid Ave. C100, Cleveland, OH, USA e-mail: [email protected]

The first successful kidney transplant was performed between identical twins, effectively circumventing the allogeneic immune response and eliminating the need for immunosuppression [2]. This accomplishment held huge potential for end-stage renal failure patients, but since most patients lack a twin to donate, broad clinical application of the new procedure meant that a means had to be found to either identify human leukocyte antigen (HLA) matched donor kidneys and/or to find a more effective means to suppress the allogeneic response elicited by unmatched kidneys (Fig.  2.1). It must be remembered that HLA-matched kidneys from close relatives means that the donor and recipient share chromosome 6, which carries the HLA complex of genes, but they do not necessarily share other chromosomes, indicating that they are not matched for the minor histocompatibility antigens (Fig.  2.2). With HLA-matched unrelated donors there is no guarantee that the donor and recipient share any chromosomes, including chromosome 6. Both of these situations require immunosuppression that was not needed in the transplant between identical twins. In the early years of histocompatibility typing, albeit in its infancy, permitted the search for HLA class I matched donors and thus aided in extending the availability of transplant to a broader segment of the end-stage renal failure patient population (Fig. 2.3). The science of HLA typing began with the identification of antileukocyte antibodies that cause lymphocyte agglutination in vitro. The original leukoagglutination assays were analogous to

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_2, © Springer Science+Business Media, LLC 2011

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Fig.  2.1  Human leukocyte antigen (HLA) antigen matching between donor and recipient. A matched HLA antigen is considered any antigen which a donor and recipient share. Conversely, any antigen that is found in the donor phenotype that is not in the recipient phenotype is considered a mismatch, as the recipient can mount an immune response towards that antigen. In certain cases, a

recipient or a donor may be homozygous at an HLA locus. In those cases, any antigen which a donor carries that a recipient does not is considered a single mismatch. Alternatively, if a donor is homozygous for an antigen carried by the recipient, a recipient has no “nonself” antigens to elicit a response and they are considered matched at that locus

Fig.  2.2   Inheritance pattern of human leukocyte antigen (HLA) genes. HLA genes travel within conserved cluster called a haplotype. These haplotypes are passed on by traditional Mendelian inheritance patterns as shown in inset. Each haplotype is assigned a letter (father is arbitrarily given AB and mother CD). Haplotypes can be traced to the children with each

child having one haplotype from the mother and one from the father. As a result, there are only four possible combinations a child may have. The exception to this is when pieces of the HLA region are exchanged between chromosomes during tetrad formation in meiosis. This exchange of DNA between chromosomes creates recombinant haplotypes

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Fig.  2.3  Diagrams of human leukocyte antigen (HLA) class I (left) and class II (right). The HLA class I and class II molecules are encoded by genes located in the major histocompatibility complex on chromorsome 6 in humans. HLA class I is made up of a single polypeptide chain consisting of three extracellular domains, a transmembrane domain and an intracellular tail. The structure is stabilized by a nonpolymorphic b-2 microglobulin domain. The peptide binding groove is found between the a1 and a2 domains. The a1 and a2 domains are the most polymorphic regions of the molecule and are where the majority of the differences in HLA antigens are found. There is a binding site for the CD8 molecule

on cytotoxic T cells located in the a3 domain. The class I molecule is found on the surface of virtually all nucleated cells. HLA class II is comprised of two polypeptide chains, each having two extracellular domains, a transmembrane domain and an intracellular tail. The a-chain is far less polymorphic than the b chain. The peptide biding groove is located between the a1 and b1 domains. The CD4 molecule on helper T cells binds to a portion on the b2 domain. Class II molecules are usually found only on the professional antigen-presenting cells (macrophage, dendrite cells, B cells) however, class II antigens can be expressed by many other cell types under inflammatory conditions

the red cell agglutination assays that were being used in blood banks to identify red cell antigens. Unfortunately, since lymphocyte function requires cellular aggregation in order to form immunological synapses, aggregation tends to occur naturally with these cells. This natural agglutination does not require antigen–antibody interaction as red cells agglutination does, but is often mediated by other molecular interactions characteristic of intercellular communications necessary for immune activation. This non-antibody-mediated aggregation, or “stickiness,” made interpretation of leukoagglutination assays difficult and progress in identification of leukocyte antigens was slow until the development of the complement-dependent

cytotoxicity (CDC) assay by Terasaki [3]. Although performing and analyzing the microcytotoxicity assay can arguably be considered at least equal part art and science, the availability of this assay single handedly facilitated the discovery of the majority of the leukocyte antigens known today. The CDC assay is exactly what its name implies, it is an assay were isolated lymphocyte are killed by complement activated by antibody bound to the cell surface. The assay is performed by mixing 1 mL each of cells and serum in a small multiwell plate, a Terasaki plate. If anti-HLA antibodies are present in the serum, they will bind to any cell that carries the corresponding HLA

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a­ ntigen. Once the antibody is bound, rabbit complement­is added. Rabbit complement is used because it is not easily inactivated by human decay accelerating factor (DAF), molecules that are natural controllers of complement activation in vivo but that can inactivate human complement in the CDC assay. If antibody is bound to the cells the rabbit complement is activated forming membrane attack complexes (MAC). MACs compromise the integrity of the cell membrane, allowing the free flow of solutes across it and resulting in cell death. The dead cells are detected by the addition of a vital or fluorescent dye, dyes that are excluded by live cells but can penetrate dead cells. The cells are then observed microscopically, shiny small round cells are alive, not having bound antibody and complement, larger dull, dark cells are dead and presumably bound antibody and were killed by complement activation. The percentage of dead cells in the well is estimated, up to 10% dead is scored a 1, 11–20% is a 2, 21–40% a 4, 41–80% a 6, and 81–100% is an 8. False-positive results are most commonly caused by spontaneous cell death or the presence of autoantibody and other non-HLA antibodies. False negative results can occur if the antibody is present in low titer or

if the antibody is of an ­isotype that does not activate­complement (Fig. 2.4). Throughout the 1950s and 1960s a number of histocompatibility groups worked simultaneously in laboratories around the world using the CDC assay to identify HLA antigens. As with any scientific endeavor there were naturally efforts to be the first to define an antigen and explain the role of these antigens in eliciting an alloimmune response. In contrast to much basic science research, however, this effort also had immediate clinical application in the pressing need to identify well-matched kidney donors for a growing number of transplant facilities. Progress in developing an HLA typing system was being hampered by the fact that each group, as it defined a novel antigen–antibody combination, was assigning their own name to that antigen. For meaningful, widespread clinical application of HLA typing, especially for sharing of donors between transplant centers, it became clear that a universally accepted nomenclature was required. Fortunately, the histocompatibility community was able to put aside their scientific rivalries and come together at the first International Histocompatibility Workshop in 1964.

Fig.  2.4  Examples of results from the complementdependent cytotoxicity (CDC) assay used for human leukocyte antigen (HLA) typing, cytotoxic cross-matching and CDC antibody screening. The left figure shows a negative reaction by CDC (score = 1). The cells within the wells remain small, refractile and free of vital dye.

Conversely, the well on the right shows a strong positive reaction (score = 8) with larger, dye filled cells that appear black under the microscope. The vital dye, which is normally membrane impermeable, can enter the lysed cells through the membrane attack complex created through the complement cascade

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At this workshop the representatives shared information and antisera with the goal of developing a universally applicable typing system and naming convention. In many regards the kind of cooperative effort exemplified by the Histocompatibility Workshops has been a hallmark of the histocompatibility community in general, a characteristic which has helped to advance many efforts within the transplant community. As the number of transplants increased and graft survival data was analyzed, the advantage of HLA matching of donors and recipients became clear [4–6]. At this time the number of deceased donors also began to increase, and finding well-matched recipients for these organs was difficult. The effort to put deceased donor organs into well-matched recipients naturally led to an agreement between regional histocompatibility laboratories in cooperation with their respective transplant centers to initiate the first organsharing organization, the South Eastern Organ Procurement Foundation (SEOPF) [7]. SEOPF was formed to permit sharing of matched or compatible grafts between centers in the southeast portion of the United States. Later this organization grew into a nationwide system for sharing organs, namely the United Network for Organ Sharing (UNOS). SEOPF initiated a system of serum sharing for sensitized recipients known as regional organ procurement crossmatch trays (ROP trays) whereby sensitized patients in the region could be cross-matched with all regional deceased donors. If the cross-

match on the ROP tray was negative the organ could be shared with that patient’s transplant center. This increased the accessibility to transplant for sensitized patients and continued to be a standard of practice in many areas until quite recently. Largely, this practice has now been replaced by virtual cross-matching, but for many years preliminary cross-matching on regional trays was central to management of sensitized candidates. Because the selection of immunosuppressive agents was limited in the early years, HLA matching assumed a central role in donor selection and increased the chances of graft and patient survival. When the histocompatibility laboratory refers to matching donors and recipients we are referring to HLA matching. ABO matching or at least ABO compatibility is absolutely required for successful transplant of solid organs in order to avoid hyperacute rejection due to the presence of natural anti-A and/or B antibodies (Fig. 2.5). Conversely, HLA mismatched organs can be transplanted without the risk of hyperacute rejection as long as there are no preformed anti-HLA antibodies present. In the absence of significant immunosuppression, which was not available in the early years of transplantation, HLA mismatched grafts were often lost to irreversible acute rejection. Although great strides were being made in standardizing HLA typing, it was obvious that the typing available was not sufficient to either explain or avoid many rejection reactions. We now know

Fig.  2.5  Blood group antigens are defined by carbohydrate residues found on the surface of cells. The two primary carbohydrates are the A group antigen, a-Nacetylgalactosamine, and the B group antigen, a-dgalactose. Typing for the blood group antigens is essential in transplantation as patients have antibodies to any blood group antigens not expressed on their own cells. These

antibodies can lead to hyperactue rejection of the graft as the blood group antigens can also be expressed on graft tissues. Although some donor–recipient ABO combinations may be compatible but not identical, the sharing of cada­ veric organs usually occurs within identical blood groups. This provides a more equitable distribution of organs and assures that no one blood group is disadvantaged

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that one reason for this was that early typing efforts were limited to detecting class I antigens. Histocompatibility laboratories were able to demonstrate that the mixed lymphocyte culture (MLC) could be used as an adjunct to serologic typing in identification of appropriate organ donors [8, 9]. The MLC identified an additional set of antigens, designated D region antigens, which elicited a strong proliferative response in some donor–recipient pairs that were previously thought to be well matched by the HLA typing that was available at that time [10, 11]. The MLC assay could help identify donors who were matched at the D region, the area which is now known to encompass the class II genes of the HLA gene complex. Use of the MLC had several significant drawbacks. First it took 5–6 days to run the assay limiting its use to living-donor transplants where there was adequate lead time to perform the testing and precluded its use in deceased donor situations where results were needed in a matter of hours as opposed to days. Second, as is now apparent, the lack of reactivity in an MLC does not always correlate well with graft survival [12]. Obviously, improved typing methods that were rapid and could reliably identify the antigens that drove the MLC were needed. Serologic typing for class II antigens lagged behind class I antigens for a number of reasons, one of the foremost being the requirement to isolate a pure preparations of B lymphocytes. When screening for antibodies with peripheral blood mononuclear cells (PBMC), which is a mixed cell population, it became clear that not all the antibodies detected reacted with all of the cells equally. The class I antibodies were recognized first because they reacted well with all of the lymphocytes in the PBMC preparation. But over time it was noticed that there were often reactions with subpopulations of the cells. Although this low frequency cell death was at first thought to indicate the presence of a weak, low titer, antibody it was found through titration experiments that some of these antibodies were actually present at very high titers yet they failed to react with the majority of lymphocytes in the PBMC preparation. Ultimately, these antibodies were shown to be reacting with

D.J. Pidwell and P.N. Lalli

the B lymphocyte subpopulation and, as is now known, were defining HLA class II antigens. Methods were developed for the separation of T and B-cell populations to facilitate serologic testing for class II antigens, but the original process was tedious, time-consuming, and yielded limited numbers of viable B cells. Nonetheless, serologic typing for class II antigens permitted improved identification of matched grafts in a time frame that was compatible with placing deceased donor grafts [11, 13–15]. Although serologic class I and later class II typing identified what appeared to be wellmatched donors, grafts continued to be lost immediately upon reperfusion, i.e., hyperacutely. It was shown by the seminal work of Patel and Teresaki that patients with positive CDC crossmatches were much more likely to lose their grafts in this fashion [16]. Following these findings, cross-matching every donor–recipient pair prior to transplant became routine. Unfortunately, as evidenced by the results in the Patel article, not all incidences of hyperacute rejection could be avoided by the methods available at that time, i.e., the basic cytotoxic cross-match. This was attributed to a lack of sensitivity in the assays and the members of the histocompatibility community worked diligently to develop methods that would improve their ability to detect relevant antibodies. These efforts led to the development of the Amos Wash and later the antihuman globulin (AHG) procedures [17]. Although antiHLA antibodies are the primary cause of hyperacute and accelerated acute rejection, other antibodies have been shown to mediate these processes as well. In most instances these antibodies are not detectable using lymphocytebased cross-match techniques [18–20]. Fortunately, these non-HLA antibodies are fairly uncommon and are not felt to constitute a major threat to graft survival in the majority of transplants. Despite the best efforts of the histocompatibility laboratory to: (1) serologically type for both class I and class II; and (2) perform sensitive cross-matches, it was evident that these efforts neither guaranteed graft survival, nor extended the availability of transplant sufficiently to satisfy the demand. There simply were not

2  The Histocompatibility Laboratory in Clinical Transplantation

enough well-matched kidneys available, even with national sharing. It was only with the advent of the first calcineurin inhibitor, Cyclosporin A, that transplant truly became broadly applicable not only for renal transplant but also for many other organs including the pancreas.

Where We Are Now When cyclosporin, and later tacrolimus, became available, the perceived need for HLA matching and therefore for HLA typing began to wane. Despite the fact that zero HLA-A,B,DR mismatched kidneys continue to enjoy significantly better graft survival, even in the calcineurin inhibitor era [21, 22], the ability of the newer immunosuppressants to allow good graft survival for totally mismatched kidneys for the first time opened this life-altering therapy to all patients in need, whether or not they had matched donors available. With the advent of the newer immunosuppressants, the primary role of the histocompatibility laboratory in kidney or pancreas transplant began to change from one of finding HLA-matched and cross-match negative organs to one of helping the physicians assess the relative risk of any particular donor–recipient pair. Many factors have been shown to contribute to the relative risk of a transplant, including the level of sensitization of the recipient, the race and gender of the recipient, prior transplants or other sensitizing event the patient has experienced such as pregnancy or transfusions, the relationship of the donor to the recipient, the level of HLA matching, and whether the overall health of the patient allows full use of the everexpanding collection of immunosuppressive medications [23–25]. Additionally, what constitutes risk at one transplant center may differ from risk at another center, depending upon the immunosuppressive protocols employed and the approach of the physicians. This has mandated that the histocompatibility laboratory establish a close relationship with their transplant programs so as to thoroughly understand the management philosophy of the physicians they serve.

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The histocompatibility lab performs risk assessment by gathering data from a variety of assays and evaluating the information in light of published outcomes data. First, labs continue to HLA type all recipients and donors. This is important since matching at DR still supplies points in the UNOS match run system and because zero antigen mismatch sharing remains available to highly sensitized patients. Zero antigen mismatched grafts have significantly better graft survival even in the current era of immunosuppression but sharing of zero antigen mismatched organs may soon be eliminated in most cases in an effort to reduce ischemia time and increase the number of African American and other ethnic minority patients that are transplanted. Nonetheless, knowing the match grade of the donor can help in decisions regarding the use of induction and immunosuppressive protocol selection and in virtual cross-matching. Serologic typing continues to be a mainstay in many laboratories but molecular typing techniques are rapidly becoming the method of choice for identification of HLA antigens [26, 27]. There are a number of reasons for the migration to molecular techniques. First, the supply of good typing grade antiserum is limited, especially for rarer antigens. This can mean that serologic typing is unable to detect some antigens, and although these antigens are usually not common in the donor population it is important to detect their presence if the recipient is sensitized to them. The UNOS matching algorithm rules out potential recipients if they have antibody to an antigen present in the donor. If antigens are missed during donor typing, then time is spent cross-matching incompatible recipients, potentially contributing to increased ischemia time and needless shipping of organs. Molecular typing, usually referred to as DNA typing, detects the presence of the HLA genes on chromosome 6 and is much less likely to miss the presence of an antigen. Second, some HLA antigens are not well expressed on the cell surface, e.g., Cw and DP, making them difficult or impossible to detect in serologic assays [1]. Antigen expression can also be markedly altered in deceased donors as a result of medications administered during donor

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management and the physiological effects of brain death [26]. It should be remembered that serologic typing methods use isolated lymphocytes and the level of antigen expression on lymphocytes is not necessarily equivalent to the level of expression of the same antigen on graft tissues. Therefore, missing an antigen in serologic typing and serologic cross-matches because of weak expression of the antigen on circulating lymphocytes can result in exposure of the graft to antibody-mediated injury due to higher antigen expression on the graft tissue. With DNA typing methods the genes for the antigens are readily identifiable. Although detection of the gene does not guarantee cellular expression in the graft, in the vast majority of cases the presence of the gene is synonymous with antigen expression. HLA null antigens, antigens that are not expressed due to mutations in the gene, have been identified [28]. The most common null antigens have been defined and most are identifiable by the molecular assays employed today. As mentioned, deceased donor management and the processes inherent to brain death can alter the cell surface expression of HLA antigens and complicate serologic detection of those antigens. Since the genes are not altered by patient management or brain death, DNA typing is unaffected by these circumstances. Lastly, there are a number of very closely related antigens referred to as splits such as A68 and A69, B57 and 58, antigens of the A19 group, etc. Splits are antigens that were initially thought to be a single antigen, but later, as antiserum became available, were recognized to be two or more different but closely related antigens [1]. Although these splits were originally identified serologically, they can be difficult to discern in CDC assays due to crossreactivity of antibodies to the epitopes shared between these structurally related antigens. Additionally, shared epitopes are not limited to the splits, many HLA antigens share epitopes and will exhibit antibody cross-reactivity. Rodey was able to define groups of antigens that shared epitopes and which tended to cross-react in CDC assays. These Cross-reactive Groups are referred to as CREGs (Fig.  2.6) [1]. Cross-reactivity is generally not an issue with DNA typing since

D.J. Pidwell and P.N. Lalli

primers or probes can be ­constructed to react specifically with the nucleotide polymorphisms that result in the amino acid differences which define the epitopes that differentiate these antigens. In fact, DNA typing can identify not only the serologically difficult splits but can actually discern HLA alleles (Fig.  2.7) [29, 30]. For example, the antigen A68 has at least 48 different alleles, all of which are identifiable by molecular typing methods, whereas only the single antigen, A68, is identifiable in serologic typing. HLA typing at the allele level, that is, identifying exactly which allele is present for each HLA antigen, is referred to as high-resolution typing. High-resolution typing is required for successful bone marrow transplantation, but at the present time matching at this level has not been shown to be advantageous for the survival of solid organ grafts. High-resolution typing may have a place in solid organ transplant in the future, however. With the new antibody detection assays it is possible to identify allele-specific antibodies, that is, antibodies that will react with only one allelic form of an HLA antigen. Frequently these allele-specific antibodies occur in a person whose HLA type contains a different allele of the same antigen. For instance a person whose HLA type is A1, A2, B7(Bw6), B8(Bw6), DR 1, DR4, may carry the allele A*0205. If they are exposed to the antigen A*0201 they can make antibodies specifically to the epitope(s) of that allele that are not present on the A*0205 allele. Those antibodies will not react with A*0205, the selfantigen, but they will react with any cell carrying the A*0201 antigen. Presently, when listing unacceptable antigens in UNOS, only the antigen A2 can be entered since very few allele level antigens are accepted by the UNOS system. For a person with anti-A*0201 the lab can only enter A2 as the unacceptable antigen. But if a candidate has A2 in their phenotype, as in the example above, A2 cannot be entered as an unacceptable antigen in UNOS because it would appear that the person had antibody to a self-antigen, which is not possible. Therefore, in the case above, despite the fact that the patient has antibody to A*0201, the most common A2 allele, that

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Fig. 2.6  Shared epitopes of the A2 CREG group-Due to the conserved nature of the human leukocyte antigen (HLA) molecules, different HLA molecules have shared antigenic epitopes. These shared epitopes can lead to antibody cross-reactivity between multiple HLA molecules. HLA antigens that share epitopes are grouped together in CREGs (cross-reactive groups). Each HLA molecule has a unique epitope which is

found only on that molecule but some epitopes, either linear or conformational, can be found on multiple HLA molecules. A patient exposed to only a single mismatched antigen, through either transplant, transfusion or pregnancy, can make antibody that reacts to other HLA molecules to which they have never been exposed if the antibody is directed toward a shared epitope

Fig.  2.7  Single human leukocyte antigen (HLA) antigens can have multiple alleles detected at the DNA sequence levels that can range from silent mutations that lead to no difference in expressed proteins to the complete lack of expression in other cases. This example

shows four different alleles of the HLA-A1 antigen. Changes in certain nucleotides can lead to amino acid substitutions as in the case of A*0102 and A*0103 or the creation of a molecule that is no longer expressed on the cell surface as in the A*0104N (null) allele

a­ ntibody cannot be entered into UNOS because the patient carries the A2 antigen, albeit a different allele of the A2 antigen. Since the A2 cannot be entered as an unacceptable antigen it will not be used to exclude donors in match runs and this candidate will show up on the match runs for all A2 donors. These donors will have to be crossmatched for this candidate even though the A*0201 allele will be present in more than 90% of the A2-positive donors encountered. Allelespecific antibodies are not terribly common but they are seen more frequently than one might presume. As a result, there is mounting pressure on UNOS to allow the entry of allele level antibodies. Entering antibodies at that level, however, is moot until donors are typed at the allele level to allow them to be ruled out based on allele

level antibodies. At present, allele level, highresolution typing takes too long to be appropriate for typing deceased donors; and until a rapid, reliable method of allele level typing is devised the UNOS system will most likely continue to function using HLA antigen level typing for listing of phenotypes and antibody specificities. As with all technologies in this field, progress is being made in high-resolution typing and more rapid methods using bead technology and microarray chips are currently on the horizon. As these procedures are developed and validated we can expect that allele level typing of donors will become more common and eventually may be required by UNOS. The second major function of the HLA lab in risk assessment is to monitor for anti-HLA

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a­ ntibody both pre- and posttransplant [31–34]. Pretransplant antibody testing is a major risk assessment tool since previously sensitized patients are at risk for hyperacute, accelerated acute, antibody-mediated, and chronic rejection if the graft carries antigens that correspond to the recipient’s circulating antibodies. Circulating antibody is also a marker for the presence of both T and B memory cells [35–37]. The presence of HLA-specific memory cells is a useful measure of risk since the immunosuppressive agents currently at our disposal are not optimally effective at controlling memory cell activity and have limited activity against B cells and plasma cells [36–38]. Whereas memory B cells can lead to accelerated antibody production, memory T cells, once reactivated, will accelerate and augment the entire immune response. This accelerated immune response can develop before optimal levels of immunosuppression can be attained. Patients with low levels of donor-specific antibody, who are not at risk for hyperacute rejection but have evidence of memory cells, are often induced with antilymphocyte therapy to help control the memory T-cell responses until therapeutic levels of other immunosuppressive agents can be attained [39–41]. Just as in HLA typing, the CDC assay was the first assay used for detection of circulating antibody. In the CDC antibody screening assay, a panel of cells with known HLA phenotypes is used to screen patient sera. The percent of panel cells that the serum reacts with is called the panel reactive antibody or PRA. Because the HLA types of the panel cells are known, the pattern of reactivity indicates the HLA specificity of the antibodies present in the serum. However, if the antibody does not react strongly or consistently, or if there is reactivity with a high percentage of the cells, the specificity of the antibody cannot easily be determined by this technique. For instance, a serum has a PRA of 98% and can be shown in a cell-based assay to contain antibodies to A2, B7, B8, and B44. Those antibodies can explain about 80% of the reactivity, but clearly there are other antibodies present. The specificity of those additional antibodies often cannot be determined because there are so few cells left in

D.J. Pidwell and P.N. Lalli

the panel that are negative for A2, B7, B8, and B44 that no pattern of reactivity for any other antigen can be determined. This can sometimes be overcome by titering the serum and testing each titer on the same cell panel. However, this process is time-consuming and labor intensive and will often fail to identify low-titer antibodies that are masked by antibodies to more common antigens that are present in higher titer. As the term complement-dependent cytotoxicity implies, this assay uses cytotoxicity, i.e., cell death, as the means of evaluating if antibody is present. Any assay that uses the death of live cells as a readout of reactivity is prone to being confounded by spontaneous cell death. First, human T and B lymphocytes have a fairly short life span once they are purified, and the spontaneous death of these cells over time can complicate the final analysis since it is impossible to differentiate between spontaneous cell death and antibody- and complement-mediated cell death. In these assays a dead cell is a dead cell and the cause of death is not always discernable. Additionally, cytotoxic assays often have limited sensitivity due to the nature of the antibody complement interaction. For the complement cascade to be initiated by the antibody-mediated pathway, complement factor C1q has to bind two adjacent antibody molecules and remain bound to those molecules long enough to generate an adequate amount of active complement factor 2a to sustain the necessary sequential reactions to produce a sufficient number of membrane attack complexes to compromise the integrity of the cell. If there are insufficient antibody molecules attached to the surface of any one cell, due either to a low titer of antibody in the serum or a scarcity of antigen on the cell surface, there is often too much distance between the antibody molecules for C1q to contact two antibody molecules simultaneously. In these cases the complement cascade cannot be initiated or sustained and cell death will not occur. This often leads to the erroneous assumption that little or no anti-HLA antibody is present, which would imply that there are few if any memory cells present and that a particular donor–recipient pair carries minimal risk when there is actually a substantial risk of

2  The Histocompatibility Laboratory in Clinical Transplantation

early antibody-mediated rejection and of memory cell responses. Misinterpretation of antibody screening can also occur if the anti-HLA antibody is of an isotype that inefficiently binds complement, such as IgG2, IgG4, or IgA [42]. In that instance a substantial quantity of antibody can be present but goes undetected in complement-dependent assays because of the absence of complement binding and activation. Over the years a number of modifications of the cytotoxic assay have been devised to overcome these shortfalls, the most effective of which is the antihuman globulin (AHG) augmented assay [1, 17]. In this assay an antibody is added that will react specifically with the anti-HLA antibody that is bound to the cell surface, forming a complex of two antibodies in close enough proximity for C1q to bind and be activated [43]. The AHG assay permits detection of both lower concentrations of antibody bound to the cell surface and of noncomplement binding isotypes, antibodies that are referred to as cytotoxicity negative absorption positive or CYNAP antibodies [43, 44]. For many years this was the most sensitive assay available and much effort went into refining the performance of the assay in individual laboratories to give the most sensitivity possible. This is not a simple assay to perform, however, and there remains large variation in the sensitivity of the AHG assay between laboratories, depending upon both the techniques being used and the reagents employed. Even with the most sensitive AHG assay, however, antibodies continue to be missed and the degree of sensitization is often underestimated when a negative cytotoxic screen is the only result available. Although CDC assays for antibody monitoring are still used and continue to provide useful information in risk assessment, newer more sensitive and specific methods are now available. The first innovation in detection of circulating antibody was a cell-based flow cytometric assay [45]. This assay uses a pool of isolated T lymphocytes with a variety of phenotypes such that all of the CREGs are represented. Since flow techniques are very good at detecting crossreactive antibody reactivity, this assay can detect a wide array of preformed antibody despite the

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limited number of HLA antigens represented. This flow antibody screen is more sensitive than even the CDC-AHG assay and is capable of detecting low titer and CYNAP antibodies that are not detectable in CDC assays but which can produce positive flow cross-matches. This flow screening procedure was the first to have the sensitivity capable of giving a more accurate estimation of flow cross-match reactivity and proved helpful for laboratories that were using flow cross-matches to determine whether or not to proceed to transplant. One advantage of a cellbased assay using flow cytometry is that they do not rely upon cell death but detect anti-HLA antibody bound to the cell surface with a secondary antihuman IgG antibody that is fluorescently tagged. Not relying on cell death as a readout eliminates a number of the disadvantages encountered in the CDC assays. There are at least two disadvantages however, of using a pool of T cells as a screen for the presence of circulating antibody: (1) it does not yield any specificity information; and (2) it cannot detect anti-class II antibody. The histocompatibility laboratory at Emory University developed a system where multiple pools of cells were employed with the cells in each pool expressing a limited number of different CREG antigens [46]. This at least allowed determination of which CREGs needed to be avoided, but identification of individual unacceptable antigens was usually not possible. Further, since this assay is cell based it is still plagued by false-positive results due to the presence of autoantibodies or other non-HLA specific antibodies that do not need to be avoided for a successful transplant. Additionally, maintaining a supply of multiple cell pools can be timeconsuming among other issues. The advantages of a screening technique with the sensitivity of the flow cytometer were obvious, but the shortcomings needed to be rectified for the technique to demonstrate its full potential. In response to this need several manufactures have developed new antibody screening techniques collectively referred to as solid phase assays. In solid phase assays recombinant or purified HLA antigens are attached to a plastic carrier, currently this is either an ELISA plate

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D.J. Pidwell and P.N. Lalli

or plastic beads but other solid phase platforms such as microarray chips are in development [34, 47– 49]. The serum to be screened for antibody is added to the well or beads and incubated to allow any antibody present to bind to the HLA antigens. The serum is then washed off and a secondary antibody specific for human IgG is added. The use of an IgG-specific secondary antibody avoids interference from IgM autoantibody. The secondary antibody is tagged with either an enzyme or a fluorescent marker. If human antiHLA antibody is present the secondary antibody will bind to it, excess secondary antibody is washed off and the bound, tagged antibody is detected by substrate development or by fluorescence in a flow cytometer or Luminexx machine (Fig.  2.8). These solid phase assays are more sensitive than CDC assays and are able to detect antibodies that fail to cause positive CDC results but are capable of producing a positive flow

cross-match. An additional advantage of these assays is that they eliminate interference from antibody specific for cell surface molecules other than HLA molecules because the only target for the antibody on the solid substrate is the purified HLA molecules. There are now solid phase assays available that have a single HLA antigen bound per bead or per well [50, 51]. These assays very precisely define the HLA specificity of any antibodies that are present (Fig. 2.9). This has introduced a new era of antibody identification where the antibody specificities can be determined even in sera with very high PRA ­values where historically it has been very difficult to determine all of the specificities due to some ­antibodies being masked by the presence of other antibodies. With the single antigen solid phase assays it is now possible to determine all of the specificities present with the only limitation being the absence of an antigen

Fig. 2.8  Assays for flow cytometric antibody screening contain plastic beads coated with human leukocyte antigen (HLA) molecules derived from cell lysates or recombinant HLA molecules. These HLA molecules are added to a percentage of the beads that represent the percent of donors in the general population that carry that HLA molecule in their phenotype. If the patient’s serum contains anti-HLA antibodies they will bind to the HLA molecules on the beads and are detected by adding a fluorescently labeled secondary antibody. If no anti-HLA antibody is present the secondary antibody will not bind and the bead population

remains on the left side of the scale, equivalent to the negative control population. If anti-HLA antibody is present the secondary antibody will bind and the bead population will shift to the right. The further to the right the bead population moves the more secondary antibody bound per bead giving a semiquantitative measure of the amount of anti-HLA antibody present in the serum. The percentage of beads above the positive cutoff value gives an estimation of the percentage of donors a recipient may be expected to have a positive cross-match with. This percent is known as the panel reactive antibody (PRA)

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Fig.  2.9  Flow single antigen beads contain multiple beads that can be identified by a fluorescent “address.” Each “address” contains a group of beads that is coated with a single recombinant human leukocyte antigen (HLA) antigen. Addition of patient serum to these beads can determine the antibody specificities present in that serum.

Each single bead group can be investigated individually to determine the strength of the antibody specificity using a MESF conversion. In this figure, the patient has antibodies specific for HLA-A24, A25 and A26, the strongest being HLA-A25, as the fluorescent shift to the right is the greatest for the bead carrying the HLA-A25 molecules

in the panels available. Luckily, the Luminex platform has largely overcome the restriction on the number of antigens that can be represented in a single assay. The Luminex platform can use up to 100 different beads, each with a unique fluorescent “address” that can be identified by the machine. Each bead can carry a single HLA antigen. By testing the class I and II antigens separately 200 different antigens can be tested in two wells of a 96-well plate. Additionally

these systems not only detect the traditionally defined anti-A,B,DR and DQ antibodies, but also allow clear definition of anti Cw and DP antibodies which were not detected in the ­cell-based assays [52]. Unfortunately, no assay is perfect and the solid phase assays also have disadvantages. An issue that is often encountered is the presence of antibody that reacts to the solid phase carrier itself [53]. These antibodies are reacting with the

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plastic or latex present in the plate or beads and they represent no threat to a graft. However, it can be difficult to determine if these nonspecific antibodies are obscuring the detection of anti-HLA antibodies. This can be overcome to some extent by employing multiple assays that use different compounds to make the carrier. Often antibodies that will react with the carrier in one assay will not react with the carrier in other assays. The need to develop and validate multiple assays does increase the complexity of testing for each laboratory, however. A second disadvantage of the solid phase assays is that the purified HLA proteins may not reassemble fully, and these incomplete or denatured proteins are bound to the beads or plate. The problem with this is that antibody may not bind well to the denatured antigens or the antibody may bind to sites on denatured molecules that are not accessible in the intact molecules that are expressed on the surface of cells. In this case the bead reactivity is not accurately representing the reaction expected in a cell-based cross-match or a transplant. The manufacturers are aware of this issue and have been working to improve the quality of the ­m olecules represented in their assays. A third, shortcoming of the solid phase assays as well as flow cytometric assays is that because of the IgG-specific secondary antibodies used they cannot detect IgM anti-HLA antibodies. It is extremely rare for a person to make anti-HLA antibody of only the IgM isotype, but it does occur occasionally. IgM anti-HLA antibody can activate complement and cause damage to the graft and therefore should be avoided when encountered. This is one reason why it can be advantageous to perform a CDC final crossmatch with serum that is not treated to remove IgM. When the information from this CDC cross-match is combined with a thorough alloantibody and autoantibody history of the patient it is possible to identifying an IgM anti-HLA antibody. The final shortcoming is that it is difficult to determine what level of reaction represents the presence of weak antibody and what level simply represents the background reactivity of any normal serum with the beads. The cutoff between negative and positive can change from

D.J. Pidwell and P.N. Lalli

patient to patient and most certainly changes from laboratory to laboratory. Each laboratory must determine the level of sensitivity that is appropriate for identifying patients that will have a positive cross-match in their hands and would therefore be ruled out for transplant. The cutoff determined however is not an absolute and transplant centers will find that some patients with very low levels of antibody pretransplant, levels that yield negative cross-matches, will still result in memory responses and antibody-mediated rejection. It is evident that the amount of antibody present pretransplant does not directly correlate with the risk of antibody-mediated rejection. What does correlate with the risk of rejection is the reactivity of the particular patient’s immune system, but to date there is no means to measure individual reactivity pretransplant and the best we can do is to use the surrogate measure of antibody level. Despite these shortcomings the solid phase assays have greatly improved the ability to identify the presence and especially the specificity of anti-HLA antibodies. The ability to identify antibody specificities precisely using solid phase assays has introduced a new approach to PRA assessment, and based on this UNOS implemented a new system of PRA assignment in the latter part of 2009. In this system the PRA values are calculated based on an algorithm that uses the antibody specificities entered into the system and the frequency of those antigens in the UNOS donor pool over the last several years. The introduction of the calculated PRA (CPRA) requires antibody specificities to be entered on every patient in order for their PRA to be calculated. If no specificities are entered the patient will have a PRA of zero, if several specificities are entered and the PRA ­calculates to >80% the patient will get the extra points allocated for the match run. For each specificity entered, the patient will automatically be eliminated from match runs on donors that carry the corresponding antigen. Depending on the philosophy of the transplant center, any HLA antigen can be listed as an antigen to avoid whether or not the patient actually has circulating antibody to that antigen. This allows previous

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mismatched antigens to be listed if that is the policy of the transplant center. As long as the antigen is listed in UNOS it will be used to calculate the PRA value. This permits the CPRA to more accurately reflect what percentage of the donor population is unacceptable for each transplant candidate. An additional advantage of the calculated PRA system is that both class I and II antibodies will be used to calculate a single PRA value. Previously, either the class I PRA or the class II PRA could be entered as the current PRA, but since no single assay gave a PRA value that reflected reactivity with both class I and II antigens a combined value was not available. Again, this is designed to allow the CPRA value to accurately represent the probability of encountering an unacceptable donor in the donor population. If two patients at different centers have the same unacceptable antigens listed they will have the exact same CPRA. The goal of using the CPRA is to produce equitable PRA values between transplant programs and it has succeeded to some extent. Variation in PRA will continue to occur depending upon what assays are used to define unacceptable antigens and upon how the assay is interpreted at a particular center. As explained, the CDC PRA was determined by testing the reactivity of a patient’s serum with a panel of lymphocytes.. The same serum could give vastly different percent PRA at different centers depending upon the cells used to make up the panel. More recently the solid phase antibody detection systems have made the panel of antigens being tested more uniform since all the laboratories buying a single manufacturer’s product will have the same panel of antigens ‑represented. However, even using the same panel of antigens, laboratories continue to get a range of PRA values depending upon how sensitive the assay is in their hands and upon what level of reactivity is considered “positive” by the laboratory. Different labs use different positive/ negative cutoffs in the solid phase assays based upon what level of antibody they find produces a positive cross-match using the cross-matching techniques available in that specific laboratory and the policies of the transplant centers they

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service [34]. Centers that require a flow cytometric cross-matches for final cross-matching might call weakly reactive antigens positive, whereas a center that uses an AHG final cross-match might consider the weak reactivity to be too sensitive and would therefore not call those antigens unacceptable. The choice of final cross-match techniques is usually an issue agreed upon between the laboratory and the transplant centers it ­services and depends on the amount of risk the physicians are willing to accept for their patients and the immunosuppressive protocols employed. Transplant centers in some areas of the United States have complained that the racial makeup of their donor population differs markedly from the racial makeup of the national donor pool and that the CPRA does not accurately represent the probability of a positive cross-match with their local donor population. This could be disadvantaging their transplant candidates in match runs by falsely reducing their CPRA and eliminating points from their scores. As the CPRA system is employed to allocate organs the transplant community will be able to assess the merits of these complaints and inequities can be addressed by further refinement of the system. With the implementation of the CPRA system UNOS has mandated that at least one solid phase assay be used for antibody identification. CDC screening methods may be used, and these continue to provide useful information for patient management, but for sensitized patients these methods must now be augmented with results from some form of solid phase testing. One of the most important aspects of the advent of solid phase testing is the ability to define all of the antibodies present without fear that some are being masked by other antibodies. This has permitted a whole new approach to donor allocation, the “virtual cross-match” [54–  58]. The use of virtual cross-matching is not just limited to renal and renal–pancreas transplant, it can be used with transplant candidates for any organ as long as the antibodies of the candidate have been clearly defined, usually with a solid phase single antigen assay, and the HLA type of the donor is known. This approach has helped expand access to donors especially

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for sensitized candidates. A virtual cross-match is performed by comparing the donor’s HLA type with the patient’s list of unacceptable antigens as defined by a solid phase assay. If an antibody has been defined to an antigen present in the donor type, then the virtual cross-match would predict a ­positive cross-match. If there are no antibodies identified to any of the donor antigens, then the virtual cross-match would predict a negative cross-match. If a donor is not typed for all the antigens to which the patient has antibody, then the virtual cross-match is incomplete and the outcome of a final cross-match cannot be accurately assessed. This often happens when allelespecific antibody is present or when there is antibody to HLA-DP or to the alpha chain of the DQ molecule. These antibodies can now be identified by some solid phase assays, but deceased donors are not routinely typed for these antigens. One caveat that must be remembered when using the virtual cross-match is that the prediction is only valid for the state of the patient at the point in time when the serum sample was drawn and tested for antibody. If several months have elapsed since the patient was last tested for antibody they may have experience sensitizing events in the interim and the antibody profile used for the virtual cross-match may not accurately reflect the current status of the patient. It is imperative that physicians ascertain if the patient has had any sensitizing events since the date of the last tested serum sample. Often transplant candidates fail to recall sensitizing events, or they do not fully understand what a sensitizing event is making it difficult to get an accurate history. Therefore, a virtual cross-match does not preclude the need for a final prospective crossmatch. With virtual cross-matching, however, organs should only be offered to patients who are expected to have a negative cross-match and who can potentially receive the graft. This should avoid needless cross-matching of multiple patients before a cross-match negative patient is identified and needless shipping of organs occurs. Since the primary antilymphocyte antibodies that have been shown to be relevant to graft ­survival are anti-HLA antibodies, the antibodies detected in the solid phase assays are antibodies

D.J. Pidwell and P.N. Lalli

of relevance. Other antibodies that react with lymphocytes in cell-based assays, such as autoantibodies, have previously been a source of confusion because they do not cause graft injury nor decrease graft survival but appear to indicate increased risk associated with a transplant because of the positive cross-match. Indeed they can obscure more dangerous anti-HLA antibody and make it extremely difficult to predict the risk associated with a particular donor–recipient pair. Unfortunately, it is not easy to determine in cellbased assays exactly what the antibody is that is causing the cell death. With the solid phase assays, using purified HLA molecules, if the antibody reacts with the antigen on the plastic then it is an IgG anti-HLA antibody and should be avoided. If, on the other hand, the antibody does not react with the HLA antigen in the solid phase assay then it is probably not necessary to avoid the transplant even if the antibody was cytotoxic in the CDC assay. The solid phase assays allow us to discern if there is anti- HLA antibody present even in the presence of autoantibody because the autoantibody will not bind to the HLA coated beads. Use of solid phase assays therefore permit increased confidence in risk assessment. With the increased awareness of the frequency of antibody-mediated rejection (AMR) posttransplant monitoring for donor-specific antibody has also increased. The Banff criteria for diagnosis of AMR includes demonstrating the presence of circulating antibody to the donor [59, 60]. Solid phase antibody testing has proved quite helpful in posttransplant monitoring. The fact that these assays are semiquantitative permits a relative assessment of the amount of antibody present at any time point. Since there is generally more inter-assay than intra-assay variation any estimation of antibody quantity usually requires concurrent analysis of multiple samples collected over a period of time pre and posttransplant. Simultaneous analysis permits a relative estimation of whether the antibody concentration is increasing or decreasing over time. It can be helpful if serum samples are obtained periodically posttransplant and stored frozen for analysis when AMR is suspected. Solid phase testing

2  The Histocompatibility Laboratory in Clinical Transplantation

is also helpful for posttransplant monitoring in patients who have received induction or rescue therapy with therapeutic antibodies. Many of the therapeutic antibodies interfere with cell-based assays because the cells express the antigens ­targeted by the therapeutic antibody such as CD3 or CD52. Some of these therapeutic antibodies can remain in the circulation for long periods of time, for example alemtuzumab or rituximab can be detected for months after administration. Most of these antibodies do not interfere with the solid phase assays because the target antigen is not present on the bead or plate and therefore does not interfere with detection of anti-HLA antibody. It should be noted that rabbit antithymocyte globulin may contain anti-HLA antibody and the secondary antibody used in the solid phase assays, antihuman IgG, cross-reacts with rabbit immunoglobulin. Therefore, any serum samples that contain rabbit antithymocyte globulin may need to have the rabbit immunoglobulin absorbed out before testing, even in solid phase assays [61]. There is an additional solid phase assay that can be used for posttransplant monitoring. This assay, the DSA assay, is designed to specifically identify the presence of donor-specific antibody by binding HLA molecules extracted from donor cells to the beads [62, 63]. One advantage of this is that only donor-specific antibody is detects and that all donor-specific antibody is detected including allele-specific antibody where the ­specific HLA allele may not be represented in the other solid phase antibody screening assays. A second approach to antibody detection is the cross-match which is typically performed prospectively for all kidney and/or pancreas transplants. Cross-matches have been used since the earliest days in the history of transplantation once it was appreciated that most hyperacute rejection could be avoided with the information a cross-match provides. There has never been a single cross-match technique that can absolutely guarantee that hyperacute rejection will not occur. There are a number of reasons for this. First, no single cross-match can detect all of the anti-HLA antibodies that can mediate hyperacute rejection hence, histocompatibility labora-

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tories usually use a battery of cross-match techniques to increase the probability of detecting as many deleterious antibodies as possible. Second, part of the sensitivity of the cross-match technique depends upon the level of expression of the HLA antigens on the cell surface. Cells can vary in the relative level of antigen expression altering the ability of the assay to detect the presence of the antibody. Third, antibodies other than anti-HLA antibodies have been shown to produce hyperacute rejection and the lymphocyte-based assays used in the histocompatibility lab cannot detect these antibodies, i.e., antiMICA and antiendothelial cell antibodies just to name a few, and different antibody isotypes are detected in some assays and not in others. Years of experience with cross-matching has shown that the single most important indicator of risk in kidney or kidney–pancreas transplantation is a positive T-cell CDC cross-match, but a negative T-cell CDC cross-match does not necessarily indicate the absence of risk. To be effective a cross-match has to be rapid, specific, and sensitive. The complement-dependent lymphocytotoxicity assay, with a variety of modifications to improve sensitivity, such as added washes, extended incubation times, and AHG, has been the gold standard. However, as when using the CDC assay for antibody identification, CDC cross-matches are prone to artifacts such as spontaneous cell death, autoantibodies, and failure to activate complement. Because of its strong correlation with hyperacute rejection, however, many centers continue to use the CDC cross-match in the final decision to transplant. The CDC cross-match has been augmented in the past 20–25  years by flow cytometric crossmatching techniques [64–66]. Each of these assays has advantages and disadvantages, but when run in combination, often the strengths of one assay will compensate for the weaknesses of the other. Using the information gleaned from a combination of CDC and flow cross-matches has proved helpful in improving both patient and graft survival [67–70]. Flow cytometric cross-matches detect antibody bound to T and B lymphocytes with a fluorescently labeled secondary antibody specific for

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D.J. Pidwell and P.N. Lalli

Fig. 2.10  Flow cytometric cross-match. Left: Negative flow cross-match. Here the patient serum demonstrates no more antibody binding to the donor cells than the negative control serum. Right: Positive flow cross-match. The cell population is shifted to the right when compared to the negative control serum. The difference between the negative control population and the population treated with the patient serum indicates the strength of the crossmatch indicating how much recipient antibody is bound

to the donor cells. The number of antibody molecules bound per cell can be estimated using the median channel fluorescence shift value, conversion to MESF values, or by a ratio of the negative control median channel to the patient median channel. Depending on the amount of fluorescence shift, a cross-match can be determined to be borderline positive, weak positive, positive or strong positive based on cutoff values determined by the laboratory

human IgG (Fig. 2.10). This assay offers several benefits over the cytotoxic assays, including the fact that spontaneous cell death does not confound assay interpretation since dead cells can be excluded from analysis based on their light scatter properties. Additionally, the use of an IgG-specific secondary antibody eliminates interference from IgM antibodies, which are most often autoantibodies. Although IgG autoantibodies can remain an issue, this too can be eliminated to some extent by pronase treatment of the cells prior to testing. One other benefit of the flow cytometric assay is that it is semiquantitative and largely eliminates the necessity for serial dilution analysis (Fig.  2.11). As with the CDC assays the cell-based flow assays are subject to interference from many of the therapeutic antibody preparations that are used for induction or treatment of rejection. A common complaint of the flow cytometric cross-match is that they may be too sensitive,

detecting levels of antibody that do not represent the presence of a dangerous amount of antibody or a significant number of memory cells and hence do not represent a significant risk of graft injury [71–74]. The ability to discern what level of sensitivity is clinically relevant is confounded by the fact that not all human immune systems respond the same. Some people will consistently mount a vigorous immune response with a minimum of antigenic stimulation, while others can encounter repeated antigenic stimuli yet respond minimally if at all. Whereas low levels of antibody may be an indicator of very significant risk for antibody-mediated graft injury in some people, the same low levels may not be at all relevant to graft injury in another patient. To date there are no means of differentiating these two types of responders pretransplant and thus no means of predicting the risk entailed in transplanting across a weak antibody. Generally, the best practice seems to be to

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Fig. 2.11  Standard curve for determining the molecular equivalents of soluble fluorochrome (MESF) values. Commercial beads with known quantities of fluorochrome molecules per bead are run on the flow cytometer to create a standard curve with the x-axis being the channel value read from the flow cytometer

and the y-axis being the number of fluorescent molecules that correspond to that channel value. The median channel value of a population of beads or cells can then be converted to MESF using the standard curve. These values are used as a quantitative reading for antibody strength

c­ onsider low levels of antibody to represent ­limited risk in a first transplant candidate, but to represent a significant deterrent to transplant in a patient who has previously rejected a graft. Patients with weak positive flow cross-matches are frequently earmarked for induction therapy, which has been shown to help reduce the incidence of AMR. Posttransplant monitoring for donor-specific antibody has proven useful in following patients transplanted across a positive flow cross-match since this can identify patients who are mounting a memory response and allow early interventions which have been shown to be effective in improving graft survival [75–79]. Long-term effects of an early AMR however have shown poorer long-term function and higher incidences of chronic graft rejection. B-cell cross-matches have proven to be a point of controversy in the assessment of risk in renal and pancreas transplant. B cells are helpful in that they generally carry a higher density of HLA antigen on their surface making them more sensitive and capable of detecting lower titers of anti-HLA antibody in the serum [80]. A classic example of this is in the case of a patient with only low titer anti-class I antibody. Frequently, these patients will have a negative T-cell CDC and/or flow cross-match with a positive B-cell cross-match. In these cases it might be thought

that if no anti-class II antibody has been detected in the patient’s serum the B-cell cross-match is false-positive and inconsequential. However, since B cells carry more class I antigens on a percell basis than do T cells a positive B-cell crossmatch can be an indicator of increased risk for AMR due to anti-class I antibody. In addition, a B-cell cross-match is the only cell-based assay available that can detect the presence of donorspecific anti-class II antibody since human T cells do not express class II antigens under normal circumstances. Since hyperacute rejection due to preformed anti-class II antibody has been reported the results of a B-cell cross-match pretransplant provides important, relevant information [81, 82]. Although HLA class II antigen is normally only expressed on antigen-presenting cells, inflammation can upregulate its expression on most human cells including T cells. Graft tissue can express HLA class II antigen under a variety of circumstances, including following reperfusion injury, surgical trauma, rejection episodes, and infection. Unfortunately, B-cell cross-matches have also proven to be a source of some confusion and consternation. B cells historically were difficult to isolate and the isolation techniques used, i.e., nylon wool separation, was hard on the cells, causing spontaneous cell death and

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loss of antigen expression on the remaining live cells. This meant that the B-cell cross-match took longer and was more difficult to perform. Fortunately, this is encountered less frequently today since newer cell isolation techniques have been developed that are more rapid and less harsh on the cells. Additionally, B cells are very frequently the target of autoantibodies. Therefore, without a thorough antibody history and knowledge of the autoantibody status of the candidate the risk attributable to a positive B-cell cross-match can be difficult to determine. Even the more modern B-cell crossmatch techniques such as flow cytometric cross-matches can be difficult to interpret due to the presence of Fc receptors which can nonspecifically bind immunoglobulin molecules to the B-cell surface. These issues have resulted in a longstanding debate in the literature as to the relevance of B-cell cross-match results in risk assessment. Although they can be controversial and difficult to interpret, this assay still provides unique, relevant information about the presence of donor-specific antibody. The usefulness of the B-cell cross-match is improved by the availability of the solid phase antibody detection systems and by pronase treatment of the cells used for flow cross-matches to remove the Fc receptors. It has been known for some time that antibodies to cellular antigens other than HLA can be deleterious to graft function and survival. With the availability of C4d staining and the sensitive, specific solid phase antibody assays it may be found that the non-HLA antibodies are a more frequent cause of graft injury than previously thought. The specificity of some of these antibodies has been determined but many antibodies remain to be identified. Often these antibodies are seen in conjunction with anti-HLA antibody, making it difficult to tease out their relative effects, but there are clear instances where C4d deposition is evident in the absence of any detectable donor-specific anti-HLA antibody. Unfortunately, assays to detect many of these antibodies are not generally available at this time. There is an anti-MICA antibody detection assay available that uses the Luminex platform

D.J. Pidwell and P.N. Lalli

and an assay has recently been introduced that detects antiendothelial cell antibodies, the XM-ONE assay [83]. XM-ONE can be run ­rapidly using the flow cytometer similar to a lymphocyte-based flow cross-match. The XM-ONE assay isolates precursor endothelial cells from donor peripheral blood using micromagnetic beads. Once isolated these cells are used as ­targets to detect antiendothelial cell ­antibody in patient serum. Preliminary work with this assay has shown that patients with a positive XM-ONE assay have increased incidence of rejection early posttransplant. As other antibodies to non-HLA antigens are identified and their relevance to graft survival is assessed, assays to detect the antibodies should become available. Due to the shortage of donor organs and the difficulty in finding compatible grafts for highly sensitized patients, there have been a number of techniques developed for the removal of antiHLA or natural anti-ABO antibody in order to permit transplant across previously positive cross-matches or of ABO incompatible grafts. Techniques employed include: (1) immunoabsorption, (2) splenectomy, (3) high- and lowdose IVIg, (4) plasmapheresis, (5) rituximab or other depleting antibodies, and most recently (6) bortezomib [84–90]. Usually the protocols use a combination of these techniques to lower the antibody concentration to a point considered safe. A number of transplant centers have had very good results with these protocols. These same techniques have been shown to be advantageous when used posttransplant to treat AMR. There are disadvantages to desensitization protocols, including the increased incidence of antibody-mediated rejection, increased susceptibility to infection following plasmapheresis, and the high cost of treatment. However, these treatments have permitted transplant of patients where transplant would previously have been precluded. Whether these approaches are employed pretransplant or posttransplant to remove anti-HLA antibody the histocompatibility laboratory usually has an active role in monitoring the levels of antibody throughout treatment and often for

2  The Histocompatibility Laboratory in Clinical Transplantation

periods of time posttreatment to determine if antibody titers return [91–93]. The success of desensitization protocols depends on good communication between the laboratory, physicians, and apheresis teams. Often solid phase assays are used to monitor antibody levels during and following desensitization procedures. In some cases high serum levels of IVIg can interfere with solid phase antibody testing, so timing of sample collection can be crucial. CDC assays for monitoring the effects of IVIg in desensitization have been developed by the histocompatibility laboratory at Cedars-Sinai when their protocol for desensitization using high-dose IVIg was being investigated [94]. Ironically, despite the fact that the role of T cells in graft rejection has been understood since early in the practice of transplantation, there are no methods for assessing the antidonor reactivity of T lymphocytes prior to transplant. The MLC was first thought to reflect the capacity of recipient T cells to respond to donor tissue, but it has been found over time that the reactivity in MLC assays does not correlate well with outcomes. This, in addition to the length of time required to perform an MLC, have made this assay of minimal use for patient management. More recently an ELISPOT assay which measures gamma interferon (IFNg) production by T cells stimulated with allogeneic B cells has been reported by Heeger and colleagues [95–97]. The procedure uses a panel of 20 B cells from different donors, analogous to the panel of cells used for PRA analysis. The B cells in the panel are chosen to give a broad representation of HLA phenotypes. These B cells are cultured on CD40 transfected feeder cells, so the B cells are not virally transformed and there is no viral antigen present to contribute to the T-cell stimulation. Recipient T cells are stimulated for 18 h with each of the 20 different cells and IFNg production is detected by ELISPOT. The percent of the B-cell panel that stimulates increased IFNg production is called the panel reactive T cells (PRT). This assay is still in the research stage, but is showing promise in identifying patients who have memory T cells that could be at risk for increased reactivity posttransplant.

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One other assay that measures T-cell activation is the ImmuKnow assay. This assay measures ATP production during polyclonal CD4+ T cell activation with the mitogen phytohemagglutinin (PHA). The ATP levels are divided into three zones, low, moderate, and high reactivity. Clinical correlation of the ATP production with patient status has demonstrated that patients who fall into the high activity range may be under immunosuppressed and are at increased risk for acute rejection, and patients in the low activity range are frequently experiencing viral infections [98–101]. Since the cells are stimulated with a polyclonal mitogen, there is no allo-­ specificity to this assay and it does not yield any information of donor-specific responsiveness.

Our Future The cooperative relationship between the renal/ renal–pancreas transplant community and the histocompatibility laboratory has been a long and productive one. Laboratories, transplant physicians, and transplant surgeons have worked together consistently and diligently to evaluate the relationship between laboratory results and transplant outcomes in an effort to expand our understanding of transplantation and the alloimmune response. Laboratories have and will continue to work to develop means of assessing the risk associated with any specific donor–­recipient pair and to help translate this information into clinical usage. Research is beginning to identify biomarkers that will help with the diagnosis of rejection and hopefully biomarkers of pre-transplant risk will begin to be identified. Many histocompatibility laboratories have large archives of transplant candidate and recipient sera that are being stored frozen. These sera should prove to be a resource for identity of pre and posttransplant markers. The goal of the laboratory is to serve the patients and physicians of the transplant centers they serve and to work in conjunction with the transplant community to further the success of transplantation as a whole.

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References 1. Rodey GE. HLA Beyond Tears: Introduction to Human Histocompatibility, 2nd edn. Durango, CO: De Novo, 2000. 2. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins. JAMA 1956;160(4):277–282. 3. Terasaki PI, McClelland JD. Microdroplet assay of human serum cytotoxins. Nature 1964;204:998–1000. 4. Sandberg L, Blohme I, Brynger H, Lindholm A, Gelin LE. The importance of HLA matching in primary cadaveric kidney transplantation in Gothenburg. Proc Eur Dial Transplant Assoc 1977;14:277–284. 5. Thorsby E, Solheim BG, Ottem A, Flatmark A, Enger E. Influence of HLA matching on kidney graft survival. Scand J Urol Nephrol 1975(29 Suppl):7–10. 6. Simmons RL, Yunis EJ, Noreen H, Thompson EJ, Fryd DS, Najarian JS. Effect of HLA matching on cadaver kidney function: experience at a single large center. Transplant Proc 1977;9(1):491–493. 7. McDonald JC, Vaughn W, Filo RS, et  al. Cadaver donor renal transplantation by centers of the Southeastern Organ Procurement Foundation. Ann Surg 1981;193(1):1–8. 8. Berg B, Groth CG, Lundgren G, Magnusson G, Moller E, Ringden O. The influence of HLA-D matching on the outcome of intrafamilial kidney transplantation with special emphasis on the predictive value of the relative response in MLC. Scand J Urol Nephrol Suppl 1981;64:46–51. 9. Ringden O, Groth CG, Lundgren G, Moller E. Prognostic value of HL-A typing and mixed lymphocyte culture tests in kidney transplantations from living related donors. Scand J Urol Nephrol 1975(29 Suppl):15–18. 10. Terasaki PI, Park MS, Opelz G, Saito S, Mickey MR. The role of B-lymphocyte antigens in MLC stimulation. Transplant Proc 1977;9(1):469–473. 11. Solheim BG, Flatmark A, Enger E, Jervell J, Thorsby E. Influence of HLA-A, -B, -C, and -D matching on the outcome of clinical kidney transplantation. Transplant Proc 1977;9(1):475–478. 12. Steinmann J, Kaden J, May G, Schroder K, Herwartz C, Muller-Ruchholtz W. Failure of in vitro T-cell assays to predict clinical outcome after human kidney transplantation. J Clin Lab Anal 1994;8(3):157–162. 13. Persijn GG, Gabb BW, van Leeuwen A, Nagtegaal A, Hoogeboom J, van Rood JJ. Matching for HLA antigens of A, B, and DR loci in renal transplantation by Eurotransplant. Lancet 1978; 1(8077):1278–1281. 14. Ting A, Morris PJ. Powerful effect of HL-DR matching on survival of cadaveric renal allografts. Lancet 1980;2(8189):282–285. 15. Svejgaard A, Thomsen M. Developments in histocompatibility testing. Proc Eur Dial Transplant Assoc 1976;12:121–128.

D.J. Pidwell and P.N. Lalli 16. Patel R, Terasaki PI. Significance of the positive cross-match test in kidney transplantation. NEJM 1969;280(14):735–739. 17. Ferguson RM, Simmons RL, Noreen H, Yunis EJ, Najarian JS. Host presensitization and renal allograft success at a single institution: first transplants. Surgery 1977;81(2):139–145. 18. Claas FH, Paul LC, van Es LA, van Rood JJ. Antibodies against donor antigens on endothelial cells and monocytes in eluates of rejected kidney allografts. Tissue Antigens 1980;15(1):19–24. 19. Moraes JR, Stastny P. A new antigen system expressed in human endothelial cells. J Clin Invest 1977;60(2):449–454. 20. Mizutani K, Terasaki PI, Shih RN, Pei R, Ozawa M, Lee J. Frequency of MIC antibody in rejected renal transplant patients without HLA antibody. Hum Immunol 2006;67(3):223–229. 21. Wissing KM, Fomegne G, Broeders N, et al. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation 2008;85(3):411–416. 22. Aydingoz SE, Takemoto SK, Pinsky BW, et al. The impact of human leukocyte antigen matching on transplant complications and immunosuppression dosage. Hum Immunol 2007;68(6):491–499. 23. Diethelm AG, Blackstone EH, Naftel DC, et  al. Important risk factors of allograft survival in cadaveric renal transplantation. A study of 426 patients. Ann Surg 1988;207(5):538–548. 24. Kerman RH, Kimball PM, Van Buren CT, Lewis RM, Kahan BD. Possible contribution of pretransplant immune responder status to renal allograft survival differences of black versus white recipients. Transplantation 1991;51(2):338–342. 25. Pascual J, Samaniego MD, Torrealba JR, et  al. Antibody-mediated rejection of the kidney after simultaneous pancreas-kidney transplantation. J Am Soc Nephrol 2008;19(4):812–824. 26. Doxiadis, II, Claas FH. The short story of HLA and its methods. Dev Ophthalmol 2003;36:5–11. 27. Schreuder GM, Hurley CK, Marsh SG, et al. HLA dictionary 2004: summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens. Hum Immunol 2005;66(2):170–210. 28. Hinrichs J, Figueiredo C, Hirv K, et al. Discrimination of HLA null and low expression alleles by cytokineinduced secretion of recombinant soluble HLA. Mol Immunol 2009;46(7):1451–1457. 29. Howell WM, Navarrete C. The HLA system: an update and relevance to patient-donor matching strategies in clinical transplantation. Vox Sang 1996;71(1):6–12. 30. Milford EL. HLA molecular typing. Curr Opin Nephrol Hypertens 1993;2(6):892–897. 31. Leffell MS, Montgomery RA, Zachary AA. The changing role of antibody testing in transplantation. Clin Transpl 2005:259–271.

2  The Histocompatibility Laboratory in Clinical Transplantation 32. Vlad G, Ho EK, Vasilescu ER, et al. Relevance of different antibody detection methods for the prediction of antibody-mediated rejection and deceaseddonor kidney allograft survival. Hum Immunol 2009;70(8):589–594. 33. Zeevi A, Lunz JG, 3 rd, Shapiro R, et al. Emerging role of donor-specific anti-human leukocyte antigen antibody determination for clinical management after solid organ transplantation. Hum Immunol 2009;70(8):645–650. 34. Bray RA, Gebel HM. Strategies for human leukocyte antigen antibody detection. Curr Opin Organ Transplant 2009;14(4):392–397. 35. Al-Lamki RS, Bradley JR, Pober JS. Endothelial cells in allograft rejection. Transplantation 2008;86(10):1340–1348. 36. Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol 2008;25:61–74. 37. Schenk AD, Nozaki T, Rabant M, Valujskikh A, Fairchild RL. Donor-reactive CD8 memory T cells infiltrate cardiac allografts within 24-h posttransplant in naive recipients. Am J Transplant 2008;8(8):1652–1661. 38. Jones ND. Memory T cells: how might they disrupt the induction of tolerance? Transplantation 2009;87(9 Suppl):S74–77. 39. Kaden J, May G, Volp A, Wesslau C. Improved long-term survival after intra-operative single highdose ATG-Fresenius induction in renal transplantation: a single centre experience. Ann Transplant 2009;14(3):7–17. 40. Taber DJ, Weimert NA, Henderson F, et  al. Longterm efficacy of induction therapy with anti-interleukin-2 receptor antibodies or thymoglobulin compared with no induction therapy in renal transplantation. Transplant Proc 2008;40(10):3401–3407. 41. Yang SL, Wang D, Wu WZ, et  al. Comparison of single bolus ATG and Basiliximab as induction therapy in presensitized renal allograft recipients receiving tacrolimus-based immunosuppressive regimen. Transpl Immunol 2008;18(3):281–285. 42. Arnold ML, Zacher T, Dechant M, Kalden JR, Doxiadis, II, Spriewald BM. Detection and specification of noncomplement binding anti-HLA alloantibodies. Hum Immunol 2004;65(11):1288–1296. 43. Fuller TC, Fuller AA, Golden M, Rodey GE. HLA alloantibodies and the mechanism of the antiglobulin-augmented lymphocytotoxicity procedure. Hum Immunol 1997;56(1-2):94–105. 44. Fuller TC, Phelan D, Gebel HM, Rodey GE. Antigenic specificity of antibody reactive in the antiglobulin-augmented lymphocytotoxicity test. Transplantation 1982;34(1):24–29. 45. Shroyer TW, Deierhoi MH, Mink CA, et al. A rapid flow cytometry assay for HLA antibody detection using a pooled cell panel covering 14 serological crossreacting groups. Transplantation 1995;59(4):626–630. 46. Bray RA, Gebel HM, Ellis TM. Flow cytometric assessment of HLA alloantibodies. Curr Protoc Cytom 2004;6(6):16.

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47. Lee PC, Ozawa M. Reappraisal of HLA antibody analysis and cross-matching in kidney transplantation. Clin Transpl 2007:219–226. 48. Tait BD, Hudson F, Cantwell L, et al. Review article: Luminexx technology for HLA antibody detection in organ transplantation. Nephrology (Carlton) 2009;14(2):247–254. 49. Zachary AA, Ratner LE, Graziani JA, Lucas DP, Delaney NL, Leffell MS. Characterization of HLA class I specific antibodies by ELISA using solubilized antigen targets: II. Clinical relevance. Hum Immunol 2001;62(3):236–246. 50. Amico P, Honger G, Mayr M, Steiger J, Hopfer H, Schaub S. Clinical relevance of pretransplant donorspecific HLA antibodies detected by single-antigen flow-beads. Transplantation 2009;87(11):1681–1688. 51. El-Awar N, Lee J, Terasaki PI. HLA antibody identification with single antigen beads compared to conventional methods. Hum Immunol 2005;66(9):989–997. 52. Qiu J, Cai J, Terasaki PI, El-Awar N, Lee JH. Detection of antibodies to HLA-DP in renal transplant recipients using single antigen beads. Transplantation 2005;80(10):1511–1513. 53. Waterboer T, Sehr P, Pawlita M. Suppression of nonspecific binding in serological Luminexx assays. J Immunol Methods 2006;309(1–2):200–204. 54. Amico P, Honger G, Steiger J, Schaub S. Utility of the virtual cross-match in solid organ transplantation. Curr Opin Organ Transplant 2009;14(6):656–661. 55. Nikaein A, Cherikh W, Nelson K, et al. Organ procurement and transplantation network/united network for organ sharing histocompatibility committee collaborative study to evaluate prediction of crossmatch results in highly sensitized patients. Transplantation 2009;87(4):557–562. 56. Tambur AR, Leventhal J, Kaufman DB, Friedewald J, Miller J, Abecassis MM. Tailoring antibody testing and how to use it in the calculated panel reactive antibody era: the Northwestern University experience. Transplantation 2008;86(8):1052–1059. 57. Zachary AA, Sholander JT, Houp JA, Leffell MS. Using real data for a virtual cross-match. Hum Immunol 2009;70(8):574–579. 58. Bielmann D, Honger G, Lutz D, Mihatsch MJ, Steiger J, Schaub S. Pretransplant risk assessment in renal allograft recipients using virtual cross-matching. Am J Transplant 2007;7(3):626–632. 59. Montgomery RA, Hardy MA, Jordan SC, et  al. Consensus opinion from the antibody working group on the diagnosis, reporting, and risk assessment for antibody-mediated rejection and desensitization protocols. Transplantation 2004;78(2):181–185. 60. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8(4):753–760. 61. Gloor JM, Moore SB, Schneider BA, Degoey SR, Stegall MD. The effect of antithymocyte globulin on anti-human leukocyte antigen antibody detection assays. Transplantation 2007;84(2):258–264.

46 62. Billen EV, Christiaans MH, van den Berg-Loonen EM. Clinical relevance of Luminexx donor-specific cross-matches: data from 165 renal transplants. Tissue Antigens 2009;74(3):205–212. 63. Billen EV, Voorter CE, Christiaans MH, van den Berg-Loonen EM. Luminexx donor-specific crossmatches. Tissue Antigens 2008;71(6):507–513. 64. Bray RA, Lebeck LK, Gebel HM. The flow cytometric cross-match. Dual-color analysis of T cell and B cell reactivities. Transplantation 1989;48(5):834–840. 65. Scornik JC, Brunson ME, Schaub B, Howard RJ, Pfaff WW. The cross-match in renal transplantation. Evaluation of flow cytometry as a replacement for standard cytotoxicity. Transplantation 1994;57(4):621–625. 66. Utzig MJ, Blumke M, Wolff-Vorbeck G, Lang H, Kirste G. Flow cytometry cross-match: a method for predicting graft rejection. Transplantation 1997;63(4):551–554. 67. Ogura K, Terasaki PI, Johnson C, et al. The significance of a positive flow cytometry cross-match test in primary kidney transplantation. Transplantation 1993;56(2):294–298. 68. Scornik JC, Bray RA, Pollack MS, et al. Multicenter evaluation of the flow cytometry T-cell crossmatch: results from the American Society of Histocompatibility and Immunogenetics-College of American Pathologists proficiency testing program. Transplantation 1997;63(10):1440–1445. 69. Thistlethwaite JR, Jr., Buckingham M, Stuart JK, Gaber AO, Mayes JT, Stuart FP. T cell immunofluorescence flow cytometry cross-match results in cadaver donor renal transplantation. Transplant Proc 1987;19(1 Pt 1):722–724. 70. Limaye S, O’Kelly P, Harmon G, et  al. Improved graft survival in highly sensitized patients undergoing renal transplantation after the introduction of a clinically validated flow cytometry cross-match. Transplantation 2009;87(7):1052–1056. 71. Bray RA, Nickerson PW, Kerman RH, Gebel HM. Evolution of HLA antibody detection: technology emulating biology. Immunol Res 2004;29(1–3):41–54. 72. Christiaans M, Van den Berg-Loonen E, Ten Haaft A, Nieman F, Van Hooff J. Effect of flow cytometry, complement-dependent cytotoxicity, and auto cross match on cadaveric renal transplant outcome. Transplant Proc 1995;27(1):1028–1030. 73. Talbot D, Givan AL, Shenton BK, Stratton A, Proud G, Taylor RM. The relevance of a more sensitive crossmatch assay to renal transplantation. Transplantation 1989;47(3):552–555. 74. Gebel HM, Harris SB, Zibari G, Bray RA. Conundrums with FlowPRA beads. Clin Transplant 2002;16(Suppl 7):24–29. 75. Akalin E. Posttransplant immunosuppression in highly sensitized patients. Contrib Nephrol 2009;162:27–34. 76. Akalin E, Dinavahi R, Friedlander R, et al. Addition of plasmapheresis decreases the incidence of acute antibody-mediated rejection in sensitized patients with strong donor-specific antibodies. Clin J Am Soc Nephrol 2008;3(4):1160–1167.

D.J. Pidwell and P.N. Lalli 77. Zhu L, Lee PC, Everly MJ, Terasaki PI. Detailed examination of HLA antibody development on renal allograft failure and function. Clin Transpl 2008:171–187. 78. Burns JM, Cornell LD, Perry DK, et  al. Alloantibody levels and acute humoral rejection early after positive cross-match kidney transplantation. Am J Transplant 2008;8(12):2684–2694. 79. Everly MJ, Everly JJ, Arend LJ, et  al. Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. Am J Transplant 2009;9(5):1063–1071. 80. Pellegrino MA, Belvedere M, Pellegrino AG, Ferrone S. B peripheral lymphocytes express more HLA antigens than T peripheral lymphocytes. Transplantation 1978;25(2):93–95. 81. Lobo PI, Spencer CE, Isaacs RB, McCullough C. Hyperacute renal allograft rejection from anti-HLA class 1 antibody to B cells – antibody detection by two color FCXM was possible only after using pronase-digested donor lymphocytes. Transpl Int 1997;10(1):69–73. 82. Scornik JC, LeFor WM, Cicciarelli JC, et  al. Hyperacute and acute kidney graft rejection due to antibodies against B cells. Transplantation 1992;54(1):61–64. 83. Breimer ME, Rydberg L, Jackson AM, et  al. Multicenter evaluation of a novel endothelial cell cross-match test in kidney transplantation. Transplantation 2009;87(4):549–556. 84. Gloor JM, Lager DJ, Fidler ME, et al. A Comparison of splenectomy versus intensive posttransplant antidonor blood group antibody monitoring without splenectomy in ABO-incompatible kidney transplantation. Transplantation 2005;80(11):1572–1577. 85. Jordan SC, Vo A, Tyan D, Toyota M. Desensitization therapy with intravenous gammaglobulin (IVIG): applications in solid organ transplantation. Trans Am Clin Climatol Assoc 2006;117:199–211; discussion 211. 86. Montgomery RA, Zachary AA. Transplanting patients with a positive donor-specific cross-match: a single center’s perspective. Pediatr Transplant 2004;8(6):535–542. 87. Perry DK, Burns JM, Pollinger HS, et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant 2009;9(1):201–209. 88. Warren DS, Zachary AA, Sonnenday CJ, et  al. Successful renal transplantation across simultaneous ABO incompatible and positive cross-match barriers. Am J Transplant. Apr 2004;4(4):561–568. 89. Pretagostini R, Berloco P, Poli L, et  al. Immunoadsorption with protein A in humoral rejection of kidney transplants. ASAIO J 1996;42(5):M645–648. 90. Yin H, Hu XP, Li XB, et al. Protein A immunoadsorption combined with rituximab in highly sensitized kidney transplant recipients. Chin Med J (Engl) 2009;122(22):2752–2756.

2  The Histocompatibility Laboratory in Clinical Transplantation 91. Leffell MS, Zachary AA. The role of the histocompatibility laboratory in desensitization for transplantation. Curr Opin Organ Transplant 2009;14(4):398–402. 92. Zachary AA, Leffell MS. Detecting and monitoring human leukocyte antigen-specific antibodies. Hum Immunol 2008;69(10):591–604. 93. Zachary AA, Montgomery RA, Leffell MS. Factors associated with and predictive of persistence of donor-specific antibody after treatment with plasmapheresis and intravenous immunoglobulin. Hum Immunol 2005;66(4):364–370. 94. Jordan SC, Vo A, Bunnapradist S, et al. Intravenous immune globulin treatment inhibits cross-match positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients. Transplantation 2003;76(4):631–636. 95. Augustine JJ, Siu DS, Clemente MJ, Schulak JA, Heeger PS, Hricik DE. Pre-transplant IFN-gamma ELISPOTs are associated with post-transplant renal function in African American renal transplant recipients. Am J Transplant 2005;5(8):1971–1975. 96. Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor-specific, IFNgamma-producing lymphocytes is a manifestation

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of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol 1999;163(4):2267–2275. 97. Poggio ED, Clemente M, Hricik DE, Heeger PS. Panel of reactive T cells as a measurement of primed cellular alloimmunity in kidney transplant candidates. J Am Soc Nephrol 2006;17(2):564–572. 98. Gautam A, Fischer SA, Yango AF, Gohh RY, Morrissey PE, Monaco AP. Cell mediated immunity (CMI) and posttransplant viral infections – role of a functional immune assay to titrate immunosuppression. Int Immunopharmacol 2006;6(13–14):2023–2026. 99. Husain S, Raza K, Pilewski JM, et  al. Experience with immune monitoring in lung transplant recipients: correlation of low immune function with infection. Transplantation 2009;87(12):1852–1857. 100. Kowalski RJ, Post DR, Mannon RB, et al. Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay. Transplantation 2006;82(5):663–668. 101. Serban G, Whittaker V, Fan J, et al. Significance of immune cell function monitoring in renal transplantation after Thymoglobulin induction therapy. Hum Immunol 2009;70(11):882–890.

Chapter 3

Immunosuppressive Therapy in Kidney and Pancreas Transplantation George Thomas, Saul Nurko, and Titte R. Srinivas

Keywords  Immunosuppression • kidney transplant • regimens

Introduction Successful transplantation in the clinical setting represents a state of dynamic interplay between adaptive alloimmune responses, the donor organ, and pharmacologic immunosuppression. As such, immunosuppressive therapy remains key to optimal graft and patient survival. This chapter provides a brief overview of the immunosuppressive drugs that are currently in use, the combination drug regimens that are commonly used in kidney and pancreas transplantation, the reported outcomes with these regimens, and some experimental immunosuppressive agents that are in advanced clinical development. We also discuss the treatment of acute rejection episodes. We then summarize the evidence that could help the transplant physician in regimen selection and design. The details of pharmacokinetics of individual drugs and an overview of clinical pharmacokinetics for the transplant physician are discussed in detail in a separate chapter (see Chap. 4).

T.R. Srinivas (*) Nephrology and Hypertension, Glickman Urologic and Kidney Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]

Trends in Immunosuppression Immunosuppression in renal transplantation has evolved from the use of total body irradiation, to the use of azathioprine and steroids in the 1960s up to the early 1980s, to cyclosporine therapy in the late 1980s [1–3]. The limited number of available immunosuppressive medications during that time resulted in little variation in protocols between centers. The 1990s then saw the introduction of tacrolimus, mycophenolate mofetil (MMF), and sirolimus, permitting a variety of combinations to be used for immunosuppressive therapy. The armamentarium continues to broaden with many potential combinations and protocols. The incidence of reported acute rejection in the current era ranges between 10% and 20%, a figure that is far lower than the 45–50% rate in the azathioprine era. However, it should also be noted that the negative impact of acute rejection episodes on graft survival has increased in recent years, likely reflecting selection pressure that allows the emergence of more treatment resistant acute rejections with potent immunosuppression [4]. Long-term allograft survival is slowly increasing, particularly among deceased donor transplants. This gain in long-term graft survival is, however, not as notable as the gains in lower acute rejection rates [3, 5]. The gain in transplant survival also presumably reflects multiple factors, including more effective but not significantly more toxic immunosuppressive regimens, better understanding in the use of

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_3, © Springer Science+Business Media, LLC 2011

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immunosuppression, better pretransplantation and posttransplantation general medical care, and more effective prevention and treatment of opportunistic infections (particularly CMV infection). This optimism has been tempered by the emergence of new threats to graft survival such as polyoma (BK virus, BKV) nephropathy [6].

Immunosuppressive Drugs Versus Regimens In the modern era of clinical transplantation, immunosuppressants are usually used in combination multi-drug regimens. The use of immunosuppressive regimens rather than individual drugs aims to increase efficacy with their use in combination, by targeting multiple pathways to dampen immune response in the allograft, and to decrease toxicity of individual agents by allowing lower doses of individual agents when used in combination. Many immunosuppressive regimens have been evaluated, with the general strategy being enhancement of long-term allograft survival without compromising short-term allograft survival, while minimizing toxicity. These regimens may involve withdrawal, avoidance, or minimization of certain classes of drugs, notably corticosteroids and calcineurin inhibitors. Transplant programs generally institute their immunosuppressive protocols based on institutional experience, risk profiles of their patient populations, cost considerations, and outcomes. Immunosuppression for renal and pancreas transplantation is delivered typically in two phases, induction and maintenance. Induction therapy involves the use of augmented immunosuppression in the immediate posttransplant phase when the risk of acute rejection is highest. This induction therapy may consist of augmented doses of a drug to be continued in the maintenance phase (tacrolimus or cyclosporine) or an adjunctive biologic agent

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(such as polyclonal or monoclonal anti-T cell antibody). The use of biologic agents affords a window of opportunity to achieve therapeutic levels of orally administered maintenance agents. Induction may also permit delayed introduction of calcineurin inhibitors in renal allografts that are not functioning optimally. Maintenance immunosuppression is usually delivered by orally administered drugs that are used in a combination which will be continued for the life of the allograft. The intensity of maintenance immunosuppression is highest in the first 3 months posttransplant and is tapered in a structured manner. This taper is critical in ensuring that toxicities of individual agents are minimized and also in preventing overimmunosuppression with the ever-present risk of infection and malignancy. Antiinfective agents are adjuncts to these regimens and are used to prevent bacterial, viral and fungal infections. The components of a conventional immunosuppressive protocol often include the following agents: 1. Induction therapy with anti-T lymphocyte depleting or nondepleting antibodies 2. Maintenance therapy (a) Calcineurin inhibitors (CNI) – cyclosporine, tacrolimus (b)  Corticosteroids (c) Antiproliferative agents – antimetabolites (azathioprine), nucleotide synthesis inhibitors (mycophenolate mofetil) and m-TOR inhibitors (sirolimus and everolimus) 3. Infection prophylaxis – sulfamethoxazole and trimethoprim (urinary tract infection, Pneumocystis jiroveci), valganciclovir (cytomegalovirus [CMV]) Table 3.1 provides a classification of clinically available agents and those under investigation currently. Table 3.2 provides an overview of mechanisms of action of clinically used maintenance agents. Table 3.3 provides an overview of dosing and pharmacokinetics of relevance in clinical practice. Table  3.4 provides an overview of currently used immunosuppressive regimens [7–9].

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation Table 3.1  Classification of immunosuppressive therapies currently in use or in experimental trials (Adapted from [7]) Glucocorticoids Small-molecule drugs Immunophilin-binding drugs Calcineurin inhibitors Cyclophilin-binding drugs: cyclosporine, ISA 247 (voclosporin) FKBP binding drugs: tacrolimus Target-of-rapamycin inhibitors: sirolimus, everolimus Inhibitors of nucleotide synthesis Purine synthesis (IMPDH) inhibitors Mycophenolate mofetil (MMF) Mizoribine (used in Japan) Pyrimidine synthesis inhibitors Leflunomide FK 778 (development stopped after no clinical benefit in initial trials) Antimetabolites: azathioprine Sphingosine-1-phosphate receptor antagonists: FTY720 (fingolimod) Janus kinase inhibitors (CP-690550) Protein kinase C inhibitors (sotrastaurin) Protein drugs Depleting antibodies Polyclonal antibody: horse or rabbit antithymocyte globulin Mouse monoclonal anti-CD3 antibody (muromonab CD3) Humanized monoclonal anti-CD52 antibody (alemtuzumab) B cell depleting monoclonal anti-CD 20 antibody (rituximab) Proteasome inhibitors (bortezomib) Nondepleting antibodies and fusion proteins Humanized or chimeric monoclonal anti-CD25 antibody (daclizumab, basiliximab) Fusion protein: belatacept (LEA29Y), alefacept Intravenous immune globulin IVIG CMVIG

Sites and Mechanisms of Action of Immunosuppressive Agents The sites of action of individual immunosuppressive drugs are depicted in Fig. 3.1. The three signal mechanistic model of T-cell activation and proliferation provides a useful paradigm for understanding the sites and mechanisms of action

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of immunosuppressive agents [7]. Signal 1 (antigen recognition) is antigen-specific and provided by the interaction of antigen presenting cells (APC) with the T-cell antigen receptor, and transduced by the CD3 molecule to the cell’s interior (see Fig. 3.1). Signal 2 (costimulation) is nonantigen specific and is provided by the interaction of B7 on the APC surface with CD28 on the T-cell surface (see Fig.  3.1). Signal 1 in conjunction with Signal 2 activates intracellular pathways that lead to the expression of IL-2 and other T-cell growth promoting cytokines (see Fig. 3.1). Signal 3 is provided by the interaction of IL-2 with its receptor (CD 25) and the activation of pathways that trigger cell proliferation, the JAK-3 pathway, and the more proximate cellcycle regulatory mammalian target of rapamycin (m-TOR) pathway (see Fig. 3.1). The calcineurin inhibitors, tacrolimus and cyclosporine, block critical pathways in the transcription of several genes critical to T-cell activation, most notably IL-2 [7]. This effect of calcineurin inhibitors (in the therapeutic range) does not affect cell surface recognition events or responses to infection. Corticosteroids in high doses block transcription of gene transcription of multiple cytokine genes involved in antigen presentation and T-cell activation/proliferation in addition to their wellknown antiinflammatory effects [7]. The m-TOR inhibitors block the ability of the T cell to respond to proliferative signals from cytokines. Antimetabolites such as azathioprine and mycophenolate mofetil block the ability of lymphocytes to proliferate by impairing nucleotide synthesis [7]. Depleting antibodies (e.g., rabbit antithymocyte globulin, r-ATG) bind to the target cell leading to their removal by the reticuloendothelial system, and thus reduce the alloreactive burden [7]. The nondepleting (anti-CD 25) antibodies block the interaction of the growth factor IL-2 to its cell surface receptor on the T-cell [7]. Based on the foregoing, one can see then that multiple avenues exist to block the immune response to alloantigen. Blockade of these pathways in combination with varying intensity and sequence of individual agents forms the cornerstone of modern clinical immunosuppression.

1. Administration with mycophenolate mofetil or sirolimus can exacerbate hematologic side effects 2. Allopurinol increases levels because of xanthine oxidase inhibition leading to toxicity 1. Cyclosporine lowers MPA exposure because of decreased enterohepatic recycling 2. Intestinal absorption may be affected by antacids, iron, and cholestyramine Sirolimus can enhance the toxicity of calcineurin inhibitors. Sirolimus can have similar interactions as calcineurin inhibitors to antituberculous agents, anticonvulsants, calcium channel blockers Anticonvulsants can lower steroid levels; oral contraceptives and ketoconazole can increase levels. Some calcium channel blockers (diltiazem, verapamil) can increase levels

Hematologic side effects – leukopenia, thrombocytopenia; hepatitis, cholestasis

GI side effects – diarrhea, nausea/vomiting; leukopenia, anemia, thrombocytopenia. (nephrotoxicity, hepatotoxicity, and neurotoxicity have not been observed with mycophenolate mofetil)

Impaired wound healing, nephrotoxicity (with calcineurin inhibitors), hyperlipidemia, cytopenias

Cosmetic changes, osteoporosis and osteonecrosis, impaired wound healing and resistance to infection, glucose intolerance, hyperlipidemia

Purine analogue that is incorporated into DNA, where it inhibits purine nucleotide synthesis and interferes with synthesis and metabolism of RNA, thereby preventing cell proliferation

Active moiety mycophenolic acid (MPA) inhibits inosine monophosphate dehydrogenase (IMPDH), affecting de novo synthesis of purines and blocking proliferation of T cells and B cells. Decreased smooth muscle proliferation

Binds to tacrolimus binding protein (FKBP) and inhibits protein known as target of rapamycin (TOR), which reduces cytokine dependent cell proliferation at the G1 to S phase of cell division cycle

Multiple effects, including blockade of T-cell-derived and antigen-presenting cell-derived cytokine and cytokine-receptor expression; blocks synthesis, release, and action of chemokines

Azathioprine

Mycophenolate mofetil (MMF)

Sirolimus, everolimus

Corticosteroids

Table 3.2  Mechanism of action, side effects and drug interactions of individual maintenance immunosuppressive drugs (Adapted from [7]) Drug Mechanism of action Side effects Drug interactions Drugs that decrease calcineurin inhibitor Renal dysfunction, hirsutism, hypertension, gum hyperplaCyclosporine Complexes with cyclophilin and binds to concentration: sia, hypercholesterolemia, hyperuricemia, hypercalcineurin, impairing transcription of kalemia, hypomagnesemia, thrombotic cytokine genes (primarily IL2) that 1. Antituberculous drugs microangiopathy promote T-cell activation 2. Anticonvulsants Drugs that increase calcineurin inhibitor concentration: 1. Calcium channel blockers Renal dysfunction, hyperkalemia, hypomagnesemia, Tacrolimus Complexes with tacrolimus binding protein glucose intolerance, neurotoxicity (tremors, posterior (FKBP) and binds to calcineurin, 2. Antifungal agents reversible encephalopathy syndrome), thrombotic impairing transcription of cytokine genes 3. Erythromycin microangiopathy that promote T-cell activation (primarily 4. Histamine blockers IL2)

52 G. Thomas et al.

Myfortic (entericcoated) Rapamune

Bioavailability (%) 30 ± 13

5–15 mg/day

720 mg twice daily

0.3 mg/kg/day in two divided doses 2–3 g/day in 2 divided doses 2–4 mg/L (MPA)

1:1

2–4 mg/L (MPA)

5–10

NA

10–15

5–10

Purported to have lower GI side effects

10–15

4:1

62 ± 16

16

18.9

11.4 ± 4.4

15

90

19.7 ± 10.4

3.5 ± 1.6 mL/ min/kg

193 ± 48 mL/ min

3.5 ± 1.6 mL/ min/kg

Mean ± SD, MMF mycophenolate mofetil, MPA mycophenolic acid, MPAG mycophenolic acid glucuronide, NA not applicable, PK pharmacokinetics Also see detailed discussion in Chap. 4

Sirolimus [149]

MMF [56]

Tacrolimus [148]

Gengraf

t1/2 (h)

Rapid GI absorption, but low bioavailability due to extensive intestinal and hepatic metabolism

Hydrolyzed to MPA (active form) which is glucuronidated to MPAG; entero- hepatic cycling of MPAG produces a second peak effect at 5–6 h

Variable oral absorption

Clearance Comments 5.7 ± 1.8 mL/ Variable oral min/kg absorption 7.3 ± 1.6 73 ± 22 4.9 ± 1.5 mL/ Better GI min/kg absorption Generic formulation with FDA AB rating (i.e., it may be substituted for Neoral without prescriber approval; equivalent PK)

Table 3.3  Pharmacokinetics of common maintenance immunosuppressive drugs Target trough concentration (ng/mL) Maintenance (tapering after Initial (first Usual starting Oral to IV 3 months) 3 months) Drug Formulation dose conversion 3:1 250–350 150–250 Cyclosporine Sandimmune 8–17 mg/kg/day [146] Neoral [147] 8–12 mg/kg/day 3:1 250–350 150–250

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation 53

Sirolimus, mycophenolate mofetil, prednisone taper Sirolimus, prednisone taper

Anti-CD 25 antibody, r-ATG, or none

Anti-CD 25 antibody

Anti-CD 25 antibody, r-ATG, or none

Anti-CD 25 antibody, r-ATG, or none Alemtuzumab

Calcineurin inhibitor withdrawal with mycophenolate mofetil maintenance [150]

Calcineurin inhibitor withdrawal with sirolimus and mycophenolate mofetil maintenance [73] Calcineurin inhibitor avoidance with sirolimus and mycophenolate mofetil maintenance [62, 120] Sirolimus with cyclosporine withdrawal [73, 74] Alemtuzumab induction [154, 155] Tacrolimus, mycophenolate mofetil

Sirolimus, mycophenolate mofetil, prednisone taper

Anti-CD 25 antibody or r-ATG

Maintenance Calcineurin inhibitor, mycophenolate mofetil, prednisone Calcineurin inhibitor, mycophenolate mofetil; corticosteroids stopped at 3–5 days Calcineurin inhibitor, mycophenolate mofetil; corticosteroid withdrawal at variable posttransplant intervals Mycophenolate mofetil, prednisone taper

Conventional treatment with steroid withdrawal [116, 118, 150–153]

Table 3.4  Summary of protocol regimens (Adapted from [7]) Protocol Induction Conventional treatment (standard Anti-CD 25 antibody, r-ATG, or triple-drug therapy) [49, 120] none Anti-CD 25 antibody or r-ATG Conventional treatment with steroid avoidance [125]

Early toxicity of sirolimus-cyclosporine combination Possible increase in acute rejection, decreased graft survival

Possible excessive early rejection and lower graft function and survival (registry analyses)

Possible increase in rejection in patients with stable graft function Possible beneficial impact on graft function and delay in graft failure in patients with chronic graft dysfunction Higher adverse effects, possible beneficial impact on graft function

Increase in rejection

Possible increase in rejection

Comments Potential excess immunosuppression

54 G. Thomas et al.

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation

Fig. 3.1  Individual immunosuppressive drugs and sites of action. Antigen triggers cognate T-cell receptors (TCRs) (signal 1) and trigger immunologic synapse formation. The CD80 (B7-1)/CD86 (B7-2) pair on the antigen presenting cells (APC) engage CD28 on the T cell to provide signal 2. These signals activate three signal-transduction pathways – the calcium–calcineurin pathway, the mitogen-activated protein (MAP) kinase pathway, and the protein kinase C-nuclear factor-kB (NF-kB) pathway – which in turn activate transcription factors nuclear factor of activated T cells (NFAT), activating protein 1 (AP-1), and NF-kB, respectively. This results in expression of CD154 (a further activator of APCs), interleukin-2 receptor a chain (CD25), and interleukin-2. Receptors for a number of cytokines (interleukin-2, 4, 7, 15, and 21) share a common g chain, which binds Janus kinase 3 (JAK3). Signal 3 is composed of interleukin-2 and interleukin-15 delivering growth signals and initiating the cell cycle through the phosphoinositide-3-kinase (PI-3  K) pathway and the molecular-target-of-rapamycin (mTOR) pathway. Lymphocytes require de novo synthesis of purine and pyrimidine nucleotides for replication, regulated by inosine monophosphate dehydrogenase (IMPDH) and

Induction Therapy The risk for acute rejection is highest in the first few weeks and months after transplantation and

55

dihydroorotate dehydrogenase (DHODH), respectively. Anti-CD154 antibody has been withdrawn from clinical trials but remains of interest mechanistically. FTY720 (fingolimod) engages sphingosine-1-phosphate (S-1-P) receptor, triggers and internalizes the receptor, and alters lymphocyte recirculation, causing lymphopenia. Antagonists of chemokine receptors (not shown) are in preclinical development. MPA denotes mycophenolic acid, an inhibitor of de novo purine synthesis. Cyclosporine and tacrolimus are prototypic calcineurin inhibitors. FK-778 is a prototypic malanonitrilamide inhibitor of pyrimidine synthesis. CTLA-4 Ig initially developed for costimulation blockade is represented now by the newer generation biological, belatacept, in advanced clinical development. Sirolimus and everolimus are inhibitors of the m-TOR pathway. Alemtuzumab is a depleting anti-CD-52 monoclonal antibody. Small molecule Janus kinases (JAK) inhibitors are in advanced clinical development. Anti-CD3 monoclonal antibodies deplete CD3 positive T cells, as epitomized by OKT3. Anti-CD 25 monoclonal antibodies produce nondepleting T-cell antagonism as exemplified by basiliximab and daclizumab

immunosuppression should be at its highest level in this period (the induction phase). Induction therapy refers to the use of depleting (rabbit antithymocyte globulin, r-ATG (Thymoglobulin, Genzyme); Fresenius

G. Thomas et al.

56

anti-T cell globulin (Europe); OKT3; anti-CD 152 (Campath); anti CD-20 (Rituximab), or nondepleting antibodies (anti-CD 25 monoclonal antibodies/IL-2 receptor antibodies) in the first 2–6  weeks after transplantation. Several studies have shown that induction with antibody regimens may prevent acute rejection [10–12]. The potential advantages of using depleting antibodies include improved graft survival, delayed episode of first rejection, possible use of less aggressive maintenance regimens, and delayed calcineurin inhibitor use [10–12]. With depleting antibodies, calcineurin inhibitors can possibly be withheld or used at a minimal dose until completion of the antibody course. The potential disadvantages include more first-dose reactions, higher rates of CMV infection and BK virus infection, and prolonged hospital stays [13]. The long-term risks include the development of posttransplant lymphoproliferative disorder (PTLD) and malignancy [14]. Depleting antibody induction is favored in immunologically high-risk patients and those where delayed graft function is anticipated. There is no general consensus regarding induction therapy, and the choice of induction therapy following renal transplant depends on institutional experience with outcomes, as well as an assessment of rejection risk. High-risk groups that are generally offered intensive lymphocyte depleting antibody regimens include African Americans, pediatric patients (younger patients tend to be more immunologically aggressive), recipients with prolonged cold ischemic time, presensitized individuals, and those with previously failed transplants. Recipients of simultaneous kidney-pancreas transplantation may also require more intense therapy. Older patients are less likely to tolerate heavy immunosuppression, and individuals with well-matched deceased donors and some living related donors (such as two haplotypematched donors) may require less immunosuppression. Repeat courses of depleting antibody are fraught with risk of opportunistic infection, PTLD, and malignancy.

Depleting Antibodies Polyclonal Antibodies • Rabbit Antithymocyte Globulin (r-ATG; Thymoglobulin, Genzyme) is a purified gamma globulin obtained by immunization of rabbits with human thymocytes. • ATGAM, a purified gamma globulin obtained by immunization of horses with human thymocytes, has largely been replaced by r-ATG. Mechanism of Action While the precise mechanism of action of polyclonal depleting antibodies remains to be elucidated, they contain antibodies to a variety of targets on T cells, B cells, integrins, and other adhesion molecules, resulting in depletion of peripheral lymphocytes [15]. r-ATG, in particular, results in prolonged lymphopenia, and prolonged suppression of the CD4 subset [15, 16].

Dosing and Administration The typical regimen of r-ATG is 1.5 mg/kg/day given in a course lasting 3–5  days (to prevent rejection) or 5–14  days (to treat rejection). Animal models have also shown a humanequivalent dose of 6  mg/kg to be associated with increased lymphocyte depletion and better allograft survival [17]. While low doses less than 3 mg/kg may not effectively prevent acute rejection, higher doses and prolonged duration carry the risk of infection and potential development of lymphoma [18]. When used for induction, r-ATG is most effective when started intraoperatively rather than postoperatively [18]. To avoid allergic reactions, premedication with antipyretics, corticosteroids (methylprednisolone), and antihistaminics are given, with close monitoring of vital signs during infusion. Calcineurin inhibitors (cyclosporine, tacrolimus) can either be omitted or given in a reduced dose when r-ATG

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation

is used for treatment of acute rejection, and it has been suggested that azathioprine and mycophenolate mofetil doses should be reduced or held to avoid exacerbating hematologic side effects and risk of opportunistic infection.

Side Effects The principal side effects of polyclonal antibodies include fever, chills, arthralgias, infectious complications, thrombocytopenia, and leukopenia, likely reflective of cytokine release with T-cell depletion. Serum sickness and aseptic meningitis have also been described. r-ATG dose is generally halved with a platelet count of 50,000–100,000 cells/mL or a white blood cell count of less than 3,000 cells/mL. Doses may need to be held for more profound cytopenias.

Monoclonal Antibodies OKT3 – also called muromonab CD3 – was the first monoclonal antibody to be approved for clinical use in humans. It is approved for use in treatment of rejection, and while unapproved for induction therapy, it is also used for this indication; the frequency of its use is only about 1% currently. It is currently only available by special request in patients who cannot use r-ATG.

57

Efficacy For induction use, OKT3 appears to be most effective in high-risk cadaveric transplant patients who are sensitized, or have 2 HLA-DR mismatches or a prolonged cold ischemia time [19, 20]. Sequential induction therapy with OKT3 followed by cyclosporine was associated with better 3-year graft survival rate as compared to cyclosporine alone. These benefits were not seen in simultaneous administration of OKT3 and cyclosporine, likely due to slow or delayed graft function as a result of vasoconstriction and nephrotoxicity [21].

Dosing and Administration The standard dose is 5 mg given as an intravenous bolus as a single daily dose for 5–10 days. Failure of CD3+ T cells to decrease, or a rapid rise following an initial decrease, indicates appearance of blocking antibodies. Premedication is recommended for the first and second doses with corticosteroids (methylprednisolone), antipyretics, and antihistaminics. In patients already on maintenance immunosuppression, low-dose calcineurin inhibitors, azathioprine, and mycophenolate mofetil can be continued. The patient should not be volume overloaded prior to initial dose (diuretics, dialysis, or ultrafiltration may be needed to achieve euvolemia in such patients; see below).

Side Effects Mechanism of Action OKT3 is a monoclonal antibody produced by hybridization of murine antibody-secreting B lymphocytes with a nonsecreting myeloma cell line. Compared with other monoclonal antibodies (e.g., basiliximab/daclizumab), OKT3 is xenogeneic because it is completely of murine origin. It binds to the CD3 complex and causes the T-cell receptor to be endocytosed and be lost from the cell surface, thus rendering T cells ineffectual.

The first few doses of OKT3 may be accompanied by a TNFa-mediated cytokine release syndrome manifested by fever, chills, headache, arthralgias, and hemodynamic effects that can delay recovery of renal function after acute rejection or delayed graft function. The most feared side effect is a noncardiogenic pulmonary edema that occurs in volume overloaded patients. This last event can be prevented by diuresis or ultrafiltration and confirmation of absence of volume overload by chest radiography prior to the first dose.

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Neurologic complications include aseptic meningitis and encephalopathy. Infections and hematologic complications with fulminant and rapidly fatal B-cell lymphoma in patients receiving multiple OKT3 courses may be seen. Rejection may recur as potent CD3+ T cells reappear in circulation. Thrombotic events involving the allograft arterial and venous circulations have also been reported [22].

Nondepleting Antibodies Anti-CD25 Monoclonal Antibodies/IL-2 Receptor Antibodies Basiliximab and daclizumab are the two agents from this class in clinical use. Both are approved for use as induction in renal transplantation. Neither agent is effective in the treatment of acute rejection. • Basliximab (Simulect). This is a chimeric murine monoclonal antibody with a mouse variable region and a human IgG constant region (75% human, 25% mouse). The affinity of basiliximab to the IL-2 receptor is greater than daclizumab. • Daclizumab (Zenapax). Humanized murine monoclonal antibody in which only the antibody binding site is of murine origin (90% human, 10% mouse).

Dosing and Administration Both basiliximab and daclizumab have a half-life longer than 7  days, permitting long dosage intervals. For basiliximab, two doses of 20 mg are given, at day 0 and day 4 postoperatively. This basiliximab regimen produces saturation of the IL-2 receptor sites for 30–45 days. Five doses of daclizumab at a dose of 1  mg/kg, starting preoperatively and then given at 2-week intervals allow IL-2 saturation for up to 12 weeks. Limited dose Daclizumab (given as 2  mg/kg in single or two separated doses) has also been reported to have similar efficacy as basiliximab [23].

Side Effects Both basiliximab and daclizumab are remarkably well tolerated. Anaphylaxis and first-dose reactions occasionally have been reported with basiliximab, and are rare with daclizumab [16].

Newer Agents for Induction Therapy Alemtuzumab (Campath). Anti-CD52 monoclonal antibody approved for use in chronic lymphocytic leukemia. Its use in transplantation was hoped to facilitate minimization of maintenance immunosuppression [24] and a state of prope or “almost tolerance.”

Mechanism of Action Mechanism of Action T-cell activation leads to IL-2 secretion, which in turn induces T-cell proliferation through autocrine and paracrine mechanisms. Humanized and chimeric anti-CD25 monoclonal are targeted against the alpha chain of the IL-2 receptor, thus blocking the IL-2 mediated responses. There is no lymphocyte depletion with these agents and they are not designed to be used in the treatment of acute rejection.

Alemtuzumab is a depleting antibody, inducing profound and rapid depletion of peripheral and central lymphoid cells by targeting CD52 on the surface of lymphocytes. Rejections in alemtuzumab treated patients are lymphocyte-deplete and monocyte predominant [25, 26]. Humoral rejection may supervene as maintenance immunosuppression is minimized [27].

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation

Dosing and Administration The dose of alemtuzumab is 30  mg as asingle infusion usually used preoperatively. Precau­ tions against cytokine release syndrome with steroids, antipyretics, and antihistaminics are recommended.

Side Effects Induction of autoimmune disease has been reported with the use of alemtuzumab, including autoimmune thyroid disease and thrombocytopenia [28, 29].

59

Sirolimus is used in some regimens in place of the calcineurin inhibitor or the antimetabolite (Table 3.4). The mechanism of action, side effects, and drug interactions of individual agents are listed in Table 3.1. A brief overview of the pharmacokinetics of each drug is shown in Table 3.2. Readers are referred to the chapter on pharmacokinetics for a detailed discussion on pharmacokinetics. Outcomes with maintenance immunosuppressive regimens are summarized in a separate section and considered at greater length in the chapter on outcomes (see Chap. 7).

Calcineurin Inhibitors Maintenance Therapy The risk for rejection diminishes after the first few weeks and months after transplant, and immunosuppression during the maintenance phase is slowly decreased over time to lower the risk of infection and malignancy. The immunosuppressive agents used in the maintenance phase, in various combinations, include corticosteroids, calcineurin inhibitors (tacrolimus, cyclosporine), antimetabolites (azathioprine, mycophenolate mofetil), and sirolimus. The most commonly used maintenance immunosuppressive regimen at discharge for kidney transplantation in the US is the “standard-triple therapy” combination of tacrolimus, mycophenolate mofetil, and corticosteroids. It should be noted that this regimen supplanted the earlier cyclosporine/mycophenolate mofetil/prednisone regimen long before the first prospective head-to-head comparisons of these regimens were reported. According to the 2008 OPTN/SRTR annual report, 66% of transplant recipients in 2007 were on steroids, 85% on tacrolimus, 75% on mycophenolate mofetil, 10% on cyclosporine, and 5% on sirolimus [30]. Figure 3.2 shows the overall graft survival by maintenance immunosuppressant regimen in deceased donor transplant recipients in the United States from 2000 to 2005 [31].

Calcineurin inhibitors in current clinical use include tacrolimus and cyclosporine. The calcineurin inhibitor to be used (cyclosporine vs tacrolimus) has largely become a choice based on side effect profiles, unique patient level risk factors, physician and institutional choice/comfort level with use, and relative cost (see below). Tacrolimus is the dominant calcineurin inhibitor in use in the US and has been associated, in combination with mycophenolate mofetil and steroids, with lower rejection rates [32]. This last attribute of tacrolimus may in part reflect the higher mycophenolate exposure in tacrolimustreated patients. We discuss the calcineurin inhibitors as a class where there is convergence in the pharmacology and toxicology, and separately when there is a divergence. Calcineurin inhibitors are selective inhibitors of the immune response and do not impair phagocytic responses or produce myelosuppression, nor do they impair cell surface events such as antigen recognition. Calcineurin inhibitors form a complex with cytoplasmic receptor proteins, the immunophilins (cyclosporine: cyclophilin; tacrolimus: FK binding protein [FKBP]). The calcineurin inhibitor– immunophilin complex binds calcineurin, a phosphatase which dephosphorylates key nuclear regulatory proteins such as nuclear factor of activated T cells (NFAT), thereby facilitating their

G. Thomas et al.

60

Overall Graft Survival (%)

100

90

80 Regimen

70

60

50

(1) TAC / MMF

73.8%

(2) CsA/ MMF

71.8%

(3) CsA/ SRL

68.9%

(4) TAC / SRL

67.6%

(5) SRL / MMF

57.7%

0

1 2 3 4

5-Year Graft Survival

12

5

24

36

48

60

Months post-transplant

TAC = Tacrolimus MMF = Mycophenolate mofetil SRL = Sirolimus CsA = Cyclosporine microemulsion

Fig. 3.2  Overall graft survival by immunosuppressant regimen for US deceased donor transplant recipients, 2000– 2005. CsA cyclosporine microemulsion, MMF mycophenolate mofetil, SRL sirolimus, TAC tacrolimus (Reproduced from [31]. With permission)

passage across the nuclear membrane [7]. This inhibition of calcineurin impairs the expression of several cytokine genes, including IL-2, IL-4, TNFa, and INFg. Expression of genes encoding proto-oncogenes such as C-myc and H-ras may also be suppressed. Inhibition of calcineurin by calcineurin inhibitors thus leads to decreased cytokine production and consequently, decreased lymphocyte proliferation. Calcineurin inhibitor treatment increases the expression of transforming growth factor beta (TGFb). TGFb is a cytokine that inhibits IL-2 and may induce fibrosis in the renal allograft (toxicity). TGFb may play a role in the proliferation of certain tumor cells (increased cancer risk with calcineurin inhibitors). TGFb may in turn block some effects of calcineurin inhibitors, and thus could play a role in modulating both salutary and deleterious effects [33–35]. Cyclosporine and tacrolimus demand therapeutic drug monitoring for safe use. This is because both drugs have a narrow therapeutic index and exhibit large intrapatient interocccasion and interpatient variability in pharmacokinetic

behavior. The treating physician should always ensure full knowledge of the type of formulation used, whether brand-name or generic, and the type of assay used to determine drug levels [36]. Neoral is an oral microemulsion formulation of cyclosporine with improved pharmacokinetic bioavailability. This formulation has equivalent graft and patient survival compared to standard (Sandimmune) cyclosporine [37]. Gengraf is another modified formulation of cyclosporine, with pharmacokinetics similar to Neoral. Little data are available on the relative effects of Gengraf and Neoral on clinical outcomes. One retrospective study showed that acute rejections were more frequent with Gengraf compared to Neoral [38]. Conversion from standard cyclosporine to Neoral is safe with careful monitoring; [39] however, dose adjustments should be done based on levels, as lower doses of Neoral may be required. The clinician should be aware that elevation of creatinine levels soon after a switch from Sandimmune to Neoral is more likely reflective of nephrotoxicity rather than rejection.

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation

61

Dosing and Monitoring

Side Effects

Cyclosporine may be administered at 8–12 mg/ kg/day as a single oral dose or twice daily starting immediately before transplantation or on the first postoperative day. Cyclosporine can be infused intravenously over 4 h or as a continuous infusion. The intravenous dose of cyclosporine is one third the oral dose. The dose of cyclosporine is adjusted to maintain 12-h trough levels of 250–350  ng/mL for the first 3  months posttransplant, then tapered to maintain levels of about 150–250 ng/mL up to 6 months, after which levels are maintained at about 100 ng/mL. By 3 months posttransplant, the dose of cyclosporine ranges between 3 and 5 mg/kg/day. In those patients receiving antibody induction, cyclosporine can be started several days before completion of the course of antibody so that adequate levels can be built up at discharge. Some programs start cyclosporine after the graft function has improved (creatinine of 3  mg/dL or lower) while maintaining immunosuppression with induction antibody, steroids, and mycophenolate mofetil. There is a poor correlation between clinical outcomes and cyclosporine trough levels. Two-hour peak cyclosporine levels (C2) may correlate more closely with exposure, and therefore with decreased acute rejection rates [40–44]. Long-term impact of C2 monitoring versus trough monitoring on clinical outcomes and optimal C2 targets are unclear. These issues are detailed in the chapter on pharmacokinetics (see Chap. 4). Tacrolimus is usually started orally at 0.15– 0.30 mg/kg/day in two divided doses administered 12 h apart. Trough levels may be difficult to achieve initially in African Americans who are more likely to be CYP3A5 expressors by the oral route [36]. Intravenous coverage can be used in these circumstances while levels build up. Tacrolimus trough levels are maintained at about 10–15  ng/mL initially in the first month posttransplant and at lower levels thereafter. These details are discussed further  in the chapter on pharmacokinetics (see Chap. 4).

Usually the differential side effect profiles of these medications may dictate the choice of agent. Given the impact of these side effects on clinical practice, we will discuss them at some length here. A side-by-side comparison of tacrolimus and cyclosporine is provided in Table 3.5. Tacrolimus is associated with an increased incidence of posttransplant glucose intolerance and neurologic side effects, including tremors and headache. Cyclosporine has more cosmetic effects, including hirsutism, coarsening of facial features, and gingival hyperplasia. Cyclosporinetreated patients also tend to have more severe hypertension, hyperlipidemia, and hyperuricemia. The calcineurin inhibitors have several drug interactions which are discussed in depth in the chapter on pharmacokinetics (see Chap. 4). Much of the side effects of the calcineurin inhibitors surround their nephrotoxicity, which was noted from the very early development of cyclosporine and later with tacrolimus. Calcineurin inhibitors constrict the afferent arteriole in a dose-dependent, reversible manner [45, 46]. This is associated with a reduced ultrafiltration coefficient likely related to mesangial cell contraction. In the initial phase, tubular function is intact with a consequent physiologically appropriate sodium avid state. Vasoconstrictor molecules such as endothelin may mediate this effect with a concomitant decrease in vasodilator molecules. Nitric oxide dependent vasodilatation may also be impaired. The sympathetic nervous system is activated as is the renin-angiotensin–aldosterone axis [46]. These influences in sum lead to the acute rise in blood pressure and sodium and water retention that is observed in patients treated with calcineurin inhibitors. Acute microvascular disease may reflect endothelial injury and is manifest as a microangiopathic hemolytic anemia, which may be renal limited or systemic in proportion. This manifestation of calcineurin inhibitor nephrotoxicity should be differentiated from de novo or recurrent disease in the allograft and acute humoral rejection with microangiopathy.

G. Thomas et al.

62 Table 3.5  Comparison of cyclosporine and tacrolimus (From [9]) Characteristic Cyclosporine Proximate mode of action Calcineurin inhibition leading to decreased IL-2 synthesis Daily maintenance dose 3–5 mg/kg Need of bile for absorption Sandimmune: NoNeoral: Yes Oral dosage forms Capsules: 100 mg and 25 mg Oral elixir available Drug interactions (CYP3A4/5 and Similar to tacrolimus P-glycoprotein mediated) Nephrotoxicity + Interaction with Mycophenolic acid (MPA) MPA exposure lower with cyclosporine Interaction with sirolimus Pharmacokinetic and pharmacodynamic interactions with higher sirolimus exposure and nephrotoxicity Effect of polymorphism on bioavailability Less marked effect of CYP3A5 expressor phenotype on bioavailability Use in steroid-sparing regimens

+

Hypertension, salt, and water retention Neurotoxicity Diabetogenicity (pancreatic islet toxicity) Hirsutism and hypertrichosis Gingival hyperplasia Diarrhea Effect of diarrhea on absorption Hyperkalemia Hypomagnesemia Gout and hyperuricemia

++ + + + + – – + + More frequent

Hypercholesterolemia

++

Calcineurin inhibitors produce a typical nodular hyalinosis in the media of arterioles in the ­kidney [47]. This should be differentiated from intimal thickening that may represent nonspecific effects of hypertension, alloimmune injury, and ­diabetes. The prevalence of lesions of calcineurin inhibitor toxicity has been reported to increase over time based on protocol biopsies [48]. However, these studies lacked a control arm, did not use strict morphologic criteria for calcineurin-­ inhibitor-mediated lesions, and the biopsies were

Tacrolimus Calcineurin inhibition leading to decreased IL-2 synthesis 0.1–3 mg/kg No 5 mg, 1 mg, and 0.5 mg capsules Oral elixir available Similar to cyclosporine + MPA exposure higher with tacrolimus Nephrotoxicity of tacrolimus is augmented by coadministration with sirolimus

Marked effect of CYP3A5 expressor phenotype on oral bioavailability. African Americans are more commonly CYP3A5 expressors ++; May be related to increased MPA exposure more than intrinsic efficacy + ++ ++ Alopecia may be seen – + Augmented ++ + Less frequent than with cyclosporine; gout is rare +

from a cohort of bladder-drained simultaneous­ kidney pancreas transplant recipients who are prone to fibrotic lesions over time based on reflux [48, 49]. When present over a prolonged period, chronic nephrotoxicity of calcineurin inhibitors manifests as interstitial fibrosis in a so-called “stripe fibrosis” pattern. In addition to pharmacokinetic interactions based on the metabolism of calcineurin inhibitors via the P-glycoprotein and CYP3A4/5 pathways, patients treated with calcineurin inhibitors

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation

are susceptible to additive nephrotoxicity when other agents with intrinsic nephrotoxic properties are used concomitantly. These include aminoglycosides, amphotericin B, and nonsteroidal antiinflammatory drugs. Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists may exacerbate both the hemodynamic effects of calcineurin inhibitors and hyperkalemia (see below). Hyperkalemia is a common side effect observed with the calcineurin inhibitors. It is more likely to manifest in the early posttransplant period with marginal renal function, low urinary flow rates, and when concomitant therapy with beta blockers and/or trimethoprim is used. Hyperkalemia may be associated with a hyperchloremic metabolic acidosis. Tacrolimus may exhibit a greater proclivity to this defect. Downregulation of tubular transport protein may lead to renal magnesium wasting with systemic hypomagnesemia. Hypercalciuria has also been reported. When severe, hypomagnesemia can predispose to seizures. Hyperuricemia may be observed with both calcineurin inhibitors, but is usually more common with cyclosporine, especially when thiazide diuretics are used concomitantly. Gastrointestinal toxicity of cyclosporine may manifest as transient cholestasis. Increased lithogenicity of bile with cyclosporine has been postulated, but is clinically not of much concern. Tacrolimus is associated with diarrhea, and diarrhea may be associated with higher tacrolimus exposure. Cosmetic side effects of cyclosporine include hypertrichosis and hirsutism, gingival hyperplasia, and coarsening of facial features [46, 50, 51]. Tacrolimus may be associated with alopecia but not the rest of the cosmetic burden of cyclosporine. Glucose intolerance with calcineurin inhibitors reflects in large part direct toxicity to the islet cell, and to varying degrees, intrinsic proneness to diabetes on the part of the patient (Hispanics, African Americans, obese, family history of diabetes, patients with hepatitis C [52]). Hyperlipidemia, principally hypercholesterolemia, is observed more frequently and with

63

greater severity with cyclosporine. This may improve or resolve by switching to tacrolimus. Neurotoxic features are much more common with tacrolimus than with cyclosporine. These include headache, tremor, and insomnia, which may relate to peak levels. When severe, these may manifest as seizures or leukoencephalopathy. Calcineurin inhibitors may contribute to greater proneness to malignancy, perhaps to a degree greater than expected from net state of immunosuppression alone. It is reasonable to switch from tacrolimus to cyclosporine and vice versa if side effects develop, and an overlap between the drugs is not necessary. The concern for intrinsic nephrotoxic effects has been an impetus to eliminate calcineurin inhibitors from immunosuppressive protocols. While removal of a calcineurin inhibitor usually results in lower creatinine levels, this improvement probably signifies nothing more than an intra-renal hemodynamic effect with removal of afferent arteriole constriction effect, resulting in an acute increase in the glomerular filtration rate (GFR). This does not necessarily have an impact on preexisting histological lesions that can continue to progress over time. The decreased immunosuppression may eventually manifest as overt rejection, or there may be subclinical rejection that is not readily apparent with cursory follow-up of serum creatinine levels (also see following sections) [49].

Antimetabolites Antimetabolites include azathioprine (Imuran; AZA) and mycophenolate mofetil (MMF). Mycophenolate mofetil is the prodrug of mycophenolic acid, MPA, derived from Penicillium fungi, with the moropholinoethyl (mofetil) moiety conferring enhanced bioavailability and oral tolerability [53]. MPA is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), a critical, rate-limiting enzyme in the de  novo pathway of purine synthesis. IMPDH catalyzes the synthesis of guanine nucleotides

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from inosine. IMPDH inhibition by MPA depletes the guanine nucleotide pool with a relatively specific antiproliferative effect on lymphocytes which preferentially use the de  novo pathway of purine synthesis [53, 54]. Additional effects include effects on vascular smooth muscle cells and reduction in glycosylation of key adhesion molecules that mediate binding of lymphocytes to vascular endothelium [55–57] MPA blocks the proliferation of T and B cells, inhibits alloantibody formation, and the generation of cytotoxic T cells. Azathioprine is a purine analogue, and is incorporated into cellular deoxyribonucleic acid (DNA) and inhibits the synthesis and metabolism of ribonucleic acid, thereby inhibiting gene replication. Azathioprine is an imidazole derivative of 6-mercaptopurine. It has been in use in transplantation for more than 4 decades [58]. With the introduction of cyclosporine, azathioprine became an adjunctive agent to be used with cyclosporine. Furthermore, with the introduction of mycophenolate mofetil, azathioprine use has declined progressively in the USA. However, newer evidence suggests that it may be worth reexamining the use of AZA (see below).

Dosing, Formulations, and Side Effects Mycophenolate mofetil is available as 250- and 500-mg capsules. The usual starting dose is 1 g twice daily when used with cyclosporine. Mycophenolate mofetil may be given intravenously. Myfortic is an enteric-coated preparation of mycophenolate, and was developed with the aim of having fewer gastrointestinal side effects. Myfortic is available in doses of 180 and 360 mg. The usual equivalent dose of Myfortic to 2 g/day mycophenolate mofetil is 720  mg bid. Symptomatic benefits with the enteric-coated formulation have been reported in studies where patients with significant gastrointestinal symptoms with mycophenolate mofetil were converted to Myfortic. However, this issue is not resolved and it is not entirely clear if the entericcoated formulation actually helps reduce the incidence of gastrointestinal side effects [59,

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60]. African-American patients may need to be given a higher mycophenolate mofetil dose of 1.5  g twice daily, as that dose was associated with better rejection prophylaxis in one subanalysis of the US Mycophenolate Mofetil registration trials [61]. Smaller doses (25–50% lower) are used when mycophenolate mofetil is used with tacrolimus or sirolimus. This last point is critical in the prevention of exposure-related side effects of MPA such as leukopenia, anemia, diarrhea, and opportunistic infections such as CMV and other herpes virus infections [62]. The pharmacokinetics of MPA are complex and detailed in Chap. 4. The most common side effects of mycophenolate mofetil are gastrointestinal, being dominated by diarrhea in up to one third of patients. Nausea, dyspepsia, vomiting, and bloating have been reported in up to one third [32, 61]. Esophagitis and gastritis have been reported in up to 5% of patients and may represent CMV or other herpes virus infection. These symptoms usually respond to temporary dose reductions. Other side effects are mainly hematologic and include leukopenia, anemia, and thrombocytopenia. Leukopenia may be particularly prominent in steroid avoidance protocols (see below) and with concomitant valganciclovir therapy. The usual maintenance dose of azathioprine is 1–2 mg/kg/day when used with a calcineurin inhibitor (dose for primary use is 2–3  mg/kg/ day). The intravenous dose is half the oral dose. The principal side effects include leukopenia and anemia. Patients treated with this agent commonly have macrocytosis, but with hemoglobin in the normal range. Leukopenia should not be equated with adequacy of immunosuppression. White blood cell counts should be monitored with particular care as steroids are being tapered. Rarely, hepatotoxicity or pancreatitis may be seen. Azathioprine is a substrate for xanthine oxidase. If allopurinol is to be used with azathioprine, the dose of azathioprine should be reduced to about 25% of the preallopurinol dose. Frequent monitoring of the white blood cell count, platelet count, hemoglobin, and liver function tests is necessary if azathioprine is to be used with allopurinol.

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This situation is fortunately not a frequent issue in current clinical practice as mycophenolate mofetil can be used when treatment with allopurinol is indicated. No monitoring of drug levels is employed with azathioprine. Concentration-efficacy relationships for mycophenolate mofetil (mycophenolic acid) have been extensively studied. The complex pharmacokinetics and therapeutic drug monitoring of mycophenolic acid are discussed in the section on pharmacokinetics (see Chap. 4). While mycophenolate mofetil is generally preferred over azathioprine in most US transplant centers, side effect profiles of these medications and patient characteristics should also dictate their use. Azathioprine can be used in most low-risk transplant patients, and especially in men and women of childbearing age when mycophenolate mofetil is not used because of its teratogenic effect. Women of childbearing potential should have a negative pregnancy test within 1  week prior to beginning therapy with mycophenolate mofetil. Two reliable forms of contraception should be used beginning 4 weeks prior to, during, and for at least 6  weeks following therapy. Males should also cease mycophenolate mofetil if childbearing is the aim. Malformations of the ear and digits have been reported in offspring of patients on mycophenolate mofetil [63–67]. Mycophenolate mofetil is of particular value in high-risk patients, including those with retransplants, an immunologic cause of renal disease such as lupus nephritis, and the presence of anti-HLA antibodies. In patients with gastrointestinal side effects, a switch from mycophenolate mofetil to Myfortic can be tried if that side effect is upper abdominal pain or esophagitis, and infections such as herpes simplex, CMV, and candidiasis have been ruled out. Frequently, proton pump blockade can help, and if that is ineffective, the dose can be further lowered, or a switch to azathioprine can be considered. If the dose of mycophenolate mofetil is lowered, one must pay close attention to other immunosuppressants, and also pay close attention to restarting mycophenolate mofetil once the inciting circumstance (e.g., diarrhea or leukopenia) has resolved.

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Mammalian Target of Rapamycin (m-TOR) Inhibitors m-TOR is a key regulatory kinase that drives cells from G1 to S phase of the cell cycle in response to proliferation signals provided by cytokines such as IL-2 [68]. The first inhibitors of the m-TOR pathway that entered clinical use are sirolimus (Rapamune) and its congener, everolimus (40-hydroxysirolimus; Certican). The m-TOR inhibitors complex to the binding protein FKBP, and the sirolimus-FKBP complex binds to m-TOR [68]. In addition to blocking lymphocyte proliferation and antibody synthesis, m-TOR inhibitors also inhibit the proliferation of vascular smooth muscle cells and fibroblasts; an effect thought to be of benefit in vasculopathy and progressive fibrosis that affects allografts. Sirolimus has been investigated as an agent that could be tolerogenic, as unlike calcineurin inhibitors, it does not block IL-2 dependent apoptotic events [69–71]. Sirolimus and everolimus are substrates for CYP3A4/5, and thus have numerous pharmacokinetic interactions like the calcineurin inhibitors. [36] Being that both calcineurin inhibitors and sirolimus are substrates for the same pathway, they themselves have pharmacokinetic interactions (detailed in Chap. 4). Sirolimus was not thought to be intrinsically nephrotoxic. However, when used with a calcineurin inhibitor, the nephrotoxicity of the calcineurin inhibitor is accentuated [72]. This has been repeatedly observed both in experimental and clinical settings. When cyclosporine is withdrawn from the sirolimus-cyclosporine combination, renal function improves [73, 74]. Furthermore, when sirolimus is removed from the sirolimus-cyclosporine combination and substituted with mycophenolate mofetil, renal function improves [75]. The antiproliferative effects of sirolimus impair recovery from delayed graft function [76, 77]. Tubular toxicity of sirolimus may manifest as hypokalemia or hypomagnesemia. Sirolimus-treated patients may develop proteinuria, which may represent varying combinations of podocyte injury, impaired proximal tubule reabsorption, and exacerbation of a prior

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proteinuric state [78, 79]. Localized lymphedema and angioedema have been noted. Impaired wound healing and lymphoceles can make the de novo use of sirolimus challenging, especially in obese recipients [71, 79]. Oral ulcers and diarrhea may also complicate management significantly. Sirolimus is toxic to the embryo, and pregnancy should not be planned until 12 weeks after stopping the drug. Reversible oligozoospermia and low testosterone levels have been reported as well [80]. Dose-dependent hypertriglyceridemia, and to a lesser extent hypercholesterolemia, can complicate the use of sirolimus, especially with cyclosporine. Usually, this hyperlipidemia is manageable with statins and fibrates, with the usual caveats pertaining to drug-drug interaction. Despite antiproliferative effects of statins on vascular smooth muscle cells, no effects on clinical coronary heart disease have been noted. Sirolimus is diabetogenic and does not ameliorate hyperglycemia when substituted for a calcineurin inhibitor. A peculiar proclivity to P. jiroveci pneumonia was noted in sirolimus-treated patients [81]. An intrinsic pulmonary toxicity of sirolimus has been described with alveolar hemorrhage and lymphocytic infiltration, with pathologic features reminiscent of bronchiolitis obliterans organizing pneumonia [82, 83]. This lesion resolves with sirolimus cessation. m-TOR inhibitors are associated with thrombocytopenia, leukopenia, and anemia [71]. These cytopenias are particularly prominent when sirolimus is used in conjunction with mycophenolate mofetil. Interestingly, both in clinical trials and smaller conversion trials, the overall incidence of malignancy has been lower in sirolimus-treated patients [5, 72, 84, 85]. Thrombotic microangiopathy has been reported with the sirolimus-calcineurin inhibitor combination, and likely reflects accentuation of calcineurin inhibitor toxicity by sirolimus [86–89].

Corticosteroids Corticosteroids have had a role in transplantation since the 1960s, and despite numerous

attempts to try and do away with them, they are an integral part of the immunosuppressive armamentarium [7]. Prednisolone, its metabolite prednisone (11-keto prednisolone), and methylprednisolone, are the common preparations used in clinical transplantation. Corticosteroids have myriad and pervasive immunosuppressive, antiinflammatory, and hormonal activity on numerous tissues, thus causing multiple side effects over the long term. Corticosteroids exert immunosuppression by blocking the expression of cytokine genes and cytokine receptors. Corticosteroids inhibit the antigen-presenting dendritic cells. Corticosteroids diffuse across the lipid bilayer of the plasma membrane and bind to cytoplasmic receptors. The steroid-receptor complex binds to glucocorticoid response elements in the nucleus and inhibits the transcription of cytokine genes. Corticosteroids also block the nuclear translocation of NF-k B, a transcription factor that regulates the expression of several cytokine genes [7]. Specifically, IL-1, IL-6, IL-2, TNFa, and IFNg expression are inhibited, impacting the T-cell activation of rejection states at multiple phases. At high doses, glucocorticoids may intercalate with cell surface receptors thereby preventing them from transducing signals to the cell’s interior, the so-called membrane stabilizing effect. Glucocorticoids also mediate lymphopenia by redistributing lymphocytes from the vascular compartment to lymphoid tissue. In contrast, a neutrophil leukocytosis is seen with steroids, representing demargination. Monocyte recruitment to sites of inflammation is impaired by steroids. Nonspecific antiinflammatory effects of corticosteroids contribute minimally to their antirejection mechanisms.

Dosing and Side Effects The side effects of steroids are many and include weight gain, impaired glucose tolerance, hypertension, osteoporosis, osteonecrosis, impaired linear growth in children, psychosis, depression, cataracts, and glaucoma, to mention a few. There is considerable interpatient variability in the propensity to these complications. A number of

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these complications have diminished in incidence in recent years with the use of progressively lower maintenance doses of steroids (also see below). The commonly used maintenance triple immunosuppression regimens include prednisone (US) or prednisolone (Europe), a calcineurin inhibitor, and an antimetabolite. Large doses of steroids are generally given perioperatively and in the immediate postoperative period. This consists of an intravenous pulse dose of 5–10 mg/kg of methylprednisolone intraoperatively, followed by 1  mg/kg/day of prednisone. This is subsequently tapered (per institution protocol), generally to a dose of about 0.1  mg/kg/day of prednisone by 1  year. Most institutional protocols generally taper the dose to a total of 5 mg/ day of prednisone by 3 months following transplantation, in the absence of acute rejection. Corticosteroids are substrates for CYP3A4/5 and P-glycoprotein pathways. As such, they are subject to many interactions. Empiric dose adjustments should be made in the presence of inducers of CYP3A4/5 such as phenytoin or rifampin. This is because assays of blood levels of steroids are not used in practice [36].

Intravenous Immune Globulin Pooled intravenous immune globulin (IVIG) has become an increasingly important component of the transplant pharmacopeia [90]. These preparations are pooled from thousands of donors with stringent antiinfective manufacturing processes in place. CMV immune globulin (CMVIG, CytoGam) represents a subset of immune globulin with higher titer of antibody to CMV and can be used for therapy of CMV disease and also in situations where IVIG is indicated. IVIG is used in transplantation in desensitization regimens to facilitate deceased donor transplantation in sensitized patients, to facilitate living donor transplant in the face of a positive cross-match or ABO incompatibility, and to treat acute antibody-mediated rejection [90]. IVIG is multifaceted in its actions, and is best described as being immunomodulatory. In the

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context of immunosuppression, IVIG inhibits anti-HLA antibody responses and produces a durable suppression of anti-HLA reactive T cells and B cells. Cytokine signaling for IgG synthesis is inhibited and alloimmunization may be blocked by T-cell receptor blockade [90, 91].

Dosing and Side Effects IVIG exhibit variation by manufacturer and preparation, and close attention to the package insert and the formulary restrictions prevalent in individual institutions is highly recommended. All preparations should be administered over several hours. The standard dose is 2  g/kg given in four to five divided doses. Premedication such as corticosteroids may be helpful but are not mandatory. Chills, flushing, headache, nausea, myalgias, and arthralgias may occur. These usually respond to reduction in infusion rates. Analgesics and antipyretics may help. Aseptic meningitis and autoimmune hemolytic anemia, both self-limited, have been reported and are rare. Of particular concern is that thromboembolic complications including myocardial infarction have been reported after IVIG infusion. IVIG may be associated with acute renal failure, likely based on osmotic tubular injury resulting from diluents like sucrose and sorbitol. This complication should be anticipated and patients counseled appropriately, especially when graft dysfunction such as with humoral rejection is being treated.

Emerging Immunosuppressive Agents Small Molecules ISA247 It is a calcineurin inhibitor, and an oral semisynthetic structural analogue of cyclosporine, which is relatively more potent. Animal studies suggest absence of nephrotoxicity. A phase II trial comparing three dose levels of ISA247 with

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tacrolimus demonstrated similar efficacy and renal function in all treatment groups [92].

Janus Kinase Inhibitors/CP-690,550 Mammals have four Janus kinases (JAKs), including JAK1, JAK2, JAK3, and tyrosine kinase 2. JAK 3 has restrictive tissue distribution compared to the others, and is found primarily on hematopoietic cells. It also associates specifically with the cg chain which is shared by tissue receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Thus, JAK 3 blockade offers some degree of specificity, although there is still some crossreactivity, especially given the structural similarities between JAK 2 AND JAK 3. An adverse effect in particular is anemia, as JAK 2 is needed for erythropoietin action. CP-690,550 has shown improved graft survival rates in animal studies. A phase II trial comparing one or two dose levels of CP-690,550 versus tacrolimus showed comparable rates of acute rejection and renal function at 6  months, with no graft loss, deaths, or malignancies, but the high-dose CP-690,550 group had more infections, CMV, and BK nephropathy [93].

PKC Inhibition/AEB071 (Sotrastaurin) Protein kinases have an important role in ­downstream signaling pathways of the T-cell receptor. AEB071 is an oral low molecular weight compound that inhibits protein kinase isoforms, thereby blocking T-cell activation and IL-2 production. It has minimal effect on nuclear factor of activated T cells (NFAT) and on cytokine and growth factor-induced cell proliferation; thus, the mechanism of blockade is independent of calcineurin inhibitors, and may not have associated toxicities. Studies that attempted calcineurin withdrawal regimens and calcineurin-free regimens with the use of AEB were both stopped due to increase in rates of acute rejection. AEB may still have a role as

adjunct therapy with calcineurin inhibitors, and a study comparing a regimen of AEB/everolimus/steroids versus tacrolimus/mycophenolate mofetil/corticosteroids is currently underway in European centers [8].

FTY 720 FTY 720 is an analogue of myricin, which is a metabolite of a Chinese herb. It acts as a functional sphingosine-1-phosphate antagonist by engaging sphingosine-1-phosphate receptors, and reduces the numbers of T and B cells in peripheral blood (while increasing their numbers in lymph nodes); thus, FTY270 drives T cells into lymphoid tissue and sequesters them, thereby preventing homing to the allograft. A 1-year, multicenter, randomized, phase III study in 696 renal transplant patients compared high-dose FTY 720/­low-dose cyclosporine or low-dose FTY 720/full-dose cyclosporine with mycophenolate mofetil/full-dose cyclosporine. The low-dose FTY 720 group was demonstrated to be non-inferior to the mycophenolate mofetil/cyclosporine group. The high-dose FTY 720 group had higher rates of acute rejection and this arm was discontinued. FTY 720 was also ­associated with significantly lower creatinine clearance at 12 months. The study concluded that the associated lower creatinine clearance of FTY 720 combined with cyclosporine provided no benefit over standard care [94]. There is also a concern about the potential for cardiac arrest with this agent, especially when combined with other medications, because of its potential to induce reversible bradycardia.

Biologic Agents Belatacept/Costimulation Blockade Belatacept (LEA29Y) is a competitive antagonist for CD28 for CD80/CD86 binding. The

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation

interaction of CD80/CD86 with the costimulatory receptor CD28 is required for full activation of T cells. Costimulation blockade inhibits T-cell activation and promotes apoptosis. Belatacept was derived from abatacept, differing from it by two specific amino acid substitutions. A non-inferiority study comparing two doses of belatacept vs. cyclosporine in patients also receiving basiliximab induction, mycophenolate mofetil, and steroids demonstrated similar incidence of acute rejection in all groups at 6  months, higher GFR and less chronic allograft nephropathy at 12  months in both belatacept groups compared to cyclosporine [95]. The phase III BENEFIT study comparing belatacept to cyclosporine enrolled 666 patients randomly assigned to three treatment groups: more intensive belatacept, less intensive belatacept, and cyclosporine; patients in both belatacept groups had improved renal function compared with patients in the cyclosporine group. At 12  months, the mean measured GFR was higher in the belatacept groups, and the prevalence of chronic allograft nephropathy was lower in both belatacept groups. It should, however, be noted that there was a significant increase in episodes of acute rejection after the first month, especially in the mote intense belatacept arm [95]. The BENEFIT-EXT trial examined extended criteria donors randomized to more intense belatacept, less intense belatacept, and cyclosporine groups; at 12  months, patient and graft survival with belatacept was nearly identical to that with cyclosporine; however, renal function was superior in the more intense belatacept group compared with the cyclosporine group. The incidence of acute rejection was 18%, 18%, and 14%, respectively, in the three groups, which are in contrast to the findings in the BENEFIT study with standard criteria donors. There was a higher incidence of posttransplant lymphoproliferative disorder seen in the belatacept groups [96]. Thus, it remains to be seen if the efficacy and safety profile of this drug is acceptable in routine clinical practice as more follow-up data accrues.

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Targeting B Cells and Plasma Cells Rituximab Rituximab is a monoclonal antibody directed against CD20 on B lymphocytes, and mediates depletion of these cells. It is approved for use in B-cell malignancies, and is used off label in transplantation, including use in attempts to reduce high levels of preformed anti-HLA antigens, treatment of humoral rejection, treatment of posttransplant lymphoproliferative disorder, and facilitation of living donor transplantation with positive crossmatch or ABO incompatibility. A retrospective review reported higher risk of death related to infectious diseases in kidney transplant patients treated with rituximab [97, 98]. Bortezomib (Velcade) Bortezomib is a proteasome inhibitor that selectively targets the 26 S proteasome complex that is involved in the degradation of excess proteins in highly metabolically active cells. Proteasome inhibition results in cell apoptosis. It was approved for use in treatment of multiple myeloma in 2005. Its use in treatment of rejection in kidney transplant was recently investigated, in both acute cellular and antibody-mediated rejection. Treatment with bortezomib was effective in rejection reversal, with marked and prolonged reductions in donor-specific antibody levels. Patients had improved renal allograft function, and suppression of recurrent rejection for at least 5 months. Bortezomib-related side effects including gastrointestinal toxicity, thrombocytopenia, and paresthesias, were reported to be transient [99].

Currently Used Combination Immunosuppressive Regimens and Outcomes Standard immunosuppressive regimens (calcineurin inhibitors, antiproliferative agents, corticosteroids with or without antibody induction)

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and the rationale for their construct have been reviewed in a preceding section and are summarized in Table 3.4. Newer approaches are aimed at minimizing exposure to calcineurin inhibitors and corticosteroids. We briefly discuss outcomes reported with the most frequently used induction and maintenance agents in the context of protocol selection. We also review outcomes relevant to the immunosuppression minimization protocols in clinical use. A detailed review of key outcome studies pertaining to immunosuppression is provided in Chap. 7.

Choice of Induction Regimen In examining trends of immunosuppression use, there has been a continuing transition from the use of OKT3 and ATGAM to r-ATG and IL-2 receptor antibodies for induction therapy [3]. According to the 2008 OPTN/SRTR annual report, 78% of renal transplant recipients received induction therapy in 2007, with r-ATG used in 44% of recipients, and basiliximab in 17% [100]. A randomized trial of basiliximab vs. placebo for induction, given at days 0 and 4 posttransplant in 376 patients (along with cyclosporine and steroids) showed lower incidence of biopsy-proven acute rejection at 6  months in the basiliximab group, along with lower incidence of steroid-resistant first rejection episodes that required antibody therapy. The incidence of adverse effects was similar in both groups [101]. A longer follow up of 1  year showed similar results for basiliximab compared to placebo [102]. When basiliximab was added to a triple therapy regimen of cyclosporine, steroids, and azathioprine, there was lower incidence of acute rejection without increase in adverse effects as compared to placebo, while 1-year patient and allograft survivals remained similar [103]. Daclizumab vs. placebo with either double (cyclosporine and steroids) or triple (cyclosporine/ steroids/azathioprine) maintenance therapy showed lower rejection rates with daclizumab at 1 year, with similar allograft survival at 3 years.

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In a randomized trial that enrolled 278 deceased donor renal transplants comparing r-ATG with basiliximab on a maintenance regimen of cyclosporine, mycophenolate mofetil and prednisone, there was no difference in 1-year allograft and patient survival, but r-ATG was associated with a significantly lower incidence of acute rejection; overall incidence of adverse events were similar [16]. The relative benefits of r-ATG were sustained over a 5-year period [104]. These observations were confirmed further in retrospective analyses [105]. Although antilymphocyte antibody preparations (e.g., r-ATG or interleukin-2 receptor antibodies) are widely used, particularly in the setting of delayed graft function and decreased acute rejection rates, their effects on long-term graft survival have not been well studied. Depleting anti T-cell antibodies have been associated with increased risk of neoplasia and opportunistic infection [106]. r-ATG use has been shown in registry studies as a risk factor for BK viremia [13]. In summary, the choice of induction regimen is dictated by the overall assessment of immunologic risk in the individual patient and clinical circumstances such as clinically estimated risk of delayed graft function.

Choice of Calcineurin Inhibitors The improvements accrued in recent years in short- and long-term allograft survival reflect, in part, the effectiveness of the newer antirejection drugs such as the calcineurin inhibitors and mycophenolate mofetil. The independent and specific contribution of long-term calcineurin inhibitor therapy, particularly in the context of currently utilized concentration targets, to chronic progressive nonimmunologic noninfective renal allograft dysfunction (and loss) remains controversial. Observational studies based on protocol biopsy data have been widely cited as evidence of contribution of calcineurin inhibitor toxicity to attrition of allograft function and ultimately graft loss [48]. However, these

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assumptions, inferences, and correlations should be considered in light of the enduring fact that the durable increases in short- and long-term graft survival in the calcineurin inhibitor era (cyclosporine and then tacrolimus, in combination first with azathioprine and later on with mycophenolate mofetil) suggest immunologic protection in the form of freedom from rejection conferred by calcineurin inhibitors far overrides the nephrotoxic effects [49]. In recent years, cyclosporine has been largely replaced in most centers by tacrolimus [3]. This shift reflects a gradual change in practice patterns based on empiric observations and expectation of less nephrotoxicity with tacrolimus that preceded actual published results of formal studies evaluating this combination. Renal function has been noted to be superior in tacrolimus-treated patients than with cyclosporine-treated patients [107]. A registry analysis compared 5-year graft survival in Neoral and tacrolimus treated patients using a paired-kidney analysis to minimize donor variability and bias. There was no difference in risk for 5-year patient survival or graft loss. Renal function was superior for tacrolimus at all time points, whereas the slope of 1/Cr over time did not differ for the two agents [106]. In summary, the choice as to which calcineurin inhibitor to employ in a regimen is largely a matter of differential systemic toxicities of the agents, physician experience with the agents, and center preference.

Choice of Antiproliferative Agent Calcineurin inhibitors are commonly used in combination with an antiproliferative agent (azathioprine, mycophenolate mofetil, or sirolimus). The evidence that can be used in making a choice of agent to use is reviewed briefly.

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the superiority of mycophenolate mofetil over the control group (azathioprine or placebo) for the primary endpoint of acute rejection [32, 108, 109]. Mycophenolate mofetil is associated with better long-term death-censored graft survival in cyclosporine treated patients independent of acute rejection [110]. African-American patients experienced a more striking reduction in acute rejection rates and clinically important and significant risk reductions in death with functioning graft, deathcensored graft loss, and chronic allograft failure [110, 111]. Mycophenolate mofetil was also associated with greater stability of long-term renal function and fewer episodes of late acute rejection, especially in African Americans [106]. However, newer evidence suggests that it may be worth reexamining the use of azathioprine (see below). The mycophenolate mofetil vs. azathioprine for prevention of acute rejection in renal transplantation (MYSS) trial compared acute rejections and adverse events in recipients of cadaveric kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with cyclosporine microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). Episodes of rejection were similar in both phases, and adverse effects, rates of allograft loss, and serum creatinine concentrations were the same in both groups. A 5-year follow-up also showed similar mean GFR, incidence of allograft loss, late rejection, and patient mortality. Similar outcomes were seen with or without steroid withdrawal [112]. A recent registry analysis reported by Schold and Kaplan suggests that tacrolimus when used with azathioprine provides excellent graft and patient survival, albeit with slightly higher risk of acute rejection and an equivalent risk of malignancy and BK virus. This study has important implications in that azathioprine is relatively inexpensive and this may be a very costeffective regimen [113].

Mycophenolate Mofetil Versus Azathioprine

Mycophenolate Mofetil Compared to Sirolimus in Cyclosporine-Based Regimens

Each of the three phase III trials of mycophenolate mofetil in renal transplantation clearly established

In a retrospective study, the regimen combining cyclosporine and sirolimus was associated

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with significantly lower graft survival and death-censored graft survival compared to cyclosporine and mycophenolate mofetil. In multivariate analyses, the cyclosporinesirolimus combination was associated with a significantly increased risk for graft loss, death-censored graft loss, and decline in renal function [5]. It should also be noted that while sirolimus was initially approved for use with cyclosporine, concerns of the nephrotoxicity of this regimen have prompted a gradual shift away from this combination toward its use with tacrolimus or mycophenolate mofetil [5].

Mycophenolate Mofetil Versus Sirolimus with Tacrolimus The perception of the lower nephrotoxicity of tacrolimus along with the renal function concerns about the cyclosporine-sirolimus combination led to increasing use of tacrolimus in combination with sirolimus [114]. Analysis of SRTR data showed that recipients treated with tacrolimus and mycophenolate mofetil exhibit better graft survival than those receiving cyclosporine and mycophenolate mofetil or tacrolimus with sirolimus [5]. A statistically and clinically significant difference was demonstrated between the tacrolimus and sirolimus regimen vs. the tacrolimus and mycophenolate mofetil arms at 3 years after transplantation [111, 115]. In summary, the bulk of the evidence thus far points to the efficacy of the use of CNIs with mycophenolate mofetil and steroids as being associated with the best renal allograft outcomes. Poor outcomes with CNI-sirolimus-steroid combinations have led to declining use of that combination. The combination of tacrolimus with azathioprine and steroids appears promising and bears further investigation. In the next section, we will discuss outcomes of immunosuppression minimization regimens in use with currently approved agents.

Calcineurin Inhibitor and Steroid Avoidance Regimens Rationale and Impetus for Use The calcineurin inhibitors (cyclosporine and tacrolimus) and corticosteroids are commonly indicted culprits in the causation of many clinically relevant undesired side effects which occur despite successful transplantation. In an effort to minimize or avoid these toxicities, attention has been directed toward avoiding, withdrawing, or minimizing exposure to corticosteroids and calcineurin inhibitors [49]. In most steroid mini­ mization regimens, in order to maintain immunologic efficacy, treatment with an antiproliferative agent and a calcineurin inhibitor is maintained after stoppage of corticosteroids to provide sufficient rejection prophylaxis. Likewise, calcineurin inhibitor withdrawal/ avoidance regimens continue corticosteroids and one or more antiproliferatives (usually mycophenolate mofetil or sirolimus) after elimination of the calcineurin inhibitor. Antibody induction is usually used to minimize rejection risk in both steroid and calcineurin inhibitor withdrawal/ avoidance. The primary impetus to eliminate calcineurin inhibitors from immunosuppressive protocols in kidney transplantation has stemmed from concerns about their intrinsic nephrotoxic effects [49]. The main impetus to do away with or minimize the use of corticosteroids in transplantation stems from the desire to forestall or mitigate the many complications associated with corticosteroids. These complications, as alluded to earlier, can be disabling in their impact on the quality of life and functional status of the kidney transplant recipient, and by no means can be dismissed as being trivial. Early attempts at minimizing steroids consisted of withdrawal after months to years of therapy. Such an approach is now known to be associated with a risk of delayed acute rejection and poor graft outcomes. As such, early steroid avoidance wherein steroids are discontinued at 3–5 days posttransplant is the currently favored approach [116–118].

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Also to be noted from the practical standpoint is that any patient on a minimization regimen (whether corticosteroid or calcineurin inhibitor minimization) who encounters even the most transient interruption of their dosing, whether due to intercurrent illness or frank noncompliance, is at a much greater risk for acute rejection. Furthermore, the incidence of acute rejection rates upon withdrawal of calcineurin inhibitors or steroids is not negligibly small; and unfortunately, effects of such rejection episodes on attrition of graft function and in turn patient survival still remain largely unknown [49]. In addition, even though the incremental rates of acute rejection in many corticosteroid and calcineurin inhibitor withdrawal studies are small, the underlying risk might be underappreciated because of the underdiagnosis of acute rejection when only for-cause biopsies are performed. The higher rates of clinically overt acute rejections might well be a marker of a much greater increase in subclinical rejections that ultimately could have a significant negative impact on long-term graft survival [49].

Calcineurin Inhibitor Avoidance: De Novo Studies Mycophenolate Mofetil with Sirolimus There has been increasing interest in avoiding the use of calcineurin inhibitors in kidney transplantation in order to avoid their nephrotoxicity. Excellent short-term results have been reported by single centers when sirolimus was used in combination with mycophenolate mofetil and corticosteroids in kidney transplantation [62, 119]. An analysis of SRTR data compared the sirolimus and mycophenolate mofetil combination regimen to other standard regimens in kidney transplantation [31]. Six-month acute rejection rates were higher with the sirolimus– mycophenolate mofetil combination. Overall graft survival was significantly lower with the sirolimus–mycophenolate mofetil combination. The combination was associated with twice the

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hazard for graft loss relative to the tacrolimusmycophenolate mofetil combination. Similar results were noted on the on-treatment analyses and across all patient subgroups [31]. These findings based on retrospective data were corroborated by the Efficacy Limiting Toxicity Elimination (ELITE)-Symphony study wherein standard-dose cyclosporine based regimens were compared to low-dose cyclosporine, tacrolimus, or sirolimus in combination with mycophenolate mofetil, daclizumab, and corticosteroids in renal transplantation. In the reported 1-year results of this study, biopsy-proven acute rejection at 6 months in patients on sirolimus-­mycophenolate mofetil was three times higher than with tacrolimus-mycophenolate mofetil. Allograft function was also superior in the tacrolimus-mycophenolate mofetil group. Lastly, 1-year graft  survival was significantly inferior in the sirolimus-­ mycophenolate mofetil group (Fig. 3.3) [120]. In the next section, we discuss regimens that involved the removal of calcineurin inhibitors from a regimen where the CNI was used either with sirolimus or mycophenolate mofetil and steroids. The primary aim of such a strategy is to remove nephrotoxic effects of the CNI and maintain immunosuppression for rejection prophylaxis with the remaining agents. These studies were carried out in patients with stable graft function where the desired end result is prevention of long-term damage to the graft from the CNI or in patients with deteriorating graft function where the aim is rescue of the graft from the CNI’s nephrotoxic effects. Calcineurin Inhibitor Withdrawal with Mycophenolate Mofetil Patients with Stable Graft Function The CAESAR (Cyclosporine Avoidance Eliminates Serious Adverse Renal Toxicity) trial investigated the safety and efficacy of maintaining recipients on cyclosporine for an abbreviated course (no longer than 6 months) or in reduced doses with the primary aim of preserving renal function [121]. In this 12-month, prospective,

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Fig.  3.3  Results of the Efficacy Limiting Toxicity Elimination (ELITE)-Symphony study. (a) The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those  receiving standard-dose cyclosporine (25.8%),

l­ ow-dose  cyclosporine (24%), or low-dose sirolimus (37.2%). (b)  Allograft survival differed significantly among the four groups, and was highest in the low-dose tacrolimus group (94.2%) (Reproduced from [121]. With permission)

randomized, open-label, parallel group multicenter study, low dose cyclosporine/mycophenolate mofetil/prednisone (target trough level of 50–100  ng/mL for 12  months), standard dose cyclosporine (target trough level of 150–300 ng/

mL up to month 4, and then 100–200  ng/mL thereafter)/mycophenolate mofetil/prednisone, or cyclosporine withdrawal (cyclosporine taper starting at month 4 posttransplant and completed by month 6 posttransplant; remaining only on

3  Immunosuppressive Therapy in Kidney and Pancreas Transplantation

mycophenolate mofetil and prednisone). Patients in the low-dose cyclosporine and cyclosporine withdrawal arms received IL-2 receptor blockade (daclizumab) induction to provide protection against acute rejection. The primary endpoint was measured GFR at 12  months and was not statistically different among the three groups [121]. However, biopsy-proven acute rejection rates were significantly higher in the cyclosporine withdrawal group than in either the low-dose cyclosporine or standard-dose cyclosporine arms. In post hoc analyses, calculated creatinine clearances were lower in rejectors in all three treatment arms. With regard to other parameters of interest that could reflect the extrarenal toxicities of cyclosporine, such as blood pressure or hyperlipidemia, no significant differences were observed between the groups [121]. The most fitting unifying explanation for these findings of the CAESAR study is that any potential advantage in terms of maintaining a better GFR or metabolic profile through cyclosporine elimination was likely annulled by the deleterious impact on allograft function of the higher rejection rate with cyclosporine withdrawal [49].

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prednisone compared with those continued on cyclosporine. Most remarkably, acute rejection did not increase after withdrawal of cyclosporine [122]. This study suggests that, in renal transplant patients with worsening renal function, cyclosporine withdrawal with the addition of mycophenolate mofetil confers significantly better renal function and possibly improved graft survival compared with cyclosporine maintenance therapy.

Calcineurin Inhibitor Withdrawal or Substitution Using Sirolimus In these studies, the baseline regimen is either a CNI–MMF–Steroid combination or a CNI– Tacrolimus–Steroid combination. In the CNI–Tacrolimus–Steroid treated patients, the study intervention takes the form of CNI withdrawal and ongoing treatment with sirolimus and prednisone [73]. In the CNI-MMF-Steroid treated patients, the intervention in such studies takes the form of withdrawal of the CNI and substitution with sirolimus as exemplified by the Spare-the-Nephron trial [123].

Patients with Deteriorating Graft Function The risk-benefit ratio changes when attempting calcineurin inhibitor withdrawal in patients with deteriorating renal function vs. stable patients. In patients with deteriorating renal function graft failure might be imminent and any risk of the approach employed to attenuate the progressive loss of renal function is more acceptable when compared to a stable patient with an outlook of 10 or more years of stable renal function. In the Mycophenolate mofetil (“Creeping Creatinine”) Study, patients who had significant deterioration in renal function (by serial reciprocal values of serum creatinine) more than 6 months posttransplantation were either maintained on their cyclosporine-based immunosuppressive regimen or withdrawn from cyclosporine and maintained on only mycophenolate mofetil and corticosteroids [122]. Significant improvement in renal function occurred in patients maintained only on mycophenolate mofetil and

Cyclosporine Withdrawal In the Rapamune Maintenance Regimen (RMR) Trial, patients were randomized at 3  months from triple therapy with sirolimus-cyclosporinecorticosteroids, to either continue that regimen unchanged, or to a cyclosporine withdrawal group with higher targeted sirolimus levels. Overall graft survival after 48  months was significantly better in the sirolimus-corticosteroid arm as compared to the triple therapy control arm, as was death with a functioning graft and death-censored graft survival [73, 74]. Also, the calculated GFR was significantly higher with the withdrawal of cyclosporine. The incidence of biopsy-proven acute rejection was similar in cyclosporine maintenance and withdrawal as one may expect; however, between 3 and 6 months into the study, more acute rejections occurred in the cyclosporine withdrawal group [73, 74].

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Analysis of protocol biopsies at 36  months revealed significantly lower chronic allograft damage index, tubular atrophy, and inflammation in the sirolimus-corticosteroid group [73, 74]. As discussed in preceding sections, this approach could well represent the dissipation of cyclosporine’s nephrotoxic effects and not a beneficial effect of sirolimus per se.

Cyclosporine Substitution with Sirolimus

opposed to 5% in 2000 [3]. This trend is driven largely by the desire of both physicians and patients to avoid or minimize the burden of metabolic, bariatric, osseous, cosmetic, ocular, and neuropsychiatric side effects of corticosteroids [49, 124]. Until recently, these corticosteroid avoidance regimens were largely driven by unrandomized large single-center experiences [118]. In a recent randomized clinical trial that compared corticosteroid avoidance and tacrolimus and mycophenolate mofetil maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and low-dose corticosteroids, rejection rates and biopsy evidence of chronic allograft fibrosis were significantly higher with steroid avoidance [125]. Weight gain was slightly higher at 5 years with steroid avoidance (approximately 2 kg higher). Insulin requiring new-onset diabetes after transplantation was higher with steroid maintenance [125]. Accruing follow-up data from single-center studies show that patients developing acute rejections on steroid avoidance regimens fare better with regard to freedom from subsequent rejections if maintained on steroids after the first rejection episode [126]. A recent registry analysis concluded that steroid avoidance regimens in the United States carried no significant risk of graft loss [127]. However, this study did not report details on acute rejection episodes and subsequent use of corticosteroid maintenance and effects thereof on graft survival [127]. In the absence of such analyses, the results reported may reflect a selection bias where such regimens were employed in patients at lowest immunologic risk and underestimate possible detrimental effects on allograft survival of acute rejection episodes.

The ongoing Spare-the-Nephron trial is investigating the substitution of a calcineurin inhibitor with sirolimus in stable renal transplant recipients on calcineurin inhibitor, mycophenolate mofetil, and prednisone [123]. Two hundred fiftyfour (254) of three hundred forty (340) recipients on mycophenolate mofetil, cyclosporine or tacrolimus, and prednisone were randomized 30–180  days posttransplantation to discontinue their calcineurin inhibitor and switch to a mycophenolate mofetil/sirolimus/prednisone regimen or to continue their current immunosuppressive regimen (calcineurin inhibitor/mycophenolate mofetil/prednisone). The primary endpoint of this trial is the percentage change in measured GFR 12 months postrandomization. In a preliminary report, iothalamate GFR increased by approximately 20% from baseline in the mycophenolate mofetil/sirolimus group, whereas those remaining on mycophenolate mofetil/calcineurin inhibitor only exhibited a 4.4% increase (including individuals taking tacrolimus). However, there was no statistically significant difference in GFR between the two groups at 24 months. The trial also reported less biopsy-proven acute rejection and graft loss from 1 to 2 years in the mycophenolate mofetil/sirolimus group, with significantly decreased mortality [123].

Treatment of Acute Rejection

Corticosteroid Avoidance Regimens

Global Considerations

Corticosteroid avoidance regimens are increasingly being used in renal transplantation, with 23% of first renal transplants in 2004 being discharged after transplantation without steroids as

Prompt and appropriate management of acute rejection provides valuable opportunities to salvage graft function and maintain durable longterm graft survival.

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The diagnosis of acute rejection should be made on the basis of a combination of change in graft function, histopathology, measures of donorspecific antibody, and presence or absence of proteinuria. This approach will help classify the rejection as being cell- or antibody-mediated. In the clinical setting, these entities can overlap and therapy should be guided by the unique circumstances that obtain in the individual patient. Global assessment of the patient should include polymerase chain reaction (PCR) assays for BK virus and CMV to assess risk of infectious complications that could occur with escalation of immunosuppression and alternate explanations for graft dysfunction such as BK nephropathy. The pathology of the allograft should be reviewed to ascertain the balance between chronic and acute lesions in order to prognosticate salvageability of the graft.

Acute Cellular Rejection Pulse Corticosteroids This subset of rejection is classified as T-cellmediated rejection (TCMR). The subclasses include a tubulointerstitial rejection (Banff 1997: Ia, Ib) or vascular rejection with arterial inflammation (intimal arteritis and endotheliitis) (Banff 1997: IIa, II b and III [rare]). Treatment of borderline or suspicious lesions is based on the clinical circumstances and the degree of allograft dysfunction or proteinuria that prompted investigation. The venerable steroid pulse remains the anchor of rejection treatment. Methylprednisolone is administered in a single IV infusion over 30–60  min via a peripheral intravenous line in a dose ranging between 500 and 1,000 mg daily over 3 days. Some institutions use lower doses of 125 or 250  mg. The choice of dose is often arbitrary and there is not much evidence to suggest that doses of over 500  mg are in any way more beneficial. Osteonecrosis, urinary tract infections, bacteremia, and bowel perforations may follow pulse steroids and they should by no means be regarded

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as benign. Empirical use is strongly discouraged, as one of the major correlates of BK nephropathy is the use of pulse ­steroids [128]. Prophylaxis against opportunistic infections with sulfamethoxazole and trimethoprim and antifungal mucosal prophylaxis should accompany the pulse. Maintenance steroids may either be resumed at previous doses or be recycled through the entire taper per clinical circumstances. With modern immunosuppression, the latter situation obtains rarely. Steroid pulses will reverse more than 75% of first episodes of Banff I acute rejection [129]. Successful therapy should be accompanied by a return of creatinine to within 10% of the prerejection baseline. Such a response is compatible with good long-term survival [6]. When the creatinine does not come down with treatment with the steroid pulse, the rejection episode may be considered steroid-resistant. Unfortunately, there is not a good uniform operational definition for this entity. A re-biopsy may be helpful (but not necessary) to rule out transient tubular injury rather than acute rejection as the cause of renal dysfunction.

Anti-T-Cell Antibody Therapy More than 90% of first episodes of cell-mediated rejection will respond to anti-T-cell antibody treatment. However, steroids have traditionally been used as first-line agents owing to ease of use, lower cost, and lower risk of infection. The anti-T-cell antibodies carry a greater risk of opportunistic infection (CMV, fungal infections, Nocardia, and BKV) and neoplasia (PTLD, other cancers). The two main agents that have been used in treatment of rejection are OKT3 and r-ATG. r-ATG, a polyclonal depleting anti-T-cell antibody, is usually chosen when the rejection grade is Banff IIa or greater. There is a greater likelihood of such rejections responding better to this treatment than is seen with pulse steroids alone [129]. r-ATG use requires a central line although protocols that employ heparin have been employed for peripheral administration. Close

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attention should be paid to recycling CMV and other antiinfective prophylaxis after a course of depleting antibody therapy. Monitoring of T cell counts and subsets may allow tailoring of doses to responses, and should be individualized. The dose of antiproliferative drugs may be reduced when using r-ATG, as cytopenias produced by either agent can confuse the clinical picture. Doses of other myelosuppressants such as valganciclovir may need to be readjusted for the same reason. OKT3 use is attended by side effects related to cytokine release which can have systemic manifestations and can confuse the clinical picture through a transient tubular injury that may take days to resolve. OKT3 can be infused via a peripheral line, is used over a 5- to 10-day course, and can be used in subjects with thrombocytopenia [130].

Treatment-Resistant Rejections and Late Rejections As a broad generalization, if a rejection episode does not respond to pulse steroids and if the infectious and neoplastic risk burden is small, antibody is exhibited. A repeat pulse of steroids may be used in selected cases with the caveat that they may do no more than add to the overall burden of side effects. Antibody depletion treatment should then be used and a good response is seen in many cases. In the specific instance of recurrent rejection occurring under adequate immunosuppression, a switch to a different antiproliferative agent or calcineurin inhibitor may be considered. Cell-mediated rejection that is not responsive to treatment with steroids and antibody depletion may be deemed refractory. Repeat courses of depleting antibody may salvage graft function in selected patients but are fraught with risk of malignancy and opportunistic infections. Late acute rejections that occur more than 3 months posttransplant may not respond as well to treatment, especially if they occur with full doses of maintenance immunosuppression or

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represent repeat episodes. This last fact is ­important in deciding on the intensity of treatment of such rejection episodes. Most importantly, nonadherence to treatment and the factors that underlie it should be sought and corrected as needed. Rejections associated with noncompliance may respond to treatment if the burden of chronic irreversible injury is not too high. Late episodes of rejection are probably best treated with steroid pulses as the first line of treatment. The decision to use antibody in such circumstances should be considered very carefully.

Treatment of Antibody-Mediated Rejection The pathology of antibody-mediated rejection and the serologic techniques that are utilized in the demonstration of an alloantibody response are discussed in the chapters on pathology, approach to graft dysfunction, and histocompatibility. The usual approach is to use plasmapheresis to remove alloantibody acutely. Plasma exchanges are usually performed every other day to allow repletion of clotting factors. Donor specific antibody titers should be monitored to ensure success of plasmapheresis. If daily plasmapheresis is employed in severe cases, one must monitor clotting factors and use replacements as appropriate. This plasmapheresis can be followed up with IVIG; a total dose of 2 g/kg of IVIG is used. IVIG may be used with CMVIG (CytoGam). The tendency to “throw everything” at antibodymediated rejection must be resisted. Intensification of tacrolimus or mycophenolate mofetil doses can be instituted. Other agents that have been used in uncontrolled fashion are rituximab and bortezomib. Preliminary data on the latter agent are promising, but it does not appear to be effective as sole therapy [99, 131, 132]. Monitoring after treatment of antibody-mediated rejection should involve monitoring of donor specific antibody titers in addition to renal function and proteinuria. Antibody-mediated rejection may occur years posttransplantation [133]. These episodes are

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not straightforward to manage as escalation of immunosuppression may be fraught with risk and the burden of pathology in the allograft may militate against effective salvage.

Immunosuppression Management in Chronic Allograft Failure This entity is frustrating to manage, and overimmunosuppression does not translate into benefit but adds risk. If immunosuppression is to be augmented, it must be based on biopsy evidence of ongoing rejection and the absence of significant scarring. Calcineurin inhibitor withdrawal with maintenance therapy with mycophenolate mofetil and prednisone may help stretch graft life. Free mycophenolic acid levels can be increased in chronic renal insufficiency and monitoring of drug levels may be needed to avoid hematologic and infectious complications. Empiric steroid pulses in this setting add nothing but metabolic and infectious risk. Sirolimus substitution for calcineurin inhibitors is not recommended in this setting and may be detrimental to renal function or precipitate proteinuria [134]. If biopsy pathology shows evidence of C4d and a donor specific antibody response is present in the absence of extensive fibrosis in the kidney, short courses of steroids and IVIG may help in the individual case. In the absence of evidence of salvageability of such kidneys, judicious counseling of the patient, and institution of stage-appropriate management of chronic kidney disease and ESRD planning should be the goal rather than renewed efforts at immunosuppression.

Immunosuppression for Pancreas Transplantation As a broad generalization, the pancreas transplants are believed to be more immunogenic and rejection-prone than kidney transplants [135, 136]. Pancreas alone and pancreas after kidney transplants appear to have a greater risk of rejection.

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It is not clear if this is perhaps due to absence of the kidney transplant that is more readily amenable to biopsy for evidence of rejection than is the pancreas. In general, the immunosuppressive regimens used in pancreas transplant are extensions of the triple drug combination of tacrolimus, MMF, and steroids [137, 138]. With this regimen, rejection rates of 10–20% are usual. Both IL-2 receptor blockade and antithymocyte globulin is used most commonly as induction [139, 140]. The use of the latter is tempered by concern for BK virus infections. Some centers report excellent results with a tacrolimus and sirolimus [137]. Steroid avoidance regimens have also been used successfully [137, 141, 142]. Experience being accrued by the Euro-SPK trials which are investigating the use of steroid avoidance regimens in simultaneous pancreas kidney transplant and thus far the experience is encouraging [143, 144].

Using Immunosuppression in the Clinic Successful management of immunosuppression is the principal tradecraft of the transplant physician. Newer advances in therapeutics occur regularly. However, immunosuppression is still delivered in the clinic with the relatively crude endpoints of avoiding rejections and overimmunosuppression or drug toxicities. In this dynamic milieu, a rational approach should include the following components: (1) An understanding of pathophysiology and pharmacology; (2) setting endpoints of efficacy for intervention; (3) setting safety checkpoints in monitoring therapy; and (4) construction of a durable therapeutic alliance with the patient. The first step in regimen selection is to establish the immunologic risk level of the patient. Most centers consider patients with high levels of preformed antibody, multiparous women, African Americans, and those who have received prior transplants as being at higher immunologic risk. Young patients may be at higher risk for rejection but also have the highest risk for

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d­ evelopment of complications such as PTLD with depleting antibody induction. Elderly patients are regarded as being at lower risk for immunologic graft loss. Pancreas transplant recipients are regarded as being at higher risk for rejection based on the perceived immunogenicity of the pancreatic allograft. As examples, low-risk patients may be treated with IL-2 receptor antibody induction and tacrolimus or cyclosporine/mycophenolate mofetil/ corticosteroid maintenance therapy. High-risk individuals and those perceived to be at higher risk for delayed graft function may be offered r-ATG induction and tacrolimus/mycophenolate mofetil/steroid maintenance therapy. Outcomes on each regimen used at a center should be evaluated frequently and appropriate changes instituted when outcomes are compromised. Attention should also be paid to cost structures and payor mix to ensure that adherence to the regimen is not an issue that could affect outcomes. In the case of living donor transplants, there is a growing tendency to offer steroid avoidance regimens to low-risk recipients. This enthusiasm demands a caveat. Such transplants can be performed with very small doses of calcineurin inhibitors, mycophenolate mofetil, prednisone, and no antibody induction, with very low rates of acute rejection. Most steroid avoidance protocols, on the other hand, employ a depleting antibody that carries an up-front and enduring risk of overimmunosuppression and an increased risk of rejection, as summarized in previous sections. Furthermore, in the absence of steroids, white blood cell counts can be low and may lead to decreases in mycophenolate mofetil dosing. This could prompt rejections as well, especially if accompanied by a concomitantly low calcineurin inhibitor level. Diligent attention must be paid to steroid taper schedules to avoid overdosing these agents. In the early posttransplant period, attention should focus on the tempo of improvement in renal function so that drugs primarily eliminated by the kidney (e.g., ganciclovir) are administered appropriately. Lack of expected improvement in graft function should prompt investigation.

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All patients should be monitored for ­concomitant medication changes and interactions. The introduction and removal of drugs that impact CYP3A4/5 and P-glycoprotein such as calcium channel blockers and antifungals, which block these pathways and inducers, such as rifampin and phenytoin should be made with careful dose adjustment and monitoring of levels of the calcineurin inhibitors [36]. Steroids are metabolized by the same pathways as calcineurin inhibitors, and appropriate empiric adjustments in doses should be made. Statins and fibrates should be introduced at lower doses than in nontransplant settings to avoid the risk of rhabdomyolysis [145]. Episodes of leukopenia should be investigated with a differential count. Neutropenia usually implies drug toxicity, while lymphopenia could represent immunosuppression or CMV infection. White cell counts can be lower in patients on steroid avoidance regimens and wide dose adjustments of the antiproliferatives may trigger rejection. Routine screening for BKV by PCR of blood is almost universal in the transplant community. The transplant physician must be familiar with the dynamic range of the assays used in his or her center and reduce immunosuppression judiciously. Proteinuria should be monitored at every visit and investigated as appropriate. Proteinuria could imply drug effect (sirolimus), alloimmune damage (chronic transplant glomerulopathy) or recurrent/de novo glomerular disease. Monitoring for alloantibody is not routine but is recommended outside a research setting for high-risk patients and should be carried out within the cost structure of the institution. Metabolic, hematologic, and cardiovascular accompaniments must be followed diligently and promptly treated. Cosmetic concerns of patients should not be ignored and counseling or appropriate switches in medication and, where appropriate, withdrawal should be considered. In the absence of such an approach, nonadherence can result. Late withdrawal of steroids may increase risk of rejection without necessarily conferring the desired metabolic benefit.

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At all times, the psychologic well-being of the recipient and their functional capacity should be tracked and prompt interventions instituted if needed. The financial fitness of the patient should be an essential part of the ongoing evaluation, as loss of insurance coverage for immunosuppression can lead to loss of the allograft. It should be kept in mind at all times that the major aim of transplantation is improved patient survival. Given that the therapeutic armamentarium has a narrow therapeutic index with longterm consequences, immunosuppression should be withdrawn when attempts to save the allograft are futile or patient safety is compromised.

Conclusion Modern immunosuppression has made transplant a clinical reality. Successful management of immunosuppression will be a major part of ensuring that continuing accrual of stellar outcomes in transplantation.

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86 135. Gruessner AC, Sutherland DE, Gruessner RW. Pancreas transplantation in the United States: a review. Curr Opin Organ Transplant 2010;15(1):93–101. 136. White SA, Shaw JA, Sutherland DE. Pancreas transplantation. Lancet 2009;373(9677):1808–1817. 137. Kaufman DB, Shapiro R, Lucey MR, Cherikh WS, R TB, Dyke DB. Immunosuppression: practice and trends. Am J Transpl 2004;4(Suppl 9):38–53. 138. Kaufman DB, Leventhal JR, Gallon LG, et  al. Technical and immunologic progress in simultaneous pancreas-kidney transplantation. Surgery 2002;132(4):545–553; discussion 53–54. 139. Cicero A, Lappin JA. Pancreas transplantation: experience at University of Texas, Houston. Transplant Proc 2010;42(1):314–316. 140. Farney A, Sundberg A, Moore P, et al. A randomized trial of alemtuzumab vs. anti-thymocyte globulin induction in renal and pancreas transplantation. Clin Transplant 2008;22(1):41–49. 141. Fridell JA, Agarwal A, Powelson JA, et al. Steroid withdrawal for pancreas after kidney transplantation in recipients on maintenance prednisone immunosuppression. Transplantation 2006;82(3):389–392. 142. Gallon LG, Winoto J, Chhabra D, Parker MA, Leventhal JR, Kaufman DB. Long-term renal transplant function in recipient of simultaneous kidney and pancreas transplant maintained with two prednisone-free maintenance immunosuppressive combinations: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus. Transplantation 2007;83(10):1324–1329. 143. Malaise J, De Roover A, Squifflet JP, et  al. Immunosuppression in pancreas transplantation: the Euro SPK trials and beyond. Acta Chir Belg 2008;108(6):673–678. 144. Nakache R, Malaise J, Van Ophem D. A large, prospective, randomized, open-label, multicentre study of corticosteroid withdrawal in SPK transplantation: a 3-year report. Nephrol Dial Transplant 2005;20(Suppl 2):ii40–47, ii62. 145. Hurst FP, Neff RT, Jindal RM, et al. Incidence, predictors and associated outcomes of rhabdomyolysis after kidney transplantation. Nephrol Dial Transplant 2009;24(12):3861–3866.

G. Thomas et al. 146. Frey F, Horber F, Frey B. Trough levels and concentration time curves of cyclosporine in patients undergoing renal transplantation. Clin Pharmacol Ther 1988;43(1):55–62. 147. Chueh S, Kahan B. Pretransplant test-dose pharmacokinetic profiles: cyclosporine microemulsion versus corn oil-based soft gel capsule formulation. J Am Soc Nephrol 1998;9(2):297–304. 148. Fitzsimmons WE, Bekersky I, Dressler D, Raye K, Hodosh E, Mekki Q. Demographic considerations in tacrolimus pharmacokinetics. Transpl Proc 1998;30(4):1359–1364. 149. Zimmerman JJ, Kahan BD. Pharmaockinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997;37(5):405–415. 150. Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000;11(10):1910–1917. 151. Opelz G, Dohler B, Laux G. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transpl 2005;5(4 Pt 1):720–728. 152. Vanrenterghem Y, Lebranchu Y, Hene R, Oppenheimer F, Ekberg H. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation 2000;70(9):1352–1359. 153. Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transpl 2008;8(2):307–316. 154. Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow-up. Clin Transplant 2008;22(2):200–210. 155. Sampaio MS, Kadiyala A, Gill J, Bunnapradist S. Alemtuzumab versus interleukin-2 receptor antibodies induction in living donor kidney transplantation. Transplantation 2009;88(7):904–910.

Chapter 4

Clinical Pharmacologic Principles and Immunosuppression Patricia West-Thielke and Bruce Kaplan

Keywords  Clinical pharmacology • immunosuppression • kidney transplantation • pharmacokinetics • pharmacogenomics

pharmacology of these agents will be presented first followed by the pharmacokinetics.

Pharmacology Introduction Corticosteroids In large part the success of solid organ ­transplantation lies in the appropriate utilization of immunosuppressive medications [1]. In simplest terms one would like to administer an adequate dosage of an agent (a dose that adequately suppresses the alloimmune response) while at the same time avoiding toxicity related to excessive immunosuppression or concentration related secondary toxicities. In reality the agents currently in use do not allow for this “perfect” scenario. However, the principle of trying to administer the minimal effective dose still holds true. A basic tenet of pharmacology is that the effect of any administered agent is related to the free concentration of the drug at its receptor or ligand binding site. Pharmacokinetics (PK) is the discipline of study of the complex processes of absorption, distribution, metabolism, and excretion of drugs which determine the amount of free drug at its effector site [2, 3]. The basic

P. West-Thielke (*) Clinical Sciences Building, Suite 402, University of Illinois at Chicago, Chicago, IL, 60612, USA e-mail: [email protected]

Due to their potent immunosuppressive ability and antiinflammatory effects, corticosteroids are widely used to treat immune-mediated diseases and inflammation. Corticosteroid receptors in cell cytoplasm are found ubiquitously throughout the body, thus serving as targets for numerous potential adverse effects. The mechanisms of action of corticosteroids are extremely complex and not fully understood. However, it is known that corticosteroid administration changes circulating peripheral leukocyte patterns. After drug administration neutrophils increase with a peak effect in 4–6 h and normalize within 24 h [4, 5]. This effect appears to be the result of an accelerated release of neutrophils from the bone marrow with diminished movement out of the circulation. This results from the inability of neutrophils to adhere to vessel walls in the presence of corticosteroids, a process which is necessary for them to migrate into tissues. The overall effect is a reduced number of neutrophils at the site of inflammation [4]. All other leukocytes (lymphocytes, monocytes, eosinophils, and basophils) also decrease in response to corticosteroid administration. After the administration of corticosteroids, circulating

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_4, © Springer Science+Business Media, LLC 2011

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T cells, more so than B cells, move from the ­circulation into extravascular compartments (spleen, lymph nodes, thoracic duct, and bone marrow). Nonrecirculating lymphocytes, however, appear to be unaffected [5, 6]. Modification of the molecular configurations on the lymphocyte surface membrane is one explanation for this redistribution theory [5]. Through antigen presentation to T and B cells, monocytes and macrophages play an important role in initiating the immune response. These cells also regulate immune activity by removing immune complexes. Administration of corticosteroids can cause a profound depletion of circulating monocytes, which also appears to follow the redistribution phenomenon [7]. Additionally, the reduction of monocytes by corticosteroids will hinder the inflammatory response by impeding chemotactic factors and macrophage activation factor, phagocytosis, pyrogen production, and secretion of collagenase, elastase, and plasminogen activator [4].

Calcineurin Inhibitors Both cyclosporine and tacrolimus inhibit the cytoplasmic calcium/calmodulin-dependent ­serine/ threonine phosphatase enzyme called calcineurin. Though pharmacologically similar, cyclosporine and tacrolimus exert their effects on calcineurin through slightly different mechanisms. This difference relates to the immunophilin protein with which each drug binds (Table 4.1) [8]. Cyclosporine’s target of binding is cyclophilin, whereas tacrolimus forms a complex with the immunophilin known as FK binding protein-12 (FKBP-12). The binding of calcium and calmodulin with both the cyclosporine-cyclophilin complex and the tacrolimus-FKBP-12 complex results in the inhibition of calcineurin. Inhibition of calcineurin causes decreased dephosphorylation of the nuclear factor of activated T cells (NFAT). Thus, NF-AT is unable to translocate across the nuclear membrane to activate gene transcription of interleukin-2 and other cytokines

needed for T-lymphocyte proliferation and ­activation. Cyclosporine and tacrolimus inhibit T-cell division between the G0 and G1 phase of the cell cycle [9].

Mycophenolic Acid The mechanism of action of mycophenolic acid (MPA) is related to inhibition of the enzyme inosine monophosphate dehydrogenase (IMPDH), a critical enzyme in the de novo generation of purine nucleotides [10]. Mycophenolic acid is a selective, noncompetitive, and reversible inhibitor­ of IMPDH. Inhibition of IMPDH results in decreased nucleotide synthesis and diminished DNA polymerase activity, ultimately reducing lymphocyte proliferation and function, including antibody formation, cellular adhesion, and migration. The actions of MPA are more specific for T and B cells, which use only the de novo pathway for nucleotide synthesis. Other cell lines within the body have a salvage pathway by which they can synthesize nucleotides, making them less susceptible to the actions of MPA, and thereby decreasing the risk for hematologic adverse effects.

M-TOR Inhibitors Similar to cyclosporine and tacrolimus, sirolimus binds to a cytosolic protein (an immunophilin) to exert its immunosuppressive activity [11]. Like tacrolimus, sirolimus preferentially binds to FKBP-12; however, its mechanism of action ­differs entirely (see Table 4.1). In contrast to tacrolimus and cyclosporine, the m-TOR inhibitors, sirolimus and everolimus, have no effect on calcineurin, but work on signal transduction, the mechanism whereby mitogenic stimuli regulate the synthesis of specific proteins needed for cell cycle progression from the G1 to S phase [10, 13–15]. Multiple pathways control cell proliferation, making the entire signal transduction cascade rather complicated. Thus far research has determined that the TOR inhibitors, as a result of binding to FKBP-12, inhibit the

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Table 4.1  Mechanism of action of calcineurin and TOR inhibitors (From [8, 9, 12]) Cyclosporine Tacrolimus Binding protein Cyclophilin FKBP-12 Enzyme inhibited Calcineurin Calcineurin Effect on IL-2 Inhibit IL-2 production Inhibit IL-2 production

Sirolimus FKBP-12 mTOR Inhibit cellular response to IL-2 Effect on cell cycle Inhibit G0-G1 Inhibit G0-G1 Inhibit G1-S phase FKBP-12 FK-binding protein-12, IL-2 interleukin-2, mTOR mammalian target of rapamycin, TOR target of rapamycin

activity of the mammalian target of rapamycin (mTOR), a kinase enzyme. In response to mitogenic stimuli, such as IL-2, insulin, and other growth initiators, mTOR phosphorylates at least two proteins, p70 S6 kinase (p70s6k) and PHAS-I. Upon activation, the p70s6k normally phosphorylates the 40  S ribosomal protein, S6, at multiple sites, causing an increase in the translation of mRNAs, ultimately enhancing protein synthesis [10]. PHAS-I, also known as 4e-BP1, is a low-molecular repressor of translation initiation [16]. When PHAS-I is in a dephosphorylated state, it is tightly bound to eukaryotic initiation factor (eIF)-4E. During stimulation, PHAS-I becomes phosphorylated causing eIF4E to break away and initiate translation and protein synthesis [15]. The drug FKBP-12mTOR complex inhibits phosphorylation of p70s6k and PHAS-I, resulting in decreased translation activation and protein synthesis. Therefore, even though the calcineurin inhibitors (CNIs) and TOR inhibitors all bind to intracellular immunophilins to exert their immunosuppressive activity, their mechanisms of action are completely different. Cyclosporine and tacrolimus inhibit production of cytokines, whereas sirolimus and everolimus block the effects of cytokines on cell proliferation.

General Pharmacokinetic Principles A major underlying hypothesis in clinical pharmacokinetics is that the concentration of the agent in blood, serum, or some other measurable compartment is related to the concentration of free (or non-protein bound) drug at its effector site [2, 3].

Three major independent parameters describe the primary processes that govern disposition of pharmacologic agents. These independent pharmacokinetic parameters are bioavailability, clearance, and volume of distribution. Although not classically defined as primary pharmacokinetic parameters, protein and erythrocyte binding significantly influence drug distribution and affect the rate of elimination of some drugs [17–19]. Figure  4.1 graphically represents ­several pharmacokinetic parameters.

Bioavailability Bioavailability (F) is a term that includes both the extent and rate of drug absorption [20, 21]. The extent of drug absorption (F) represents the fraction of the administered amount of drug that reaches the peripheral circulation in its active form. It is calculated from formal pharmacokinetic analysis or by comparing the area under the curve (AUC) or urine recovery of unmetabolized drug after intravenous and oral dosing [2, 22, 23]. Simultaneous administration of a stable isotope labeled intravenous dose and a standard oral dose permits formal pharmacokinetic analysis of absolute bioavailability and rigorous characterization of both the extent and rate of absorption of an oral drug formulation [22]. However, absolute bioavailability in most cases is determined by comparing measurements made after separate intravenous and oral administration of the drug. When two different oral drug formulations are compared, only relative rather than absolute bioavailability can be measured.

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Fig. 4.1  A representative concentration-time curve which describes several pharmacokinetic parameters

Bioavailability of an orally administered agent is determined by physicochemical barriers to absorption presented by gastrointestinal mucous membranes, by gastrointestinal transit rate, and by first-pass or presystemic metabolism and/or excretion by the gut and/or liver [2, 22, 23].

Calcineurin Inhibitors (Cyclosporine and Tacrolimus; CNI ) As the majority of data pertaining to CNIs has been generated with cyclosporine, we emphasize this data. It is presumed that these principles qualitatively pertain to tacrolimus as well. Also of note, cyclosporine is available as two formulations: oil-based and microemulsion. The oilbased formulation was the first cyclosporine product marketed and was shown to have variable and inconsistent absorption, resulting in drug levels that do not correlate well with AUC. Proposed reasons for this range in absorption include dependency upon bile for cyclosporine emulsification, drug administration in relation to meals, fat content of meals, and gastrointestinal motility [8]. Microemulsion cyclosporine was developed in order to address the unpredictable absorption and pharmacokinetics of the oil-based

product. Microemulsion cyclosporine is so named because it forms an emulsion with ­gastrointestinal fluid resulting in a dispersion which is more readily absorbed than the oilbased product [24]. Microemulsion cyclosporine has a decreased time to peak concentration (Tmax) and increased peak concentration (Cmax) ­compared with oil-based cyclosporine [25]. The resultant differences in bioavailability in these products translate into non bioequivalence. Cyclosporine’s oral bioavailability is governed by absorption, gut metabolism by the isoenzymes of the cytochrome P-4503A (CYP3A) family, and  counter-transport by P-glycoprotein(P-gp) [26–  31]. The intestinal lining is rich in both CYP3A and in P-gp. These systems work in concert to prevent access of the CNI to the circulation. In more elaborate terms, P-gp, the 170-kDa ATP-binding cassette transporter protein product of the mdr-1 gene mediates efflux countertransport of xenobiotics in the small intestine brush border and biliary canaliculi [32]. The actions of P-gp and CYP3A are complementary and repeat efflux-influx cycles of a drug via P-gp may serve to enhance exposure to and accelerate ­metabolism by intestinal CYP3A (P-gp causes recirculation through the intestinal P 450 compartment) [33]. Consistent with this line of thought, CYP3A and

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P-gp show considerable overlap in substrate selectivity, tissue localization and coinducibility [30, 33]. Based on different patient populations, the extent and rate of absorption of tacrolimus is extremely variable, with the bioavailability ranging from 5% to 67% in solid organ transplant recipients [34]. Peak plasma concentrations following a single 0.15 mg/kg oral dose achieved levels ranging from 0.4 to 5.6 mg/L [9]. Absorption is decreased with meals with moderate fat content. Sirolimus and everolimus are also substrates for the CYP3A system and P-gp and therefore experience similar constraints to bioavailability [35, 36]. Sirolimus is rapidly but poorly absorbed after oral administration, with an estimated bioavailability of 15%. Everolimus’ dose requirements are higher and plasma concentrations more variable in lung transplant recipients with cystic fibrosis, a situation similar to that for CNIs [37].

Mycophenolate Mofetil (MMF) Presystemic hydrolysis of mycophenolate mofetil (MMF) by systemic esterases release mycophenolic acid (MPA), the active compound [38]. This illustrates a situation where bioavailability is again influenced by presystemic processes. While MMF can be absorbed from the stomach, entericcoated MPA sodium has a coating which cannot undergo dissolution at the normal pH of the stomach and is therefore absorbed almost entirely in the small intestine [39]. In lung transplant recipients with cystic fibrosis, increased doses of MMF may be required to achieve a given plasma concentration, the reasons for which are unclear but likely involve impaired enterohepatic circulation of MPA glucuronide [40].

Corticosteroids Prednisolone and methylprednisolone are poorly water soluble but have high oral bioavailability [41]. They are administered as water-soluble salts of esters for intravenous administration; the

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esters are rapidly hydrolyzed in the liver to the free alcohol form. Prednisone, an inactive prodrug is rapidly hydrolyzed after oral administration to its active form, prednisolone. Oral corticosteroids are rapidly and completely absorbed from the gastrointestinal tract.

Apparent Volume of Distribution (Vd ) Apparent volume of distribution (Vd) describes drug distribution in the body and is a measure of the apparent space within the body that is available to contain the drug, referenced to concentrations measured in blood, plasma, or serum [2, 17, 23]. Drugs and other compounds, such as immunoglobulins, that are avidly bound to serum protein have Vd that approximates the extracellular space [42]. Highly lipophilic agents, such as cyclosporine and tacrolimus, which have high tissue affinity, have a Vd that is greater than that of total body water and have extensive tissue ­distribution [43]. For most clinical applications, the body can be regarded as having only a single, homogeneous fluid compartment into which the drug distributes [17, 23, 42]. In these cases, Vd may be calculated using the equation Vd = Dose/C0, where C0 is the Y-intercept of the extrapolation of the linear terminal elimination phase of the concentration-time profile to t = 0, yielding an estimate of the hypothetical initial plasma concentration. Under steady state conditions, Vd is of minor clinical relevance and has no effect on the averaged drug concentration during a dosing interval. However, Vd is a primary determinant of the peak drug concentration resulting from a loading dose and affects observed half-life and peak and trough levels even at steady state [2, 3, 17, 23, 42]. The t½ is not a primary pharmacokinetic parameter as it can be expressed in terms of CLT and Vd as t½ = 0.693 X Vd/CLT, for drugs exhibiting monoexponential kinetics. Given this relationship, an increase in Vd in the face of constant CLT is accompanied by an increased elimination t½. The effect of Vd on the disposition of immunosuppressive medication is illustrated by

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everolimus and sirolimus [36, 44]. Everolimus, a hydrophilic derivative of the more lipophilic sirolimus, has a smaller Vd (110 L as opposed to 1,600 L for sirolimus) and exhibits a shorter t½ (30  h) than sirolimus (60  h) despite sirolimus having a higher CLT (19  L/h) than everolimus (8.8 L/h). Thus, as CLT only measures the ability of a mechanism of drug elimination to act on the delivered drug concentration, an elevated Vd will be associated with an increased t½ without a concomitant decrease in clearance.

Binding Immunosuppressive drugs, after absorption into the systemic circulation are bound to serum ­proteins, cellular constituents of blood or tissues [2]. Binding is largely a function of charge, ­affinity of the binding site, number of binding sites, drug concentration, and the presence of specific receptors for a drug at the binding site. Perturbations in protein binding of a drug will thus affect the free drug concentration resulting in changes in efficacy, toxicity, or elimination of the drug [18, 19]. As examples, cyclosporine and tacrolimus are bound to erythrocytes, which dictates that the matrix of choice for their clinical measurement is whole blood [45–47]. Cyclosporine is also bound to lipoproteins (90%) and the free cyclosporine levels may in fact be higher in malnourished subjects with hypolipoproteinemia [48]. Erythrocyte membranes have immunophilins that bind tacrolimus [45]. The exact clinical relevance of this finding is not known. Tacrolimus is also bound to alpha-1 acid glycoprotein, an acute phase reactant whose plasma concentration increases posttransplantation an interaction that can potentially affect free tacrolimus concentration [49]. Sirolimus is highly lipophilic and therefore, enters cells easily. Since erythrocytes contain more FKBP than lymphocytes, 95% of sirolimus can be found bound to erythrocytes [50]. Over 75% of an everolimus dose is distributed into erythrocytes; therefore, whole blood concentrations should also be used for

therapeutic drug monitoring. Of the plasma ­fraction, about 75% is protein bound [51]. Mycophenolic acid MPA, the active metabolite of mycophenolate mofetil is bound to albumin [38]. Prednisolone undergoes saturable nonlinear binding to transcortin and the extent of this binding can change in states of inflammation or renal impairment; free prednisolone concentrations probably better reflect patient exposure [52]. This nonlinear binding of prednisolone to transcortin implies that even small dose reductions in prednisone may confer disproportionate decreases in total prednisone exposure. This complexity of prednisolone kinetics is further illustrated by the observation that due to the ­saturable binding of prednisolone to transcortin, prednisolone clearance may actually decrease as concentrations fall, due to the operation of restrictive elimination kinetics (see section below) [53–57]. Methylprednisolone in contrast is primarily bound to albumin and exhibits doselinear PK unchanged by inflammatory states or renal impairment.

Clearance Clearance (total body clearance, CLT) is defined as the volume of serum or blood completely cleared of a drug per unit time [2, 23]. Thus clearance is expressed in units of volume over time and may be normalized to body weight. The metabolic pathways that participate in clearance are collectively termed biotransformation [2]. Phase I biotransformation reactions introduce or expose functional groups by hydroxylation, oxidation, or dealkylation, render compounds inactive and improve water solubility. Phase I reactions are typified by the cytochrome P-450 system. In phase II biotransformation reactions, the phase I product (or parent compound) is conjugated to glucuronide or sulfate and the water soluble phase II product is excreted in urine or bile. While clearance is now known to occur at many organ sites throughout the body major sites of clearance are the liver and the kidney [2, 3, 23].

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The kidney excretes drugs by glomerular filtration, tubular secretion (via the organic anion and cation transport pathways) and also may be a site for metabolic breakdown of some drugs. Most drugs of relevance in clinical transplantation exhibit first-order clearance kinetics where a constant fraction of drug is eliminated per unit of time. Thus, for most drugs, a dose change will change steady state plasma concentrations in a proportionate manner, a property termed doseproportionality [2, 3, 17, 23]. Oxidation, N-demethylation, or hydroxylation reactions are prominent in the metabolism of cyclosporine, tacrolimus, sirolimus, everolimus, and corticosteroids [2, 28, 58–61]. The major pathway that mediates these oxidative biotransformation reactions is through the cytochrome P-450 system (CYP) [26, 27, 29, 31, 62]. The CYP enzymes, located in the microsomes of hepatocytes are broadly classified into several families of isoenzymes (e.g., CYP1, 2 and 3) based on protein sequence homology. [26, 28, 29, 62, 63] These isoenzyme families are further subdivided into more closely related functional groupings (CYP2D [e.g., subclass CYP2D6] or CYP3A [e.g., subclasses CYP3A4 and CYP3A5]) [2, 26, 27, 29, 30, 62–66]. There is well known interpatient heterogeneity in these enzyme ­systems and much of this heterogeneity accounts for the interpatient variability noted with using medications [63, 64, 67, 68]. For cyclosporine, tacrolimus, sirolimus, and everolimus, the CYP3A isoenzyme family is ­primarily responsible for the metabolism of these drugs [69–72]. The CYP3A isoenzyme family is now known to contain a number of single nucleotide polymorphisms (SNPs) which may mediate much of the interpatient difference in clearance of clinical relevance [73–78]. CYP3A isoenzymes are present in the liver and in progressively decreasing concentration down the small bowel [62, 64]. The cDNA sequences of hepatic and intestinal CYP3A4 are identical suggesting that the proteins themselves may be identical [79]. Hepatic CYP3A accounts for the majority of CYP3A activity and is a site of many pharmacokinetic interactions of cyclosporine and tacrolimus, However it is now appreciated

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that small bowel CYP3A and P-gp also play a large role in drug-drug interactions [68]. Hepatic and intestinal CYP3A4 may not be coordinately regulated and interpatient differences in the bioavailability and clearance of Cyclosporine may not be readily apparent from studies measuring differences in exposure [68]. In a well-known interaction, grapefruit juice, an inhibitor of both CYP3A4 and P-gp, enhances oral bioavailability of cyclosporine without effect on systemic elimination of CYP3A4 substrates [80]. However, selective knockout of intestinal CYP3A4 without P-gp inhibition does not affect cyclosporine oral bioavailability, ­suggesting that P-gp in this case is the major determinant of cyclosporine bioavailability. The second major clearance process that occurs mainly in the liver is that of glucuronidation [2, 81–83]. Of the major immunosuppressants in use, mycophenolate mofetil (MMF) undergoes this process of clearance [2, 11, 38]. UDP-glucuronosyltransferase (UGT) found in the liver (and other organ sites) inactivate the active moiety of MMF, mycophenolic acid (MPA) to an inactive phenolic glucuronide (MPAG) [84]. The UGT superfamily is subclassified into UGT1 and UGT2 based on amino acid sequence homology [85]. UGT isoforms responsible for MPA glucuronidation include UGT1A8, UGT1A9, UGT1A10 and UGT2B4, and UGT2B7 [86, 87]. A more recent report based on in  vitro incubation studies suggests that UGT1A9 (hepatic) and UGT 1A8 (extrahepatic) may contribute predominantly to MPA glucuronidation in transplant recipients [84]. While it was initially believed that the glucuronidation product of MPA was entirely inactive, it is becoming increasingly clear that a minor, metabolically active glucuronidation product of MPA, MPA acyl glucuronide may play a role in mediating some of the toxicity of MPA (most notably GI toxicity) and contribute to some of the immunosuppressive effect [88–90]. The major inactive metabolite is 7-O-MPAG, the phenolic glucuronide of MPA. Renal glucuronidation is a relatively minor contributor to MPA glucuronidation in  vivo [91, 92]. Figure  4.2 shows the metabolism of mycophenolic acid and drug

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Fig. 4.2  Metabolism of mycophenolic acid and drug interactions with immunosuppressants

interactions with cyclosporine, tacrolimus, and corticosteroids. MPAG also undergoes significant enterohepatic recirculation where it can be acted on by intestinal glucuronidases and converted back to the active MPA [11, 38]. It is known that up to 30% of MPA exposure may be secondary to this enterohepatic circulation. MPAG is excreted by the kidney and concentrations of this metabolite increase with decreasing renal function [11, 38, 93–95].

Restrictive Clearance and Protein Binding The concept of restrictive clearance facilitates an understanding of the effects of altered proteinbinding on blood or plasma clearance and consequently on total and free drug concentrations [18, 19]. A drug is said to undergo restrictive clearance if the extraction efficiency of an eliminating organ is less than or equal to the unbound (free) fraction of drug measured in the venous circulation. Under certain circumstances, restric-

tive clearance concepts may explain clinically relevant pharmacokinetic behavior of MPA [95–97]. Both MPA and MPAG are highly bound to albumin [11, 38]. MPAG can competitively ­displace MPA from albumin binding sites [11, 95, 98]. In severe renal insufficiency, MPA is less avidly bound to albumin and the free fraction is increased [93, 94, 97]. This effect seems to be mediated by the uremic state per se and also the competitive displacement of MPA from albumin binding sites by retained MPAG [95, 96, 99]. Acutely, this increase in MPA free fraction is accompanied by an increase in MPA clearance [96, 99]. As a consequence, total MPA levels may decrease with little change in free MPA exposure; concomitant hypoalbuminemia accompanying renal insufficiency accentuates this effect [99, 100]. This phenomenon is consistent with a restrictive type of clearance [93, 95, 96, 99]. In chronic renal impairment, however, MPA free fraction may actually increase and contribute to toxicity [97]. Herein, MPA strays from the restrictive clearance model, the exact mechanisms of which are unclear. The key pharmacokinetic terms and definitions are summarized in Table 4.2.

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Table 4.2  A concise glossary of pharmacokinetic terms and equations (From [2, 3, 17, 23, 42]) Apparent volume of distribution (Vd): Vd describes drug distribution in the body and is a measure of the apparent space within the body that is available to contain the drug, referenced to concentrations measured in blood, plasma, or serum. For oral dosing, Vd can be calculated by the relationship, Vd = administered dose ÷ C0, where C0 is the extrapolation of the linear portion of the terminal elimination phase of the drug to time = 0 AUC: Area under the concentration-time profile. A measure of systemic drug exposure Bioavailability (F): The extent of drug absorption (F) represents the fraction of the administered amount of drug that reaches the peripheral circulation in its active form. It is calculated from formal pharmacokinetic analysis or by comparing the AUCs or urine recovery of unmetabolized drug after intravenous and oral dosing. Oral bioavailability of drug can be represented as, F = (AUCoral ÷ AUC intravenous) × 100% Cav: Average drug concentration AUC ÷ t Clearance (CL): Clearance (total body clearance, CLT) is defined as the volume of serum or blood completely cleared of a drug per unit time. Thus clearance is expressed in units of volume over time and may be normalized to body weight Cmin or Cpredose: Minimum concentration or predose trough level Cmax: Maximum obtained drug concentration Css: Drug concentration at steady state. For an intermittently dosed drug, this is expressed as Css = Dose/t CL Elimination t½: The time required for half an administered drug dose to be eliminated. This can be derived by using the equation, t½ = 0.693 ÷ ke. The t½ of a drug is generally measured from a time point when drug excretion is constant. The t½ may be calculated once steady state is achieved or t½ can be calculated after a single dose. In the case of a single dose, postdistribution concentrations are plotted and then extrapolated to determine a terminal slope and thus a terminal t½. The distinction between these two types of calculations may occasionally explain discrepancies in t½ noted in the literature as the terminal elimination phase may not be observed after a single dose in some instances. The t½ for multicompartment models can be divided into two phases usually depicted as a and b. The a phase describes drug distribution into the tissues, and the b phase describes elimination First-order kinetics: An elimination process wherein the rate of drug elimination is directly proportional to the drug concentration in plasma ke: the elimination rate constant = –2.303 × slope of terminal elimination phase ka: Absorption rate constant t: Dosing interval Tmax: Time to attainment of Cmax from time of dose administration

Pharmacogenetics Pharmacogenetics is the study of the genetic variations that lead to diverse pharmacologic responses. The wide variation in drug concentrations observed with patients receiving the same dose of a CNI is a result of interindividual differences in pharmacokinetics and is primarily the result of genetic differences in metabolism. Given the contributions of the CYP3A system to interpatient variability in PK of CNIs, attention has been focused on the study of genetic polymorphism in the CYP3A system and the multidrug resistance 1 (MDR1) gene as a determinant of interpatient variability in CNI PK [73–78, 101–107]. The data on the pharmacogenetics of cyclosporine are controversial. There are a variety of single nucleotide polymorphisms (SNPs)

associated with reduced CYP3A5 activity. There are several studies examining the effects of CYP3A5 SNPs on cyclosporine PK. One study demonstrated that CYP3A5*1 carriers had lower cyclosporine concentrations compared with patients with two low activity alleles; however, subsequent studies did not confirm this association [75, 104, 108–111]. Studies on CYP3A4 SNPs and cyclosporine PK have also found conflicting results. One study found that patients carrying a CYP3A4*1B variant allele have a significantly higher oral cyclosporine clearance compared with patients homozygous for CYP3A4*1 [109]. Again, subsequent studies have been unable to confirm this data [73, 76]. Perhaps the most notable of the genotypic variations in the CYP3A system are the variations of the CYP3AP1 genotype phenotypically characterized by differential CYP3A5 protein expression

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[77, 78, 112, 113]. MacPhee et al. [59]. showed that kidney transplant recipients with the CYP3AP1 genotype CYP3AP1*1, linked to CYP3A5*1 (CYP3A5 expressors) required up to twofold higher doses of tacrolimus to achieve target blood levels at 3  months posttransplantation than transplant recipients with the CYP3AP1*3/*3 genotype (CYP3A5 nonexpressors) [77]. In a subsequent study, using concentration-controlled dosing the same group has shown that the CYP3A5 expressor phenotype is associated both with lower mean tacrolimus trough concentrations in the first week posttransplantation, longer time to achieve target trough concentrations, and increased risk of early acute rejection [78]. Other studies demonstrate higher cyclosporine dose requirements in CYP3A5 expressors [113]. Genetic polymorphism could thus explain well known ethnic differences in tacrolimus pharmacokinetics [75–78, 101, 102, 107, 112–117]. Black and nonwhite South American patients require higher doses to achieve target blood concentrations of tacrolimus as 70–80% of this patient population have the CYP3A5 expressor phenotype vs. only 5–10% of whites. These findings also underscore the fact that race and ethnicity are imprecise markers of genotype. Polymorphisms of the MDR1 gene have also been identified [75, 106, 107, 113, 114]. A recent study with 69 renal transplant patients showed a significantly lower AUC and C2 in carriers of the MDR1 3435  T allele at 3  days posttransplant, but this difference did not remain significant at 1 month. Data with tacrolimus showed that carriers of the 2677 T or the 3435 T MDR1 alleles had higher dose-corrected trough levels compared to 2677 G-homozygous (GG) and 3435 C-homozygous (CC) renal transplant patients [104, 118, 119]. In general, however, association of MDR1 gene polymorphism to calcineurin inhibitor pharmacokinetics is less consistent than that reported for CYP3A5 [105, 120]. With respect to glucuronidation, the primary metabolic pathway for mycophenolate mofetil, the exact contribution of genetic polymorphism in UGT to interpatient variability in MPA PK is not clear [121, 122]. The UGT site may be ­especially critical in the pediatric population as the activity of this enzyme changes in the first 3 years of life.

A recent study in pediatric renal transplant patients found that patients who were homozygous for UGT1A9-331 T > C developed leukopenia and heterozygotes had significantly more toxicity [123]. Another study found that UGT1A9*3 carriers had higher MPA and AcMPAG exposure, whereas homozygosity for the UGT1A8*2 allele and heterozygosity for UGT1A8*3 allele had no impact on MPA PKs [124]. A study in renal transplant recipients found that mycophenolic acid dose-corrected trough concentrations were 60% higher in subjects heterozygous or homozygous for UGT1A8*2 than in those with the wild-type (p = 0.02); however, this effect was dependent on concomitant calcineurin inhibitor [125]. When subjects were stratified by calcineurin inhibitor status, the UGT1A8*2 effect was only apparent in the tacrolimus group (p < 0.01).

Interactions Given the central role of the CYP3A and P-gp system in the metabolism and clearance of CNIs, m-TOR inhibitors, and corticosteroids and also given that a number of other commonly administered drugs are substrates for these systems a number of clinically relevant drug interactions are possible. Drug interactions involving CYP3A or P-gp may take place at the liver (largely affecting clearance) or at the small intestine (largely affecting oral bioavailability) [31, 68]. Most inhibitors of CYP3A are reversible competitive inhibitors of the system and are themselves substrates for the CYP3A system (e.g., cyclosporine or tacrolimus) [31]. In addition, most substrates for CYP3A are also substrates for P-gp and their interactions are likely to work via both pathways. Commonly observed interactions such as those between calcineurin inhibitors and erythromycin, ketoconazole, and the calcium channel blockers verapamil and diltiazem likely increase concentrations by both decreasing hepatic clearance and by facilitating bioavailability. It is also likely that the degree of interaction is correlated to CYP3A activity, P-gp activity, and concentration and timing of

4  Clinical Pharmacologic Principles and Immunosuppression

the interacting medication. The spectrum of interactions pertinent to cyclosporine, tacrolimus, and cyclosporine, based on their metabolism by CYP3A and transport by P-gp, are expected to be similar. However, recent investigation reveals that cyclosporine induces intestinal CYP3A4 and inhibits hepatic and intestinal P-gp activity in renal transplant recipients in comparison with tacrolimus or sirolimus; thus the actual spectrum of expected interactions with these agents could well be different [126]. As an example, sirolimus exposure is almost twofold higher when cyclosporine is administered concurrently as opposed to 4 h apart from the sirolimus [127]. This interaction is thought to be due to competitive inhibition of intestinal P-gp and a consequent increase in oral bioavailability of sirolimus attendant to decreased firstpass clearance. As a corollary, withdrawal of cyclosporine from sirolimus or everolimus containing regimens is expected to reduce mTOR exposure [128]. CYP3A4 inducers such as rifampin or phenytoin bind to a nuclear receptor, pregnane X  receptor­ (PXR) [129]. This binding of the inducer to PXR results in transcriptional activation of the CYP3A4 gene, increased enzyme synthesis, and consequently, increased quantity of active enzyme, as exemplified by the clinically observed drop in cyclosporine concentrations when transplant recipients receive inducers such as rifampin [31]. Prednisolone is metabolized in part by the CYP3A isoenzyme family and subject to the many interactions with inducers and inhibitors of the CYP3A system described above [41, 130]. However, cyclosporine, TRL and grapefruit juice do not significantly affect PK of prednisolone or methylprednisolone [41]. Interactions pertinent to MMF are largely thought to be dependent on interactions in the context of UGT, P-gp, and the enterohepatic circulation of MPAG. Concomitant cyclosporine therapy decreases MPA AUC with attenuation of the enterohepatic peak (Fig.  4.3) [131, 132]. Kidney transplant recipients on MMF and prednisone alone (or on tacrolimus instead of cyclosporine) have higher MPA exposure than patients receiving a cyclosporine and MMF combination [133, 134].

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In addition, due to the decrease in the enterohepatic peak the relationship between trough and AUC is altered in patients on cyclosporine as opposed to those patients on tacrolimus. Withdrawing cyclosporine from regimens containing cyclosporine, MMF, and prednisone increases MPA Cmin [135]. Whether tacrolimus augments MMF exposure or cyclosporine decreases exposure to MMF is uncertain [131, 132]. While much of the difference in MPA exposure between tacrolimus and cyclosporine coadministration may be explained by cyclosporine’s inhibition of MPAG enterohepatic recirculation, perhaps by inhibition of transporters present in the hepatobiliary membrane [108], it is also possible that tacrolimus impairs MPA glucuronidation [131, 136]. Investigation of MPA pharmacokinetics in the context of steroid withdrawal studies show MPA exposure is lower and its clearance higher in the presence of prednisone, an effect attributed to the ability of steroids to induce UGT [122].

Therapeutic Drug Monitoring Utilization of PK principles and dose-concentration relationships is central to therapeutic drug monitoring (TDM) in optimizing drug dosing to target concentrations [17]. A synopsis of current status of TDM of immunosuppressants is presented in Table 4.3. Various disease states where TDM may be useful in delivering optimal immunosuppression are summarized in Table 4.4.

C2 Monitoring The variable pharmacokinetics and narrow therapeutic window of cyclosporine necessitate drug monitoring to balance efficacy and toxicity. In order to assess the concentration-time curve or AUC, the use of trough or C0 levels were originally employed as the indicator of total cyclosporine drug exposure and hence, the extent of immunosuppression achieved. However, it

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Fig. 4.3  (AUC) of mycophenolic acid (MPA) with CSA compared to TAC showing the effect of CSAs inhibition of enterohepatic recycling

has since been proposed that C0 levels correlate poorly with true drug exposure and adequacy of immunosuppression [137–139]. Interpatient variability with regard to cyclosporine absorption is greatest during the first 4 h following drug administration. It is during this absorption phase that adequate cyclosporine exposure is most crucial to ensuring effective immunosuppression [140]. Several different methods have been attempted to accurately measure cyclosporine exposure. Full 12-h AUCs would provide the most accurate measurement; however, this is too inconvenient for clinical practice. Abbreviated AUCs have been shown to correlate well with full 12-h AUCs [141–145]. Amante and Kahan showed a correlation of greater than 0.9 between full 12-h AUCs and those predicted from blood cyclosporine concentrations measured at 2 and 6 h [142]. The formula is AUC = 2.4 × [2 h] = 7.7  × [6  h] + 195.8. Kaplan and colleagues tested several different models and found the model that utilized concentrations at time 0, 1.5, and 4  h to be the most accurate and convenient (AUC = 24 + 3.66 [0 h] + 2.11 [1.5 h] + 4.54 [4 h]) [141]. Recent studies have advocated the use of a 2-h post-dose or C2 measurement as a better assessor of AUC than C0 levels [146]. C2 measurement also been proposed as the more accurate measure

upon which to base cyclosporine dosing adjustments. In a review of 11 studies evaluating C2 monitoring, Nashan et al. found C2 levels to be more predictive of acute rejection as opposed to the use of C0 levels [140]. The MO2ART (monitoring of 2 h absorption in renal transplantation) trial was a prospective, multicenter, randomized study that examined the efficacy and safety of MF cyclosporine with C2 monitoring in 296 de novo renal transplant recipients [147]. In this study C2 levels were targeted to goal range of 1,200– 2,000  ng/mL over the first 3  months posttransplant. After 3 months, patients were divided into two different groups: a high target C2 and low target C2 with goal levels to be maintained for the remaining nine study months. All patients received corticosteroids and either mycophenolate or azathioprine. At the 3-month followup, the overall biopsy proven acute rejection (BPAR) rate was11.5%, with patient and graft survival rates at 96.6% and 91.2%, respectively. The study authors also noted that 29 MF cyclosporinerelated serious adverse events (e.g., renal dysfunction, hemolytic uremic syndrome, and hepatotoxicity) occurred in 24 patients. Most of these events resolved and 14 of the 24 patients continued in the study throughout the 3 months. Overall, 47 patients discontinued the study before the 3-month followup was complete. The study

Cyclosporine: The actual values used vary based on assay employed and body fluid utilized. Since cyclosporine distributes into erythrocytes, whole blood concentrations are always higher than plasma or serum concentrations. In general antibody-based assays such as RIA, FPIA, or EMIT tend to show cross-reactivity with metabolites and parent compound concentrations may be overestimated. It is important to determine which assay methodology the laboratory is using because target ranges vary between nonspecific assays, such as RIA, which quantitate parent plus metabolite concentration, and specific assays, such as HPLC using mass spectrometry, which quantitate only the parent compound. Thus, the target concentrations will be lower for the specific assays (HPLC) compared to nonspecific assays (RIA, FPIA, or EMIT) by approximately 20–25%. Cmin-based monitoring is usual and targeted concentrations depend on time since transplant, concomitant medications, and clinical circumstances. However, proponents of AUC0–12, C2, and limited sampling strategies have published their experiences A broad range of concentrations are given below. Please note that the specific target concentrations will depend on a multitude of factors Cmin: 75–300 ng/mL using the FPIA assay AUC0-12: 3,600–6,000 ng/h/mL C2: ³1,700 ng/mL AUC0–4: ³4,400 and £ 5,500 ng/mL Mycophenolate mofetil: TDM is not used routinely. Cmin correlates poorly with AUC. AUC shows better correlation with outcome Target concentrations: AUC0–12: 30–60 mg/h/mL Cmin: Under investigation Sirolimus and everolimus: Cpredose shows fair correlation to exposure and is used for TDM. Cmin correlates with freedom from acute rejection in kidney transplants and some dose-related toxicities Target concentrations: Sirolimus: With CNI: 5–10 ng/mL Without CNI: 10–12 ng/mL Everolimus: 3–8 ng/mL; published data with cyclosporine Tacrolimus: Cmin monitoring is used in routine practice. Emerging data indicate that the AUC may be of value in TDM Therapeutic range: 5–15 ng/mL depending on the clinical circumstances

Table 4.3  Evidence for therapeutic drug monitoring of immunosuppressants (From [11, 36, 43, 96, 121, 134, 149, 156, 157, 170–175]) The actual drug concentrations used in TDM vary depending on the clinical situation and the specific agent. These target concentrations are selected based on clinically significant endpoints of efficacy (e.g., freedom from acute rejection), dose-related toxicity (e.g., nephrotoxicity of CNIs or thrombocytopenia in the case of everolimus), or known time course of drug action. Knowledge of factors influencing intra and interpatient variability such as hepatic function, age, time after transplantation, and concomitant medications is essential

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100 Table  4.4  Special circumstances affecting pharmaco­ kinetics of immunosuppressants (From [11, 40, 41, 44, 48, 93, 96, 98, 170, 176–178]) Renal failure: Calcineurin and m-TOR inhibitors: Pharmacokinetics unaffected Mycophenolate mofetil: Decreased protein binding; increased free fraction with increased clearance in acute renal failure; total MPA level may be low with normal free fraction. In chronic renal impairment, free MPA levels may actually be elevated Corticosteroids: Methylprednisolone: Unaffected by renal failure Prednisolone: Decreased Clearance Hepatic failure: Calcineurin and m-TOR inhibitors: Clearance is decreased Mycophenolate mofetil: Hyperbilirubinemia is associated with decreased protein binding and elevation of MPA free fraction; glucuronidation may be impaired; hypoalbuminemia with decreased protein binding and increased MPA free fraction Corticosteroids: Prednisolone: Clearance can decrease almost by half Methylprednisolone: Minor decrease in clearance Gender: Corticosteroids: Methylprednisolone: Clearances higher in women Prednisolone: Moderate increases associated with estrogen intake Age: (Pediatric age group) Calcineurin and m-TOR inhibitors: Increased clearance Corticosteroids: Increased clearance for prednisolone but not methylprednisolone Mycophenolate mofetil: Variable increase in glucuronosyltransferase activity over first 3 years of life with increasing clearance; clearance modulated by concomitant corticosteroid exposure (Elderly age group) Sparse data on pharmacokinetics Cystic fibrosis: Cyclosporine: Decreased bioavailability and increased intrapatient variability of pharmacokinetics Tacrolimus: Decreased bioavailability; sublingual administration has been used to increase drug delivery Mycophenolate mofetil: Increased dose requirement Gastroparesis: Enteric-coated preparations may not be delivered consistently to distal sites of absorption

authors concluded that this 3-month analysis validated the use of C2 monitoring with regard to safety and efficacy. Stefoni and colleagues reported on the

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12-month follow-up results from the ­original MO2ART study population [148]. The 12-month results are garnered from the 250 patients who remained in the study from the original 296 recruited patients. The primary ­endpoint in this 12-month follow-up was glomerular filtration rate (GFR) between the high (levels between 800 and 1,200  ng/mL, n = 131) and low (levels between 600 and 1,000 ng/mL, n = 119) C2 target groups. There was no significant difference in GFR between the two groups throughout the 3- to 12-month period of followup. Secondary efficacy endpoints included BPAR incidence and patient/ graft survival. Similar to the Thervet study, there was an 11.5% incidence in BPAR at 3  months. Between months 3–6, five episodes of BPAR (n = 2 in the high C2 group, n = 3 in the low C2 group) were reported with no statistically significant differences noted. There were no occurrences of BPAR between months 7 and 12. The overall 12-month rate of BPAR was 13.7% across all patients and 10.4% in the patients who remained in the study after 3 months. There was no significant difference in incidence of renal impairment between the two study groups (19% in the high C2 group vs. 15% in the low C2 group). There were no significant differences between the two C2 target ranges with regard to safety or efficacy outcomes data in the first year following transplant. However, there was no comparison group in this study. The Consensus on Neoral C2: Expert Review in Transplantation (CONCERT) group has developed guidelines for C2 monitoring of cyclosporine [149]. Among the recommendations are directives regarding the 15-min “window of opportunity” before and after the 2-h time point that the blood level must be drawn in order to remain within a 10% margin of error. Drug levels drawn outside of this 15-mine window should not be used to make dosage adjustments because the possibility of error is too great. Target levels for C2 range from 0.8 to 1.5 mg/mL for kidney transplant recipients. It has been suggested that a simple ratio-proportion formula (e.g., new dose = old dose × desired C2 level/observed C2 level) may be used to perform dosing adjustments based upon C2 levels [140]. However, C2

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measurement has not been routinely accepted in clinical practice due to difficulties in patient compliance with this method. In addition, studies examining the benefit of cyclosporine C2 monitoring compared to C0 monitoring in maintenance therapy are lacking. In comparison, a good correlation between tacrolimus trough concentrations and 12-h AUC has been demonstrated [150–153]. However, most of these studies were either retrospective, utilized heterogeneous populations, or had flawed endpoints. Two studies have successfully demonstrated this relationship prospectively [152, 154]. The first analyzed the incidence of acute rejection 42 days after transplant and the second examined clinical endpoints 12  weeks after transplant. Current regimens utilizing tacrolimus show very low acute rejection rates with simple trough monitoring; however, the key issues of safety and long-term balance between immunologic protection and safety are still lacking. The pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) are quite complex, which makes MPA a logical candidate for TDM. Data have shown that the 12-h AUC, but not C0, correlates well with the likelihood of acute rejection under immunosuppressive regimens utilizing cyclosporine and nondepleting antibodies. Two formulas commonly used for MPA AUC are:

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monitoring, and OPTICEPT, which addressed trough level monitoring, have thus far not validated the RCCT trial under current IS strategies [161, 162]. The smaller APOMYGRE STUDY did demonstrate lower acute rejection in the group monitored as opposed to a fixed dose; however, this was offset by an increase in viral infections [163]. Currently, the value of MPA monitoring, particularly in nonminimization strategies, remains undetermined. Pharmacodynamic monitoring looking at inosine monophosphate dehydrogenase (IMPDH) suppression has not been validated in large-scale studies. It has been suggested that routine monitoring of sirolimus serum concentrations may not be necessary in some patients because a linear relationship exists between the dose and trough concentration [164]. However, this has not been routinely accepted in clinical practice. Several specifics justify therapeutic drug monitoring of sirolimus. One study demonstrated a strong association between sirolimus trough concentrations and AUC (r2 = 0.94) at steady state. However, this same study noted large intrapatient and interpatient variability. Weight, body surface area, and body mass index were not effective for dose calculation or whole blood concentrations [165]. In addition, if given with cyclosporine, a pharmacokinetic drug interaction occurs, which may increase the unpredictable pharmacokinetics of sirolimus [127]. 1. With cyclosporine: [155] AUC = 11.34 + 3.1 ×  Another study evaluated the utility of thera[0 h] + 1.102 × [0.5 h] + 1.909 × [2 h] peutic drug monitoring in 150 patients with kid 2. With tacrolimus: [156] AUC = 7.75 + 6.49 × ney transplants [166]. The majority of patients [0 h] + 0.76 × [0.5 h] + 2.43 × [2 h] were white males receiving cadaveric kidneys. The minimum recommended MPA AUC of No correlation was found between age, gender, 30 mg*h/L was derived from the randomized con- ethnicity, body mass index, or weight, and AUC, centration-controlled trial (RCCT) in renal trans- trough concentration (Cssmin), peak concentration plant patients receiving cyclosporine, MMF, and (Cmax), or clearance. Good correlations did exist corticosteroids [157]. No additional reduction in with AUC and trough concentrations (r = 0.83). rejection was observed with MPA AUCs greater Large intrapatient and interpatient variability than 60  mg*h/L. This trial was limited by the existed. Patients with sirolimus trough concentrashort-term follow-up of 6  months. Additional tions less than 1.7 ng/mL were statistically more studies with cyclosporine and tacrolimus have likely to experience acute rejection (p = 0.03) and hinted at improvement in early efficacy by utiliz- patients with trough concentrations greater than ing MPA monitoring; however, these studies had 5 ng/mL were more likely to be free from acute several flaws [158–160]. The recent large scale rejection. Significant correlation with trough studies FDCC, which assessed abbreviated MPA concentration was noted with thrombocytopenia

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(p = 0.028), ­leukopenia (p = 0.0008), and ­hypertriglyceridemia (p = 0.04). These adverse effects were more common once sirolimus trough concentrations surpassed 15 ng/mL. These results suggest a therapeutic trough concentration range  for kidney transplantation between 5 and 15 ng/mL and confirm the necessity of therapeutic drug monitoring with sirolimus.

Everolimus In clinical trials evaluating everolimus in patients with renal and heart transplants, the drug has been administered in doses of 0.75 mg twice daily and 1.5 mg twice daily. Therapeutic drug monitoring has been recommended for this drug. Studies have shown that maintaining an everolimus whole blood trough concentration 3  ng/mL or greater reduces the risk for acute rejection and graft loss [167–169]. Renal transplant patients with everolimus concentrations between 3 and 8 ng/mL had a biopsy proven acute rejection rate of 17% and graft loss of 4%. The risk of acute rejection increased 3.4-fold when trough concentrations dropped below 3 ng/mL compared to patients in the range of 3–8 ng/mL (p < 0.0001) [167].

Conclusion Transplant patients exhibit heterogenous immunologic behavior and extremely variable toxic thresholds. In addition, they display considerable variability in pharmacokinetic behavior. The study of pharmacokinetic principles is important in the development and practice of rational therapeutics in solid organ transplant recipients. Recent findings in the field of pharmacogenomics and pharmacogenetics will likely have considerable impact on this field. The central role of pharmacokinetic investigation in accurate description of phenotypes will be especially critical in this regard. The integration of pharmacogenomic and pharmacogenetic data with pharmacokinetics is likely to go a long way

toward individualizing immunosuppression in transplantation.

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108 recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation 2003;76(6):903–908. 148. Stefoni S, Midtved K, Cole E, Thervet E, Cockfield S, Buchler M, et  al. Efficacy and safety outcomes among de novo renal transplant recipients managed by C2 monitoring of cyclosporine a microemulsion: results of a 12-month, randomized, multicenter study. Transplantation 2005;79(5):577–583. 149. Levy GA. C2 monitoring strategy for optimising cyclosporin immunosuppression from the Neoral formulation. BioDrugs 2001;15(5):279–290. 150. Undre NA. Pharmacokinetics of tacrolimus-based combination therapies. Nephrol Dial Transplant 2003;18(Suppl 1):i12–15. 151. Undre NA, Stevenson P, Schafer A. Pharmacokinetics of tacrolimus: clinically relevant aspects. Transplant Proc 1999;31(7A):21 S–24 S. 152. Laskow DA, Vincenti F, Neylan JF, Mendez R, Matas AJ. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation 1996;62(7):900–905. 153. Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996;62(7):920–926. 154. Venkataramanan R, Shaw LM, Sarkozi L, Mullins R, Pirsch J, MacFarlane G, et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol 2001;41(5):542–551. 155. LeMeur Y, Buchler M, Lavaud S. Concentrationcontrolled versus fixed dose of MMF in kidney transplant recipients: preliminary results of a French multicenter randomized study. Seattle, WA: American Congress of Transplantation, 2005. 156. Pawinski T, Hale M, Korecka M, Fitzsimmons WE, Shaw LM. Limited sampling strategy for the estimation of mycophenolic acid area under the curve in adult renal transplant patients treated with concomitant tacrolimus. Clin Chem 2002;48(9):1497–1504. 157. van Gelder T, Hilbrands LB, Vanrenterghem Y, Weimar W, de Fijter JW, Squifflet JP, et al. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999;68(2):261–266. 158. Kiberd BA, Lawen J, Fraser AD, Keough-Ryan T, Belitsky P. Early adequate mycophenolic acid exposure is associated with less rejection in kidney transplantation. Am J Transplant 2004;4(7):1079–1083. 159. Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther 2004;75(5):434–447. 160. Pillans PI, Rigby RJ, Kubler P, Willis C, Salm P, Tett SE, et al. A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute

P. West-Thielke and B. Kaplan rejection in renal transplant recipients. Clin Biochem 2001;34(1):77–81. 161. van Gelder T, Le Meur Y, Shaw LM, Oellerich M, DeNofrio D, Holt C, et  al. Therapeutic drug ­monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28(2):145–154. 162. Gaston RS, Kaplan B, Shah T, Cibrik D, Shaw LM, Angelis M, et  al. Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial. Am J Transplant 2009;9(7):1607–1619. 163. Le Meur Y, Buchler M, Thierry A, Caillard S, Villemain F, Lavaud S, et  al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant 2007;7(11):2496–2503. 164. Napoli KL, Kahan BD. Routine clinical monitoring of sirolimus (rapamycin) whole-blood concentrations by HPLC with ultraviolet detection. Clin Chem 1996;42(12):1943–1948. 165. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997;37(5):405–415. 166. Kahan BD, Napoli KL, Kelly PA, Podbielski J, Hussein I, Urbauer DL, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 2000;14(2):97–109. 167. Lorber MI, Ponticelli C, Whelchel J, Mayer HW, Kovarik J, Li Y, et al. Therapeutic drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy, and safety data. Clin Transplant 2005;19(2):145–152. 168. Vitko S, Tedesco H, Eris J, Pascual J, Whelchel J, Magee JC, et  al. Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 2004;4(4):626–635. 169. Starling RC, Hare JM, Hauptman P, McCurry KR, Mayer HW, Kovarik JM, et  al. Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling. Am J Transplant 2004;4(12):2126–2131. 170. Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet 2001;40(8):573–585. 171. Ferron GM, Mishina EV, Zimmerman JJ, Jusko WJ. Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther 1997;61(4):416–428. 172. Hale MD, Nicholls AJ, Bullingham RE, Hene R, Hoitsma A, Squifflet JP, et al. The pharmacokineticpharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 1998;64(6):672–683. 173. Holt DW, Marsden JT, Johnston A, Bewick M, Taube DH. Blood cyclosporin concentrations and renal allograft dysfunction. BMJ (Clin Res Ed) 1986;293(6554):1057–1059. 174. Kovarik JM, Kaplan B, Tedesco Silva H, Kahan BD, Dantal J, Vitko S, et  al. Exposure-response

4  Clinical Pharmacologic Principles and Immunosuppression relationships for everolimus in de  novo kidney transplantation: defining a therapeutic range. Transplantation 2002;73(6):920–925. 175. Weber LT, Lamersdorf T, Shipkova M, Niedmann PD, Wiesel M, Zimmerhackl LB, et al. Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: a longitudinal study in pediatric patients. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. Ther Drug Monit 1999;21(5):498–506.

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176. Ferron GM, Mishina EV, Jusko WJ, Zimmerman JJ. Population pharmacokinetics of sirolimus. Clin Pharmacol Ther 1998;63(4):494. 177. Kovarik JM, Sabia HD, Figueiredo J, Zimmermann H, Reynolds C, Dilzer SC, et al. Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment. Clin Pharmacol Ther 2001;70(5):425–430. 178. Scott JP, Smyth RL, Higenbottam TW, McGoldrick JP, Wallwork J. Cyclosporine dosing in cystic fibrosis after transplantation. Transplantation 1989;48(3):543–544.

Chapter 5

Pathology of Kidney and Pancreas Transplants Lillian Gaber and Byron P. Croker

Keywords  Rejection • pathology • kidney transplant • pancreas transplant

Introduction General Our evolution of knowledge in transplantation pathology has paralleled that of renal pathology in general. It is founded in basic experimental study of inflammation and immunology, genetics, and molecular biology and their clinical application. Regardless, many observers agree that the core component has been biopsy pathology. Biopsy pathology is the focus of this chapter. We will cover kidney then pancreas pathology. Allograft biopsy, like native kidney biopsy, has been the diagnostic standard. Noninvasive studies are neither as sensitive nor sufficiently specific an indicator to select from divergent therapeutic interventions: increase, decrease, or change immunosuppression. Biopsy also has the discrimination to identify several coincident but distinct pathologic processes in the graft (e.g., acute rejection superimposed on chronic disease). Information potentially gained must still be weighed against the risks of an invasive ­procedure. The art and science of transplant B.P. Croker (*) Pathology and Laboratory Medicine Service, NF/SG Veterans Health System, Gainesville, FL 32608, USA e-mail: [email protected]

pathology has become more sophisticated and precise with the application of new tests and ­procedures. Though approaching two centuries of use, classic histopathology is still the mainstay of biopsy evaluation and diagnosis. It is supplemented by additional conventional stains, antibody-based stains, and molecular biologic techniques. The classic indications for renal biopsies of (unexplained) proteinuria and hematuria and loss of renal function [1] still apply in transplantation. They are expanded because of the unique transplant setting. Thus we have “for cause” indications for biopsy of signs and symptoms of a change in status of the graft as well as: (1) donor biopsies to assess preexistent disease; (2) implantation biopsy to evaluate events or effects of procurement and transplantation procedure; (3) “protocol” biopsies performed at selected time intervals to evaluate subclinical or preclinical disease; and (4) a subset of protocol biopsies as a sensitive indicator of progress in evaluation of new drug or other therapeutic intervention [2, 3].

Immunology Transplantation pathology, like the whole of trans­ plantation, is intimately tied to immunology. Each field has variously been the beneficiary and provocateur of advances in the other. The interaction is traced back to the turn of the twentieth century with experiments in the surgery of transplantation. A Nobel Prize was awarded to Alexis Carrel in 1921. Descriptions of rejection, the

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_5, © Springer Science+Business Media, LLC 2011

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concepts of histocompatibility and consequences of immune responses to incompatibility, and the clinical use of immune strategies began in the 1950s. There was the subsequent recognition by another Nobel Prize to Drs. Joseph E. Murray and E. Donnall Thomas for their earlier work in transplantation [4]. To date, we have seen one or more resurgence and impact of antibody and humoral immunity, cell-mediated immunity, and innate immunity and inflammation theory and practice of on transplantation and transplantation pathology. Immunologic and inflammatory reactions have been characterized and classified in various schema. Classifications of transplant pathology are aids to understanding graft dysfunction, directing therapy, and predicting functional behavior. Our discussion of pathology is temporized by events that typically occur within time intervals about the initial surgery. These are divided into: (1) the peritransplanation period, (2) the next 3 months (acute rejection and other events), and (3) after 3 months.

Allograft Biopsy Processing The three classic techniques of biopsy evaluation (light, immunofluorescence, and electron microscopy [EM]) have been used for over 50 years. No one technique provides optimal evaluation in every clinical setting or given case [1]. With adequate sample of cortex (two cores) portions of the biopsy may be fixed and prepared for each method of evaluation. Representative sampling of each core of cortex would be: 1–2 mm for electron microscopy, 4–5  mm for immunofluorescence, and the remainder of the cortex and any medulla fixed in neutral buffered formalin for light microscopy. The portion for light microscopy will also suffice for most, but not all, immunohistochemistry and molecular chemical analysis. For relatively normal tissue, cortex may be determined by the naked eye of the experienced observer, but aided by a hand lens (loop) or dissecting microscope. In the acute interval of transplantation the glomeruli may be obscured by general hyperemia or congestion, or hemorrhage or granulation tissue in the bed of the

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graft. In older grafts (even weeks to months of age) the characteristic hyperemia and variation in density of the cortex may be obscured by the fibrous pseudocapsule or intraparenchymal fibrosis or atrophy, and the cortex may be indistinguishable from medulla for the purposes of gross dissection. In addition, with difficult biopsies (including CT-guided biopsies by radiology) minimal cortex may be obtained. While clinical history is always important to the pathologist, the importance of clinical history and the clinical differential goes up dramatically with a decrease in the amount of cortex for evaluation. It is not unlikely that a 2-mm biopsy of cortex should all be submitted for EM depending on the clinical differential. For processing at an on-site laboratory it is best to deliver moist, fresh tissue to the pathology laboratory for gross dissection. The biopsy should be placed on a saline-moistened gauze sponge. It is important not to let it dry out or “float” in water, as either of these will produce confounding artifacts. If the biopsy is sent to a reference laboratory, then the majority (approximately two thirds) should be placed in neutral buffered formalin (to be divided later for light and electron microscopy) and the remainder placed in Michel’s solution (such as a commercially sourced product) for overnight transport. The product of histology processing is stained slides. Depending on the complexity of the stains and initiation of processing slides will generally be available in 4–18  h. As with the processing choices, there is no single panel of stains that will be optimal for all clinical situations and set of pathologic conditions. We strive to have a set of histologic stains that will yield definitive diagnosis most of the time on the first round of staining in a cost effective manner. Following this logic, hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) stains are together the two best initial general stains. A trichrome (Masson) is useful for evaluation of fibrosis and to confirm the general findings. A periodic acid methenamine silver (PAMS, or variation) is a valuable basement membrane and matrix stain for de novo or recurrent glomerulonephritis, transplant glomerulopathy, and vascular rejection. These are

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typically accompanied by immunofluorescence for immunoglobulin and complement localization. IgG, IgM, IgA, C3, C4d, and albumin is a representative panel. Robust immunoperoxidase stains for formalin fixed tissue are CD3, CD68, and S100 for marking infiltrating mononuclear cells (T cells, monocytes, and dendritic cells) and BK virus. This panel will give diagnostic and prognostic results for most biopsies. If necessary, second-level stains would be based on the original panel results. An example might be posttransplant lymphoproliferative disease. This is a rare complication to present in a kidney allograft, but will likely be indicated by the initial studies. B-cell (CD20) and EBV markers (such as Epstein-Barr Early RNA, EBER) would be added as a second-level study. A general approach to evaluation of the sections as for native biopsies [1] would include a summary of the tissue present (cortex with glomeruli and vessels and/or medulla). Then the four anatomic compartments of glomeruli, tubules, interstitium, and vessels are examined to note changes or abnormalities in the number and type of cells and extracellular material in each compartment to arrive at a histologic interpretation. The histologic interpretation is then correlated with the clinical features to determine one or more clinical-pathologic diagnosis.

Early Allograft Biopsies from Zero-Time to the Early Posttransplant Period Donor Biopsies Biopsy evaluation at the time of procurement has increasingly become an integral part of the assessment of kidneys from extended criteria donors, donors with impaired renal function, and donors after cardiac death. The integration of histologic evaluation, as part of organ acceptance criteria, has refined the selection process and ensured adequate quality of the transplanted kidneys. Long-term survival of these marginal grafts

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approaches that of standard donor kidneys, and is better than nonbiopsied marginal kidneys [5, 6]. Furthermore, donor biopsy results can influence the choice of the recipient and the decision to use a double kidney graft. Donor biopsies are often evaluated by frozen sections in order to obtain an immediate diagnosis. While there is an ongoing debate as to whether the biopsies should be obtained by wedge excision or by a core needle, most organ procurement programs perform wedge biopsies [7]. Reports follow a checklist based on criteria recommended by UNOS. Lesions of senescence and nephrosclerosis are by far the most common findings. Older donors and donors with history of hypertension are increasingly being considered for donation. Histologic features of nephrosclerosis are assessed in the donor biopsies and often semiquantitated (Fig.  5.1). Glomerulosclerosis (GS) in donor biopsies is reported as the percentage of obsolescent glomeruli. Most studies agree that an increase in the percentage GS is associated with increased risk for poor immediate and long-term graft function. The negative effect of GS is more powerful if combined with older donor age; both, however, are independent in their impact on graft function [8, 9]. Interstitial fibrosis and tubular atrophy (IFTA) greater than 5% is present in about 5–7% of donor biopsies. When present, interstitial fibrosis is irreversible and increases progressively in subsequent graft biopsies [10]. Vasculopathy appears to be a major determinant of both short- and long-term graft dysfunction. Fibrous intimal thickening of the intrarenal arteries more than doubles the risk for developing progressive graft fibrosis and dysfunction [11]. High blood pressure in the recipient augments the impact of the preexisting vasculopathy on graft function; therefore, it is advisable that grafts with fibrous intimal thickening be allocated to recipients with controlled blood pressure [12]. Biopsies from kidneys of standard criteria donors with terminal renal failure are more likely to show features of acute tubular necrosis (ATN). The etiology of ATN is usually hypovolemia, but other causes, such as myoglobulinuric ATN and heroin toxicity, have been reported [13]. Although these kidneys are prone to suffer

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Fig. 5.1  Donor biopsy with arteriosclerosis and glomerulosclerosis

delayed or a slow recovery of graft function, most will have acceptable long-term graft function and as a group have function superior to that of kidneys from extended-criteria donors without renal failure [13]. As yet, there is no guideline as to the quantitation of the amount of structural damage and cell necrosis that would preclude successful transplantation. Microvascular thrombosis, an unusual finding with an estimated frequency of 3.5% in donor biopsies, is frequently caused by disseminated intravascular coagulation in the donor (Fig. 5.2). While it is expected that the glomerular thrombi will resolve following transplantation, the rate of delayed graft function (DGF) is almost doubled for these recipients. Once these grafts recover, their 1- and 2-year graft survival is comparable to kidneys without thrombi [14]. Subclinical glomerular disease may be difficult to diagnose on frozen section and is usually diagnosed on a subsequent postperfusion biopsy or by an evaluation performed on permanent sections of the donor kidney. Donor biopsies should also be evaluated for diabetic nephropathy and overt glomerular pathology. Occasionally a frozen section is requested when an incidental mass is found in the kidney. Angiomyolipomas are benign and do not preclude transplantation if enough renal mass is left after resection. It is

sometimes ­difficult to distinguish between renal cell carcinoma and tubular adenoma in a frozen section. Tumors of clear cell type are considered carcinomas regardless of size, while small (less than 6  mm), papillary non-clear cell epithelial lesion are considered benign.

Immediate Posttransplantation Biopsies Implantation biopsies (IBx) are obtained at the time of engraftment, typically within 1  h after revascularization of the graft. Most of the biopsies are performed by the open wedge technique, but some centers elect to do core needle biopsies. One of the primary reasons for obtaining these biopsies is to establish a reference point of the morphological architecture of the kidney at the time of transplantation. This serves as a baseline for the interpretation of future changes encountered in the allograft. Longitudinal studies are carried out in some transplant centers to evaluate the evolution of pathologic changes over the life of the allograft [15]. Several schemas are used to semiquantitate the morphologic elements of nephron loss and nephrosclerosis, such as glomerulosclerosis, the complex of

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Fig. 5.2  Donor biopsy with fibrin and platelet thrombus in glomerular capillaries (lower mid-center) of disseminated intravascular coagulation

Fig. 5.3  Immediate posttransplantation biopsy showing ischemia-reperfusion injury with vacuolization sloughing, necrosis, and apoptosis

i­nterstitial fibrosis and tubular atrophy (IFTA), and vascular sclerosis. These classifications include the Chronic Allograft Disease Index (CADI) score, the Banff schema, and other morphometric techniques. IBx is also evaluated for ischemic and immunologic insults to allow for early intervention. Importantly, IBx aids in documentation of preexisting donor disease and helps discern ­preexisting from acquired pathology. The majority of IBx from deceased donor kidneys will display some evidence of ischemiareperfusion injury (IRI) in the renal tubules.

Features of IRI, as depicted in Fig. 5.3, are similar to those described in experimental models of ­sepsis and acute ischemic injury [16]. As yet, there is no defined, reproducible, clinically relevant system to grade or quantify the morphologic lesions of acute tubular necrosis. Injury of the renal microvasculature is an integral component of IRI that is underrepresented in the biopsies. Studies using intravital videomicroscopy documented the occurrence of microvascular dysregulation in the superficial peritubular capillaries almost immediately following reperfusion [17].

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While these microvascular changes are usually reversible and self- limiting, they may potentially contribute to the development of chronic allograft nephropathy (CAN), as has been shown in animal models, by rarefaction of peritubular capillaries density and promotion of fibrogenesis. Further­ more, tissue injury during ischemia activates the innate immune system to create an inflammatory microenvironment that initiates or accentuates immunologic injury of the allograft. The complexity of these vascular and immunologic changes indicates the need to go beyond conventional biopsy examination in the evaluation IBx. Occasionally, margination of neutrophils in the peritubular capillaries with or without involvement of the glomerular capillaries is detected in the IBx (Fig. 5.4). In our early experience, ischemia, or an accelerated immunologic response, has been proposed as a potential mechanism for neutrophilic capillaritis which correlated with early acute rejection. Similarly, neutrophilic glomerulitis was also reported in recipients of kidneys from living donors who later developed rejection of their allografts. Although it is now rare that we detect intragraft margination of neutrophils in the IBx, increased transplantation of  highly sensitized and ABO-incompatible recipients warrant careful examination for resurgence of this early inflammatory marker. A more ­specific marker for antibody-mediated injury,

Fig. 5.4  Immediate posttransplant biopsy showing neutrophilic peritubular capillaritis

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C4d deposition in the peritubular capillaries, has also been detected in a few cases in association with presensitization.

Early Posttransplant Graft Dysfunction Hyperacute rejection, traditionally defined as a catastrophic immunologic attack on the allograft microvasculature by preformed antibodies, is characterized by necrotizing intravascular neutrophilic inflammation and thrombosis that leads to immediate or accelerated graft loss. This type of rejection has all but been eliminated in the modern transplant era by advances in HLA typing and antibody techniques. A handful of cases caused by antiendothelial antibodies are recently reported [18, 19]. Today, accelerated antibodymediated acute rejection, usually detected by early surveillance biopsies or by for-cause biopsies obtained from ABO-incompatible kidney transplant recipients or recipients with DSAs, has become the dominant form of early antibodymediated rejection (AMR). The pathology could vary from very mild tissue damage in association with c4d deposition in the renal microvasculature, to widespread glomerular thrombosis and diffuse capillaritis (Fig. 5.5).

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Fig. 5.5  Early graft biopsy with prominent arteriolar hyaline (two arterioles, lower center) extending into the media

Fig. 5.6  Acute tubular injury (ATI). (a) This is a medium magnification showing several tubules with flattened cuboidal epithelium. (b) High magnification showing a mitotic figure in a tubule representing regeneration

Between 20% and 30% of recipients of deceased donor kidney transplants develop delayed graft function (DGF). The most common cause for DGF is acute tubular necrosis related to IRI. Other less common causes include early acute rejection, cholesterol atheroembolization, hemolytic uremic syndrome which could be a manifestation of humoral rejection, and vascular thrombosis. An allograft biopsy is critical for the accurate management of kidney transplant patients with DGF. Finally, early graft dysfunction could be the result of acute nephrotoxicity caused by calcineurin

(CNI) inhibitors or sirolimus. Regardless, acute toxicity is rarely seen today in kidney transplants. It is more commonly seen in biopsies of the native kidney in association with transplantation of other solid organs (heart and liver). CNI nephrotoxicity could present with a reversible isometric vacuolization, or a more damaging thrombotic microangiopathy and arteriolar hyalinosis (Fig. 5.6). Sirolimus induces tubular and podocyte apoptosis, particularly in grafts with DGF. Obstructive intratubular casts surrounded by regenerating tubular epithelium and tubular dilatation are also features of sirolimus-induced tubulopathy.

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Early Transplant Interval General For purpose of this discussion, the early transplant period means several days (3  days) to several months (3 months). This interval is characterized by most of the de  novo transplant diseases that tend to evolve over several days and are clinically acute or subacute. Acute kidney injury (AKI) in the graft is from diverse etiologies that include: acute tubular injury necrosis (ATI); acute rejection; infection (ascending bacterial and BK virus); and drug-induced toxicity. Any of these processes may occur later, but then they will be more likely to occur in conjunction with acquired chronic ­kidney disease (CKD) in the transplant and will be more frequently associated with changes in therapy or other interceding events. ATI may be present at implantation and continue for an extended period.

Acute Tubular Injury Acute tubular injury (ATI) in the first week may overlap with ATI in the peritransplant period and present as delayed graft function. In any event,

Fig. 5.7  Acute tubular injury (ATI). This is the same biopsy as above stained for CD34 which primarily labels all the vascular endothelial cells in the kidney and shows the arteries (e.g., arteriole, right) extensive capillary network in the glomerulus (center), and peritubular capillaries ­(periphery). The capillaries appear collapsed and are not inflamed (compare with Fig. 5.4)

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ATI is a diagnosis of exclusion since many other causes of acute kidney injury (AKI) will have secondary or associated ATI and must be reasonably excluded. Thus ATI secondary to nephrotoxin, ischemia, or a combination remain. Toxic and ischemic ATI will generally be indistinguishable by biopsy and the process and pathology indistinguishable from AKI in the native kidney setting. A fully developed case of ATI will begin with injury-producing necrosis or apoptosis of tubular epithelial cells. There will be peritubular capillary congestion, and margination of inflammatory cells with noticeable polymorphonuclear neutrophils (PMNs) particularly evident in the outer medulla. It is common that these early stages have largely progressed at the time of the biopsy and the recovery phase will have started with variable levels of success or evolution (Fig. 5.6a and b). This figure shows a lower magnification with a nonspecific lymphocytic infiltrate in the vessel adventitia and a number of tubules with flattened or cuboidal epithelium. The higher magnification shows mitosis in one tubule representing regeneration. Figure 5.7 is the same biopsy with CD34 stain to highlight the vascular endothelium: arteriole (right), glomerulus (center), and peritubular capillaries (periphery), which appear collapsed and are not inflamed.

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Acute Rejection The classification of acute rejection has evolved over the years in conjunction with technological and conceptual advances in our ability to distinguish types and correlation with clinical outcomes and therapy. One early classification was based on the principal of renal tissue affected and identified acute interstitial rejection which was characterized by lymphocytic tubulitis and associated with cell-mediated immunity [20]. The second type, acute vascular rejection, was characterized by endovasculitis and associated with humoral and cellular immunity. Acute vascular rejection was subsequently classified [4] as separate cell-and antibody-mediated rejection. It is appreciated that a given patient may exhibit evidence for both cell- (tubulointerstitial or vascular) and antibody-mediated (vascular) rejection [21]. Regardless, a predominant pattern is often present and correlates with response to therapy. There is no evidence that direct antibody-mediated mechanisms produce rejection outside of the vasculature.

Acute Tubulointerstitial Rejection The characteristic histologic feature of acute tubulointerstitial rejection is a tubular infiltrate

Fig. 5.8  Acute (T-cellmediated) tubulointerstitial rejection. Histologic sections show lymphocytic tubulitis with lymphocytes infiltrating the epithelium. The lymphocytes often have a characteristic perinuclear halo (arrow)

(tubulitis) of CD8 (cytotoxic) T cells. On histologic sections (Fig. 5.8) lymphocytes with small oval dense nuclei are infiltrating the tubular epithelium. There is often a characteristic perinuclear halo. These cells label for CD3 (Fig. 5.9) and CD8 (Fig.  5.10). Tubulitis is accompanied by an interstitial infiltrate of lymphocytes. This type of rejection is generally responsive to antirejection therapy. Interstitial inflammation in longer-term grafts is more likely to be composed of CD4 T cells with monocytes/macrophages and is poorly responsive to traditional therapy. This is the phenotype of delayed-type hypersensitivity (DTH) and is better considered as a subacute or chronic form of rejection [22, 23]. Acute tubulointerstitial rejection must reasonably be distinguished from other causes of interstitial nephritis. BK virus nephropathy, as an example, will be discussed later in this section.

Rejection in the Vasculature Both cell- and antibody-mediated immunity may injure the vasculature and cause acute rejection. The characteristic histologic features of cellular rejection are injury to the arterial and capillary intima (endothelium) in the presence of T cells and monocytes. Figure 5.11 shows a tubular crosssection (T) with peritubular capillaries. The arrow

Fig. 5.9  Acute vascular rejection. The pan T-cell marker CD3 labels the lymphocytes in glomerular (right center) interstitial capallaries (top)

Fig. 5.10  Acute tubulointerstitial rejection. The infiltrating T cells in tubulitis are primarily CD8 phenotype

Fig. 5.11  Rejection in the vasculature – endothelialitis (endotheliitis). This high magnification view shows a tubular (T) cross-section with peritubular capillaries endothelium infiltrated by lymphocytes (arrow) and mononuclear cells (arrowhead). This represents peritubular capillaritis

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Fig. 5.12  Rejection in the vasculature – endothelialitis. This figure shows several arterioles (left and right) with lymphocytic infiltration and partially denuded endothelium (arrow). Tubulitis is also present (arrowhead)

Fig. 5.13  Rejection in the vasculature – endothelialitis. This is the same case as above labeled for CD3 demonstrating T cells attached to the damaged intima ((a) medium and (b) high magnification)

shows a small lymphocyte in a partially denuded capillary with swollen endothelial cells. The arrowhead shows a mononuclear cell with larger nucleus and cytoplasm in another capillary with partially denuded and degenerating endothelium and another small lymphocyte. Figure 5.12 shows several lumina of arterioles with marginated lymphocytes. One (arrow) shows a denuded section of intima with an adherent cluster of mononuclear cells with lymphocytes. The next (Fig.  5.13a and b) show a similar area from the same biopsy as above but stained for CD3 to label T cells attached to the damaged endothelium.

Figure  5.14 shows a larger artery with endothelial damage and several large lymphocytes. Figure 5.15 shows lymphocytic glomerulitis which is typical of cell mediated rejection in the vasculature with numerous labeled T cells infiltrating the partially occluded capillaries. Antidonor antibodies have classically been associated with graft vascular damage for decades and were from graft nephrectomies but the real-time evaluation of antibody has been difficult because of small amounts present in the circulation or graft. Using flow cytometry to detect circulating antibodies (flow cross-match)

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Fig. 5.14  Rejection in the vasculature – endothelialitis. This figure shows endothelialitis in a larger artery with CD3 positive T cells. This is also called endoarteritis

Fig. 5.15  Rejection in the vasculature – glomerulitis. Glomerular capillaries show glomerulitis with CD3 labeled T-cells and partially occluded capillaries

offers improved sensitivity. The C4d tissue assay provided a screening test that would detect activation of complement in biopsies [24] and provide a surrogate marker for antibody binding to the graft. Antibody-mediated rejection is characterized by circulating antibody, C4d staining of peritubular capillaries, inflammation of endothelium in arteries or glomerular or peritubular capillaries, activation of the clotting cascade with capillary microthrombi, graft injury, and dysfunction. Antibody to ABO and HLA class I and II antigens are the best described systems and the character, rate of onset, and severity of response

depend on the antigen system and antibody titer. Therapy is aimed at avoiding an antigenic match or reducing the antibody titer below an empiric level. Like cell-mediated rejection in the vasculature, the characteristic histologic findings are capillaritis with significant morphologic similarity between the two mechanisms in most cases. In some cases of acute antibody-mediated rejection there tends to be a greater neutrophilic leukocytic component in the peritubular capillaries and interstitium and/or a greater monocyte than lymphocytic infiltrate (percentage and

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Fig. 5.16  Rejection in the vasculature – antibody mediated. This figure shows glomerulitis with few CD3 labeled lymphocytes (a) and numerous CD68 labeled monocytes (b)

Fig. 5.17  Rejection in the vasculature – antibody mediated. The immunohistologic characteristic of antibody-mediated rejection is C4d labeling of the peritubular capillaries shown at medium (a) and high (b) magnification

­absolute number) in the glomerulus (Fig  5.16a and b). The microvascular thrombosis may be subtle or similar to that seen in thrombotic microangiopathy of any other cause. Advanced or severe changes are characterized by transmural arterial inflammation and fibrinoid necrosis. Any of the above features suggest antibody mediated acute rejection but confirmation depends on a positive C4d stain (Fig.5.17a and b) and demonstration of circulating antibody.

Infection The transplanted kidney is susceptible to infection seen in native kidney. We have seen gram-

negative and gram-positive bacteria and candida. The morphologic patterns of neutrophilic tubulitis and interstitial nephritis are similar to native kidney disease if not somewhat muted by antiinflammatory therapy. Most viral infections are also similar in morphology to native kidney disease and uncommon. One exception is BK virus-associated nephropathy (BKVAN) because of the remarkable prevalence in kidney transplantation and evolving concepts in management [25]. BKVAN has histologic features which overlap those of cell-mediated tubulointerstitial rejection and include lymphocytic tubulitis (Fig. 5.18a and b) and lymphocytic interstitial inflammation. The spectrum of BKV infections ranges from normal histologic appearance to patchy tubular destruction

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Fig. 5.18  BK virus nephropathy (BKVN). This figure shows lymphocytic tubulitis (PAS stain) and T cells (CD3 stain) at high magnification. Compare with Figs. 5.8 and 5.9

Fig. 5.19  BK virus nephropathy (BKVAN). Early BKVAN tends to be focal and has a propensity for the medulla

and atrophy. Early BKVAN is more focal (Fig. 5.19), and tends to have a propensity for the medulla in contrast to acute cellular rejection, the diagnostic feature is intranuclear inclusions, or virus capsid arrays on electron microscopy or immunostaining for capsid antigen (Fig.  5.20) which is sensitive and readily performed.

Recurrent Disease Recurrent glomerulonephritis such as anti-GBM disease, membranous glomerulonephritis and focal segmental glomerulosclerosis (FSGS) have

long been described. They develop in the early transplant period. These are generally diagnosed in biopsy where adequate tissue and studies outlined above are available by carefully applying the same criterion used in native kidney biopsies [23, 26]. The diagnosis of FSGS is problematic in the early transplant period since significant proteinuria may precede diagnostic histopathologic features by weeks. Only EM shows foot process fusion (retraction) which is characteristic of FSGS but not pathognomonic. FSGS at this stage is a diagnosis of exclusion based on history of native kidney disease, clinical suspicion, and biopsy findings.

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Fig. 5.20  BK virus nephropathy (BKVAN). The diagnostic histologic features are nuclear immunostaining for capsule antigen as shown here

Intermediate and Late Transplant Period Any de novo process (e.g., acute rejection, infection, drug toxicity) that occurs in the acute transplant period can occur later, and while the incidence is reduced, the pathology is similar. The caveat is acute changes will be characteristically superimposed on a background of chronic disease associated with a slow decline in renal function. In early classifications the chronic pathologic changes were variously called chronic rejection [20, 27], chronic transplant nephropathy [23], and chronic allograft nephropathy [28]. The constellation of histologic findings of arteriosclerosis and arteriolosclerosis, glomerulosclerosis, tubular atrophy, and interstitial fibrosis with chronic inflammation are seen in most allografts with chronic disease and are largely the same as chronic kidney disease (CKD) in native kidney regardless of the etiology [29]. It was argued that these changes represented in essence a final common pathway of CKD and could represent the accumulation of injury incidental to transplantation as well as alloimmune responses [4, 23]. Since most of the histopathologic features of CKD in the allograft could not be specifically attributed to allospecific response (chronic rejection), chronic allograft nephropa-

thy (CAN) was adopted for the Banff working classification [28] and was highly successful based on the literature citations. Chronic allograft injury is clinically characterized by progressive deterioration of graft function, proteinuria, and hypertension [30]. The elimination of the generic term chronic allograft nephropathy and its replacement by the description of chronic allograft injury (CAI) was recommended at the Banff 2005 conference [31]. The recommendation was based on the lack of specificity of the pathologic lesions, the ambiguity in defining this syndrome, and apparent misuse in the literature. The pathogenesis of chronic allograft injury could be related to immune mediated or nonimmune-dependent mechanisms. Thus we would envision the need to replace CAI in another 10 or so years. A candidate term for Banff 2021 might well be chronic renal allograft pathology. Chronic antibody-mediated rejection is diagnosed when interstitial fibrosis and tubular atrophy are associated with one or more of these features: chronic transplant glomerulopathy (CTG), chronic microvascular injury, C4d intragraft deposition, and the presence of donor-specific antibody (DSA) [32]. Chronic T-cell-mediated rejection is suspected in grafts that display evidence of tubulitis along with thickening of the elastic layer of the blood vessels, fibrous intimal hyperplasia, and variable inflammation in the intima, which

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are all features of chronic transplant vasculopathy. A long list of non-immune-mediated conditions can also cause chronic allograft injury or exacerbate an immune injury. Causes of nonimmune chronic allograft injury include donor factors such as senescence, nephrosclerosis, donor vasculopathy, or recipient ­diseases such as hypertension, diabetes, hyperlipidemia (the metabolic syndrome). Other nonimmune causes of chronic injury include insults unique to the allograft or those complicating transplantation such as exposure to nephrotoxins, viral infections, and reflux nephropathy [15, 30, 33]. Subsets of allograft CKD exhibit chronic transplant glomerulopathy (CTG), which has been associated with allograft rejection since its earliest descriptions [27]. More recently studies have accumulated to suggest that transplant glomerulopathy may be caused by specific alloimmune responses [34, 35]. These glomeruli are typically large, with expanded mesangium and thickened capillary walls (H&E, trichrome). PAS and silver basement membrane stains show a double-contoured basement membrane with mesangial interposition (Fig.  5.21a and b). The light microscopic features are similar to membranoproliferative glomerulonephritis (MPGN). Immunofluorescence studies are generally mild compared with MPGN. Electron microscopy shows a characteristic expansion of the subendothelial layer by flocculent material. Mesangial interposition contributes to the capillary wall double contour. Along with

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capillary wall thickening there is a variable increase in glomerular mesangial matrix, an increase or decrease in glomerular cellularity, glomerular tuft enlargement, and hypertrophy of the podocytes with intracytoplasmic packing of protein transport droplets. All of these changes ultimately lead to progressive sclerosis of the glomerular tuft. Clinically CTG is characterized by severe proteinuria and progressive deterioration of graft function. Antibody-mediated graft injury plays a major role in the pathogenesis of CTG in a subset of patients [34, 35]. These patients show evidence of antibody-mediated microvascular injury such as multilayering of the basal lamina of the peritubular capillaries and GBM thickening, capillaritis, glomerulitis, intragraft C4d deposition, the presence of DSA, and a history of previous antibody-mediated rejection. Emerging studies indicate the association of conditions that induce endothelial damage and a thrombotic microangiopathy with CTG. A list of these conditions now includes HCV infection, CMV infection, and nephrotoxicity induced by use of calcineurin inhibitors or sirolimus. Increased cellularity may be mild or accompanied by T cells (CD3) and/or monocytes (CD68) in sufficient numbers to also be classified as glomerulitis. Over half of the patients with TG have evidence of antibody mediated rejection [34, 35], but in a separate study TG also had a significant increase in Th1 CD4 T cell activity [36]. Thus the role of antidonor antibody

Fig. 5.21  Chronic transplant glomerulopathy. This figure (a and b) shows the double-contoured capillary basement membrane with mesangial interposition. Note mitosis (b, lower center)

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or cell-mediated immunity remains to be resolved. Either mechanism may drive in monocyte based inflammation which is inversely related to graft survival [37–39]. Chronic transplant arteriopathy has also been described since the early years of clinical transplantation and associated with rejection [40, 41], and whether the cause was antibody- or cellmediated immunity or both is debated. While arteriosclerosis with myointimal cells and duplicated elastic lamina indistinguishable from chronic native kidney disease may be present, chronic transplant arteriopathy has variable degrees of swelling or edema in the intimal thickening and T cells and monocytes in addition to the myointimal cells. In the Banff Classification ’09 [32] this lesion with increased inflammatory cells is considered chronic active T-cell-mediated rejection. In the absence of evidence for T-cell-mediated rejection, but in the presence of markers for antibody-mediated rejection the arterial lesion is classified as “chronic active antibody mediated rejection.” This terminology is meant to consider or endorse the possibility of ongoing alloimmune rejection at a tempo less than acute rejection, but might be amenable to antirejection therapy. The earliest hypothesis, chronic transplant arteriopathy, was the sequel of prior episodes of acute rejection. These are not mutually exclusive hypotheses, but it remains to be determined if there is an effective therapy for either mechanism of chronic active rejection. De novo and recurrent glomerulonephritis and other diseases often increase in prevalence in this period. Recurrent glomerulonephritis depends on the patient population, and the biopsy diagnosis is based on criterion as for native kidney disease [1]. Membranoproliferative glomerulonephritis, IgA nephropathy, familial (hereditary) thrombotic microangiopathy, FSGS, and diabetic nephropathy reoccur in a high percentage of patients. Distinguishing recurrent FSGS or thrombotic microangiopathy from de novo disease may not be possible on histologic terms. Glomerulonephritis is the underlying cause of end-stage renal failure in 30–50% of kidney transplant recipients. Recurrent GN is a major

cause of proteinuric graft failure in patients whose original disease was glomerulonephritis. Risk factors for recurrence of glomerulonephritis are largely unknown, as is the timing of recurrence which could be immediate or occur years after transplantation. Immunosuppressive therapy is generally ineffective in the prevention or treatment of recurrent disease. Contribution of recurrent GN toward graft dysfunction is complicated by other comorbidities such as chronic allograft injury. It is important to obtain accurate pretransplant history, as recurrences of various types of glomerulonephritis vary widely, with focal segmental glomerulosclerosis and IgA nephropathy topping the list of recurrent diseases [30]. Renal biopsy remains important in determining the differential diagnosis of proteinuria as the biopsy may provide results that are important for treatment or for giving the patient and the physician information that aids in determining the prognosis of the allograft.

Posttransplant Proteinuria Posttransplant proteinuria is frequent among ­kidney transplant recipients, with varied prevalence rates depending on the cutoff values used to define the condition. The etiology of posttransplant proteinuria is influenced by whether proteinuria is persistent or transient, and by the time of its onset. Early and mild proteinuria, with protein excretion rates less than 500  mg/24  h, is a frequent finding and occurs in about 45% of the kidney transplant recipients [42]. A large number of these patients have defective tubular absorption or podocyte dysfunctions, which result in protein leakage. These abnormalities are usually caused by ischemic acute tubular injury or drug-induced nephrotoxicity, e.g., calcineurin inhibitors and sirolimus. This type of proteinuria is transient, and is usually reversed by treatment of the cause. Biopsies are rarely obtained in these patents because of the known transient nature of this ­condition. Surveillance biopsies done 1  year ­posttransplant demonstrated the prevalence of glomerular pathology in patients with proteinuria.

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On the other hand, patients with less than 1,500 mg/dL of protein in the urine had no specific pathology in the kidney [43, 44]. There are now, however, data that suggest that proteinuria in the early posttransplant period is correlated to a multitude of donor and procurement parameters such as donor age, donor cardiovascular death, warm and cold ischemia, and delayed graft function. Patients with rejection were also more likely to have early proteinuria, which was correlated with reduced graft outcomes. The reduction in graft outcome in patients with early proteinuria was observed as early as 1 month after transplantation and was not related to the degree of protein excretion [23]. Late and persistent nephrotic or subnephroticrange proteinuria is usually a manifestation of glomerular disease. Persistent posttransplant proteinuria has low prevalence, estimated at about 7–13%, and is associated with high rates of graft loss. The major pathological findings in kidney transplant recipients that develop nephrotic range proteinuria can be grouped into two large categories: one is chronic allograft nephropathy/injury and the second is glomerulonephritis. Chronic transplant glomerulopathy is a histopathologic entity with distinctive light microscopic and ultrastructural features. Central to the pathology of CTG is the duplication of the glomerular basement membranes, which is best illustrated by PAS or silver staining of histological sections. Electron microscopy shows a characteristic expansion of the subendothelial layer by flocculent material. Mesangial interposition contributes, to a lesser extent, to the capillary wall double contour. Along with capillary wall thickening there is a variable increase in glomerular matrix, an increase or decrease in glomerular cellularity, glomerular tuft enlargement, and hypertrophy of the podocytes with intracytoplasmic packing of protein transport droplets. All of these changes ultimately lead to progressive sclerosis of the glomerular tuft. Clinically CTG is characterized by severe proteinuria and progressive deterioration of graft function. Antibody-mediated graft injury plays a major role in the pathogenesis of CTG in a subset of patients [5].These patients show evidence of antibodymediated microvascular injury such as; multilayer-

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ing of the basal lamina of the peritubular capillaries and GBM thickening, capillaritis, glomerulitis, intragraft C4d deposition, the presence of DSA, and of a history of previous antibody mediated rejection. Emerging studies indicate the association of conditions that induce endothelial damage and a thrombotic microangiopathy with CTG [6]. A list of these conditions now includes HCV infection, CMV infection, and nephrotoxicity induced by use of calcineurin inhibitors or sirolimus [7]. Similar to CTG, chronic allograft injury is clinically characterized by progressive deterioration of graft function, proteinuria, and hypertension. The elimination of the generic term chronic allograft nephropathy and its replacement by the description of chronic allograft injury was recommended at the Banff 2005 conference. The recommendation was based on the lack of specificity of the pathologic lesions and the ambiguity in defining this syndrome. The pathogenesis of chronic allograft injury could be related to immune mediated or non-immune-dependent mechanisms. Chronic antibody-mediated rejection is diagnosed when interstitial fibrosis and tubular atrophy are associated with one or more of these features: CTG, chronic microvascular injury, C4d intragraft deposition, and the presence of DSA [8]. Chronic T-cell-mediated rejection is suspected in grafts that display evidence of tubulitis along with thickening of the elastic layer of the blood vessels, fibrous intimal hyperplasia, and variable inflammation in the intima, all features of chronic transplant vasculopathy. A long list of non-immune-mediated conditions can also cause chronic allograft injury or exacerbate an immune injury. Causes of non-immune chronic allograft injury include donor factors such as senescence, nephrosclerosis, donor vasculopathy, or recipient diseases such as hypertension, diabetes, hyperlipidemia, and the metabolic syndrome. Other non-immune causes of chronic injury include insults unique to the allograft or those complicating transplantation, such as exposure to nephrotoxins, viral infections, and reflux nephropathy [9]. Glomerulonephritis is the underlying cause of end-stage renal failure in 30–50% of kidney transplant recipients. Recurrent GN is a major

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cause of proteinuric graft failure in patients whose original disease was glomerulonephritis. Risk factors for recurrence of glomerulonephritis are largely unknown, as is the timing of recurrence which could be immediate or occur years after transplantation. Immunosuppressive therapy is generally ineffective in the prevention or treatment of recurrent disease. Contribution of recurrent GN toward graft dysfunction is complicated by other comorbidities such as chronic allograft injury. It is important to obtain accurate pretransplant history, as recurrences of various types of glomerulonephritis vary widely, with focal segmental glomerulosclerosis and IgA nephropathy topping the list of recurrent diseases [10]. Renal biopsy remains important in determining the differential diagnosis of proteinuria, as the biopsy may provide results that are important for treatment or for giving the patient and the physician information that aids in determining the prognosis of the allograft.

Banff Schema and Rejection Classification Pathologic examination of renal tissue remains the gold standard for the diagnosis of acute rejection and for understanding the functional-morphologic correlates of various forms of graft injury. The Banff schema for classification of kidney allograft pathology was adopted by the Fifth Banff Conference in 1997 became an accepted template for grading and scoring of the histological changes of rejection. It’s adaption standardized the pathologic reporting in the clinic, in many multicenter studies and pharmaceutical clinical trials [28, 31, 45, 46]. The major features and designations within the schema are presented in Tables  5.1–5.3. The schema continues to be upgraded based on new evidence in a regular basis. The Banff schema distinguishes antibody from cell-mediated rejection (AMR and CMR). Each rejection category is then subtyped according to morphologic features. Three grades for CMR are defined: Grade I is characterized by the presence of pure tubulointerstitial inflammation

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and is further divided into A and B based on the severity of the tubular inflammation; Grade II is distinguished by the presence of intimal arteritis that is either mild (A) or moderate (B), while Grade III is rejection with severe vascular inflammation. Acute (a) and chronic (c) lesions in the glomeruli (g), interstitium (i), tubules (t), and arteries (v) are scored for severity on a scale of 0–3. This system of semiquantitative analysis standardized the assigning of numerical values to morphologic lesions and thereby allowed, for the first time, comparisons to be made with some objectivity. The wide adoption of the grading schema quickly led to standardized reporting and grading of graft pathology across institutions, and provided clinical studies with a standardized quantitative technique to evaluate graft biopsies as outcome endpoints or as entry points and tools for randomization of research subjects. The clinical relevance of this grading system has been validated by several clinical studies which generally demonstrated a grading in clinical response to therapy and of the subsequent outcomes that correlated with the pathological grading and/or scoring. Despite the verification of the overall clinical utility of the Banff classification, it should be noted that the reproducibility has been less than ideal among various pathologists. This weakness of the schema could be overcome by further refinement of the scoring of morphologic changes, including recognizing lesions with higher clinical impact, introducing morphometric measures for quantification, and inclusion of additional data that help improve the predictive ability of histologic changes such as genomic and proteomic data. Additional updates and modifications were adopted during the subsequent Banff meetings. In 2005, features of antibody-mediated rejection (AMR) were outlined driven by the emerging clinical data regarding the association between intragraft deposition of C4d, the presence of antidonor antibodies and rejection. Establishing the features of chronic vascular rejection and distinguishing it from the broad category of chronic allograft nephropathy were important steps that concluded the 2005 meeting. The ensuing validation studies and clinical research

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Table 5.1  Banff ’97 diagnostic categories for renal allograft biopsies – Banff ’05 update (From [28, 31, 45, 46]) 1. Normal 2. Antibody-mediated rejection Due to documented antidonor antibody (“suspicious for” if antibody not demonstrated) (may coincide with categories 3–6) Acute antibody-mediated rejection Type (grade) I. ATN-like – C4d+, minimal inflammation II. Capillary-margination and/or thromboses, C4d+ III. Arterial – v3, C4d+ Chronic active antibody-mediated rejectiona Glomerular double-contours and/or peritubular capillary basement membrane multilayering and/or interstitial fibrosis/tubular atrophy and/or fibrous intimal thickening in arteries, C4d+ 3. Borderline changes: “suspicious” for acute T-cell-mediated rejection This category is used when no intimal arteritis is present, but there are foci of tubulitis (t1, t2, or t3 with i0 or i1), although the i2 t2 threshold for rejection diagnosis is not met (may coincide with categories 2, 5, and 6) 4. T-cell-mediated rejectiona (may coincide with categories 2, 5, and 6) Acute T-cell-mediated rejection Type (grade) IA. Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2) IB. Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of severe tubulitis (t3) IIA. Cases with mild to moderate intimal arteritis (v1) IIB. Cases with severe intimal arteritis comprising >25% of the luminal area (v2) III. Cases with “transmural” arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3) Chronic active T-cell-mediated rejectiona “Chronic allograft nephropathy” (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neointima) 5. Interstitial fibrosis and tubular atrophy, no evidence of any specific etiologya I. Mild interstitial fibrosis and tubular atrophy (<25% or cortical area) II. Moderate interstitial fibrosis and tubular atrophy (26–50% of cortical area) III. Severe interstitial fibrosis and tubular atrophy (>50% of cortical area) 6. Other: Changes not considered to be due to rejection – acute and/or chronic; may coincide with categories 2–5 a Indicates changes in the updated Banff ’05 criteria

Table 5.2  Changes from Banff ’97 and ’01 diagnostic categories (From [28, 31, 45, 46]) Category 2. Antibody-mediated rejection now includes two subcategories: Acute antibody-mediated rejection Chronic active antibody-mediated rejection Category 3. Borderline changes: “suspicious” for acute T-cell-mediated rejection This category is used when no intimal arteritis is present, but there are foci of mild tubulitis (t1) and at least i1. It is now defined more clearly that t2, t3 with i0, or i1 is also under the borderline category Category 4. Acute/active cellular rejection is now replaced with T-cell-mediated rejection and includes two subcategories: Acute T-cell-mediated rejection Chronic active T-cell-mediated rejection Category 5. Chronic/sclerosing allograft nephropathy CAN is now replaced with: Interstitial fibrosis and tubular atrophy, no evidence of any specific etiology Category 6. Other changes not considered to be due to rejection-acute and/or chronic. The specific diagnoses responsible or chronic allograft injury, given in Table 5.1, are represented under category 6

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Table 5.3  Morphology of specific chronic diseases (From [28, 31, 45, 46]) Etiology Morphology Chronic hypertension Arterial/fibrointimal thickening with reduplication of elastica, usually with small artery and arteriolar hyaline changes Calcineurin inhibitor toxicity Arteriolar hyalinosis with peripheral hyaline nodules and/or progressive increase in the absence of hypertension or diabetes. Tubular cell injury with isometric vacuolization Chronic obstruction Marked tubular dilation. Large Tamm-Horsfall protein casts with extravasation into interstitium and/or lymphatics Bacterial pyelonephritis Intratubular and peritubular neutrophils, lymphoid follicle formation Viral infection Viral inclusions on histology and immunohistology and/or electron microscopy

that evaluated c4d deposition and capillaritis and their effect on graft outcome parameters led to the development of new scoring systems for peritubular capillaritis and C4d deposition adopted at the Banff 2007 conference. The concept of the total inflammatory burden on graft viability led to proposing a new score that evaluated inflammation in all of the biopsy, including the subcapsular cortex and regions with fibrosis, which are not accounted for in the traditional descriptions of interstitial inflammation. This total inflammatory score was assigned the prefix ti (total interstitial inflammation) [47]. Schemas other than those proposed by the Banff group also have been used in research and clinical practice. One is the CADI score (chronic allograft damage index) which reports on interstitial inflammation, interstitial fibrosis, mesangial matrix increase, glomerulosclerosis, tubular atrophy, and intimal vascular thickening. Each of these histological features is scored on a scale of 0–3. Other systems were developed to measure the chronicity of kidney lesions by scoring for glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular sclerosis [48]. One of the great difficulties that face all of these scoring systems is reproducibility. The use of these scoring systems such as Banff or CADI is being advocated by some published studies that indicate their usefulness in evaluating of chronic lesions in periimplantation biopsies or in early protocol biopsies of stable allograft. It is important to note, however, that chronic lesions in these circumstances are often very mild and under the threshold of these systems, thus pointing to the need of further refining of these

s­ coring systems to increase their utility in these early biopsies [48, 49]. The tenth Banff Conference held in 2009 designated six areas of special interest for investigation by multicenter trials. These areas are: isolated intimal arteritis (v-lesion), fibrosis scoring, glomerular lesions, molecular pathology, poliomavirus nephropathy, and quality assurance. In addition, there has been increasing interest in the pathobiology of endothelial cells and monocytes during AMR and in their role in the progression to or in the development of lesions of chronic transplant glomerulopathy [32].

Pancreas Transplant Pathology General Pancreas transplantation is indicated for patients with insulin-dependent diabetes who are receiving a simultaneous pancreas kidney (SPK), or who received a pancreas after kidney (PAK). Pancreas transplant alone (PTA) is offered for nonuremic diabetics experiencing recurring or severe metabolic complications. The deceased donor pancreas is procured with the duodenum attached. This segment is anastomosed to the small intestine or the bladder to drain the exocrine secretions. Venous drainage is through either the systemic or portal venous system. Clinical features for the diagnosis of acute rejection, such as elevated serum amylase or lipase levels, decrease in urinary amylase, unexplained

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fever, and hyperglycemia are associated with a positive predictive value of only 75% [50]. Furthermore, calcineurin inhibitor islet toxicity, use of steroids, increased peripheral resistance to insulin, and type 2 diabetes mellitus limit the utilization of endocrine function in graft monitoring. Pancreas allograft biopsy is the gold standard for the diagnosis of acute rejection. Kidney biopsy has been used as a surrogate for a pancreas rejection in patients with an SPK, although discordance between kidney and pancreas biopsies justifies biopsy of both organs. Pancreas biopsies are used for surveillance, particularly in PAK or PTA recipients [51]. Percutaneous pancreas biopsy was popularized in the US by our group [52]. The procedure is performed under local anesthesia, using an 18-gauge needle, with guidance by computed tomography or ultrasound. The rate of adequate tissue yield using this technique is 90% [52]. Complications of biopsy are usually minor and self-limiting, with the most common being a transient rise of serum amylase levels. The incidence of major complications, such as bleeding or inadvertent biopsy of other organs, was 2.8%. Surgical intervention was only required in 1.2% of biopsied patients [53]. There are no definitive guidelines as to the number of cores of tissue needed for an adequate biopsy or whether or not multiple-site biopsies should be obtained, although in one study pancreatic tail biopsy was claimed to be better for identification of cellular rejection [54]. Tissue samples are collected in 10% buffered formalin, and then processed for paraffin embedding by standard techniques. In addition to H&E stains Masson trichrome stain is used to determine the extent of fibrosis and chronicity in older grafts, and periodic acid-Schiff stain to highlight acinar architecture. A sample of the pancreas composed of at least two lobules of acinar tissue associated with two or three septal areas is considered adequate for evaluation [45].

Acute Rejection Acute rejection in the pancreas is characterized by inflammatory cellular infiltrates associated with features of target tissue injury. The inflammatory cells are typically a mix of mononuclear cells, T lymphocytes, and varying number of plasma cells and eosinophils. Immunoblasts and activated lymphocytes may also be detected. Inflammation commences in the interlobular septae in mild rejection, and progressively involves the lobules and islets. Venous endotheliitis, accompanied by hypertrophy of the endothelial lining, is important to diagnose acute rejection, particularly when inflammation is restricted to the interlobular septae. Pancreatic ducts can also exhibit inflammatory cells in the wall, a pattern identified as ductulitis. Inflammatory cells permeate into the connective tissue surrounding the acini and produce acinar inflammation, leading to destruction of acinar cells and confluent acinar and lobular necrosis in severe rejection. Apoptotic cells have been identified with high frequency in acute pancreas rejection, while intimal arteritis is not frequently seen in the biopsies. Inflammation of the islets of Langerhans, islitis, is easily overlooked in routine H&E-stained sections. It is better illustrated with immunohistochemical staining for T lymphocytes and mononuclear cells. Drachenberg and colleagues [45] developed a  grading system for pancreas acute rejection. In this system, grade I is called inflammation of undetermined significance, and describes isolated inflammation in the septal areas without other histologic features of rejection, while four grades of acute rejection are defined (grades II–V). The histologic grades correlate with the degree of graft dysfunction and with treatment response [55]. Diffuse moderate-to-severe acinar inflammation with necrosis, intimal arteritis, and venulitis correlates with graft failure [55]. A modified iteration of this scheme was adapted as the Banff schema for pancreas allograft pathology and is presented in Tables 5.4 and 5.5. Antibody-mediated acute rejection of pancreas allografts is poorly understood, mostly due to difficulty in establishing the diagnosis. Deposition

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Table 5.4  Diagnostic categories Banff working grading schema for pancreas allograft rejection (From [59])a 1. Normal. Absent inflammation or inactive septal, mononuclear inflammation not involving ducts, vein, arteries, or acini. There is no graft sclerosis. The fibrous component is limited to normal septa and its amount is proportional to the size of the enclosed structures ducts and vessels. The acinar parenchyma shows no signs of atrophy or injury 2. Indeterminate. Septal inflammation that appears active but the overall features do not fulfill the criteria for mild cell-mediated acute rejection 3. Cell-mediated rejection: Acute cell-mediated rejection – Grade I/Mild acute cell-mediated rejection Active septal inflammation (activated, blastic lymphocytes, ± eosinophils) involving septal structures: venulitis (subendothelial accumulation of inflammatory cells and endothelial damage in septal veins, ductitis (epithelial inflammation and damage of ducts). Neural/perineural inflammation and/or Focal acinar inflammation. No more than two inflammatory foci per lobule with absent or minimal acinar cell injury – Grade II/Moderate acute cell-mediated rejection Multifocal (but not confluent or diffuse) acinar inflammation (³3 foci per lobule) with spotty (individual) acinar cell injury and dropout and/or Minimal intimal arteritis – Grade III/Severe acute cell-mediated rejection Diffuse (widespread, extensive) acinar inflammation with focal or diffuse multicellular/confluent acinar cell necrosis and/or Moderate or severe intimal arteritis and/or Transmural inflammation – Necrotizing arteritis Chronic active cell-mediated rejection. Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neointima) 4. Antibody-mediated rejection = C4d positivity** + confirmed donor specific antibodies + graft dysfunction Hyperacute rejection. Immediate graft necrosis (£1 h) due to preformed antibodies in recipient’s blood Accelerated antibody-mediated rejection. Severe, fulminant form of antibody-mediated rejection with morphologic similarities to hyperacute rejection but occurring later (within hours or days of transplantation) Acute antibody-mediated rejection. Specify percentage of biopsy surface (focal or diffuse). Associated histologic findings: ranging from none to neutrophilic or mononuclear cell margination (capillaritis), thrombosis, vasculitis, parenchymal necrosis Chronic antibody-mediated rejection. Features of categories 4 and 5 5. Chronic allograft rejection/graft sclerosis Stage I (mild graft sclerosis) Expansion of fibrous septa; the fibrosis occupies less than 30% of the core surface, but the acinar lobules have eroded, irregular contours. The central lobular areas are normal – Stage II (moderate graft sclerosis) The fibrosis occupies 30–60% of the core surface. The exocrine atrophy affects the majority of the lobules in their periphery (irregular contours) and in their central areas thin fibrous strands criss-cross between individual acini) – Stage III (severe graft sclerosis) The fibrotic areas predominate and occupy more than 60% of the core surface with only isolated areas of residual acinar tissue and/or islets present 6. Other histologic diagnosis. Pathological changes not considered to be due to acute and/or chronic rejection, e.g., CMV pancreatitis, PTLD, etc. Categories 2–6 may be diagnosed concurrently and should be listed in the diagnosis in the order of their clinicopathological significance a If there are no donor-specific antibodies or these data are unknown, identification of histologic features of antibody-mediated rejection may be diagnosed as “suspicious for acute antibody-mediated rejection,” particularly if there is graft dysfunction

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Table 5.5  Pathologic changes “other” than rejection in pancreas needle biopsies (From [59]) Diagnosis Main histologic findings Clinical presentation Posttransplant Inflammation: neutrophils, foamy macrophages Increase in amylase and ischemic pancreatitis lipase in serum Location: septal if mild or diffuse if severe Decrease in urinary amylasea Hyperglycemia if there is Other features: fat necrosis, edema and extensive necrosis interstitial hemorrhage. Patchy coagulation necrosis of clusters of acinar cells may be present. No fibrosis, the septa may be expanded due to edema/fat necrosis Local or systemic infectious Inflammation: mixed (lymphocytes, plasma Peripancreatitis/ symptoms, abdominal cells, eosinophils, neutrophils) peripancreatic fluid pain, peritonitis. collection Location: septa and periphery of lobules Peripancreatic fluid Other features: dissecting bundles of active accumulation. Increase in fibroblastic proliferation with obliteration of amylase and lipase in septal structures, relative preservation of the serum center of lobules (“cirrhotic appearance”)

Cytomegalovirus pancreatitis

Inflammation: mostly mononuclear Location: septal and acinar, patchy Other features: cytomegalovirus cytopathic changes in acinar, endothelial or stromal cells

Posttransplant lymphoproliferative disorder

Bacterial or fungal infection

Recurrent autoimmune disease/diabetes mellitus

Acute calcineurin inhibitor toxicity

In bladder-drained grafts

a

Inflammation: ranging from polymorphic with lymphoblasts, plasma cells, eosinophils in low-grade disease, to monomorphic, predominantly lymphoid in high-grade disease (lymphoma). Other features: lymphoid proliferation is nodular, expansive. Necrosis may be present Inflammation; variable; acute, chronic, purulent, necrotizing (abscess), granulomatous Location: random Other features: same as bacterial and fungal infections in other organs Inflammation: islet-centered lymphocytic inflammation (isletitis). No inflammation in late stages after disappearance of beta cells Other features: immunohistochemical stains for insulin and glucagon demonstrate absence of insulin producing beta cells in some or all islets depending on whether early or late disease Absence of inflammation. Variable degrees of islet cell injury (cytoplasmic swelling, vacuolization, islet cell dropout, formation of empty spaces (lacunae), apoptotic fragments) Immunoperoxidase stains: markedly diminished staining for insulin in comparison to controls and to glucagon stain. Electron microscopy: loss of insulin dense core granules with preservation of glucagon-dense core granules

Increase in amylase and lipase in serum. Decrease in urinary amylasea Systemic symptoms if generalized disease Other: duodenal cuff perforation Asymptomatic, or increase in serum amylase and lipase. Lymphadenopathy. Tumor mass. May coexist with acute rejection

Systemic and/or localized infectious symptoms. Peritonitis, duodenal cuff perforation. Increase in serum amylase and lipase Acute or chronic deterioration in glucose metabolism with increasing need for insulin. Although not pathognomonic, islet cell autoantibodies typically present (i.e., GAD 65, IA-2, etc.) Acute hyperglycemia. High levels of cyclosporine or tacrolimus with return to normoglycemia with adjustment of drug dose or discontinuation

135

5  Pathology of Kidney and Pancreas Transplants Fig. 5.22  Pancreas biopsy. Pancreas stained for C4d with polyclonal antisera

of complement fragment C4d in allografts, in conjunction with evidence of tissue and microvascular injury, and/or detection of donor-specific antibodies, is diagnostic for antibody-mediated rejection. Recently developed polyclonal antibodies against C4d have allowed for testing paraffinembedded biopsies (Fig. 5.22).

Chronic Rejection Pancreas transplants exhibit chronic rejection to a greater degree than other solid organs in multivisceral transplants [55]. In a large study, the rate of chronic rejection in PAK and in PTA was 11.5%, and was only 3.7% in SPK. Graft loss occurred in 8.8% of these cases [56]. The histologic features of chronic rejection are the result of vascular sclerosis, progressive fibrosis, and loss of functioning structures. Variable mononuclear inflammatory infiltrates are detected in these late biopsies. Fibrosis causes expansion of the interlobular septae and erodes the periphery, then the center of the lobules, causing distortion of the architecture and loss of acini. The lobules become encircled by dense fibrous tissue and display a pattern similar to hepatic cirrhosis. Eventually, the graft becomes progressively replaced by fibrous tissue. Vascular lesions of

chronic rejection are similar to those in other organs and include fibrocellular intimal hyperplasia with or without foam cells and lumen compromise. These vessels are not necessarily present in the needle biopsy and are more likely to be detected in pancreatectomy specimens. A three-tier grading system devised for chronic rejection has reasonable reproducibility [57]. These chronic rejection grades correlate with the time elapsed since transplantation (i.e., the higher the grade, the longer the posttransplantation period), but do not correlate with graft loss.

Pancreatitis Biopsies of pancreas allografts taken 30–90 min after implantation show margination of leukocytes in blood vessels and perivascular connective tissue, reduction in the density of zymogen granules, and large autophagolysosomes in the acinar cells. These post-reperfusion changes may explain the occurrence of early posttransplant pancrea­ titis, which is usually self-limiting, although severe cases have been associated with progression to thrombosis or pancreatic necrosis. Reflux pancreatitis is caused by reflux of urine or gastrointestinal secretions into the pancreatic

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duct, and is aided by dysregulated motility of the sphincter of Oddi. This form of pancreatitis is characterized by hyperamylasemia and graft tenderness. It usually occurs starting a few months after transplantation and could be recurrent. Differentiation between pancreatitis and rejection could be problematic; however, venulitis and a predominantly monocytic graft cellular infiltrate favors rejection. In rare cases, biopsies may show localized fat necrosis and autodigestion of the pancreas without significant inflammation. Cytomegalovirus pancreatitis (CMV) is rare, and characterized by multifocal, predominantly mononuclear acinar inflammation in association with CMV-cytopathic changes. Confirmation of CMVpancreatitis could be achieved by immunohistochemistry. In rare instances, CMV-pancreatitis could be associated with acute rejection.

Lesions in the Islets of Langerhans Islet inflammation and their infiltration by mononuclear cells is seen typically in higher grades of rejection (III–V) along with inflammation of the septal areas and acinar tissue. The integrity of the islets is usually well preserved without apparent necrosis. Inflammation of the islets is also seen in recurrent diabetes in the allograft. Mononuclear cellular inflammation of the islets in these cases is associated with selective loss of b cells. Immunohistochemical tissue examination using antibodies directed against b and a cells could be helpful in establishing the diagnosis of recurrent autoimmune diabetes mellitus and in differentiating it from rejection [58]. In chronic pancreatitis, islets are more resilient and survive longer than the exocrine acinar tissue. A unique lesion has been identified in the islets of Langerhans during episodes of calcineurin inhibitor toxicity with vacuolar degeneration and significant swelling of the cytoplasm and the formation of pseudoglandular spaces within the islet. Clearing of the cytoplasm is more prominent in the center of the islets rather than in the peripheral zone. Occasionally, evidence of cellular necrosis (e.g., condensation of the cytoplasm, apoptosis, and

cellular dropout), could be identified. During these toxicity episodes, staining for b cells reveals decreased density of the intracytoplasmic granules.

References 1. Croker B, Tisher, CC. Indications for and interpretation of the renal biopsy: evaluation by light, electron and immunohistologic microscopy. In: Schrier R (ed.). Diseases of the Kidney, 8th edn. Philadelphia: Lippincott Williams & Wilkins; 2007:420–447. 2. Hazzan M, Labalette M, Copin MC, et al. Predictive factors of acute rejection after early cyclosporine withdrawal in renal transplant recipients who receive mycophenolate mofetil: results from a prospective, randomized trial. J Am Soc Nephrol 2005;16(8): 2509–2516. 3. Kuypers DR, Le Meur Y, Cantarovich M, et  al. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol 2010;5(2):341–358. 4. Croker B, Salomon DR. Transplant rejection, transplant glomerulopathy and recurrent and de-novo glomerulonephritis. In: Tisher C (ed.). Renal Pathology. Philadelphia: Lippincott, 1989:1518–1544. 5. Sung RS, Galloway J, Tuttle-Newhall JE, et al. Organ donation and utilization in the United States, 1997–2006. Am J Transplant 2008;8(4 Pt 2):922–934. 6. Remuzzi G, Cravedi P, Perna A, et al. Long-term outcome of renal transplantation from older donors. NEJM 26 2006;354(4):343–352. 7. Muruve NA, Steinbecker KM, Luger AM. Are wedge biopsies of cadaveric kidneys obtained at procurement reliable? Transplantation 15 2000;69(11):2384–2388. 8. Gaber LW, Moore LW, Alloway RR, Amiri MH, Vera SR, Gaber AO. Glomerulosclerosis as a determinant of posttransplant function of older donor renal allografts. Transplantation 1995;60(4):334–339. 9. Randhawa PS, Minervini MI, Lombardero M, et al. Biopsy of marginal donor kidneys: correlation of histologic findings with graft dysfunction. Transplantation 2000;69(7):1352–1357. 10. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. Evolution and pathophysiology of renal-transplant glomerulosclerosis. Transplantation 2004;78(3):461–468. 11. Bosmans JL, Woestenburg A, Ysebaert DK, et  al. Fibrous intimal thickening at implantation as a risk factor for the outcome of cadaveric renal allografts. Transplantation 2000;69(11):2388–2394. 12. Woestenburg AT, Verpooten GA, Ysebaert DK, Van Marck EA, Verbeelen D, Bosmans JL. Fibrous intimal thickening at implantation adversely affects long-term kidney allograft function. Transplantation 2009;87(1):72–78.

5  Pathology of Kidney and Pancreas Transplants 13. Anil Kumar MS, Khan SM, Jaglan S, et al. Successful transplantation of kidneys from deceased donors with acute renal failure: three-year results. Transplantation 2006;82(12):1640–1645 14. McCall SJ, Tuttle-Newhall JE, Howell DN, Fields TA. Prognostic significance of microvascular thrombosis in donor kidney allograft biopsies. Transplantation 2003;75(11):1847–1852. 15. Chapman JR. Longitudinal analysis of chronic allograft nephropathy: clinicopathologic correlations. Kidney Int Suppl 2005(99):S108–112. 16. McLaren BK, Zhang PL, Herrera GA. P53 protein is a reliable marker in identification of renal tubular injury. Appl Immunohistochem Mol Morphol 2004;12(3): 225–229. 17. Yamamoto T, Tada T, Brodsky SV, et  al. Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am J Physiol Renal Physiol 2002;282(6): F1150–1155. 18. Grandtnerova B, Laca L, Jahnova E, et al. Hyperacute rejection of living related kidney graft caused by IgG endothelial specific antibodies with a negative monocyte cross-match. Ann Transplant 2002;7(4):52–54. 19. Montgomery RA, Locke JE, King KE, et al. ABO incompatible renal transplantation: a paradigm ready for broad implementation. Transplantation 2009;87(8):1246–1255. 20. Zollinger H, Mihatsch, MJ. Renal Pathology in Biopsy: Light, Electron and Immunofluorescent Microscopy and Clinical Aspects. New York: Springer-Verlag, 1978. 21. Milford E, Carpenter CB. Immunopathogenetic mechanisms of renal allograft rejection. In: Tisher C, Brenner BM (eds.). Renal Pathology. Philadelphia: Lippincott, 1989:440–462. 22. Milford E, Hancock W, Carpenter CB. Immunopathogenic mechanisms of allograft rejection. In: Tisher C, Brenner BM (eds.). Renal Pathology: With Clinical and Functional Correlations. Philadelphia: Lippincott, 1994. 23. Croker B, Ramos, EL. Pathology of the renal allograft. In: Tisher C, Brenner BM (eds.). Renal Pathology: With Clinical and Functional Correlations. Philadelphia: Lippincott, 1994. 24. Feucht HE, Felber E, Gokel MJ, et al. Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection. Clin Exp Immunol 1991;86(3):464–470. 25. Womer KL, Meier-Kriesche HU, Patton PR, et  al. Preemptive retransplantation for BK virus nephropathy: successful outcome despite active viremia. Am J Transplant 2006;6(1):209–213. 26. Morzycka M, Croker BP Jr, Siegler HF, Tisher CC. Evaluation of recurrent glomerulonephritis in kidney allografts. Am J Med 1982;72(4):588–598. 27. Porter K. Renal transplantation. In: Heptinstall R (ed.). Pathology of the Kidney. Boston: Little, Brown, 1966 28. Solez K, Axelsen RA, Benediktsson H, et  al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993;44(2):411–422.

137 29. Heptinstall R. Pathology of the Kidney. Boston: Little, Brown, 1974. 30. Chan L, Wiseman A, Wang W, Jani A, Kam I. Outcomes and complications of renal transplant. In: Schrier R (ed.). Diseases of the Kidney and Urinary Tract. Philadelphia: Lippincott William & Wilkins, 2007. 31. Solez K, Colvin RB, Racusen LC, et  al. Banff ’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (CAN). Am J Transplant 2007;7(3): 518–526. 32. Sis B, Mengel M, Haas M, et al. Banff ’09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 2010;10(3):464–471. 33. Kasiske BL, Gaston RS, Gourishankar S, et al. Longterm deterioration of kidney allograft function. Am J Transplant 2005;5(6):1405–1414. 34. Gloor JM, Sethi S, Stegall MD, et  al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant 2007;7(9): 2124–2132. 35. Cosio FG, Gloor JM, Sethi S, Stegall MD. Transplant glomerulopathy. Am J Transplant 2008;8(3):492–496. 36. Homs S, Mansour H, Desvaux D, et al. Predominant Th1 and cytotoxic phenotype in biopsies from renal transplant recipients with transplant glomerulopathy. Am J Transplant 2009;9(5):1230–1236. 37. Srinivas TR, Kubilis PS, Croker BP. Macrophage index predicts short-term renal allograft function and graft survival. Transpl Int 2004;17(4):195–201. 38. Kieran N, Wang X, Perkins J, et al. Combination of peritubular c4d and transplant glomerulopathy predicts late renal allograft failure. J Am Soc Nephrol 2009;20(10):2260–2268. 39. Ozdemir BH, Demirhan B, Gungen Y. The presence and prognostic importance of glomerular macrophage infiltration in renal allografts. Nephron 2002;90(4): 442–446. 40. O’Connor J, Couch NP, Lindquest R, Deammin GJ, Murray JE. A correlation of arteriography, histology and clinical course in kidney transplantation. Ann NY Acad Sci 1966;129:637–653. 41. Porter KA, Thomson WB, Owen K, Kenyon JR, Mowbray JF, Peart WS. Obliterative vascular changes in four human kidney homotransplants. BMJ 1963; 2(5358):639–645. 42. Amer H, Cosio FG. Significance and management of proteinuria in kidney transplant recipients. J Am Soc Nephrol 2009;20(12):2490–2492. 43. Halimi JM, Laouad I, Buchler M, et  al. Early lowgrade proteinuria: causes, short-term evolution and long-term consequences in renal transplantation. Am J Transplant 2005;5(9):2281–2288. 44. Amer H, Fidler ME, Myslak M, et  al. Proteinuria after kidney transplantation, relationship to allograft histology and survival. Am J Transplant 2007;7(12): 2748–2756.

138 45. Drachenberg CB, Papadimitriou JC, Klassen DK, et al. Evaluation of pancreas transplant needle biopsy: reproducibility and revision of histologic grading system. Transplantation 1997;63(11):1579–1586. 46. Solez K, Colvin RB, Racusen LC, et  al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8(4): 753–760. 47. Racusen LC, Colvin RB, Solez K, et  al. Antibodymediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003;3(6):708–714. 48. Isoniemi H, Taskinen E, Hayry P. Histological chronic allograft damage index accurately predicts chronic renal allograft rejection. Transplantation 1994;58(11): 1195–1198. 49. Gough J, Rush D, Jeffery J, et al. Reproducibility of the Banff schema in reporting protocol biopsies of stable renal allografts. Nephrol Dial Transplant 2002;17(6):1081–1084. 50. Kuo PC, Johnson LB, Schweitzer EJ, et al. Solitary pancreas allografts. The role of percutaneous biopsy and standardized histologic grading of rejection. Arch Surg 1997;132(1):52–57. 51. Gaber LW, Stratta RJ, Lo A, et  al. Role of surveillance biopsies in monitoring recipients of pancreas alone transplants. Transplant Proc 2001;33(1–2): 1673–1674. 52. Gaber AO, Gaber LW, Shokouh-Amiri MH, Hathaway D. Percutaneous biopsy of pancreas transplants. Transplantation 1992;54(3):548–550.

L. Gaber and B.P. Croker 53. Klassen DK, Weir MR, Cangro CB, Bartlett ST, Papadimitriou JC, Drachenberg CB. Pancreas allograft biopsy: safety of percutaneous biopsy – results of a large experience. Transplantation 2002;73(4):553–555. 54. Bernardino M, Fernandez M, Neylan J, Hertzler G, Whelchel J, Olson R. Pancreatic transplants: CT-guided biopsy. Radiology 1990;177(3):709–711. 55. Papadimitriou JC, Drachenberg CB, Klassen DK, Weir MR, Bartlett ST. Histologic grading scheme for pancreas allograft rejection: application in the differential diagnosis from other pathologic entities. Transplant Proc 1998;30(2):267. 56. Takahashi H, Delacruz V, Sarwar S, et  al. Contemporaneous chronic rejection of multiple allografts with principal pancreatic involvement in modified multivisceral transplantation. Pediatr Transplant 2007;11(4):448–452. 57. Papadimitriou JC, Drachenberg CB, Klassen DK, et  al. Histological grading of chronic pancreas allograft rejection/graft sclerosis. Am J Transplant 2003;3(5):599–605. 58. Drachenberg CB, Klassen DK, Weir MR, et al. Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 1999;68(3): 396–402. 59. Drachenberg CB, Odorico J, Demetris AJ, et al. Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel. Am J Transplant 2008;8(6): 1237–1249.

Chapter 6

Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ Transplantation Agnes Costello and D. Scott Batty

Keywords  Endpoints • Analysis • Clinical ­trials • Immunosuppression • Study protocol

Designing a Clinical Study What Is the Question?

Introduction The prospective, randomized, controlled clinical trial is the foundation of evidence-based ­medicine that guides clinical practice and optimum patient care. Although randomized controlled clinical trials (RCT) are considered to be the gold standard for evaluating the efficacy and safety of new or existing therapies, there are many other types of clinical research that may be relevant in evaluating immunosuppressive therapies in solid organ transplantation. In this chapter, we review and discuss ­essential elements of designing and conducting clinical research that lead to successful reporting of clinical trial results. We highlight key considerations in designing a clinical study that evaluates the safety and efficacy of a theoretical novel immunosuppressive agent, as well as in execution of such a study.

A. Costello (*) Transplant Business Unit, Genzyme Corporation, 500 Kendall Street, Cambridge, MA, 02142, USA e-mail: [email protected]

The foundation of any research is clearly ­defining the question and generating a measurable hypothesis for study. Once the hypothesis is defined, the investigator can start with selecting the most appropriate study design to address the research question. In evaluating any novel immunosuppressive agent in renal transplantation, the fundamental question is often whether this novel immunosuppressive agent is “better” than existing immunosuppressive agent(s). Depending on the mechanism of action, pharmacology, pharmacokinetics, and safety profile of the experimental agent as well as limitations of the existing immunosuppressive agent or regimen, “better” may imply many different measures of transplant outcomes, such as better in preventing acute rejection, better in safety profiles, or better in prolonging long-term allograft functions.

How to Choose the Study Design? One of the challenges in conducting clinical research is determining the most appropriate study design (Table 6.1). When designed and conducted appropriately, randomized controlled clinical trials (RCT) can change clinical practice and influence health care policy [1]. However, there are many scientific and logistics challenges that limit the routine use of RCT in solid organ ­transplantation [2].

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_6, © Springer Science+Business Media, LLC 2011

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140 Table 6.1  Overview of different study designs Study design Key features Observation designs   Cohort study A group followed over time Cross-sectional study A group examined at one point in time Case–control study Two groups, based on the outcome Experimental design Randomized controlled study Cross-over study

  Two groups created by random process and an assigned intervention Subjects are treated with the control and then switch to experiment treatment after a wash-out period

Regardless of the study design, the core design of clinical research remains a parallel-arm study with two or three groups, which includes a control group and at least one experimental group. Figure  6.1 provides a simple decision tree that highlights the  different types of study design that may be ­considered [1, 3]

Randomized Control (Placebo or Active) Studies Randomized control studies are comparative studies with an experimental group and a control group. The assignment of the research subject to the treatment group is determined by randomi­ zation. Randomization ensures that an eligible study subject has equal opportunity to being assigned to either group. Randomization is extremely important in clinical trials because it minimizes selection bias in allocating subjects to either study group. Randomization also ensu­ res to the best extent possible that confounding ­factors that can influence study outcomes are equally distributed among the treatment groups. The control group can be one of two types: placebo-controlled or active-controlled. Placebocontrolled is sometimes considered the true gold standard because it truly evaluates the effect of the experimental intervention against an inactive intervention. Success in this placebo-controlled clinical study provides the clearest clinical

g­ uidance as to the risk and benefit of doing ­nothing or to best define the risk and benefit of the ­additional ­intervention. Although a randomized, placebo-controlled study design is viewed as the gold standard, it may not always be necessary, appropriate, or ethical. For example, it would be unethical to randomize renal transplant recipients to receive either tacrolimus or placebo when determining the safety and efficacy of ­tacrolimus. When the effect of an experimental intervention is dramatic or otherwise well-understood, it may not  be appropriate to use an experimental intervention. For example, a study that compares Thymoglobulin to placebo in the treatment of steroid-resistant, biopsy-proven acute cellular rejection is unnecessary and would be considered unethical based on results from previous published studies as well as the clinical implications of not treating steroid-resistant, biopsy-proven acute rejection [4]. In this case, the randomized, active-controlled study design is the preferred method of study. This study would allow comparison of an experimental therapy with a known therapy (Thymoglobulin), which seeks to measure the difference of a prespecified effect (rejection reversal) common to both therapies. It is this incremental improvement that is measured and determined to be clinically and statistically relevant. Due to the need for suppression of the alloimmune response, the randomized, activecontrolled study design forms the core of clinical trials in solid organ transplantation. However, depending on the properties of the experimental therapy, placebo-controlled study designs may still be feasible and appropriate such experimental therapy can be added to current accepted and approved immunosuppressive regimens. In the polypharmacy approach of  current immunosuppressive regimens, this type of add on experimental therapy, placebo-controlled study design may be employed. This will be discussed later as it relates to selection of an appropriate control group. Often, the outcome of interest or the primary endpoint makes conducting a prospective, randomized, controlled clinical study inappropriate. If the event is very rare, the target population is very small, or takes a long time to occur, it may

Qualitative

Cross Over

Parallel Group

Experimental

Case Control Before the exposure was determined

Cross Sectional At the same time as the exposure or intervention

Cohort Study Some time after the exposure or intervention

When were the outcomes determined?

Observational

No

Will the intervention be randomly allocated?

Analytical

To quantify a relationship between factors

Yes

What is the aim of the study?

Fig. 6.1  Decision tree for determining study design

Survey

Descriptive

To describe a population

All Studies

6  Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ 141

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not be practical to conduct a prospective, ­randomized, controlled study [2, 5]. For example, if the study is to determine the impact of an immunosuppressive agent on the development of posttransplant proliferative disorder (PTLD), it will require a very large sample size to conduct this study because the incidence of PTLD is less than 5% [6]. Another important component in randomized, controlled clinical studies is blinding to the treatment assignment. The patient (single-blinded), the investigator (single-blinded), or both (double-blinded) can be blinded to the treatment assignment. The purpose of blinding is to avoid biases that might occur if an individual (patient or physician) changes his or her behavior because he/she knew which treatment he/she is receiving. For example, an investigator may actively seek for adverse events and assigned causality because he or she knew that the study subject is receiving the new treatment. Unfortunately, it is not fea­ sible to conduct double-blinded study in solid organ transplantation because of the complexity of managing multiple immunosuppressive drug regimens and the need to monitor therapeutic drug levels. Double-blinded studies are mostly done in Phase 3 pivotal, company-sponsored clinical studies.

Observational Studies There are three broad categories of observational studies: cohort study, cross-sectional study, and case–control studies [3]. The decision on which observational study design to use depends on the  research question, available data, and circumstances. A cohort study is one of the most frequently used study design in solid organ transplantation. In this type of study design, a new therapy is used in a series of patients and the results are compared to the outcomes in a series of comparable patients receiving the standard of care or accepted therapy. A cohort study can be prospective or retrospective, but retrospective cohort studies are more frequently used in solid organ transplantation. A retrospective cohort study is also referred to as a historical cohort

A. Costello and D.S. Batty

study. For example, the clinician has adapted using sirolimus at 3  months posttransplant in stable renal transplant recipients (intervention) and is interested in determining if this approach has resulted in improvement in renal allograft function at 3 years posttransplant (outcome) without an increase in acute rejection (outcome). The clinician designs a retrospective cohort study comparing outcomes in a group of patients who have been treated with sirolimus at 3  months posttransplant with a previous group of patients who received standard of care regimen (without sirolimus). The advantage of the retrospective cohort study is that it is much less costly and time-­ consuming than a prospective, randomized, ­controlled clinical study. Retrospective cohort studies can provide some useful data to support future research. However, retrospective cohort studies are vulnerable to many different types of bias. The investigator has no control over selection bias, presence of confounding variables, and the changes in clinical practice over time. Importantly, the existing data (medical records) may be incomplete, inaccurate, or collected in ways not ideal for determination of identification of study subjects, key variables, and outcomes. Using the earlier example, the transplant database might not contain all the information regarding the dose and exposure of sirolimus, not all patients received the same concomitant immunosuppressive agents, not all patients had renal allograft protocol biopsies, and renal allograft function are likely not evaluated consistently among all patients. The historical control group might have been managed very differently and such practices could have influenced outcomes substantially but in a manner not accessible to measurement. While attempts can be made to minimize bias by matching cases (experimental cohort) and controls (historical cohort) for known risk factors or known confounding variables, limitations of prior data collected likely limit the ability to reliably draw any conclusions from retrospective cohort studies. Cross-sectional studies are similar to the cohort study, except that all the measurements including interventions and outcomes are all

6  Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ

measured at a specific moment in time without any follow-up period. Cross-sectional studies are not commonly use in solid organ transplant because it is difficult to establish or examine causal relationships between intervention and outcomes from the data collected at a specific moment in time. The last category of observational study is the  case–control study. In case–control studies, the prevalence of a specific risk factor or ­outcome variable (cases) is compared with those who do not have the specific risk factor or disease (controls). This type of study design is also frequently used in solid organ transplantation. For example, within a transplant database, patients with BK nephropathy (cases) are compared with patients without BK nephropathy (controls) and their respective immunosuppressive regimens are compared. Case–control studies are challenging because of the potential for bias and confounding variables. They also do not establish a temporal sequence of events and are often limited to one outcome variable. Further, they may result in the inference of false conclusions if key relevant variables are excluded by or unavailable to the investigator. This exclusion of relevant variables is not deliberate, and variable exclusion can result from significant influences and causative factors as yet not fully understood in the nos­ ology at the time of study. As such, the association between disease and treatment or outcome (cause and effect) should only be considered to be hypothesis-generating for future prospective investigations.

Systematic Reviews and Metaanalysis Systematic review is a means of reviewing a specific research question using an explicit methodology to minimize bias in the location, selection, critical evaluation, and synthesis of research evidence using existing studies that may or may not involve quantitative analyses [7]. Metaanalysis is a technique commonly used in systematic review by which results from all clinical studies meeting the inclusion criteria and not the exclusion criteria are quantitatively

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combined to provide an overall summary statistic [8]. Both systematic review and metaanalysis have been used with increasing frequency in other disciplines. However, their uses in solid organ transplantation have been limited mostly due to the limited number of well conducted, large, prospective, randomized, controlled clinical studies that allow such an analysis [9–12]. Pooling results from these studies is often ­difficult because of the heterogeneity in study design, patient population, and lack of standardized immunosuppression across studies. Again, systematic reviews and metaanalyses are useful for understanding what the aggregate of studies may indicate or to show a trend, but caution must be exercised in imputing causal relationships outside the scope of the original designs of the trials [8].

Registry Analyses Another frequently used tool in transplant research is the analysis of registry databases such as data from the United Network for Organ Sharing (UNOS; www.unos.org, Richmond, VA) and the Scientific Registry of Transplant Recipients (SRTR; www.ustransplant.org, Ann Arbor, MI) [13]. Study of large datasets is a tool best utilized to examine patient demographics, identify risk factors, or describe major and easily captured or measured outcomes, such as patient and graft survival. Any database analysis is ­necessarily limited by the data captured; the more detailed the data, the more useful the analysis, but the higher the requirement for storage and maintenance. This creates a tension between the ability to acquire and the desire to analyze. Current databases do not provide the details necessary to draw “cause and effect” conclusions [13, 14]. In a randomized controlled clinical study, there are specific set criteria over the duration and the magnitude of exposure of the intervention for a defined group of patients. Failure to  adhere to these criteria usually disqualifies the  patient from receiving the intervention and from being included in the per-protocol or pertreatment analysis. In contrast, registry ­databases,

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as they reflect routine clinical practice, do not capture decision making on why a therapeutic strategy was chosen for a particular patient or patient group, and thus limit the ability to analyze intent in therapeutic uses and changes in therapy during follow-up. For example, if a patient was reported to be receiving cyclosporine at 30 days posttransplant, but was reported to be receiving tacrolimus at 1-year posttransplant, was the change of therapy planned per protocol or was the change of therapy due to toxicity or lack of efficacy? Did the change occur at day 31 or day 364? Thus, database analysis should be limited to hypothesis generating for future studies rather than to determine any causal relationship between intervention and outcome. Another limitation of registry analysis is data quality. In contrast to a prospective randomized controlled clinical study where data are monitored and audited for accuracy and completeness for each study subject, data from most national registries are not monitored or audited. Although, occasionally infrequent audits may be performed with a registry database, it is limited to random sampling and auditing a small subset of the data for accuracy. Reporting to some of these registries may not be required or enforced; therefore, reporting may be incomplete and these registries never capture the true number of patients exposed or the “denominator” of the population reported. This creates an obvious selection bias, with the attendant limits in drawing conclusions. Despite its many limitations, database ­analysis is a very useful research tool. This is especially true in rare or infrequent diseases or in other small populations where conducting a randomized controlled clinical study is simply not feasible. Construct of these databases is critical, to include as much relevant data as possible to best utilize this analytic tool. Databases are also quite useful for spotting rare or infrequent trends within a defined patient population. Events with low incidence rates will almost always fail to occur in significant frequencies for evaluation in randomized controlled clinical study with limited follow-up period. Therefore, databases are useful in monitoring the occurrences of these events as well as in identifying particular patient cohort at risk for these events.

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It is beyond the scope of this chapter to describe the methods and analytical approaches to registry analyses. For further discussion on this topic, the reader should review the article by Levine and colleagues, which provides an excellent overview database design and analytical methods for databases and the chapter by Schold et al. in this volume [14].

How to Determine the Experimental Group? In designing a clinical trial to evaluate the safety and efficacy of a novel immunosuppressive agent, one must consider not only the study treatment within the context of its mechanism of action, clinical pharmacology, clinical pharmacokinetics, and safety profile, but also the concomitant immunosuppressive agents to be used with the study treatment. The concomitant immunosuppressive agents may interact with the study treatment, which may result in synergistic immunosuppressive effects or enhance toxicities of both agents. Depending on the study endpoint and intervention, target study populations may be restricted to certain risk factors to increase the likelihood of occurrence of a desired endpoint. For example, to ensure that patients vulnerable to a particular toxicity are included in a study that is designed to determine if the experimental intervention can ameliorate these toxicities, only patients with certain risk factors for this particular toxicity will be included in the study. The converse is also true. Exclusions of particular study subjects at disproportionate risk of adverse events, unlikely to receive clinical benefit, or those otherwise inappropriate for the trial should be considered actively and prospectively.

How to Select the Control Group? One of the most controversial aspects of study design is the selection of the comparison group. When there is no effective or proven therapy; a placebo is considered as the control. However, it

6  Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ

continues to remain controversial as to whether placebo or “conventional/ standard of care” ­therapy should be employed in the control group. The selection of either placebo or “standard of care” therapy will dependent on whether the study treatment is meant to add to the existing immunosuppressive regimen or to replace a component of the existing regimen. In solid organ transplantation, the “standard of care” immunosuppressive regimen remains controversial. The “standard of care” immunosuppressive regimen could be a regimen that has  been approved by the Food and Drug Administration (FDA), a consensus based treatment protocol, or a commonly used regimen adapted by a particular transplant center [2]. However, patient characteristics and physician experience or preference often influence the choice of “standard of care” immunosuppressive regimen. The investigator should also differentiate if the study is designed to compare immunosuppressive agents or immunosuppressive regimens. If the purpose of the study is to compare safety and efficacy of two different immunosuppressive agents, then there should only be one variable being tested between the two groups. For example, the experimental group will be exposed to Drug X and mycophenolate mofetil and the ­control group will be exposed to tacrolimus and mycophenolate mofetil. If the purpose of the study is to compare two immunosuppressive regimens, then more than one variable is being evaluated. In this case, the experimental group will be exposed to Drug X and mycophenolate mofetil and the control group will be exposed to tacrolimus and sirolimus. To ensure that study groups are comparable and to minimize bias, the target therapeutic ­levels of concurrent immunosuppressive agents must be kept identical in both treatment groups. When the study is designed to compare two immunosuppressive regimens and the only variable that is different between the regimens is the target therapeutic level, the target ranges between the two regimens should be far apart so as not to overlap or converge over time. Lastly, whether the findings of a clinical trial can be extrapolated to the general population is

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dependent on the selection of the control group for comparison. For example, the tacrolimus and mycophenolic acid combination is currently the most commonly used component of maintenance immunosuppressive regimens in kidney and ­pancreas transplantation according to the recent SRTR data [15]. All new therapies should be compared to this regimen to generate meaningful results that can be extrapolated to the general transplant population.

What Are the Endpoints? In clinical trials, an endpoint is an outcome ­measure. Depending on the research question, endpoints can be dichotomous (i.e., yes or no outcome such as biopsy-proven acute rejection), continuous (such as glomerular filtration rate), or categorical. Study endpoints can be classified as primary, secondary, and tertiary endpoints. The primary endpoint should directly answer the research question. In renal transplantation, the incidence of acute rejection at 6 or 12 months has traditionally been considered as the primary endpoint [2, 5]. However, the introduction of potent immunosuppressive agents and innovation in immunosuppressive regimens has dramatically reduced the incidence of acute rejection to less than 15% [2, 5, 15]. A study that is designed to evaluate the efficacy of a novel immunosuppressive agent in lowering the incidence of acute rejection will require a very large samples size (>500 subjects) [2]. Importantly, ­further reductions in acute rejection rates (to less than 15%) may not necessarily equate to better safety profile and long-term transplant outcomes; it may be statistically significant but may be clinically irrelevant. Although it is desirable to evaluate long-term outcomes, it is impracticable, costly, and time consuming to conduct randomized controlled clinical trials with long-term follow-up. Clinical trials such as the recently reported ­prospective, randomized, double-blind, placebo controlled trial by Woodle and colleagues that compared chronic low dose corticosteroids with early corticosteroid cessation with a 5-year followup period are very rare [16]. The investigators of

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this study are to be commended for the execution and dedication to a project of that scope. Recent focus in transplant clinical research has been on using biomarkers as a surrogate for clinical endpoint [17, 18]. A validated surrogate endpoint is expected to predict clinical benefit (or harm, or lack of benefit). Surrogate outcomes are often measures of the underlying disease process (e.g., C-reactive proteins), a measurement of preclinical diseases (e.g., coronary artery calcifications), or a well-accepted risk factor that predicts diseases (e.g., systolic blood pressure). Common surrogate endpoints used in transplant are serum creatinine and ­biomarkers for immune activation such as mRNA ­levels for granzyme B in urine [17, 19]. Clinical trials that use surrogate markers as an endpoint measurement tend to be smaller in size, less costly, and shorter duration. Although numerous biomarkers have been evaluated in solid organ transplantation, none of these biomarkers has been validated as a surrogate endpoint predictive of outcome. Importantly, unlike in other disciplines, none of the biomarkers in solid organ transplantation have been accepted by regulatory authorities as a validated surrogate endpoint for approving and licensing of new immunosuppressive ­therapies [18]. Although most clinical studies focused on efficacy outcomes, it is just as important to evaluate safety outcomes. Safety outcomes are traditionally captured by spontaneous reporting of expected and unexpected adverse events and serious adverse events by investigators and clinicians; however, capturing events alone do not necessary give a clinically meaningful safety profile on the immunosuppressive regimens. For  example, when two immunosuppressive ­regimens are relatively comparable in preventing acute rejection, the decision to adapt either regimen in clinical practice will be dependent on the  its impact on long-term transplant-related complications such as the incidence of various opportunistic infections, posttransplant lympho­ proliferative disorders, and metabolic complications. To truly capture these safety outcomes, the investigators need to prospectively identify the events of interest, define these events, and ­capture

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these events accurately and completely in the case report forms. One of the challenges in designing a clinical study that compares the safety of two regimens is determining which safety endpoint to use for sample size and power calculation and how to account for unknown and unexpected adverse events. It is also equally challenging to determine the margin of difference in incidences and severity that would be considered clinically significant and relevant. The National Cancer Institute (NCI) has established the Common Toxicity Criteria (CTC) that can be used to capture the frequency and severity of adverse events using standard definitions as well as standardized grading schema. The NCI CTC can be accessed on this website: http://ctep. cancer.gov/reporting/ctc.html.

How Do We Define the Study Population? The study population should represent the patients to whom the results of the study might be applied. Typically, the target population is defined by the inclusion and exclusion criteria. Inclusion criteria typically are set in “positive” terminology having specific conditions or attributes; for example, patients with end-stage renal disease older than 18 years of age. Exclusion criteria are a list of criteria that exclude an eligible patient from participating in the study because of safety considerations or to avoid introduction of confounding variables. Determining the right balance of inclusion and exclusion criteria is challenging, as these criteria influence patient enrollment, results of the study, and the ability to generalize or extrapolate the findings to a clinically relevant patient population. For example, if an investigator is interested in determining if rabbit antithymocyte globulin (Thymoglobulin) is more effective in preventing acute rejection than basiliximab (Simulect) in renal transplant recipients, the inclusion criteria should be sufficiently broad to allow inclusion of most renal transplant recipients and to ensure that the study findings are applicable to the

6  Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ

t­ypical renal transplant recipients in clinical practice. Yet, the exclusion criteria should be minimized and specific to ensure patient safety. Since prior rabbit exposure is a known contra­ indication to receiving Thymoglobulin, prior exposure to rabbits should be an exclusion criterion. Since previous studies have concluded that Thymoglobulin is superior to Simulect and daclizumab (Zenapax) in high immunologic risk renal transplant recipients; these patients should be excluded in this study [20, 21]. It would not be safe, and perhaps even would be unethical to include high immunologic risk patients in such a study. Likewise, kidney transplant recipients seronegative for cytomegalovirus (CMV) antibody who receive organs from seropositive donors are at high risk for CMV infection and disease; as such, these patients should be excluded from a clinical study that would ­compare valganciclovir (Valcyte) to placebo for CMV prophylaxis [22].

How Many Study Subjects Do We Need? The number of study subjects will be dictated by the purpose of the study as well as the study design. For a proof of concept study or a pilot study, 30–50 subjects may be sufficient; but for a Phase 3 registration study, 400–500 subjects may be needed. In short, the sample size needs to be realistic and practical. For example, let us say that the purpose of a study is to evaluate the efficacy of a new immunosuppressive agent in preventing delayed graft function in reci­ pients of organs from donation after cardiac death (DCD). Using the appropriate statistical ­methods, the sample size is estimated to be 50 patients in each treatment group for a total of 100 patients. However, the center only performs 10 DCD renal transplants per year and after accounting for 10% ineligible subjects and 10% withdrawal rate, it would take more than 10 years to recruit the necessary subjects to complete the study.

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Further, the purpose of the study can impact sample size estimates. Comparisons between two treatments that are intended to conclude superiority of one treatment group over another will require a different sample size than one designed to demonstrate either non-inferiority or equivalence between two treatment group [23]. The selection superiority, noninferiority, and equivalence study depend on the magnitude of the treatment effect to be studied, available patient populations, disease incidence, and a number of other variables beyond the scope of this review [2, 23].

Conducting a Clinical Study It is beyond the scope of this chapter to discuss all the aspects of the management and conduct of clinical trial. A brief overview of the research process and the research personnel involved is described in Fig. 6.2. For more detailed information, the reader is asked to refer to a practical review by Knatterud [24]. As conducting and executing clinical trials becomes more complex and coupled with the rigorous regulatory environment, the investigator may wish to consider using a contract research organization or a data management company to help with conducting or handling the logistics of the study.

How Do We Write the Protocol? One of the challenges in conducting clinical research is simply writing the protocol. The study protocol is essentially the research plan. A typical study protocol outline is provided in Table 6.2. The protocol is the foundation for the development of many different regulatory documents such as the patient informed consent form and the Investigational New Drug (IND) application. Depending on the complexity of the study, the study protocol can also function as a manual of operations.

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148 Activities Integrate Literature Create Hypothesis Write Protocols IRB Interactions Secure Funding

Planning

Create CRFs Enrollment Collect Data Monitor Study

Execution

Organize Data Data Analysis Coordinate Write-up Generate Output Abstracts Manuscripts Presentation Study Reports

Dissemination

Research Roles Administrative Staff Investigators

Study Subjects Study Coordinators Technical Staff

Biostatisticians Investigators

Fig. 6.2  Overview of research process: planning, execution, dissemination (Adapted from Jon Putzke, Ph.D., M.S.P.H., ScienceTRAX)

How Do We Manage the Data? Regardless of the study design employed, the major challenge in conducting a clinical study is data collection and data management. Data collection should be limited to the items essential for the study objectives. It should be practical, yet detailed enough to answer the posed research question. The investigators need to determine the list of variables that need to be collected at baseline and at follow-up study visits. Baseline variables are collected to confirm the eligibility of the study subjects and to determine if the study subjects are comparable between treatment groups. Common baseline variables include patients’ demographics and transplant characteristics such as panel reactive antibodies (PRA), human leukocyte antigen (HLA) matching, cold ischemia time, and donor demographics and cause of death. Baseline variables should include those variables that can influence outcomes (confounders) or influence the interpretation of the findings. These variables sometimes also form the basis of subgroup analyses. Follow-up variables serve different purposes and include capturing the primary and secondary efficacy endpoints, safety data, and compliance with

study treatment and protocol. Although tempting, collecting data in addition to the primary research question should be limited. Avoiding “mission creep” is essential to the successful execution of a clinical trial, as you are asking participation from real, living transplant recipients. A classic example is unnecessary blood draws and study visits in hopes of “finding something.” The greater the complexity or burden of the clinical study, the less likely transplant recipients are to consent initially, and the more likely that they will drop out or withdraw from the study. Most transplant centers have a system that collects transplant data (such as TeleResults or OTTR) for clinical and administrative purposes. Although these administrative/clinical transplant databases are excellent for generating summary statistical report for many different purposes, they are not designed to collect research information. Data can be extracted from these transplant databases into a research database. Although the transplant database is an attractive and efficient source of data, it has several important limitations from the clinical trial standpoint. The data in the transplant database are usually not monitored for quality and veracity. Thus

6  Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ Table 6.2  Typical study protocol outline 1. 2. 3.

Background, rationale, and previous studies Study aims and objectives Design (a)  Study overview (b)  Inclusion and exclusion criteria (patient enrollment and screening) (c)   Interventions (i) Experimental group (ii) Control group (iii) Outcome variables (iv) Primary endpoint (v) Secondary and tertiary endpoints (vi) Study visits/study flow sheets (vii) Measuring and collecting data (viii) Concurrent treatments (ix) Study timeline (d)  Statistical considerations (i) Planned sample size and power calculation (ii) Randomization procedures (iii) Interim analysis plan (iv) Final analysis plan (e)  Regulatory considerations (i) Institutional review board (ii) Informed consent process (iii) Data and safety monitoring (f)  Study organization (i) Participating units (ii) Study administration (g)  Quality assurance (i) Adherence to protocol (ii) Performance monitoring (iii) Performances reporting (iv) Site visits (h)  Data collection and processing (i) Case report forms and study materials (ii) Data entry (iii) Data editing (iv) Database (v) Backup procedures Special study procedures, e.g., iothalamate GFRs, sonography

additional steps must be taken to ensure data quality. The fields created to capture data in the transplant database may not necessarily capture the desired research variables and outcomes. Data collection should also be timed appropriately to ensure that both safety and efficacy endpoints are captured and detected. For example, if a patient’s routine follow-up visit is every month for the first 6  months post-transplant, then it

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would be ideal to have the study visits coincide with these routine follow-up visits. This eliminates the extra costs associated with the study visits as well as minimizes the incidence of missing study visits and missing data. Considerations should also be made to accommodate changing follow-up circumstances that obtain when a study is designed to evaluate a maintenance immunosuppressive agent that is to be used beyond the first year posttransplant and requires frequent study visits. Most kidney transplant recipients will likely be seen by their local nephrologists and only be seen at the transplant center infrequently. If such considerations are not incorporated into the study design and budget, up-front substantial loss to follow-up and incomplete data capture could result.

How Do We Analyze the Data? Ideally, the statistical analytical plan (SAP) should be prespecified and preplanned to avoid bias. The SAP should include a description of the statistical model used to evaluate the primary endpoint, planned interim analyses, and handling of missing data. It is also important to include any planned subgroup analyses. Table  6.2 provides a brief overview of some of the common statistical tests used based on the type of variables.

What Are the Regulatory Considerations? All clinical research should be reviewed by the institutional review board (IRB). Depending on the scope of the study and study design, occasionally the IRB will allow for exemption in the case of retrospective studies that use existing data without patient identifiers. Most Phase 4 clinical studies do not required an Investigational New Drug (IND) application to the FDA. However, if this involved the use of an approved product outside the approved therapeutic area (such as using an oncology product in solid organ

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Table 6.3  Commonly used statistical tests in immunosuppressive clinical trials Number of Type of data Statistical tests variables Examples Categorical data Fisher exact test Univariate The incidence of acute rejection at 6 months is 15% in group A and 30% in group B Chi-square test Logistic regression t-test or paired-t test Univariate Comparing the serum creatinine between two Continuous data at groups at 6 months posttransplant (t-test) a single time Analysis of variance point (ANOVA) Survival data Kaplan Meier method Univariate Time to first acute rejection (or defined event) between two groups (log-rank) Log-rank Risk factor Logistic regression Multivariable The odds ratio of developing delayed graft function based on predefined clinically relevant variables adjusting for possible confounders Risk factor Cox regression Multivariable The hazard ratios of developing time to first acute rejection based on predefined clinically relevant variables adjusting for possible confounders

transplant), it may be advisable to contact the FDA regarding the need for an IND submission prior to starting the study. It is now mandatory that all clinical studies be registered prior to patient enrollment as well as reporting study findings within 1  year of study completion regardless of study results (i.e., positive or negative findings). The reader should be familiar with the recently released FDA guidance on “Investigator Responsibilities – Protecting the Rights, Safety, and Welfare of Study Subjects.” This guidance document is available from the FDA website using this link: http://fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/UCM187772.pdf .

Reporting Clinical Trials How Do We Report Clinical Trials Results? Guidelines have been developed to assist investigators with reporting their research to the medical community. The International Committee of Medical Journal Editors (ICMJE) guideline on uniform requirements for manuscripts submitted to biomedical journals is the most commonly

used (www.icmje.org). Understanding these guidelines may also be useful in designing and executing the clinical study, since the ultimate goal of clinical research is to share and disseminate findings. It is of paramount that prior to enrolling patients in a prospective clinical study that involves an intervention, the study is registered with http://clinicaltrials.gov or similar registration agencies. Without documentation of clinical study registration, the findings of the study will not be considered and accepted for publication. It is important to note that the results have to be reported within 1 year of its completion on http://clinicaltrials.gov, if the study was initially registered there. The Consolidated Standards for Reporting of Trials (CONSORT statement, www.consortstatement.org) consists of a checklist of standardized details that should be included in a clinical study report. The CONSORT statement is designed to improve the quality of reports of clinical trials. The CONSORT checklist may also help the investigators in designing the study to ensure that all elements are considered during the study design phase as well as during the data collection and data analysis phases. Two independent groups evaluated the quality of reporting of randomized controlled clinical studies in transplantation [25, 26]. It is alarming that both groups concluded that reporting of

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clinical studies in our field needs to be improved. The quality of reporting study results should improve if investigators design and conduct the study appropriately and adapt both CONSORT statement in preparing the manuscript as well as compliance with the ICMJE guidelines. [27]

Clinical Research Collaboration Transplantation has been one of the great ­successes of research partnerships between researchers, ­clinicians, and the pharmaceutical industry. There are many benefits and some caveats to this relationship that are highlighted here.

Postapproval Company-Sponsored Clinical Studies Most products once approved and marketed as a result of the initial Phase 3 pivotal studies have a series of post-approval or Phase 4 clinical studies. Phase 3 pivotal studies are often designed to meet regulatory approval and may not necessary reflect how the new therapy will be used in the clinic. Therefore, these Phase 4 studies explore new uses or combinations as well as identify the target patient population in the real world. Importantly, these postapproval clinical trials often form the basis of new drug development and/or label expansion. However, the clinicians’ critical eye should always judge the actual novelty or clinical utility of these Phase 4 clinical studies. Generally speaking, the population of transplant patients is relatively fixed with approximately 16,000 patients undergoing renal transplant annually in the United States [15]. The competition for eligible and available patients to enroll either into Phase 4 clinical studies with approved, marketed drugs or truly novel or innovative research efforts must be balanced by the clinician and researcher. This is especially relevant in the arena of chronic use of maintenance medications. In this ­competitive landscape, company-sponsored Phase 4 clinical

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trials often serve as little more than vehicles to protect market share and insure that once a patient is enrolled in a clinical study, the study patient is maintained on that therapy. The underlying and unstated proviso is that a patient enrolled in such a trial then pays dividends to the sponsor far in excess of the cost incurred in executing the clinical study. With the limited number of eligible transplant patients, it is incumbent on the clinician and the sponsor to insure that sponsored research is providing the appropriate benefit to the critical end-user, the patient.

Post approval Clinical Studies Safety Monitoring Apart from monitoring the quality of the data, large, prospective, randomized, controlled, multi-center clinical studies sponsored by pharmaceutical industry are also designed to monitor drug safety. In these Phase 2 and 3 clinical studies as well as company-sponsored Phase 4 clinical studies, all adverse events and serious adverse events regardless of frequency of occurrences and causality that may impact the safe and eff­ ective use of the new therapy are rigorously ­followed and tracked by the sponsoring entity. These events are then reported to regulatory authorities who monitor the frequency and seve­ rity of these events and subsequently report these events to the practicing community at large. The Food and Drug Administration (FDA) warnings are well known in the transplant community. The majority, if not all of these FDA warnings are a direct result of the safety reporting from these company-sponsored clinical studies as well as spontaneous reporting from the community. Although the investigators and clinicians are encouraged to report any adverse events or ­serious adverse events, investigator-sponsored single-center or multi-center studies may not have the infrastructure to rigorously report these safety outcomes to either the pharmaceutical companies providing the funding support or the regulatory authorities for formal evaluation. While the conclusions generated by these

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i­nvestigator-sponsored, independent studies may influence clinical practice and adaption, the safety results from these studies may not be ­sufficient or robust to allow a true assessment of the risk and benefit ratio on the new therapy. This is especially true in transplantation, where a variety of drugs from other therapeutic areas, such as oncology or rheumatology, may be ­studied or used off-label [28–30]. In an effort to improve clinical outcomes or to adapt a novel approach, conclusions from these clinical studies may rapidly influence clinical practice without adequate quantification of the safety and long-term impact on patient outcomes. Further, it becomes even more difficult to perform confirmatory studies once the conclusion is made that these new therapies should be adapted as “standard of care” for all patients. Unfortunately, few off-label research efforts include sufficiently robust populations to draw significant conclusions. Last, most pharmaceutical companies are mandated by regulatory agencies to monitor long-term safety outcomes and most companies do make a good-faith effort to publish long-term outcomes of the initial Phase 3 pivotal studies as well as Phase 4 postapproval studies.

Summary Clinical research is an extremely complex and demanding undertaking. The necessity of proper planning, critical thinking, and focus are the keys to the successful execution of answering a clinical question. In transplantation, further limitations as to eligible populations, low incidence rates, and other challenges add to the complexity of trial design and completion. Many types of research tools are available to clinician, each with its own strength and weakness. Appropriate selection by the educated researcher depends on the question to be answered, patients and endpoints to be studied, and available resources to name a few. The partnership between clinician and industry has provided numerous breakthroughs and improvements in the lives of transplant patients.

References 1. Devereaux P, Yusuf S. The evolution of the randomized controlled trial and its role in evidence-based decision making. J Intern Med 2003;254(2):105–113. 2. Schold JD, Kaplan B. Design and analysis of clinical trials in transplantation: principles and pitfalls. Am J Transplant 2008;8(9):1779–1785. 3. Friedman L, Furberg C, DeMets D. Fundamentals of clinical trials, 3rd edn. New York: Springer-Verlag, 1998. 4. Gaber A, First M, Tesi R, Gaston R, Mendez R, Mulloy L, et  al. Results of the double-blind, randomized, ­multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998;66:29–37. 5. Vincenti F, Klintmalm G, Halloran P. Open letter to the FDA: new drug trials must be relevant. Am J Transplant 2008;8(4):733–734. 6. Bustami R, Ojo A, Wolfe R, et al. Immunosuppression and the risk of posttransplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004;4:87–93. 7. Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: synthesis of best evidence for clinical decisions. Ann Intern Med 1997;126(5):376–380. 8. Egger M, Smith G. Meta-analysis: potentials and promise. BMJ 1997;315(7119):1371–1374. 9. Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 1999;318 (7191):1104–1107. 10. Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000;11 (10):1910–1917. 11. Atul VM, Naser H, Dean F, Greg AK. Calcineurin inhibitor withdrawal from sirolimus-based therapy in  kidney transplantation: a systematic review of ­randomized trials. Am J Transplant 2005;5(7): 1748–1756. 12. McAlister VC, Haddad E, Renouf E, Malthaner RA, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. Am J Transplant 2006;6(7): 1578–1585. 13. Dickinson D, Dykstra D, Levine G, Li S, Welch J, Webb R. Transplant data: sources, collection and research considerations, 2004. Am J Transplant 2005; 5(4p2):850–861. 14. Levine GN, McCullough KP, Rodgers AM, Dickinson DM, Ashby VB, Schaubel DE. Analytical methods and database design: implications for transplant researchers, 2005. Am J Transplant 2006;6(5p2):1228–1242 15. Andreoni KA, Brayman KL, Guidinger MK, Sommers CM, Sung RS. Kidney and pancreas transplantation in the United States, 1996–2005. Am J Transplant 2007; 7(s1):1359–1375.

6  Design, Conduct, and Report of Clinical Trials of Immunosuppressive Regimens in Solid Organ 16. Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation ­versus long-term, low-dose corticosteroid therapy. Ann Surg 2008;248(4):564–577 doi:510.1097/ SLA.1090b1013e318187d318181da 17. Lachenbruch P, Rosenberg A, Bonvini E, CavailléColl M, Colvin R. Biomarkers and surrogate endpoints in renal transplantation: present status and considerations for clinical trial design. Am J Transplant 2004;4(4):451–457. 18. Burckart G, Amur S, Goodsaid F, Lesko L, Frueh F, Huang S, et  al. Qualification of biomarkers for drug development in organ transplantation. Am J Transplant 2008;8(2):267–270. 19. Li B, Hartono C, Ding R, Sharma VK, Ramaswamy R, Qian B, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for ­perforin and granzyme b in urine. NE JM 2001;344 (13):947–954. 20. Brennan D, Daller J, Lake K. Rabbit antithymocyte globulin versus basiliximab for induction in renal transplantation. NEJM 2006;355(19):9–19. 21. Noel C, Abramowicz D, Durand D, Mourad G, Lang P, Kessler M, et  al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol 2009;20(6):1385–1392. 22. Carlos P, Atul H, Ed D, Kenneth W, Emily B, Barbara A, et  al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease

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in solid organ transplant recipients. Am J Transplant 2004;4(4):611–620. 23. Christensen E. Methodology of superiority vs. equivalence trials and non-inferiority trials. J Hepatol 2007;46(5):947–954. 24. Knatterud G. Management and conduct of randomized controlled trials. Epidemiol Rev 2002;24(1):12–22. 25. Fritsche L, Einecke G, Fleiner F, Dragun D, Neumayer H, Budde K. Reports of large immunosuppression trials in kidney transplantation: room for improvement. Am J Transplant 2004;4(5):738–743. 26. Pengel LHM, Barcena L, Morris P. The quality of reporting of randomized controlled trials in solid organ transplantation. Transplant Int 2009;22(4): 377–384. 27. Kane R, Wang J, Garrard J. Reporting in randomized clinical trials improved after adoption of the CONSORT statement. J Clin Epidemiol 2007;60:241. 28. Farney A, Doares W, Rogers J, Singh R, Hartmann E, Hart L et  al. A randomized trial of alemtuzumab ­versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation 2009;88(6): 810–819. 29. Vo A, Lukovsky M, Toyoda M, Wang J, Reinsmoen N, Lai C, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. NEJM 2008;359:242. 30. Everly M, Everly J, Susskind B, Brailey P, Arend L, Alloway R, et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation 2008;86(12):1754–1761.

Chapter 7

Outcomes of Kidney and Pancreas Transplantation Titte R. Srinivas, Herwig-Ulf Meier-Kriesche, and Jesse D. Schold

Keywords  Graft survival • Patient survival • Kidney and pancreas transplantation • Outcomes

Introduction Worldwide, the kidney is the most commonly transplanted solid organ. As of the end of 2008 more than 160,000 persons were living with a functioning kidney transplant in the United States alone [1]. The waitlist for kidney transplants continues to grow against a relatively ­limited rate of transplantation. As such, the renal transplant is a relatively scarce resource and transplant outcomes elicit understandable ­interest among patients, physicians, the general ­public, payers, and regulators. Data sources pertinent to transplant outcomes include databases maintained by single transplant centers, cooperatives of single centers and industrysponsored trials and large multi-center registries. Analyses of data from large databases are an important source of information on transplant outcomes. Examples of such databases include US Renal Database System (USRDS) [2], the Scientific Registry of Renal Transplant Recipients (SRTR), [1] the United Network for Organ Sharing (UNOS) [3], and the  Collaborative Transplant Study (CTS) [4]. Similar databases T.R. Srinivas (*) Nephrology and Hypertension, Glickman Urologic and Kidney Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]

are maintained in the UK, Australia and New Zealand (ANZDATA), and in Canada. The USRDS and SRTR report on almost all transplant recipients in the United States based on mandatory reporting of outcomes. The CTS reports data submitted on a voluntary basis by participating centers in many countries. The SRTR and USRDS database, through cross-links with the US Social Security Death Master File and the Medicare database, contains pertinent information with a high degree of validity on dates of patient death and return to dialysis. However, the large registries may lack specific details such as drug dose or concentration, blood pressures, lipid panels, and similar clinically ­relevant patientlevel variables. In this regard, single center observational studies and clinical trials frequently provide valuable input on the implication of such variables on graft and patient survival. Outcomes of renal allografts can be understood in the form of “hard outcomes” such as survival of allografts or patients or “soft outcomes” which are surrogates thereof. Serum creatinine, incidence of proteinuria, rates of rejection, and biopsy-derived pathologic indices constitute examples of the latter. Other important measures include days of hospitalization, patient satisfaction, and qualityof-life indices. The accuracy of registry data in portraying transplant outcomes is dependent on correct and complete reporting of outcomes and appropriate selection of cohorts included in the analyses [5]. In general, despite the intrinsic superiority of study design, randomized controlled trials of interventions such as immunosuppressive regimens or

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_7, © Springer Science+Business Media, LLC 2011

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individual drug therapies are often impractical for comparing effects on allograft survival [5]. This is because it is usually difficult to design an adequately powered trial to demonstrate statistically significant differences in graft or patient survival within the short periods of follow-up, given practical and financial constraints for the sample sizes needed in such trials. Furthermore, given the tightly defined populations that are necessary to maintain internal validity of well designed clinical trials, external validity of the results may also be limited [5].

Understanding Survival Models The primary methodology used in analyzing and reporting transplant outcomes is broadly defined as survival analysis, which is also referred to in other contexts as failure time analysis or time to event analysis. The event applicable for outcomes studies in transplantation can comprise a number of clinical occurrences including graft failure, return to dialysis or re-transplantation, patient death, time to acute rejection, or time to deterioration in renal function among many others. Allograft survival is calculated from the date of transplantation to the date of reaching a defined endpoint such as death, return to dialysis or retransplantation. Most modern analyses use the Kaplan-Meier method, which yields an actuarial estimate of graft survival. The assumptions underlying these models and the relevant terminology are summarized in Table 7.1. These methods necessarily imply estimation or projection of survival, as not all patients will have been followed for the same period of time. Also, as not all patients will have reached the defined endpoint, censoring of such patients is required. Censoring allows inclusion of subjects with varying lengths of follow-up, assuming that if subjects could be followed beyond the point in time when they are censored, they would have the same rates of outcomes as those not censored at that time point. Subjects may be censored if they are lost to fol-

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low-up, reach the last date of data collection, or suffer an outcome that precludes the outcome of interest (alternative outcome or competing risk). This assumption may not always be valid (informed censoring), and the use of censoring should be scrutinized for its statistical, clinical, and practical plausibility. For instance, when investigating the outcome of time to patient death, censoring subjects at the time of graft loss can be misleading (as patients who lose a graft are often more likely to die), while censoring at the most recent data collection date may often be considered reasonable. Most reports from the national registries present 1-, 5-, and 10-year actuarial survival rates. These survival rates may be reported without adjustment or as being adjusted for age, gender, and ESRD diagnosis. This adjustment using multivariate techniques accounts for differences in baseline characteristics of subjects included in the analysis that may otherwise confound the results. Given the considerable variability that exists in graft failure times, another relevant ­measure is the median graft survival, commonly referred to as the allograft halflife. This is ­distinct from the conditioned half-life, which is defined as the time to loss of 50% of allografts among those who have already survived the first year after transplantation [6] This parameter has been advocated as being one that largely measures ­factors impacting graft survival after the first year  posttransplantation into the long-term [6]. Survival of the allograft following transplantation may be reported as cumulative graft survival or its reciprocal, cumulative graft loss depending on the context. When the death of a patient is counted as a graft loss event, such an analysis is reported as overall graft loss (or survival). Another endpoint that is used in transplantation is death with a functioning graft. The three most important causes of death with a functioning transplant are heart disease, infection, and malignancy [1]. As more elderly patients receive a kidney transplant, death with a functioning kidney transplant is assuming an increasingly prominent position as a cause of late allograft loss. The immunosuppressed state that is inevitable with transplantation and the toxicities of individual immunosuppressive medications interact with

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7  Outcomes of Kidney and Pancreas Transplantation Table 7.1  Assumptions and key features of Kaplan-Meier and proportional hazard models

• Survival analysis models time to the event of interest. All possible events may not have occurred by the end of the observation period; the only information available about some subjects is that they were free of the event of interest at the time of last follow-up (censoring assumption). However, if the probability that a subject is censored is related to the probability of that subject suffering an event, then the application of censoring may be inappropriate (noninformative censoring). • A common descriptor of the survivorship of a cohort is the hazard function, which is commonly interpreted as the event rate at a particular point in time, conditional on surviving to that point in time. • There are different types of survival models, which also are based on varying levels of assumptions. KaplanMeier plots do not require any distributional assumptions. Cox proportional hazard models do not specify a form for the underlying hazard, but assume a proportional multiplicative effect of treatments, and are also referred to as a semiparametric model. • Differences in survival between two groups can be compared by using a variety of tests. For Kaplan-Meier plots, Log-rank and Wilcoxon tests are most commonly utilized. The relative hazard describes the ratio of time to outcome given a particular risk factor, to time to outcome when the risk factor is not present. • Cox Regression (Proportional hazard model) is a multivariate method that allows an analysis of the relative contribution of numerous explanatory variables and/or potential confounders to the variable of interest, time to event. Cox models assume that the relative hazard between groups does not change with time. Cox regression models can include multiple covariates but assume that the impact of these covariates do not change over time (proportional hazards assumption).

recipient factors and the ambient level of allograft function in modifying the expression of each of the principal etiologic factors mediating the ultimate outcome of death with a functioning allograft. Death with a functioning allograft would, in a teleological sense, reflect success of transplantation. When the death of the patient with a functioning allograft at the time of death is not counted as a graft loss event, the analysis is reported as death-censored graft loss (survival). This parameter allows the statistical analysis of factors that predominantly affect the rate of attrition of allograft function independent of factors that mediate mortality. If there is an increased risk of patient death (this mortality risk experienced by the recipient independent of the risk of graft loss, such as that observed in the elderly), the systemic toxicity of a drug regimen or ­cardiovascular mortality with preserved graft function will manifest as increased overall graft loss and relatively preserved death-censored graft loss. However, estimates of rates of deathcensored graft loss may be influenced in a biased manner by risk factors that influence both patient death and attrition of graft function. As an ­example, diabetes mellitus and hypertension are risk factors for both patient death and renal insufficiency, through synergistic effects that

enhance the development of or the progression of ­cardiovascular disease. Conventionally, graft survival is assessed under two distinct-time phases: early and late. Loss of the allograft in the first 12 posttransplant months is termed early graft loss, and late graft loss refers to grafts lost after the first 12 posttransplant months. This differentiation is not arbitrary, as the causes of graft loss in the early and late posttransplantation periods and potentially addressable mechanisms are different [7]. Graft loss in the first 12 posttransplant months is usually dominated by technical failures (thrombosis), primary nonfunction recipient death, or severe rejection. After 12 months posttransplant, the rate of graft loss is lower and remains remarkably stable over time [6]. The dominant causes underlying late allograft loss in the current era include but are not limited to chronic rejection, interstitial fibrosis and tubular atrophy not otherwise specified (IF/TA NOS, formerly designated chronic allograft nephropathy [CAN]) [8], calcineurin inhibitor (CNI) nephrotoxicity, recurrent disease, and patient death. The predominant causes of patient mortality, in turn, are cardiovascular, infectious, and neoplastic death. The various factors that impact graft and patient survival after the first posttransplant year are summarized in Table 7.2 [7].

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158 Table 7.2  Causes of kidney transplant failure Death with function Failure of the transplant kidney Chronic allograft nephropathy (chronic transplant glomerulopathy 5%) Recurrent or de novo disease (including BK virus nephropathy: 1–10%) Miscellaneous and mixed picture (unknown, multifactorial, end-stage renal disease from medical illness) Technical and thrombosis Outright rejection

40–45% 55–60% 30% 10% 10%

The better the function of the transplanted kidney (as reflected by serum creatinine), the lower the cardiovascular mortality [10]. One likely mechanism underlying the survival advantage of transplantation and its close relationship to the level of allograft function is that the cardiovascular morbidity and mortality that afflicts the ESRD population is largely reduced considerably by successful transplantation [11].

2% 5%

Transplantation Confers a Durable Survival Advantage Over Dialysis Transplantation is no longer considered a mere lifestyle choice over remaining on dialysis and is accepted as conferring a durable survival benefit over dialysis [9]. That said, the comparison of survival experiences between transplanted and dialyzed patients is not straightforward. This is because there is an intrinsic selection bias in only offering transplantation as an option to the fittest of the dialysis patients. In that regard, patients who have been placed on a waiting list and presumably passed the initial evaluation for viability for transplantation but not yet received a renal transplant form the next best comparison group. In their seminal study using the USRDS database Wolfe et al. showed that on average, after the first 106  days posttransplantation the relative risk of death was higher for those waitlisted patients who continued to remain on dialysis [9]. This excess risk of mortality in the first 3½ months posttransplantation likely reflected the medical and surgical risk associated with the transplant procedure per se. An important caveat is that the time to equal risk of mortality observed in this study varied widely between 5 and 673  days after transplantation (Fig.  7.1). In this study which reported up to 4  years of follow-up, transplantation, on an average, was associated with a 68% lower risk of death. The benefit of transplantation was particularly prominent in diabetics and prevailed across all patient subgroups [9].

Donor Source and Quality Transplant kidneys are derived from living related (LRD) or unrelated (LURD) donors or deceased donors (DD). Deceased donors may be further subclassified as those where donation occurs after brain death or after cardiac death (DCD) or may be obtained from extended criteria donors. DCD kidneys form an increasingly valuable addition to the deceased donor pool. DCD and non-ECD kidneys exhibit similar outcomes to SCD kidneys. In addition, donors may be classified as being expanded criteria donors (ECD) or standard criteria donors (SCD). It has been shown that this classification schema of ECD vs. non-ECD kidneys, while it has practical utility and does influences graft survival, may unfortunately be overly simplistic and there is a continuous spectrum of donor quality that impacts graft survival [12](Table 7.3).

Patient and Graft Survival in Kidney Transplantation The figures quoted in this section were obtained from the 2008 report of the SRTR pertaining to first and subsequent transplants [13]. At the end of 2006, 103,312 patients had a functioning ­kidney transplant compared with 64,779 in 1998, an increase of 59%. For single kidney transplants performed prior to 2006, 1-, 5-, and 10-year patient survival was best for recipients of living donor kidneys, intermediate for non-ECD deceased donor

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Fig. 7.1  Survival advantage conferred by transplantation Adjusted relative risk of death among 23,275 recipients of a first cadaveric transplant. The reference group was the 46,164 patients on dialysis who were on the waiting list (relative risk, 1.0). Patients in both groups had equal lengths of follow-up since placement on the waiting list.

Values were adjusted for age, sex, race, cause of end-stage renal disease, year of placement on the waiting list, geographic region, and time from first treatment for end-stage renal disease to placement on the waiting list. The points at which the risk of death and the likelihood of survival were equal in the two groups are indicated (log scale) [9]

Table 7.3  Deceased donor source and quality (From 2004 OPTN/SRTR report) Term Definition Expanded criteria donors (ECD)

Donation after cardiac death (DCD)

Standard criteria donors (SCD)

For kidney, any deceased donor over the age of 60 years; or from a donor over the age of 50 years with two of the following: a history of hypertension, a terminal serum creatinine >1.5 mg/dL, or death resulting from a cerebrovascular accident (stroke) Donation of any organ from a patient whose heart has irreversibly stopped beating. Includes donors who also qualify as ECD under the kidney definition above For kidney, a deceased donor who is neither ECD nor DCD. These donors have fewer risks associated with graft failure

recipients, and lowest for those receiving ECD kidneys (Fig.  7.2a) [13]. Unadjusted patient survival rates at 5 years were 91% for recipients of living donor kidneys, 83% for non-ECD deceased donor kidneys, and 70% for ECD kidney transplants. Kidney allograft survival followed the same pattern as that seen for recipient survival. Graft survival was best for recipients of living donor kidneys, intermediate for non-ECD transplants, and lowest for ECD transplants (Fig.  7.2b). At 5 years, the unadjusted graft survival rate was 81% for living donor, 71% for non-ECD, and 55% for ECD transplants [13]. Although kidney transplant patient survival percentages were not different when the first 5 years of the decade were compared with the second half (all, p > 0.05), there was a significant trend toward improvement in allograft survival (all, p < 0.05) [13]. It should be noted that patient survival figures are usually higher than

graft survival figures, as patients with lost grafts may return to dialysis. First transplants consistently have slightly better survival than subsequent ones, likely reflecting a better immunologic risk profile. Oneyear graft survival has improved steadily over the past 25  years [14]. The principal causes of patient death in the first year are cardiovascular disease and infection (malignancy is a much less common cause).

Patient and Graft Survival in Pancreas Transplantation The figures quoted here are derived from the 2008 SRTR Report on pancreas transplants in the USA [13]. At the end of 2007, there were

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Fig. 7.2  (a) Unadjusted 1-year (2005–2006), 5-year (2001–2006), and 10-year (1996–2006) kidney recipient (patient) survival by donor type. (b) Unadjusted 1-year (2005–2006), 5-year (2001–2006) and 10-year kidney graft survival (death is included as an event), by donor type [13]

3,836 people waiting for a solid organ pancreas transplant, 2,314 for a simultaneous pancreas kidney (SPK), 932 for a pancreas after kidney (PAK), and 590 for a pancreas transplant alone (PTA). This represented a 73% increase over the total number in 1998, pointing to a growing discrepancy between the number of candidates waitlisted for pancreas transplantation and organs available. Thus, there was an increase in waiting times for all types of pancreas candidates. The total number of patients alive with a functioning pancreas allograft increased 78%, from 5,364 in 1998 to 9,556 in 2005, but then declined slightly to 9,453 in 2006. The largest relative increases occurred in the PAK and PTA populations, both of which experienced a roughly fourfold increase. SPK recipients represented

the largest cohort of patients alive with a ­functioning pancreas allograft. Patient survival rates were similar for SPK, PAK, and PTA recipients at 1 year (ranging from 95% to 98%) and 3 years (ranging from 91% to 93%) (Fig. 7.3a). The 5- and 10-year unadjusted patient survival rates were statistically (p £ 0.05) lowest for PAK recipients at 84% and 65%, respectively, and higher for SPK (87% and 70%, respectively) and PTA recipients (89% and 73%, respectively) [13]. Among pancreas recipients, those with SPK transplants experienced the best unadjusted pancreas graft survival rates: 86% at 1  year (p = 0.08) and 53% at 10  years (p < 0.001) (Fig.  7.3b) [13]. Graft survival rates for PAK and  PTA recipients were lower than for SPK recipients, with 1-year rates of 77% and 81%,

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Fig. 7.3  (a) Unadjusted 1-, 3-, 5-, and 10-year pancreas patient survival, by transplant type. (b) Unadjusted 1-, 3-, 5and 10-year pancreas graft survival (death is included as an event) [13]

respectively, and 10-year rates of 35% and 26%, respectively [13].

Long-Term Outcomes in Renal Transplantation There has also been a steady improvement in long-term allograft survival. This largely represents increases in graft survival that accrue in higher risk patients, such as those undergoing re-transplantation [14]. When first deceased donor transplants alone are assessed, recent improvements are less impressive [15]. It should also be noted that dramatic improvements in graft survival were reported using

projected half-lives [14]. Projected survival estimates must, however, be interpreted with caution as the variability inherent to the generation of such statistical estimates can subsequently manifest as significant differences between actual outcomes and actuarial estimates thereof [15]. When projected half-lives were contrasted to actual allograft half-lives, the dramatic improvements suggested by the projections were much more modest in terms of actual outcomes [15]. Analyses of SRTR data have shown significant decreases in acute rejection rates in the first 6  months, first year and the second year after transplantation [15]. This impressive decline in acute rejection rates  did not however translate into improved long-term allograft survival. Furthermore,

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a ­disturbing statistically ­significant worsening of  death-censored graft survival was noted. Moreover, a disturbing trend was noted in the clinical behavior of the acute rejection episodes. A greater proportion of acute rejection episodes were associated with a lack of restoration of renal function to prerejection stable baseline values. Lack of return to baseline level of renal function after treatment of an acute rejection episode was associated with an incremental increase in the relative hazard for deathcensored graft survival [15, 16]. These findings suggest that improving long-term allograft survival is likely not just a simple matter of preventing acute rejection. It is well recognized that rejection episodes that are accompanied by return to renal function to baseline after treatment are less likely to be associated with chronic progressive renal dysfunction compared to those that do not. In an earlier study of USRDS data pertaining to the recent era in transplantation, a greater proportion of patients were noted to have more severe, treatmentresistant behavior associated with the acute rejection episodes and that the deleterious impact of an acute rejection episode on longterm allograft survival has increased in recent times [17]. The teleological explanation that can be offered to explain the phenomena ­highlighted is that the more potent immunosuppression in use in transplantation in the ­current era probably selects out the expression of more severe episodes of acute rejection while ­suppressing the more treatment-­ responsive rejections noted under less potent ­immunosuppressive regimens of the past. There have also been ­significant increases in recipient ­comorbidity, decrease in donor quality (increasing ­numbers of older donors), and the ­disturbing rise in emerging pathogens with impact on graft ­survival such as polyoma virus infections that accompany increased intensity of immunosuppression. Taken together, the foregoing discussion ­suggests that the earliest paradigm that directed clinical transplantation, i.e., early immunologic success translates to preserved long-term outcome, is probably altogether too simplistic.

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Beyond the first posttransplantation year, the principal causes of renal allograft loss are patient death and chronic progressive fibrosis of the allograft, formerly termed chronic allograft nephropathy (CAN) and now termed interstitial fibrosis/tubular atrophy not otherwise specified (IF/TA/NOS). Less common causes are late acute rejection and recurrent disease [18]. Chronic allograft nephropathy is now eschewed as being too nonspecific a term that often (and likely erroneously) encompasses chronic damage due to ischemia, rejection, and calcineurin inhibitor (CNI) toxicity. Observational studies have attributed fibrotic and vascular changes in allografts to calcineurin inhibitor nephrotoxicity [19]. However, establishment of a specific and independent causal relationship between CNI and histologic lesions observed in an observational study is not a straightforward matter in the absence of a suitable calcineurin inhibitor-free control group, without strict morphologic criteria, no information on alloantibody effects, a high background rate of subclinical rejections, and the fact that such observations were made on recipients of bladder-drained pancreas kidney transplant recipients who are salt depleted and prone to reflux [20]. A recent study using ­pathologic data and precise diagnostic classifications from the Mayo Clinic points out that alloimmune causes still underlie the majority of cases with chronic fibrosis of the allograft as opposed to a nonspecific fibrotic process [21]. Increasingly, BK viremia and BK virusassociated nephropathy (BKVAN) are being recognized as contributors to attrition of graft function with more potent immunosuppression [22]. Perceptions regarding the increasing complexity of chronic allograft dysfunction are reflected in recent iterations of pathologic ­classification schema pertaining to allografts which advocate the use of more precise histo­ pa­thologic definitions and recommend against ­universal adoption of the more nonspecific ­designation, CAN [8]. Overall, the predominant cause of death after 1 year posttransplantation remains cardiovas­cular disease, followed by infection and malignancy.

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In  children, however, death is a much less ­common cause of graft loss; conversely, in the elderly, as can be expected, it is more common.

risk factor although its exact contributions to the pathogenesis and maintenance of DGF are difficult to assess due to inaccurate reporting. Early single-center reports suggested that the negative impact of DGF on graft survival could be explained in part by a high incidence of acute rejection in cases with DGF [24]. Analyses of USRDS and UNOS data showed that DGF was independently associated with significant reductions in both long- and short-term graft survival [25, 26]. Whereas large databases provide data pertaining to graft survival in large numbers of patients, they are unfortunately lacking in the detailed patient level data that is the inherent advantage of a wellperformed albeit small single-center study. In one such study, DGF’s adverse effects on graft survival were suggested as largely explicable by inferior renal function at 1  year [27]. ECD and DCD kidneys are more susceptible to DGF. Increasing cold ischemia time is associated with increased likelihood of DGF with DCD kidneys. In an ana­ lysis of SRTR data, pulsatile machine perfusion of allografts (compared with static cold-preservation) was associated with better utilization of ECD organs, lower DGF rates, and slight improvement in death-censored graft survival [28]. In a recently published randomized clinical trial comparing machine perfusion with static cold preservation, machine perfusion was associated with a lower incidence of DGF, faster decline in creatinine, decreased duration of DGF, and better allograft survival at 1 year posttransplantation [29]. Overall, the impact of DGF on graft survival remains a controversial area and will likely evolve with advances in immunosuppression and organ preservation. This area is of immense ­clinical importance and will likely gain ­additional prominence with the larger numbers of ECD and DCD transplants that are being ­performed each year.

Factors Affecting Renal Allograft Survival Myriad factors impact renal allograft survival and they mediate their effects on allograft ­outcome in a complex fashion. However, for purposes of discussion, these can be conveniently broken down as (1) donor factors, (2) recipient factors, and (3) donor-recipient interactions. From the perspective of clinical management and targeting therapeutic interventions, another convenient way of ­discussing these factors is as alloimmune or nonalloimmune factors.

Donor–Recipient Factors Delayed Graft Function Both donor and recipient factors are associated with it. Delayed graft function (DGF) is generally defined as failure of the renal allograft to function immediately posttransplantation, with the need for one or more dialysis sessions in the first posttransplantation week. DGF affects approximately 20% of cadaveric transplants. Slow graft function (SGF) defines moderate early-graft dysfunction, as reflected in a plasma creatinine greater than 3.0  mg/dL (264  mmol/L) and no dialysis within 1 week of transplantation [23]. The main risk factors for DGF that are identifiable in the clinical setting include donor age and/or comorbidity (ECD status), cold ischemia time, and warm ischemia time. DGF and SGF likely reflect the dynamic interplay of varying contributions of paren­chymal pathology (e.g., advanced donor age, donor history of hypertension) and peritransplantation injury (e.g., ischemia-reperfusion as a consequence of agonal events or during procurement followed by reperfusion) or injury from coldpreservation of the allograft (preservation injury) [23]. Warm ischemia time is also an important

HLA Matching As a general theme, even with currently used potent immunosuppression, better HLA ­matching translates to superior allograft survival. This is

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the fundamental basis for the operation of national and international sharing systems for zero-mismatched renal allografts, even though this practice prolongs cold ischemia times and increases DGF rate. With improved immunosuppression available today, HLA matching has taken on less significance. Notably, excellent results have been noted in living donor transplants using unrelated donors where HLA mismatch is more the rule than the exception. However, it is clear from registry data that the fewer HLA mismatches, the better the long-term graft survival. This holds particularly true for a donor-recipient pairs with zero mismatches [30]. The effect of HLA matching is not merely one of decreased acute rejection, as the effect of HLA mismatches persists after correcting for acute rejection in multivariate analyses. Certain studies have found a particularly negative effect of mismatch at the DR locus [31]. This relationship of HLA matching and long-term graft survival is one of the strongest lines of evidence for an immunologic basis of chronic attrition of allograft function [32]. The effect of HLA matching is much less pronounced in living donor recipients. It should also be noted that kidneys from unrelated donors and spouses have excellent outcomes that are independent of the degree of HLA matching [33]. The possible reason underlying this effect is that the transplantation surgery itself is asso­ ciated with minimal ischemic injury; such injury  likely increases the immunogenicity of allografts.

Waiting Time and Preemptive Transplantation An analysis of the USRDS data showed that increasing waiting times for a transplant (on dialysis) adversely impacted both graft and patient survival for the primary endpoints of death with functioning graft and death-censored graft loss. A longer waiting time on dialysis emerged as a significant risk factor for both death-censored graft survival and patient death

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with functioning graft after renal transplantation (p < 0.001 for each). Relative to preemptive transplants, increasing waiting times incrementally increased both mortality risk and risk for death-censored graft survival after transplantation [34]. In a retrospective cohort study that included 8,481 patients, preemptive transplantation was associated with a 52% reduction in the relative hazard for graft failure in the first year after ­transplantation [35]. These risk reductions were 82% in the second year posttransplantation and 86% in the subsequent year compared with transplantation occurring after the start of ­dialysis. Interestingly, increasing duration on dialysis prior to transplantation significantly increased the relative odds for acute rejection within the first 6 months posttransplantation [35]. Paired kidney studies offer a useful method to minimize confounding by donor related factors. In a paired kidney study involving 2,405 pairs of kidneys, each kidney of the pair was transplanted into recipients with differing times on ESRD [36]. Six antigen-matched kidneys were excluded from this study as a disproportionate number of these kidneys, through a national sharing program in the USA were transplanted preemptively, bypassing the waiting time requirement. Five- and 10-year unadjusted graft survival and death censored graft survival were significantly inferior in those subjects with more than 24  months of dialysis time versus those who incurred less than 6 months on dialysis (Fig. 7.4). These trends remained significant after adjustment for multiple significant confounders that influence waiting time such as high panel reactive antibody, advanced recipient age, and African-American race. Indeed, part of the advantage of living-donor compared with deceased-donor transplantation may be explained by the effect of waiting time on outcome. This effect of waiting time is dominant enough that a recipient of a deceased donor kidney with an ESRD time less than 6 months may be expected to obtain graft survival roughly equivalent to that availed by living donor transplant recipients who wait for their transplant on dialysis for more than 2 years [36].

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Fig. 7.4  Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes [36]

Whereas the exact mechanisms underlying the deleterious effects of pretransplant waiting time on posttransplant outcomes are not entirely elucidated, it has been shown that alloreactivity is higher with increasing waiting time; an effect more pronounced in African-Americans [37]. In summary, increasing time accrued with ESRD is a strong independent risk factor that adversely affects both graft and patient survival in a dose-dependent fashion. Importantly, this risk factor is potentially the most modifiable in the practical clinical setting and underscores the need to refer all patients with ESRD for transplantation in a timely manner, efficient listing of candidates so identified and the adoption of preemptive transplantation before the start of dialysis wherever possible.

Center Effect Transplant outcomes can be expected to vary across centers. This variability is reflects varying combinations of levels of expertise in the centers, the patient population that they serve, their geographic location and proximity to the patients’ residence, the socioeconomic milieu in

that region, in addition to the statistical ­variability inherent to any measure of interest. The mortality experience in the transplant candidate pool (waitlist mortality) is the single biggest correlate of mortality after transplantation [38]. It is thus possible that centers whose waitlist mortality is low either through selective listing of such candidates or through other socioeconomic or geographic factors may be expected to have better posttransplant mortality statistics. It has been shown that centers with longest waiting times also have lower graft survival rates. Past performance and donor quality also significantly impact survival and have been noted to be independent of center volume. Center effects may contribute up to a 4-year difference in life expectancy. It is gratifying to note that at least in the United States, centers with characteristics associated with good outcomes were distributed more or less uniformly across the country [39].

Year of Transplant (Era Effects) Long-term allograft survival is slowly increasing particularly among deceased donor transplants. This gain in transplant survival presumably

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reflects multiple factors, including more effective but not significantly more toxic immunosuppressive regimens, better understanding in the use of immunosuppression, better pre- and posttransplantation general medical care, and more effective prevention and treatment of opportunistic infections (particularly CMV infection). That said, it should also be noted that the negative impact on acute rejection episodes on graft survival has increased in recent years, likely reflecting selection pressure that allows the emergence of more treatment-resistant acute rejections with potent immunosuppression [17]. As noted previously, long-term graft survival has not improved in a manner that would be expected based on progressive reductions in acute rejection rates over the same time period (see the following) [16].

k­ idneys of higher quality, the absence of brain death, the general benefits of elective as opposed to semiemergency surgery, avoidance of ischemia-reperfusion injury, higher nephron mass transplanted, and probably the effects of a shorter waiting time (see previous discussion). In particular, the living donor transplant can be timed in such a way that the recipient is in the optimal physiologic state at the time of transplantation [33]. An unmeasured effect attributable to better social support, compliance, and emotional state and a greater sense of obligation to maintain medical compliance may mediate some of the salutary advantages of living donation. It should be noted however that in recent years the age of the living donors as well as the waitlisted candidates have continued to increase, and interactions between these two trends will likely impact living donor transplant outcomes in the future.

Donor Factors As can be expected, the quality of the kidney immediately prior to transplantation has a major impact on long-term graft function. The various donor factors that impact renal allograft outcomes are discussed below.

Donor Source: Deceased Versus Living Donor The donor source is one of the most important predictors of short- and long-term graft outcomes. In general, living donor grafts are associated with superior outcomes to deceased donor grafts. Not only does a living donor kidney contribute to superior long-term graft survival, there also appears to be mortality benefit that is not fully understood associated with a live donor source as compared to a deceased donor kidney. The advantage of living donor kidneys holds equally true for spousal and unrelated donors and appears to be in large part non-immunologically mediated (at least non-HLA mediated) [18, 33]. The better outcomes with living donors reflect several factors: healthy living donors with

Donor Age Deceased donor and living donor allografts from those aged older than 50 years, and particularly older than 65 years, have poorer outcomes. These results are thought to reflect a higher incidence of DGF and of “nephron underdosing.” Grafts from older donors have fewer functioning nephrons because of the involutive changes associating with the aging process and the age-related accumulation of conditions such as hypertension and atherosclerosis. However, because of the organ donor shortage relative to the growing waitlist, more organs from elderly donors are being used. The older the donor kidney (above the age of 18), the shorter the expected graft life [40]. This effect persists after correction for recipient characteristics, which could produce similar effects. The likely reason underlying this poorer outcome with increasing donor age is the limited functional reserve of the older kidney along with the progressive accumulation of agerelated involutive changes that could further impair the kidney’s ability to adapt to injurious stressors. It has also been hypothesized that the  older kidney itself may be on a path to

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p­ rogrammed senescence post transplantation which would be most manifest in an older donor kidney [41]. The effects of donor age interact with those of recipient age, and we discuss these in the section on recipient age in this chapter. Deceased donor age younger than 5 years is also associated with poorer outcomes, which likely reflects higher rates of technical complications and possibly nephron underdosing relative to the metabolic demand of the recipient (see later discussion). Transplantation of pediatric kidneys en bloc (in which the graft consists of both kidneys with a segment of aorta and inferior vena cava) from donors aged 0–5 has been associated with excellent survival rates [42].

females have smaller renal mass (proximal tubule mass) than males. It is controversial as to whether there may be difference in the antigenic repertoire between female and male kidneys. It is noteworthy that the donor gender effect was not observed in the pre-CNI era and that this effect may reflect differential susceptibility of the female donor kidney to CNI toxicity [46].

Cold Ischemia Time Prolonged cold ischemia times are associated with incrementally higher risk of DGF and poorer allograft survival particularly when cold ischemia times exceed 24 h (also see discussion on delayed graft function) [18, 43].

Donor Race In the United States, the survival of deceased donor grafts obtained from African Americans is poorer than grafts from Caucasians. The exact reasons that underlie this finding remain unclear. Facile attribution of this effect to “nephron underdosing” may be overly simplistic as it is controversial as to whether or not AfricanAmericans truly have a decreased number of nephrons compared to Caucasians [44].

Donor Gender There is evidence that grafts from deceased female donors have slightly poorer survival, particularly in male recipients [45]. This probably reflects “nephron underdosing” (see later discussion), as

Donor Nephron Mass An imbalance between the metabolic/excretory demands of the recipient and the functional transplant mass has been postulated to play a causative role in the development and progression of chronic attrition of allograft function. “Nephron underdosing,” a possible consequence of perioperative ischemic damage and postoperative nephrotoxic drugs, may lead to hyperfiltration and eventual failure, similar to the mechanisms postulated to mediate progression of native kidney disease. Thus, kidneys from small donors transplanted into recipients of large body surface area or large body mass index (BMI) would be at highest risk of this problem [47]. There is limited support for this hypothesis from animal studies and retrospective human studies. In a relatively small, single-center study, higher transplant kidney volumes in living donor transplantation correlated with better allograft function [48]. Consistent long-term data from prospective studies of optimal matching of kidney allograft size to recipient body size are, however, unavailable.

Expanded Criteria Donors As the discrepancy between the number of patients awaiting kidney transplantation and the number of available organs increases, there is increasing use of expanded criteria donor (ECD) allografts. ECD allografts have poorer survival than ideal deceased donor allografts as the definition of an ECD allograft are associated with an

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estimated adjusted relative risk of failure of greater than 1.7 compared to the reference group of ideal donors [49]. The clinical criteria used to define ECD are shown in Fig.  7.2. Survival of ECD kidneys is, on average, shorter than regular deceased donor kidneys, as the baseline level of function of these kidneys is likely to be lower and, second, ECD kidneys tend to be preferentially transplanted into older recipients who have higher rates of posttransplantation death. In a study of 122,175 patients on the UNOS transplant waitlist between 1992 and 1997, the effect of an ECD transplant on survival of recipients was examined relative to those who remained on the waitlist [50]. On an average, the ECD recipient lived 5  years longer than the waitlisted patient whereas the recipient of an ideal cadaveric kidney accrued a 13-year survival benefit. Diabetics obtained the greatest proportional survival benefit and those with hypertensive renal disease incurred the greatest absolute gains in life-years. Transplantation of an ECD kidney did not increase mortality risk in any subgroup examined. UNOS has implemented policies that allow consenting patients to opt for both an ECD kidney and the ideal kidney. Those patients who decline listing for an ECD kidney could potentially incur the increased mortality associated with increased durations of waiting time on dialysis. It is conceivable that the younger non-diabetic waitlisted patient could wait longer on the list than an older diabetic recipient who would gain the mortality benefit conferred by transplantation [51]. It should be emphasized that transplantation with an ECD kidney confers a significant survival advantage compared to remaining on the waitlist. Furthermore, this survival benefit from the ECD transplant can be expected to be proportionately greater in regions with historically higher waiting times [50]. Other nontraditional donors are non-heartbeating donors, where the organs are procured after cardiac death (donation after cardiac death; DCD). Rates of DGF and primary nonfunction are generally higher with DCD donors than with standard donors [52]. There is accumulating evidence, however, that long-term graft survival with DCD is similar to heart-beating deceased donors, although this is likely reflective of ­careful

selection criteria and renal function may be slightly inferior at discharge immediately after transplantation [53].

Recipient Factors Recipient Age In general, graft survival rates are poorer in those at the extremes of age: younger than 17 and older than 65 years [2]. In the young, technical causes of graft loss such as vessel thrombosis, aggressive rejection and noncompliance with immunologic graft loss are relatively more common. Conversely, death with a functioning graft is relatively rare in the young. In most Western countries, the elderly (those older than 65 years) are forming an increasing percentage of the incident and prevalent end-stage renal disease (ESRD) population. Many of these patients have significant comorbidities particularly cardiovascular disease and type 2 diabetes mellitus. Despite these significant limitations, age per se is no longer regarded a contraindication to transplantation as transplantation does confer a survival advantage in the well-screened elderly ESRD recipient [9]. It should be noted, however, that it is critical to consider the effect of increasing waiting times on mortality in the elderly patient with ESRD and their suitability for transplantation at the time that the waitlisted elderly candidate is actually offered a transplant. A recent study using SRTR data showed that more than half of waitlisted patients above the age of 60 now placed on the waiting list are expected to die before receiving a renal transplant [54]. This underscores the importance of stratifying transplant options for the waitlisted population based on age and comorbid burden. While rejection is relatively infrequent in the elderly, return to baseline function after treatment of acute rejection episodes may be suboptimal. Death with functioning graft is expectedly more common with increasing recipient age. However death-censored graft loss also worsens with increasing age. In a study, compared to the age group of 18–49 years, the recipient aged 50–64

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accrued a 29% higher relative risk of graft loss while those 65 years or greater incurred a 67% higher relative risk for graft loss [55]. This effect of increasing age on incrementally increasing the risk for death- censored graft loss was independent of traditional determinants of graft survival such as DGF and acute rejection. These effects also were independent of the type of immunosuppressive regimen employed. While rejection is relatively infrequent in the elderly, return to baseline function after treatment of acute rejection episodes may be suboptimal. Both increasing donor and recipient age were independent risk factors for graft survival. The best graft survival was obtained in the situation where a kidney from a young donor was transplanted into a young recipient and the worst graft survival obtained when kidneys from older donors were transplanted into older donors [56]. It thus appears that the combination of advanced donor and recipient age has a synergistic detrimental impact on graft survival. Whether this reflects the dynamic interplay of an intrinsically senescent kidney transplanted into a senescent biologic milieu is unclear. Death rates due to infection increase linearly with increasing recipient age in waitlisted elderly ESRD patients [57]. In the transplanted elderly patient, infectious mortality rises exponentially [57]. Overall mortality and cardiovascular mortality rise with increasing age in both the transplanted and waitlisted elderly [57]. However, the magnitude of this increased mortality is not greater in transplanted patients [57]. The slope for cardiovascular mortality is halved with successful transplantation in the elderly [57]. Malignancy-related death is increased in elderly transplanted patients perhaps reflecting the additive effects of pharmacologic immunosuppression to the effects of senescence on the immune system [57]. Teleologic constructs based on expectation of decreased infection and malignancy in elderly recipients with decreased levels of immunosuppression, while at the same time retaining the ability to maintain freedom from acute rejection, may be overly simplistic, as we do not have at this point in time a reliable measure of the delivery of immunosuppression in the clinic.

Recipient Race From the early days of transplantation, AfricanAmerican patients experienced inferior graft and patient survival rates. Explanations have included heightened rejection risk, differing HLApolymorphisms between the black recipient and the predominantly white donor pool, differing pharmacokinetics of immunosuppressants, hypertension, noncompliance, and socioeconomic status. However, the difference between African-Americans and Caucasians is becoming narrower with newer immunosuppressive regimens and perhaps differential dosing of the agents (see section on immunosuppressants) [58, 59]. Despite the need for increasing immunosuppression to maintain freedom from acute rejection, African-American transplant patients are at decreased risk for infectious death. This represents a potential modifiable factor wherein increased immunosuppression may be delivered relatively safely to confer protection against ejection risk and possibly obviate some of the racial differences in graft survival that were seen in the past. Deceased donor transplant outcomes are inferior to living donor transplant outcomes in African-Americans. Outcomes after living donor transplants are superior to deceased donor transplants in African-Americans [60]. Living donationisrelativelyunderutilizedinAfrican-Americans and represents a potential target for intervention to improve transplant outcomes. Socioeconomic factors associated with inability to pay for transplant medications (an issue particularly resonant in the United States where universal health coverage does not exist), poorer access to high-quality medical care, and noncompliance may also play a role.

Recipient Gender SRTR data consistently demonstrate better graft survival in male recipients as compared to female recipients of living donor kidneys [61]. An important difference between female and male transplantation candidates is the higher degree of sensitization of the former to HLA antigens and

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possibly non-HLA antigens due to pregnancy and transfusions related to anemia that likely reflects menstrual blood loss and pregnancy related blood losses. In the aggregate, female recipients are at greater risk for acute rejection but show lower rates of progressive attrition of graft function [62].

Recipient Sensitization: Before or after Transplantation Patients who are broadly sensitized (e.g., panel reactive antibody [PRA] status >50%) at the time of transplantation generally have poorer early and late graft survival compared to non-sensitized recipients [18]. This decrement in survival is mainly related to an increased incidence of complications in the early posttransplantation period such as DGF and acute rejection. The most important reasons for sensitization are previous transplants, pregnancy, and previous blood transfusions. Highly sensitized patients are often given more intensive immunosuppression to reduce the risk of rejection, but this also exposes them to infectious and neoplastic risk. The donor-specific alloimmune response is increasingly recognized as the predominant contributor to chronic attrition of graft function and ultimately graft loss [32]. Recent reports suggest that conditioning regimens incorporating apheresis and depleting antibodies or intravenous immunoglobulin can permit transplantation of highly sensitized individuals [63]. However, long term outcomes of such transplants are still in debate.

Acute Rejection Acute rejection is the single greatest risk factor for chronic rejection and graft loss. While acute rejection rates are decreasing the association of acute rejection and chronic allograft failure is increasing over the last 10 years [17]. The histological grade of rejection, severity of renal

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functional impairment at the time of diagnosed rejection, timing of rejection episode, and completeness of response to antirejection treatment have all been shown to have prognostic significance. As a broad generalization, acute rejection episodes that are accompanied by a return of allograft function to prerejection baseline levels are associated with little impact on longterm allograft survival [18]. Humoral rejection is typically more difficult to reverse and is felt to prejudice long-term graft survival to a greater extent than cell-mediated rejections [18]

Recipient Hepatitis C Virus Antibody and Hepatitis B Virus Surface Antigen Positivity Recipients who are hepatitis C virus (HCV) antibody positive at the time of transplantation incur inferior allograft and patient survival to those who are HCV negative. Higher mortality rates in this population are attributed mainly to infection and worsening liver disease [64]. Despite these limitations, transplantation of selected HCVpositive patients confers a survival benefit over remaining on the waiting list [65, 66]. The adverse effects of hepatitis B virus (HBV) surface antigen positivity on posttransplantation outcomes are much less pronounced in recent years. This trend may in part reflect the availability and increasing utilization of effective anti-HBV therapies in transplant recipients in recent years.

Recipient Immunosuppression The improvements accrued in recent years in short- and long-term allograft survival reflect, in part, the effectiveness of the newer antirejection drugs such as the calcineurin inhibitors (CNIs) and mycophenolate mofetil. The independent and specific contribution of long-term CNI therapy, particularly in the context of currently utilized concentration targets, to chronic progressive nonimmunologic noninfective renal allograft dysfunction (and loss) remains controversial.

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Observational studies based on protocol biopsy data have been widely cited as evidence of contribution of CNI toxicity to attrition of allograft function and ultimately graft loss. However, these assumptions, inferences, and correlations should be considered in light of the enduring fact that the durable increases in short- and long-term graft survival in the CNI era (cyclosporine and then tacrolimus; in combination first with azathioprine [AZA] and later on with mycophenolate mofetil [MMF]) suggest that immunologic protection in the form of freedom from acute rejection conferred by CNIs far override their nephrotoxic effects [20]. The choice as to which CNI to employ in a regimen is largely a matter of differential systemic toxicities of the agents and center preference. CNIs are commonly used in combination with an antiproliferative agent (AZA, MMF, or sirolimus [SRL]). Each of the three Phase III trials of MMF in renal transplantation clearly established the superiority of MMF over the control group azathioprine (AZA) or placebo for the primary endpoint of acute rejection [67]. However, the registration trials for MMF were not adequately powered to allow analysis of differences in other measures of clinical interest such as graft and patient survival. The impact of MMF on long-term graft loss in kidney transplantation was addressed in a USRDS database analysis [68]. Four-year death censored graft loss was significantly better with MMF as opposed to AZA (85.6% vs 81.9%), and 4-year patient survival with MMF was significantly superior to that with AZA (91.4% vs 89.8, p = 0.002). These effects of MMF were independent of acute rejection (AR) [69]. African-American patients experienced a more striking reduction in 6 month acute rejection rates with MMF (20.5%) versus AZA (32.8%) [58]. MMF therapy was associated with clinically important and significant risk reductions in death with functioning graft, death-censored graft loss, and chronic allograft failure, particularly in African-Americans. Importantly, the beneficial effects of MMF on acute rejection and graft loss were not accompanied by an increase in the risk of death with a functioning graft implying a superior therapeutic index with AZA [58].

Subsequent analyses of USRDS and SRTR data have shown that MMF is associated with fewer episodes of late AR and greater stability of graft function as compared to AZA. The effects on preventing late AR are particularly prominent in African-Americans and may account in part for the superior graft survival observed in that population with MMF [69–71].

Tacrolimus in Combination with MMF In recent years, cyclosporine has been largely replaced in most centers by Tacrolimus [72]. This shift reflects a gradual change in practice patterns based on empiric observations and expectation of lesser magnitude of nephrotoxicity with Tacrolimus that preceded actual published results of formal studies evaluating this combination [73].

MMF Compared to Sirolimus in Cyclosporine-Based Regimens In an analysis of SRTR data, the regimen combining cyclosporine and sirolimus was associated with significantly lower graft survival (74.6% vs 79.3% at 4  years, p = 0.002) and death-censored graft survival (83.7% vs 87.2%, p = 0.003) compared to cyclosporine and MMF. In multivariate analyses, the cyclosporine-sirolimus combination was associated with a significantly increased risk for graft loss, death-censored graft loss, and decline in renal function (HR = 1.22, p = 0.002; HR = 1.22, p = 0.018; and HR = 1.25, p < 0.001, respectively). Furthermore, regimens combining MMF with cyclosporine or tacrolimus were associated with better serial creatinine clearances than regimens combining sirolimus with cyclosporine (also see the following). It should also be noted that while sirolimus was initially approved for use with cyclosporine, concerns of the nephrotoxicity of this regimen have prompted a gradual shift away from this combination toward its use with Tacrolimus or MMF.

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MMF Versus Sirolimus with Tacrolimus The perception of the lower nephrotoxicity of tacrolimus along with the renal function concerns about the cyclosporine–sirolimus combination led to increasing use of tacrolimus in combination with Sirolimus [74, 75]. Analysis of SRTR data showed that recipients treated with tacrolimus and MMF exhibit better graft survival than those receiving cyclosporine and MMF or tacrolimus with sirolimus [76]. A statistically and clinically significant difference was demonstrated between the tacrolimus and sirolimus regimen versus the tacrolimus and MMF arms at 3 years after transplantation (Tacrolimus + Rapamycin, 80.3% vs Tacrolimus + MMF, 85.9%, p < 0.001). This difference in graft survival was similar in magnitude to the previously shown difference  between Cyclosporine + Rapamycin and Cyclosporine + MMF, in both the univariate analysis and the multivariate analysis in consonance with the results of a prospective study [77, 78]. MMF with Sirolimus There has been increasing interest in avoiding the use of calcineurin inhibitors (CNI) in kidney transplantation in order to avoid their nephrotoxic effects. Excellent short term results have been reported by single centers when sirolimus was used in combination with MMF and corticosteroids in kidney transplantation [79, 80]. In an analysis of SRTR data pertaining to the sirolimus (SRL) and mycophenolate mofetil (MMF) combination regimen (SRL/MMF) in solitary kidney transplant recipients, 6  month acute rejection rates were higher with SRL/ MMF (SRL/MMF:16.0% vs other regimens:11.2%, p < 0.001). Overall graft survival was significantly lower on SRL/MMF. SRL/MMF was associated with twice the hazard for graft loss (AHR = 2.0, 95% C.I. 1.8, 2.2) relative to TAC/ MMF (Fig. 7.5). Similar results were noted on the on-treatment analyses and across all patient subgroups [81]. These findings based on retrospective data were corroborated by the Symphony study wherein standard-dose CsA

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based ­regimens were ­compared to low-dose CsA, TAC, or SRL in combination with MMF, daclizumab, and corticosteroids in renal transplantation [82]. In the reported 1-year results of this study, biopsy-proven acute rejection at 6 months in SRL/MMF patients was 33% versus 11% with TAC/MMF (p < 0.01) and 22% with CsA/MMF. With regard to allograft function, calculated glomerular filtration rate was 57.3 mL/min with SRL/MMF versus 65.4 mL/ min with TAC/MMF (p < 0.0001). Last, 1-year graft survival was significantly inferior in SRL/ MMF patients (TAC/MMF: 94%; SRL/MMF: 89%; p = 0.017) [82].

Corticosteroid Avoidance Regimens Corticosteroid avoidance regimens are increasingly being used in renal transplantation with 23% of first renal transplants in 2004 being discharged after transplantation without steroids as opposed to 5% in 2000 [72]. This trend is driven largely by the desire of both physicians and patients to avoid or minimize the burden of metabolic, bariatric, osseous, cosmetic, ocular, and neuropsychiatric side effects of corticosteroids. Until recently, these corticosteroid avoidance regimens were largely driven by non-randomized large, single-center experiences [83]. In a recent randomized clinical trial that compared corticosteroid avoidance and tacrolimus and MMF maintenance immunosuppression with tacrolimus, MMF, and low-dose corticosteroids, rejection rates and biopsy evidence of chronic allograft fibrosis were significantly higher with steroid evidence [84]. Weight gain was slightly higher at 5  years with steroid avoidance (approximately 2 kg higher) and lipid profiles similar at 1 year. Insulin-requiring new onset diabetes after transplantation was higher with steroid maintenance [84]. Accruing follow-up data from single-center studies show that patients developing acute rejections on steroid avoidance regimens fare better with regard to freedom from subsequent rejections if maintained on steroids after the first rejection episode [85].

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Overall Graft Survival (%)

100

90

80 Regimen

70

60

50

(1) TAC / MMF

73.8%

(2) CsA/ MMF

71.8%

(3) CsA/ SRL

68.9%

(4) TAC / SRL

67.6%

(5) SRL / MMF

57.7%

0

1 2 3 4

5-Year Graft Survival

12

5

24

36

48

60

Months post-transplant

TAC = Tacrolimus MMF = Mycophenolate mofetil SRL = Sirolimus CsA = Cyclosporine microemulsion

Fig.  7.5  Overall graft survival by immunosuppressant regimen for deceased donor transplant recipients [81]TAC Tacrolimus, MMF Mycophenolate mofetil, SRL Sirolimus, CsA Cyclosporine microemulsion

A recent registry analysis suggested that s­ teroid avoidance regimens in the United States carried no significant risk of graft loss [86]. However, this study did not report details on acute rejection episodes and subsequent use of corticosteroid maintenance and effects thereof on graft survival [86]. In the absence of such analyses, the results reported may reflect a selection bias where such regimens were employed in patients at lowest immunologic risk and underestimate possible detrimental effects on allograft survival of acute rejection episodes. Although antilymphocyte antibody preparations (e.g., antithymocyte globulin or interleukin-2 receptor blockers) are widely used, particularly in the setting of DGF and decreased acute rejection rates, their effects on long-term graft survival have not been well studied [87]. Depleting anti T-cell antibodies have been associated with increased risk of neoplasia and opportunistic infection [88]. Antithymocyte globulin use has been shown in registry studies as a risk factor for BK viremia [22].

Recipient Compliance Poor compliance with the immunosuppressive regimen is known to increase the risk of acute rejection, particularly late acute rejection, and chronic allograft dysfunction. The exact magnitude of this problem is difficult to define. In a study of patients followed up to 5  years after transplantation, almost a quarter of the patients were identified as being noncompliant based on direct questioning regarding missing medication doses, and this was associated with a large increase in risk of late acute rejection and of higher serum creatinine [89].

Obesity Obesity (body mass index; BMI >30  kg/m2) ­constitutes an important risk factor for cardiovascular disease, hypertension and diabetes mellitus in the general population. Obesity may also

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predispose to progressive renal insufficiency as it has been accompanied by the development of proteinuria and focal and segmental glomerulosclerosis, both of which are attributed to hyperfiltration in the obese. Obese dialysis patients may have a survival advantage. In the transplanted population, obese patients have been shown to be at increased risk for death. The effects of obesity (BMI) on long term graft and patient survival were examined in a study of 51,927 patients reported to the USRDS between 1988 and 1997 [90]. Increased mortality was noted at extremes (both low and high) of BMI [90]. This U-shaped relationship resembles that seen in the general population and also describes the relationship between obesity and cardiovascular and infectious mortality. Furthermore, increasing BMI was associated with worsening death-censored graft survival [91]. Transplantation does confer a survival advantage to the obese dialysis patient. This survival advantage holds true for both living donor and cadaveric transplantation [92]. However, weight loss among renal transplant candidates prior to the procedure did not impact transplant outcomes, based on a retrospective study [93].

Hypertension in the Recipient Increasingly, severe posttransplant hypertension is associated with increased risk of graft loss, and control of hypertension is associated with improved allograft survival [94]. Unfortunately, these data are derived from retrospective studies, which by themselves cannot establish a causal relationship between hypertension and graft loss. At this time, no prospective human studies studying the effect of treating hypertension on renal allograft outcomes are available. Based on extrapolations from studies in nontransplant populations, optimal treatment of hypertension is a reasonable goal to treat its effects on progression of renal dysfunction and the extrarenal complications associated with hypertension. Of note, posttransplant hypertension may represent the effects of calcineurin inhibitors (CNI),

whose effects on blood pressure are mediated by activation of the renin–angiotensin and sympathetic systems. Animal studies also show the salutary effects on CNI nephrotoxicity of RAS blockade with angiotensin receptor blockers (ARB) [95]. Small clinical studies have shown beneficial effects of ACEI on progressive renal dysfunction after transplantation [96]. A prospective trial of ACE-inhibition in renal transplantation has been initiated in Canada (see following text) [97].

Recipient Dyslipidemia Chronic progressive attrition of allograft function is associated with fibrointimal hyperplasia in the arterioles of the graft; a lesion morphologically reminiscent of atherosclerosis. Treatment of hyperlipidemia in the renal transplant recipient thus represents a reasonable target. The ALERT trial randomized renal transplant recipients to fluvastatin or placebo. In the ALERT trial, fluvastatin treatment was associated with slight decreases in cardiac death and nonfatal myocardial infarction without effects on progressive renal dysfunction or graft loss [98]. In a retrospective study, statin use was associated with decreased risk of patient mortality but without any effects on graft survival [99]. As with treatment of hypertension, the use of lipid-lowering treatment after transplantation is based on evidence that largely represents extension of experiences from nontransplant populations (see following text).

Recurrence of Primary Disease in the Allograft Determining the incidence and prevalence of recurrent or de novo renal disease is not straightforward. The original cause of ESRD is often listed as being unknown in both single center and large databases and most published studies are small retrospective studies with variable

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f­ ollow-up length and prone to reporting bias. In one of the best performed studies of transplant recipients whose cause of ESRD was glomerulonephritis, the cumulative incidence of graft loss at 10 years was 8.4%. In that population, recurrence of glomerulonephritis was the most important cause of graft loss, after chronic rejection and death [100]. It is likely that as renal allograft survival improves with decreasing acute rejection rates, recurrent or de  novo disease will become a more important cause of late graft loss, especially given the current trend of minimizing immunosuppression. Recurrent disease in renal allografts is discussed further in Chap. 8 on evaluation of the kidney transplant recipient.

from directly to practice should not ­necessarily be expected to translate automatically into outcomes, assuming a causal relationship. The clinician thus faces the challenge of distilling all the evidence available from diverse sources in the care of the individual patient. These limitations stated, we offer some broad general recommendations for practice based on outcomes data available to date. Minimization of waiting time on dialysis or avoiding it altogether with preemptive transplantation is associated with the best outcomes. Early referral to transplantation to patients with chronic kidney disease appears to be the best practice that can help optimize transplant outcomes. In addition to planning for dialysis access, priority should be placed on identifying suitable living donors, if available and appropriate in the transplant recipient. In the elderly recipient, careful attention must be directed to functional status, comorbidity, social support and rehabilitation in the ­evaluation process. As noted previously, transplantation carries a survival benefit. However, the time when this benefit outweighs the risks of transplantation is highly variable. The challenge that faces the transplant physician evaluating the elderly recipient is to identify that candidate who will accrue benefit from transplantation and not suffer mortality or a morbid event either while waiting for the transplant or immediately thereafter. Given the excess mortality incurred among the elderly on the waitlist, identification of suitable living donors and consideration of methods to minimize waiting time such as sel­ ective listing for ECD transplants and dual ­marginal kidneys may be options to minimize waiting time and accrue the survival advantage of transplantation. Waitlisted elderly patients should be reevaluated yearly with focus on ­cardiovascular, infectious, neoplastic, and ­functional-cognitive domains, to ensure continuing candidacy. The continuing challenge for the transplant community is to balance equity, justice, and access so that the elderly transplant recipient receives an organ whose expected ­survival is optimal for the expected lifespan of the candidate.

Proteinuria The degree of proteinuria correlates with poorer renal outcome in both native and transplant kidney disease [101]. Proteinuria may simply be a marker of renal damage, but there is speculation that proteinuria per se may accelerate allograft loss in addition to other pathogenetic factors. The role of ACE inhibitors and ARBs in slowing the progression of proteinuric transplant renal diseases is extrapolated from non-transplant studies.

Applying Outcomes Data in Practice As discussed above, outcomes data are derived from clinical trials or observational studies involving hundreds to thousands of patients. These studies yield estimates of outcomes that have an inherent variability and relate most closely to the types of patients included in the studies. In practice, one deals with individual patients. As such, utilization of outcomes data which were obtained in the aggregate for prognostication in the individual patient carries an up-front built-in element of imprecision. Furthermore, observational studies can only show associations and application of data derived there

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Fig. 7.6  Cardiovascular death is associated with increasing levels of renal insufficiency after transplantation [10]

Living donation is associated with better transplant outcomes than is observed with deceased donors. This benefit is particularly prominent in African-Americans who have otherwise inferior outcome with cadaveric transplantation than Caucasians. Thus, every effort must be made within appropriate ethical constraints to identify suitable living donors for every transplant candidate. In the case of the pancreas transplant recipient, SPK transplants have the best pancreas graft survival. This may represent the fact that the kidney affords an opportunity to monitor for rejection as the pancreas is more difficult to biopsy. Many Type 1 diabetics who have living donors may accrue the benefit of that transplant and list for a PAK transplant rather than go through a waiting period. The value of pancreas transplant alone has been called into question by one study [102]. It is advisable that such transplants be performed in candidates who undergo careful screening for indications. PAK transplant outcomes are inferior in those subjects with impaired renal allograft function at the time of pancreas transplant. This may relate to the fact that such subjects may not tolerate

full doses of CNI that are used in the early posttransplant period. An additional issue may relate to the net state of immunosuppression and the occurrence of opportunistic infections. These issues are discussed further in the chapter on pancreas recipient selection and preparation. Maintenance of cardiovascular health in the transplant recipient is predicated on the level of renal function that is maintained. Increasing levels of renal insufficiency are associated with increasing cardiovascular mortality (Fig.  7.6) [10]. As such, selection of regimens that allow optimal graft survival (predicated on durable maintenance of function) appears to be the key factor that helps maintain freedom from cardiovascular mortality posttransplantation. In addition to posttransplant screening for cardiovascular health, adjunctive measures such as control of blood pressure, lipids, obesity, and glycemia based on extrapolations from nontransplant populations is recommended at this time. The growing body of evidence suggests that RAS blockade mitigates hypertension and progressive allograft dysfunction. This strategy is being tested in appropriately powered clinical trials.

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The type of immunosuppressive regimen used affects graft survival. To date the best long-term allograft survival has been observed with triple therapy utilizing a calcineurin inhibitor, MMF, and corticosteroids. While CNI sparing regimens have been advocated and have shown promise in single center studies, their widespread applicability in ensuring acceptable graft survival is questionable based on both registry studies and prospective clinical trials. Corticosteroid avoidance regimens should be considered with caution in view of the higher rates of acute rejection observed in recently published clinical trials. In the context of corticosteroid avoidance, it is noteworthy that the relative negative impact of a single acute rejection episode on allograft survival is far greater than that of posttransplant diabetes mellitus. It should also be kept in mind that results from both clinical trials and observational studies represent estimates that apply most closely to the types of patients included, the era of the study, the duration of follow-up, and the particular combinations of drug(s) utilized in the study period. Importantly, registry studies lack detail on drug dose and concentration and most importantly the criteria used to select regimens for particular patients; all of which are important in making valid inferences from the results. The physician translating the use of these studies to the care of the individual patient should keep such limitations in mind. In conclusion, outcomes data pertaining to renal transplants are influenced by practice and can also be used to guide practice. Given the limitations in our understanding of the dynamic of continually evolving complexity of relationships between risk factors, treatments, practice, and outcomes, the transplant physician must use all current sources of information on outcomes to make suitable decisions in the individual patient.

2. United States Renal Data System: 2008 Annual Report. 2008, Available from: www.usrds.org 3. United Network for Organ Sharing: 2008 Annual Report. 2008. 4. Available from www.ctstransplant.org 5. Kaplan B, Schold J, Meier-Kriesche HU. Overview of large database analysis in renal transplantation. Am J Transplant 2003;3(9):1052–1056. 6. Opelz G, Mickey MR, Terasaki PI. Calculations on long-term graft and patient survival in human kidney transplantation. Transplant Proc 1977;9(1):27–30. 7. Halloran PF, Gourishankar S, Vongwiwatan, A, Weir MR. Approaching the renal transplant patient with deteriorating function: Progressive loss of function is not inevitable. In: Weir MR (ed.). Medical Management of Kidney Transplantation. Philadelphia: Lippincott, Williams & Wilkins, 2005: 389–402. 8. Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et  al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8(4):753–760. 9. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et  al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. NEJM 1999;341(23):1725–1730. 10. Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation 2003;75(8):1291–1295. 11. Meier-Kriesche HU, Schold JD, Srinivas TR, Reed A, Kaplan B. Kidney transplantation halts cardiovascular disease progression in patients with end-stage renal disease. Am J Transplant 2004;4(10):1662–1668. 12. Schold JD, Kaplan B, Baliga RS, Meier-Kriesche HU. The broad spectrum of quality in deceased donor kidneys. Am J Transplant 2005;5(4 Pt 1):757–765. 13. McCullough KP, Keith DS, Meyer KH, Stock PG, Brayman KL, Leichtman AB. Kidney and pancreas transplantation in the United States, 1998–2007: access for patients with diabetes and end-stage renal disease. Am J Transplant 2009;9(4 Pt 2):894–906. 14. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. NEJM 2000;342(9):605–612. 15. Meier-Kriesche HU, Schold JD, Kaplan B. Longterm renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004;4(8): 1289–1295. 16. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004; 4(3):378–383. 17. Meier-Kriesche HU, Ojo AO, Hanson JA, Cibrik DM, Punch JD, Leichtman AB, et  al. Increased impact of acute rejection on chronic allograft failure in recent era. Transplantation 2000;70(7):1098–1100.

References 1. Scientific Registry of Renal Transplant Recipients: 2008 Annual Report. 2008, Available from: http:// www.ustransplant.org

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T.R. Srinivas et al. 33. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. NEJM 1995;333(6): 333–336. 34. Meier-Kriesche HU, Port FK, Ojo AO, Rudich SM, Hanson JA, Cibrik DM, et al. Effect of waiting time on renal transplant outcome. Kidney Int 2000; 58(3):1311–1317. 35. 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(10):726–731. 36. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis. Transplantation 2002;74(10):1377–1381. 37. Augustine JJ, Poggio ED, Clemente M, Aeder MI, Bodziak KA, Schulak JA, et  al. Hemodialysis vintage, black ethnicity, and pretransplantation antidonor cellular immunity in kidney transplant recipients. J Am Soc Nephrol 2007;18(5):1602–1606. 38. Schold JD, Srinivas TR, Howard RJ, Jamieson IR, Meier-Kriesche HU. The association of candidate mortality rates with kidney transplant outcomes and center performance evaluations. Transplantation 2008;85(1):1–6. 39. Schold JD, Harman JS, Chumbler NR, Duncan RP, Meier-Kriesche HU. The pivotal impact of center characteristics on survival of candidates listed for deceased donor kidney transplantation. Med Care 2009;47(2):146–153. 40. Takemoto S, Terasaki PI. Donor age and recipient age. Clin Transplant 1988:345–356. 41. Halloran PF, Melk A, Barth C. Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol 1999;10(1):167–181. 42. Dharnidharka VR, Stevens G, Howard RJ. En-bloc kidney transplantation in the United States: an analysis of united network of organ sharing (UNOS) data from 1987 to 2003. Am J Transplant 2005;5(6): 1513–1517. 43. Salahudeen AK, Haider N, May W. Cold ischemia and the reduced long-term survival of cadaveric renal allografts. Kidney Int 2004;65(2):713–718. 44. Hughson M, Farris AB, 3rd, Douglas-Denton R, Hoy WE, Bertram JF. Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int 2003;63(6):2113–2122. 45. Zeier M, Dohler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13(10):2570–2576. 46. Neugarten J, Srinivas T, Tellis V, Silbiger S, Greenstein S. The effect of donor gender on renal allograft survival. J Am Soc Nephrol 1996;7(2):318–324. 47. Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992;3(2):162–169. 48. Poggio ED, Hila S, Stephany B, Fatica R, Krishnamurthi V, del Bosque C, et al. Donor kidney

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volume and outcomes following live donor kidney transplantation. Am J Transplant 2006;6(3):616–624. 49. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM. Expanded criteria donors for kidney transplantation. Am J Transplant 2003;3(Suppl 4):114–125. 50. Ojo AO, Hanson JA, Meier-Kriesche H, Okechukwu CN, Wolfe RA, Leichtman AB, et  al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001;12(3):589–597. 51. Merion RM, Ashby VB, Wolfe RA, Distant DA, Hulbert-Shearon TE, Metzger RA, et  al. Deceaseddonor characteristics and the survival benefit of kidney transplantation. JAMA 2005;294(21):2726–2733. 52. Cho YW, Terasaki PI, Cecka JM, Gjertson DW. Transplantation of kidneys from donors whose hearts have stopped beating. NEJM 1998;338(4):221–225. 53. Cooper JT, Chin LT, Krieger NR, Fernandez LA, Foley DP, Becker YT, et  al. Donation after cardiac death: the University of Wisconsin experience with renal transplantation. Am J Transplant 2004;4(9):1490–1494. 54. Schold J, Srinivas TR, Sehgal AR, Meier-Kriesche HU. Half of kidney transplant candidates who are older than 60 years now placed on the waiting list will die before receiving a deceased-donor transplant. Clin J Am Soc Nephrol 2009;4(7):1239–1245. 55. Meier-Kriesche HU, Ojo AO, Cibrik DM, Hanson JA, Leichtman AB, Magee JC, et  al. Relationship of recipient age and development of chronic allograft failure. Transplantation 2000;70(2):306–310. 56. Meier-Kriesche HU, Cibrik DM, Ojo AO, Hanson JA, Magee JC, Rudich SM, et  al. Interaction between donor and recipient age in determining the risk of chronic renal allograft failure. J Am Geriatr Soc 2002;50(1):14–17. 57. Meier-Kriesche HU, Ojo AO, Hanson JA, Kaplan B. Exponentially increased risk of infectious death in older renal transplant recipients. Kidney Int 2001;59(4):1539–1543. 58. Meier-Kriesche HU, Ojo AO, Leichtman AB, Punch JD, Hanson JA, Cibrik DM, et  al. Effect of mycophenolate mofetil on long-term outcomes in African American renal transplant recipients. J Am Soc Nephrol 2000;11(12):2366–2370. 59. Neylan JF. Effect of race and immunosuppression in renal transplantation: three-year survival results from a US multicenter, randomized trial. FK506 Kidney Transplant Study Group. Transplant Proc 1998;30(4): 1355–1358. 60. Light JA, Barhyte DY, Lahman L. Kidney transplants in African Americans and non-African Americans: equivalent outcomes with living but not deceased donors. Transplant Proc 2005;37(2):699–700. 61. Kayler LK, Rasmussen CS, Dykstra DM, Ojo AO, Port FK, Wolfe RA, et al. Gender imbalance and outcomes in living donor renal transplantation in the United States. Am J Transplant 2003;3(4):452–458. 62. Meier-Kriesche HU, Ojo AO, Leavey SF, Hanson JA, Leichtman AB, Magee JC, et al. Gender differences

in the risk for chronic renal allograft failure. Transplantation 2001;71(3):429–432. 63. Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, et  al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. NEJM 2008;359(3):242–251. 64. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Dulai G. Hepatitis C virus antibody status and survival after renal transplantation: meta-analysis of observational studies. Am J Transplant 2005;5(6):1452–1461. 65. Pereira BJ, Natov SN, Bouthot BA, Murthy BV, Ruthazer R, Schmid CH, et al. Effects of hepatitis C infection and renal transplantation on survival in ­end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1998; 53(5):1374–1381. 66. Meier-Kriesche HU, Ojo AO, Hanson JA, Kaplan B. Hepatitis C antibody status and outcomes in renal transplant recipients. Transplantation 2001;72(2):241–244. 67. Srinivas TR, Kaplan B, Schold JD, Meier-Kriesche HU. The impact of mycophenolate mofetil on longterm outcomes in kidney transplantation. Transplan­ tation 2005;80(2 Suppl):S211–220. 68. Meier-Kriesche H, Ojo AO, Arndorfer JA, Magee JC, Cibrik DM, Leichtman AB, et  al. Mycophenolate mofetil decreases the risk for chronic renal allograft failure. Transplant Proc 2001;33(1–2):1005–1006. 69. Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman AB, Cibrik D, Magee JC, et  al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000;69(11):2405–2409. 70. Meier-Kriesche HU, Steffen BJ, Hochberg AM, Gordon RD, Liebman MN, Morris, JA, et al. Longterm use of mycophenolate mofetil is associated with a reduction in the incidence and risk of late rejection. Am J Transplant 2003;3(1):68–73. 71. Meier-Kriesche HU, Steffen BJ, Hochberg AM, Gordon RD, Liebman MN, Morris JA, et  al. Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration. Transplantation 2003;75(8):1341–1346. 72. Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML, et  al. Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant 2006;6(5 Pt 2):1111–1131. 73. Gonwa T, Mendez R, Yang HC, Weinstein S, Jensik S, Steinberg S. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6  months. Transplantation 2003;75(8):1213–1220. 74. MacDonald AS. Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas, and kidney transplantation. Transplant Proc 2003;35(3 Suppl):201S–208S. 75. Formica RN, Jr., Lorber KM, Friedman AL, Bia MJ, Lakkis F, Smith JD, et al. Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation. Transplant Proc 2003;35(3 Suppl):95S–98S.

180 76. Meier-Kriesche HU, Schold JD, Srinivas TR, Howard RJ, Fujita S, Kaplan B. Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus. Am J Transplant 2005;5(9):2273–2280. 77. Meier-Kriesche HU, Steffen BJ, Chu AH, Loveland JJ, Gordon RD, Morris JA, et al. Sirolimus with Neoral versus mycophenolate mofetil with Neoral is associated with decreased renal allograft survival. Am J Transplant 2004;4(12):2058–2066. 78. Mendez R, Gonwa T, Yang HC, Weinstein S, Jensik S, Steinberg S. A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year. Transplantation 2005;80(3):303–309. 79. Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 2002;74(8):1070–1076. 80. Larson TS, Dean PG, Stegall MD, Griffin MD, Textor SC, Schwab TR, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 2006;6(3):514–522. 81. Srinivas TR, Schold JD, Guerra G, Eagan A, Bucci CM, Meier-Kriesche HU. Mycophenolate mofetil/sirolimus compared to other common immunosuppressive regimens in kidney transplantation. Am J Transplant 2007;7(3):586–594. 82. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. NEJM 2007;357(25):2562–2575. 83. Matas AJ, Kandaswamy R, Gillingham KJ, McHugh L, Ibrahim H, Kasiske B, et al. Prednisone-free maintenance immunosuppression-a 5-year experience. Am J Transplant 2005;5(10):2473–2478. 84. Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7  day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008;248(4):564–577. 85. Humar A, Gillingham K, Kandaswamy R, Payne W, Matas A. Steroid avoidance regimens: a comparison of outcomes with maintenance steroids versus continued steroid avoidance in recipients having an acute rejection episode. Am J Transplant 2007;7(8):1948–1953. 86. Luan FL, Steffick DE, Gadegbeku C, Norman SP, Wolfe R, Ojo AO. Graft and patient survival in kidney transplant recipients selected for de novo steroid-free maintenance immunosuppression. Am J Transplant 2009;9(1):160–168.

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t­ransplantation, relationship to allograft histology and survival. Am J Transplant 2007;7(12):2748–2756. 102. Venstrom JM, McBride MA, Rother KI, Hirshberg B, Orchard TJ, Harlan DM. Survival after pancreas transplantation in patients with diabetes and ­preserved kidney function. JAMA 2003;290(21): 2817–2823.

Chapter 8

Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate Richard A. Fatica, Stuart M. Flechner, and Titte R. Srinivas

Keywords  Kidney transplant • Pretransplant evaluation • Pretransplant risk stratification

Introduction Kidney transplantation is the modality of choice for management of end-stage renal disease (ESRD). Successful transplantation is more than a lifestyle choice for the ESRD patient; it offers patients a durable survival advantage over maintenance hemodialysis. The risk of mortality on the waitlist is halved by successful transplantation [1]. Health related quality of life measures are also substantially improved compared to wait listed patients [2]. Transplantation involves upfront risks to mortality stemming from a major surgical procedure in a recipient with medical and surgical comorbidity that is compounded by pharmacologic immunosuppression. As such, the transplant evaluation must be carried out by a dedicated multidisciplinary team of skilled medical professionals with specific training and experience in the field. The importance of such an approach is underscored by the fact that transplant centers are mandated to staff their centers with such teams in order to maintain accreditation [3]. The major domains in which patients are

T.R. Srinivas (*) Nephrology and Hypertension, Glickman Urologic and Kidney Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]

evaluated for a kidney transplant are (1) Medical, (2) Surgical, (3) Psychosocial, and (4) Financial. Specific input from ancillary consultants such as specialists in bioethics or psychiatry may be sought. The complexities of this process are underscored by the fact that both age and comorbid burden of the waitlisted patient are increasing progressively in the US [3, 4]. This chapter details the evaluation of the adult patient with advanced kidney disease or ESRD being considered for kidney transplantation.

Who Is a Kidney Transplant Candidate? There is no strict cutoff level of estimated GFR when referral for kidney transplant should be made. As a general guideline, the patient with advancing chronic kidney disease (CKD), with a glomerular filtration rate (GFR) estimate or measurement approaching 20 mL/min should be referred for transplant evaluation as an integral part of their medical management. Ideally, thought should be given to transplant referral when the prospective candidate is at NKF Stage 4 CKD, i.e., estimated GFR less than 30  mL/ min or is anticipated to progress to ESRD within the next 2  years. Diabetics have both a more rapid progression to ESRD and acceleration of vascular disease on dialysis and should be referred for transplantation earlier in the course of their renal disease to minimize the lead time to transplantation.

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_8, © Springer Science+Business Media, LLC 2011

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Preemptive Transplantation is Preferable When Feasible It is no longer considered appropriate to wait until a patient is on dialysis to initiate the transplant process, as preemptive transplantation confers a definite survival advantage over waiting on dialysis. In most situations preemptive transplantation prior to initiation of dialysis, has been shown to have a better outcome. Waiting time on dialysis has a dose-dependent deleterious effect on graft survival. Relative to preemptive transplants, increasing waiting times are associated with incrementally increased mortality risk and risk for death-censored graft survival after transplantation [4, 5]. Duration on dialysis prior to transplantation is also significantly associated with increased rejection risk post-transplant [5]. Alloreactivity is higher with increasing waiting time, an effect more pronounced in AfricanAmericans [6]. The previous discussion underscores the need to refer all patients with ESRD for transplantation in a timely manner, keep an efficient listing of candidates so identified, conduct a diligent search for suitable living donors, and adopt preemptive transplantation before the start of dialysis wherever possible. It is important that access planning for dialysis not be delayed if there are uncertainties about the time frame wherein successful living donation will occur. There are some exceptions to this. Patients with active lupus nephritis or other active systemic vasculitides may have a higher risk of recurrent disease in the allograft and may be advised to wait until quiescence, usually 6–12 months after initiation of dialysis.

Who Is Not Eligible for a Transplant? Every patient with chronic kidney disease should be regarded as a transplant candidate unless demonstrable otherwise. Situations that are ­considered absolute contraindications to transplantation are outlined in Table 8.1. In addition, some kidney diseases may be associated with

R.A. Fatica et al. Table  8.1  Indications and contraindications to kidney transplantation Indications: Advancing CKD with estimated GFR approaching 20 mL/min and Projected survival of ³5 years irrespective of kidney disease Contraindications: Reversible renal disease Active or recent malignancy (or metastatic) Active or recent untreated infection Severe irreversible extrarenal disease Severe functional disability with limited rehabilitation potential Unmodifiable nonadherence to treatment Psychiatric illness: not remitting with treatment and could affect consent and/or adherence Active current recreational drug use Prohibitively high risk of recurrence of native kidney disease

either an unacceptably high rate of recurrence such as membranoproliferative glomerulonephritis (MPGN) type 2 such that transplantation might not be advisable, or solitary kidney transplant is not advisable without other interventions such as combining liver and kidney transplantation for primary hyperoxaluria. Apart from the foregoing considerations, there is considerable variability from program to program as to which patient is accepted as a transplant candidate and which one is denied. The following examples illustrate this variability. Some transplant programs have strict upper limits of age that determine eligibility. Others have cutoffs for the upper limit of an acceptable body mass index (BMI). Most transplant programs are also considering smoking as a contraindication to kidney transplantation, as more evidence is accumulating that smoking may be associated with risk of accelerated loss of allograft function, compromised patient survival and perhaps acute rejection [7]. The majority of transplant programs advise candidates to quit smoking and require strict validation of cessation. Others are more liberal. Transplant programs are facing a progressively older and more complex patient being referred for evaluation. The clinical challenge in deciding on candidacy stems from the fact that there is a considerable

8  Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate

degree in overlap of risk factors for graft failure and patient death among candidates who are listed vs. not listed for a kidney transplant [8]. Conditions thought to be barriers to transplantation in the past such as advanced liver or heart disease, HIV infection, and hematologic malignancy are now being offered kidney or combined organ transplantation at selected centers or in the context of investigational studies. As a generalization, as age advances, so does the accumulated comorbidity. Despite the obvious limitations to life span posed by age and the incremental risk of infection and malignancy with immunosuppression, transplantation carries a survival benefit [9]. Mere chronologic age does not predict functional status or burden of comorbidity. As such, we submit that there is not an upper limit cutoff for age that determines eligibility (also see the following). In general, patients who are denied eligibility for transplantation after being evaluated are usually older with a prohibitive degree of comorbidity or have other financial or psychosocial factors that preclude transplantation. Unfortunately, despite the mandatory requirement for referral to transplantation for all patients receiving maintenance hemodialysis in the USA, a number of them do get lost in the complexity of the evaluation process and providers of dialysis and transplant centers need to exercise all due diligence in minimizing the incidence of such occurrences. The mandatory process of referral of a transplant candidate also allows a process of appeal whereby a candidate denied eligibility can ask for a second opinion if they are unsatisfied by the decision of the transplant center.

Referral for Transplantation It is very important that patients be referred early for transplantation for many reasons, not the least of which is to minimize waiting time (as discussed above). A major challenge to achieving this goal is the fact that referral to a nephrologist often occurs very late in the course of chronic renal disease in the United States.

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Based on the framework of the current United Network for Organ Sharing (UNOS) deceased donor ­kidney allocation algorithm in the United States, patients may begin to accrue points on the deceased donor transplant waiting list when the estimated GFR is 20  mL/min or lower. Unfortunately, fewer than 1 in 20 patients on the waiting list get offered a cadaveric kidney preemptively through the national zero mismatch kidney-sharing algorithm. The rest, depending on the region of the country, may be destined to wait for years before receiving a kidney offer. Perhaps the single greatest advantage of early referral to transplantation is that it allows the transplant physician and the patient an opportunity to explore suitable living-donor options that could translate into the superior outcomes associated with preemptive transplantation.

Process of Evaluation The major components of the transplant evaluation process are presented in Table 8.2.

Education and Consent Transplant candidates and their caregivers cope with the disease process, dialysis regimen, vicissitudes of life, and our ever more complex healthcare system with a tremendous degree of fortitude. This fortitude is borne of hope and an enduring faith in the medical system and the success of transplantation. Therefore, transplant programs must structure their evaluation process in such a manner that it is not centered on the delivery of a paternalistic, categorical eligible– not eligible verdict at the end of the evaluation process. Instead, the transplant evaluation must be a fruitful, interactive, respectful dialogue among the patient, caregivers, relatives, relevant social support circle, and the transplant team. This dialogue is centered on two central facets: Education and Consent.

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186 Table  8.2  Suggested elements of patient education during transplant candidate evaluation   1. Surgical Episode: Nature of the operation, surgical risks, medical and surgical complications, expected length of stay, risks and side effects of medication, return to work dates, expected functional improvement   2. Transplant Modalities: Relative benefits of living vs. deceased donor transplant and type of deceased donor kidney (ECD vs. SCD, DCD, centers for disease control (CDC) High risk, etc.)   3. Waiting Time: Discuss relative impact of deceased donor kidney choice on waiting time. Provide reasonable estimates of expected waiting time. Explain pros and cons of listing at multiple centers. Explain the cadaver kidney allocation process. 4. Immunologic Risk: Explain the process of establishing histocompatibility and measuring sensitization for cadaveric and living donation, nature of immunosuppression, risks of immunosuppression (infection, malignancy, side effects), rates of rejection, and types of regimens used at the center   5. Expected Outcomes: Patient and graft survival statistics and rejection rates for the transplant center; and explain in the context of national statistics   6. Donor Quality: Particularly applicable in the context of cadaveric donor transplants   7. Compliance: Emphasize need for an enduring therapeutic alliance; compliance with dialysis when waitlisted and with followup and treatment adherence post-transplant   8. Miscellaneous: Impact of transplant on functional status, fertility, employment   9. Financial: Explain costs associated with the transplant episode followup, waitlist followup, cost of immunosuppression; educate regarding assistance/fundraising 10. Psychosocial: Explain possible stressors through the process and means for coping

In the USA, the Center for Medicare and Medicaid Services mandates that a formal structured consent process be available to transplant candidates. It is important to ensure that this be treated not as a mere legal hurdle but a balanced presentation of all available options that helps the patient make an educated decision regarding his or her care.

Education The elements of the education process are ­presented in Table 8.2. The major topics covered include the transplant operation, process of ­listing, donor

options, risks posed by immunosuppression and surgery, expected outcomes and alternatives to transplantation, medication burden, and costs. This opportunity should also be used to explain the ­benefits of live-donor transplants and assess the prospects for live donation in each case. The finite life of transplants should be presented realistically and in the context of a life plan of treatment. The need to maintain compliance if waiting on dialysis cannot be overemphasized. Measures to minimize sensitization such as avoiding transfusions must be discussed. Center-specific outcomes should be made available upon request, and patients and their families must be made aware of formal educational opportunities on the subject as also sites and reliable sources where more information can be sought. In the US, information of high quality ­pertaining to transplantation is available in the public domain both in print and online formats from the American Society of Transplantation (http://www.a-s-t.org), the United Network for Organ Sharing (UNOS) (http://unos.org), and the National Kidney Foundation (http://www. kidney.org).

Consent In addition to consenting to the evaluation and listing process, candidates should be presented information on standard criteria donor kidneys (SCD) versus extended criteria donors (ECD). The definitions of these donor organs are dealt with in detail in Chap. 7. The use of ECD kidneys has the beneficial effect of shortening waiting time at the cost of foreshortened expected graft survival. The presentation of the risks and benefits associated with ECD transplants and formal documentation of the patient’s consent to receive such organs is mandatory. In general, those patients who are older than age 60 and have a lower life expectancy on ­dialysis, patients who live in a donor service area with prolonged waiting times, or those who are at high risk for death from access failure are expected to fare best with the waiting time benefits conferred by ECD kidneys. On the other

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hand, robust young individuals who are expected to have a favorable survival experience on dialysis can afford to wait for a SCD kidney [10, 11].

Medical Evaluation The prospective candidate is brought in for a comprehensive evaluation including same- day appointments with transplant nephrologists, transplant surgeons, transplant coordinators and educators, social services, financial counselors, and in selected cases psychiatrists and consultants in bioethics. All patients receive a comprehensive history; physical examination and a battery of testing, as outlined in Table 8.3; and are recommended to have age-appropriate cancer screening and vaccinations appropriate for age and ESRD. The major aims of this evaluation are to estimate the risk of posttransplant adverse events and possibly minimize the risk of such events by detection and treatment of contributing or underlying conditions whenever possible. The three major contributors to morbidity and mortality after transplantation are cardiovascular disease, infections, and malignancy. Cardiovascular Disease Cardiovascular disease is the primary contributor to mortality both in the dialysis patient and after transplantation. Despite the fact that successful transplantation reduces the risk for cardiovascular death compared to that associated with dialysis, cardiovascular death risk in transplant recipients remains elevated above that in the general population [12]. This risk for cardiovascular mortality is highest in diabetics, those with prior history of atherosclerotic heart or peripheral vascular disease, and smokers. Other issues in the ESRD patient include calcific aortic and mitral valve disease with or without stenosis, hypertrophic cardiomyopathy, and congestive heart failure engendered in part by the uremic state. These features should be sought

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Table 8.3  Pretransplant evaluation of the renal transplant candidate   1. History (a) Cause of renal disease and pre ESRD treatment especially steroids, cytotoxics and immunosuppression. Review biopsy pathology (b) Dialysis: duration, modality, access, progress (c) Previous transplants: If yes, rejections, antibody induction, complications, compliance (d) Blood Transfusions: establish sensitization (e) Allergies and Medication intolerance (f) Occupation, addiction (smoking, alcohol, other drugs), functional status, hobbies, social support (g) Recent hospitalizations (h) History of thromboembolic events   2. Review of systems   3. Past medical/surgical history including exposure to TB, travel, pets   4. Psychosocial evaluation   5. Medications: identify potential interactions with immunosuppressants and possible substitutes   6. Physical examination (a) BMI, vitals (b) Visual and auditory deficits (c) Heart murmur, evidence of heart failure (d) Lungs: signs of COPD, fluid overload (e) Abdomen: hepatomegaly, ascites, pain, herniae, organomegaly, scars, dialysis access, bruits (f) Vascular: Bruits: carotid, iliac, femoropopliteal, peripheral pulses, ischemic ulcers (g) Neurologic: Cognitive deficits, sequelae of CVAs (h) Cutaneous: Skin cancers   7. Age and gender appropriate cancer screening (colonoscopy, mammogram, pap smear, PSA)   8. Laboratory battery (a) Complete blood count, coagulation profile, chemistries including liver function panel, calcium phosphorus and PTH (b) Urinalysis and Culture: (Routine but difficult to interpret at times) (c) Infectious Disease Panel: CMV serologies, EBV serology, VZV titers, hepatitis B and C serologies, HIV antibody, PPD with anergy panel, rapid plasma reagin (RPR; syphilis) (d) Immunologic profile: Blood type (ABO), HLA typing, and panel reactive antibody (PRA)   9. 12-lead EKG and chest X ray 10. Cardiac workup (a) Assessment of exercise capacity (b) Stress test: Dobutamine stress echocardiogram, dipyridamole or adenosine stress test (c) 2-D echocardiogram with Doppler (d) Coronary angiography if needed (continued)

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188 Table 8.3  (continued) 11. Urologic workup (select patients) (a) Voiding cystourethrogram (b) Urodynamic studies (c) Cystoscopy

with diligence in the clinical evaluation and directed imaging. It is widely accepted in the transplant community that transplant candidates should have cardiac screening tests, but there is no consensus on the optimal modality and frequency of testing. Guidelines have been published previously for the evaluation of the transplant recipient [13] and the waitlisted patient [14]. Diabetics and patients with prior ischemia, as well as those with advancing age and dialysis vintage, all have higher rates of coronary events after transplantation and should be monitored annually. In general, lesions amenable to revascularization either by percutaneous technique or surgery are dealt with as such. Whether these will reduce posttransplant event rates is an unanswered question. All patients should have an EKG or echocardiogram investigating for left ventricular hypertrophy, since persistent LVH after transplant may be associated with worse patient and graft outcomes [15]. Other echocardiogram-derived parameters that correlate with posttransplant cardiovascular death include a low ejection fraction [16] and higher estimated pulmonary pressures [17]. The choice of noninvasive cardiac stress testing is largely institution dependent; however, exercise stress testing should be limited to the very functional patient who can achieve 85% of maximum predicted heart rate. Dobutamine stress echocardiograms are attractive default options in most ESRD patients, as a number of them have difficulty with ambulation. Even the dobutamine stress echo has a minimum target heart rate to adjudicate adequacy and in cases not meeting target heart rate, chemical stress or myocardial perfusion study should be done. In a review of 600 consecutive transplant recipients, Patel et al [18]. showed that cardiovascular event free survival at 42  months was 97% in patients with negative SPECT imaging, and 85% in patients with positive scans. Most centers tend to have a low

Table  8.4  Cardiac evaluation of potential kidney transplant recipient No prior history of coronary artery disease: If patient is less than 40 years of age, has two or fewer risk factors, normal ECG, and has excellent functional capacity (e.g., can climb two flights of steps quickly without stopping, jogging; or other equivalent to 6 METS or greater), proceed directly to surgery or listing. Repeat assessment based on team judgment. If patient does not qualify with all of the above, then cardiac stress testing or catheterization is required within the year prior to evaluation. Exercise or dobutamine-based testing must reach greater than 85% maximum predicted heart rate to be accepted as a valid test. If stress testing is acceptable, proceed with surgery or listing. Repeat evaluation(s) at regularly interval at discretion of evaluating team. If a positive stress test is discovered, then cardiology referral or catheterization is required to complete cardiac evaluation. Prior history of coronary disease: All patients who have a prior coronary disease history must have an acceptable stress test or cardiac catheterization available within the year prior to evaluation and listing. Repeat evaluation intervals will be at the discretion of the evaluating team, usually every 1–2 years while on the waitlist.

threshold to proceed to cardiac catheterization in diabetics and in those with known prior coronary or peripheral vascular disease if they are already on dialysis. If dialysis is impending, unless manifest symptomatology or the results of noninvasive tests dictate it, there is an understandable reluctance to resort to cardiac catheterization. The outline in Table 8.4 is in use at our institution and is presented with the caveats that there is no single best algorithm for management of cardiovascular disease in renal transplant recipients and that detection of stenotic coronary lesions and their technical revascularization is but a poor predictor of subsequent morbidity or mortality.

Pulmonary Disease The single greatest contributor to pulmonary ­disease in this population is cigarette smoking. As a general rule, in addition to a diligent search

8  Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate

for the physical signs of chronic obstructive ­pulmonary disease (COPD), pulmonary function tests (PFTs) and a review chest radiograph for signs of COPD and neoplasm are needed in smokers. If PFTs reveal evidence of airway obstruction, ancillary testing should focus on degree of hypoxemia, need for home oxygen therapy, or significant pulmonary hypertension. Hypoxia and pulmonary hypertension militate against candidacy and are associated with poor outcome after transplantation. Active smokers should be advised to quit or go through a smoking cessation program.

Cerebrovascular and Peripheral Vascular Disease Smokers also tend to have a higher incidence of carotid disease. The presence of a carotid bruit or history suggestive of transient ischemic attacks in that territory should prompt carotid sonograms. Diabetics and smokers are at obvious risk for peripheral vascular disease. In the diabetic it is important to make the distinction between neuropathic and ischemic foot ulcers. Symptoms such as claudication should be sought on history; the examination should document presence or absence of pulses and bruits in a systematic manner that can be retrieved to follow progression. Stenotic lesions impacting the lower extremity must be evaluated using pulse volume recording. Computed tomography (CT) of the abdomen is an excellent means of measuring plaque burden in the aortoiliac territory and indicating operability with regard to a site for the transplant arterial anastomosis. Patients who have had previous reconstructive vascular surgery or vascular interventions on the aortoiliac territory may present surgical challenges that are insurmountable.

Evaluation of the Abdomen and Gastrointestinal Tract The physical examination will reveal scars, burden of pannus, organomegaly, and herniae. In addition, a screening abdominal ultrasound or a

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CT scan of the abdomen is valuable to pick up asymptomatic pathology such as renal masses or complex cysts, which portend a high risk for malignancy in the ESRD patient. The presence of diverticulosis is not uncommon in the ESRD patient and is especially prominent in the patient with polycystic kidney disease. Diverticulitis should be adequately managed and cleared before transplantation, as it is one of the most common causes of abdominal pain and intraabdominal infection after transplantation. The size of polycystic kidneys on abdominal imaging may prompt removal of one or both kidneys to facilitate placement of the transplant kidney. Peptic ulcer disease should be sought by history and managed with proton pump blockade and treatment for Helicobacter pylori infection as appropriate because steroids may trigger a perforation after transplantation. Cholelithiasis should be treated with surgical means if cholecystitis is present. Some centers may decide to perform cholecystectomies on diabetics with asymptomatic gallstones. This remains a gray area.

Infections Active infections are a contraindication to transplantation that need to be appropriately treated and resolved, including surgical drainage if needed. At all times, infections are the second leading cause of death of transplant recipients, except for the very old (>75 years) when infection related mortality exceeds cardiac mortality [19]. The evaluation of the potential recipient should include a history of any rtecent infections, including severe infections such as bacterial endocarditis, dialysis-related infections such as line-associated bacteremia or peritonitis, and viral infections such as hepatitis B and C. Catheter-related infections will need to be investigated thoroughly with a review of all antimicrobial therapy, organisms, sensitivities, and imaging. In addition, potential infection risks posed by zoonoses or endemic molds by occupational or hobby exposures, pets in the home, and travel should be assessed. Since reactivation of prior viral exposures is an important cause of

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morbidity after transplantation, patients should be assessed by serology for their prior exposure to cytomegalovirus, Epstein Barr virus, polyoma virus, and Herpes simplex viruses. Such evaluations are particularly germane in the case of the patient who is coming in for a retransplant and has received immunosuppression and/or treatment of rejections with the previous transplant. A prior exposure to depleting antibody therapy should elicit a higher degree of suspicion for such infections. Similar considerations apply to  the patient with immunologic renal disease  that has received cytotoxic therapies or immunosuppression. HIV infection is no longer regarded as an absolute contraindication to transplantation. HIV infected patients on HAART who are in virologic remission by strict criteria are eligible for transplantation. Their evaluation demands expertise in both pharmacokinetics and dedicated infectious disease specialty follow-up. Appropriate vaccinations for the transplant patient include hepatitis B series, Pneumovax, annual influenza, tetanus booster, varicella in seronegative patients, and in certain situations, sexually active HPV naïve women should be counseled to receive the HPV vaccine. The urinary tract should be sterile for transplantation. Recurrent urinary tract infections require a full urologic evaluation including upper tract imaging, a voiding cystogram, cystoscopy and retrograde studies. Recipients with a prior history of tuberculous disease or exposure should receive a year of Isoniazid prophylaxis prior to transplantation. ESRD patients may be anergic to skin testing. Hepatitis C viral infection affects 3% of patients worldwide, with 1–4% of these patients developing hepatocellular carcinoma annually. Hepatitis C is the most common liver disease in  dialysis patients, with reports ranging from 10% to 40% incidence in US dialysis units, to as  much as 85% in Middle Eastern countries [20]. Outcomes of transplantation in hepatitis C-infected individuals have been variable, but survival is diminished in those with impaired liver function or cirrhosis. HCV-negative (HCV−) recipients of HCV positive (HCV+) donor kid-

neys have diminished survival compared to HCV + recipients; however HCV + recipients will still fare better with an HCV − donor [21]. Recipients who are hepatitis C virus (HCV) antibody-positive at the time of transplantation exhibit inferior allograft and patient survival to those who are HCV negative. Higher mortality rates in this population are attributed mainly to  infection and worsening liver disease [22]. Despite these limitations, transplantation of selected HCV + patients confers a survival benefit over remaining on the waiting list [23]. We discuss the workup of the HCV + recipient in the section on infectious diseases. Briefly, the workup is geared to establishing (1) histologic grading of cirrhosis if present, (2) the degree of chronic hepatitis and its amenability to treatment pre-transplant, and (3) identifying need for a simultaneous liver–kidney transplant. The adverse effects of hepatitis B virus (HBV) surface antigen positivity on posttransplantation outcomes are much less pronounced in recent years. This trend may in part reflect the availability and increasing utilization of effective anti-HBV therapies in transplant recipients in recent years. Depending on coexistent disease, pulmonary function testing, vascular imaging, or hematologic testing for hypercoagulability may be performed. The goal of such testing is not to “rule out” patients, but to risk assess the patient for adverse events or diminished survival post transplant and help the patient make an informed decision about proceeding with waitlisting and transplantation or remaining on dialysis. As awareness of functionality or frailty has increased, the association of these with the progressively aging population referred for transplantation has been reported [24].

Malignancy Renal transplant recipients are three to five times more likely to develop malignancy than the general population, with virally mediated malignancies being 5–22 times more likely [25]. Common epithelial-derived tumors such as breast and prostate appear to occur at the same rate as in the

8  Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate

general population. The overall recurrence rate of malignancy posttransplant is 21% [26], with the highest risk of recurrences occurring among symptomatic renal cell carcinomas, sarcomas, melanocytic skin cancers, bladder cancers, and multiple myeloma. The safe waiting period for transplantation after surgical removal of solid tumors varies and depends on the grade and stage of tumor on presentation and the associated risk of recurrence, but most published sources recommend a cancer-free period of 2–5 years before transplantation, as outlined in Table 8.5. Patients must be educated that immunosuppression increases the likelihood of primary and recurrent malignancy, and survival with malignancy after transplant (other than skin cancer) is poor. The transplant evaluation process is an opportune time to discuss age- and comorbid diseaseappropriate cancer screening. Substance use such as tobacco predisposes to lung, bladder, and head and neck cancer; hepatitis B and C predispose to hepatoma; and prior cyclophosphamide exposure may predispose to bladder cancer. In addition, family history of malignancy such as early breast or prostate cancer, and conditions such as familial polyposis may warrant screening tests earlier than usually indicated. More recently is has been suggested that rather than using fixed waiting times, it is more logical to use cancer recurrence nomograms to establish risk. This has been well established for localized prostate cancer, where risk for recurrence can be compared to mortality risk on dialysis to establish an individualized a­ ssessment [27]. Table  8.5  Recommended survival pretransplant a Tumor Renal Cell (Incidentally found) Renal Cell (< 5 cm) Renal Cell (> 5 cm) Prostate Invasive bladder Colorectal Breast Uterus Lung Melanoma

wait times of cancer freeWait time (years) None 2 years 5 years 2 years 2 years (none for in-situ) Clinically guided; 2–5 years Clinically guided; 2–5 years Clinically guided; 2–5 years (none for in-situ) Clinically guided; 2–5 years 5 years

 For more information see www.ipittr.org

a

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Patients who have had prior pelvic radiation may present formidable surgical challenges. Prior radiation also increases the risk of cytopenias on immunosuppression. Careful attention to choice and intensity of immunosuppression is mandated in patients with prior malignancy. If possible, depleting antibody should be avoided. The risks of progression of malignancy on immunosuppression must be discussed up front with the patient, acknowledging the uncertainties inherent to such prognostications. An excellent resource, with continuously updated information of high quality on impact of cancer on transplant candidacy, is available from the Israel Penn International Transplant Tumor Registry (http:// www.ipittr.org).

The Elderly Transplant Recipient In general, graft survival rates are poorer in those at the extremes of age (age < 17  years and >65  years). In most Western countries, the elderly (those older than 65 years) are forming an increasing percentage of the incident and prevalent end-stage renal disease (ESRD) population. Many of these patients have significant comorbidities particularly cardiovascular disease, peripheral and cerebrovascular disease and type 2 diabetes mellitus. Despite these significant limitations, age per se is no longer regarded a contraindication to transplantation, as transplantation does confer a survival advantage in the well-screened elderly ESRD recipient [1]. It should be noted, however, that it is critical to consider the effect of increasing waiting times on mortality in the elderly patient with ESRD and their suitability for transplantation at the time that the waitlisted elderly candidate is actually offered a transplant. A recent study using SRTR data showed that more than half of waitlisted patients above the age of 60 died before receiving a renal transplant [28]. This underscores the importance of stratifying transplant options for the waitlisted population based on age and comorbidity. While rejection is relatively infrequent in the  elderly, return to baseline function after

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t­reatment of acute rejection episodes may be suboptimal. Death with functioning graft is expectedly more common with increasing recipient age. Death-censored graft loss also worsens with increasing age independent of delayed graft function and acute rejection [29]. Advancing donor and recipient age impact graft survival negatively [9]. Whether this reflects the dynamic interplay of an intrinsically senescent kidney transplanted into a senescent biologic milieu is unclear. Death rates due to infection increase linearly with increasing recipient age both in waitlisted elderly ESRD patients and in those transplanted, and overall mortality and cardiovascular mortality rise with increasing age in both the transplanted and waitlisted elderly. However, the magnitude of this increased mortality is not as great in transplanted patients. Cardiovascular mortality is halved by successful transplantation in the elderly. Malignancy related death is increased in elderly transplanted patients perhaps reflecting the additive effects of pharmacologic immunosuppression to the effects of senescence on the immune system [29]. In addition to the hard endpoints that have been reported in the literature, several clinical issues need to be addressed in the individual patient. Cognitive and motor deficits must be sought and their severity quantified. Functional recovery can be slow after transplantation and the postoperative course can be complicated by delirium. Neurologic side effects of immunosuppression and medication in general are more common in the elderly. Fall risk is constant. Cancer screening should be complete. Durable social support must be identified and the necessity for such should be emphasized in no uncertain terms. Elderly patients may be more reluctant to seek living donation from a younger relative based on their own pessimism about expected survival after transplant. Likewise, relatives of such patients may be more reluctant to donate a kidney to them. The decision to transplant the elderly patient must in the end be individualized and nonjudgmental and done in a spirit of education and respect. Immunosuppression poses further complexities in decision making. Teleological constructs based on expectation of decreased

infection and malignancy in elderly recipients with decreased levels of immunosuppression while at the same time retaining the ability to maintain freedom from acute rejection may be overly simplistic, as we do not have at this point in time a reliable measure of the delivery of immunosuppression.

Financial Considerations ESRD costs as of 2007 were $24 billion, or 5.8% of the entire Medicare budget [30]. There is a cost benefit to transplantation after the first year: the cost per patient per year (PPPY) for hemodialysis is $72,064 compared to first year of transplantation of $106,373, whereas prevalent transplant patient cost PPPY is $24,572. The financial burden of transplantation is often more difficult to predict for each individual patient for several reasons: (1) the patient is more functional and theoretically able to reenter the work force, (2) Medicare covers 80% of the cost of medication for the only the first 3 years in patients not otherwise eligible for Medicare benefits, and (3) patients may incur additional costs from treatment of complications such as viral or resistant organism infections, which require expensive medication. Financial counseling should be offered to each candidate to ensure that a full understanding of the economic burden associated with transplant is achieved.

Patients with Prior Transplants There are special considerations for the patient with a previous solid organ or kidney transplant, and the history must reflect the following elements: (1) time to failure of prior allograft(s); (2) events leading to failure, i.e., immunologic, technical, thrombotic, nonadherence; (3) type of induction and maintenance immunosuppressive therapy; (4) prior infectious complications or exposures; and (5) a comprehensive review of pathologic materials. Exposure to the allograft

8  Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate

may lead to sensitization and prolonged wait time and difficulty finding a suitable living donor. In addition, prior transplantation increases total burden of immunosuppression with subsequent kidney transplant, and therefore increases the risk of long-term complications such as malignancy, especially posttransplant lymphoproliferative disease, and viral diseases. In the multiple kidney transplant recipient, unique surgical challenges may exist with vascular anastomoses and need for nephrectomy.

Coagulopathy Dialysis patients have unique coagulation system abnormalities, with impaired platelet function most commonly secondary to deficient adhesion and spreading. Patients who frequently clot their arteriovenous fistula (AVF), however, have been shown to have increased platelet aggregation and thrombogenic glycoprotein profile [31]. In addition, the balance between prothrombotic and fibrinolytic systems is disrupted in ESRD patients and may vary depending on modality of dialysis. Common laboratory abnormalities in the dialysis patient are shown in Table  8.6. The candidate who has experienced frequent AV access thromboses, or otherwise unexplained deep venous thromboses, should undergo a hypercoagulability evaluation. A pretransplant finding of a traditi­ onal laboratory abnormality for hypercoagulability (protein C and S deficiency, antiphospholipid, Table 8.6  Alterations in coagulation measurements in dialysis patients Hemodialysis: Hyperfibrinogenemia Enhanced factor VII, VIII, vWF activity Low AT-III Low protein C, S activity Low factor II, IX, X, XII activity Increased antiphospholipid Abs Peritoneal dialysis: Hyperfibrinogenemia Enhanced factor II, VII, VIII, IX, X, XII activity High protein S concentration Normal protein C, and AT-III concentrations

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or factor V Leiden to name a few) should undergo perioperative anticoagulation under the auspices of a professional in PVD and anticoagulation.

The Highly Sensitized Patient Approximately 40% of waitlisted patient are highly sensitized to HLA antigens, with a panel reactive antibody greater than 50% (see Chap. 2). These patients should be counseled that a longer wait time is expected, and induction and maintenance immunosuppression regimens are utilized for such patients (see Chap. 3). Alternative donor options such as expanded criteria donor or high-risk donor kidneys, and paired donor exchange programs should be discussed to attempt to mitigate a long waiting period.

Waitlist Management Guidelines for the management of the wait list have been published previously [14]. As waitlists across the country grow, so does the burden of managing complex patients. The UNOS 2008 data report list over 83,000 candidates on the kidney waitlist [3]. Many of these patients may be inactive or “status 7”; such an acute event or recoverable condition can be corrected. More than half of the waitlisted patients over the age of 60  years will not survive to transplantation [28]. Intimately related with this is monitoring of waitlist candidate mortality. It has been shown that candidate mortality is the best predictor of center outcomes [32]. Surveillance of the waitlisted patients is critical to maintaining a viable and robust waitlist of imminently transplantable patients. Cardiac reevaluation has been outlined previously and is suggested annually in highrisk diabetic patients and those with positive initial evaluation or prior revascularization [13]. In addition to annual cardiac evaluation, however, the waitlisted patient should have, at regular intervals, an update in the following domains:

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(1) peripheral vascular and cerebrovascular health, especially important in diabetics and smokers; (2) neurologic health; (3) cognitive health, especially in elderly candidates; (4) functional status as discussed previously; and (5) commitment to transplantation and its attendant responsibilities. The repeat evaluation is also an opportune time to reeducate the candidate and family concerning immunosuppression medication and risks, financial burden, and responsibilities of the patient for returning to appointments. Screening for depression can be performed, as this has been closely linked with compliance with dialysis and transplantation medications [33]. It is critical to reaffirm candidate commitment to transplantation. Prolonged waitlist times and accumulated morbidity may change the outlook of candidates. Conversely, many patients may have unrealistic expectations of the gains transplantation can offer; candidates over age 65 on dialysis for more than 4  years may have no survival advantage over staying on dialysis [28].

Native Kidney Disease and Recurrence Ascertaining the cause of kidney disease in the transplant recipient is an important step in the evaluation process. Some glomerular diseases such as focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (MPGN) have high recurrence rates in the allograft, and a high suspicion should be kept in these patients. Interstitial or metabolic diseases stemming from systemic diseases such as primary hyperoxaluria or sarcoidosis can have effects on the renal allograft. Some of these recurrent diseases are indolent and may only be seen on microscopy, but others such as FSGS or primary hyperoxaluria may be fulminant in onset. De novo glomerular diseases may occur and only be differentiated from recurrence of original disease (if known) by kidney biopsy.

Focal and Segmental Glomerulosclerosis Primary FSGS accounts for about 1–5% of all adult ESRD patients and historically has a 25–50% recurrence rate. This must be carefully distinguished from a secondary from of FSGS usually stemming from prior injury or nephron loss or hyperfiltration, since this disease does not typically recur in the allograft. Historical information suggests that living donation was associated with higher risk of recurrence in the allograft, although results on this have been variable. In a retrospective review of UNOS data, Cibrik et  al. [34] analyzed over 2,400 patients from the UNOS and scientific registry database and showed that HLA-identical living donation had the lowest death-censored graft loss rates compared with all others. It therefore appears safe if there is a well-matched living donor, to proceed with transplant. There is no convincing evidence that preemptive plasmapheresis is beneficial for prevention of recurrence [35]. Disease recurrence in this study was highest in the group that progressed rapidly to ESRD (<10  years), and recurrence heralded by proteinuria was often evident in the first few days after transplantation. Risk factors for recurrent disease are prior allograft loss to FSGS, rapid progression to ESRD in fewer than 3 years, and childhood onset of disease [36]. MPGN type 2 and atypical (nondiarrheal) HUS have been associated with abnormalities in the fluid phase complement regulators Factor H and I, and have high recurrence rates after kidney transplant ranging from 35% to 80% for atypical hemolytic uremic syndrome (aHUS) and 60–100% for MPGN2. Allograft loss from recurrent disease is also uniformly high [37]. Given the inability to treat recurrence of these diseases successfully, many centers discourage transplantation for these patients. Eculizumab is a monoclonal antibody inhibitor of the C5b-9 membrane attack ­complex and has been used successfully as compassionate therapy in a transplant recipient with recurrent aHUS [38].

8  Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate

Membranous nephropathy usually recurs less than 2  years from transplant, while de  novo membranous usually appears more than 2 years from transplant. Many patients will eventually become nephrotic and have high rates of graft loss in the 10 years following diagnosis. No specific risk factors for recurrence have been identified. Rituximab, a monoclonal antibody directed against CD 20 cells has been successfully used as therapy in patients with recurrent membranous glomerulonephritis [39].

IgA Glomerulonephritis Reports of recurrence rates of IgA nephritis, the most common glomerulonephritis worldwide, vary in association with timing and reason for kidney biopsy. Protocol biopsy series indicate higher rates of histologic recurrence on the order of 50–60% of cases, while biopsy series for clinical disease indicate recurrence from 13% to 50%. The 10-year rate of graft loss due to recurrent disease is estimated to be about 10% [40]. Donor source has been also been variably reported to be associated with risk of recurrence and graft loss and remains a contented issue. Choy et al. [40] in a pooled analysis showed that related donor source was associated with a higher risk of recurrence (OR 2.14) but not with graft loss. Since IgA can also be familial disease, and 0 HLA mismatch kidneys have been associated with a higher risk of recurrent disease [41], extreme care should be taken to ensure there is no disease in the potential donor before proceeding. Allograft loss from recurrence portends a poor outcome for subsequent transplant.

Obesity Obese subjects on dialysis exhibit a paradoxical survival advantage. Successful transplantation restores the mortality experience closer to the pattern observed in the general population, i.e., subjects at the highest and lowest ends of the

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BMI spectrum exhibit the highest risk for ­mortality. Morbid obesity is associated with a higher risk of postoperative wound infections and technical vascular and wound complications, postoperative death, death-censored graft loss, and a higher risk of post transplant diabetes mellitus [42]. Obese subjects are at risk for poor mobilization after transplantation and a greater tendency to deep vein thromboses. It is controversial as to whether or not to make the transplant candidate lose weight as a precondition to  listing. A registry analysis based on a large ­number of obese transplant candidates concluded that gain or loss of weight on the weight list did not correlate with outcome [43]. Morbidly obese subjects may benefit from bariatric surgery, and successful transplantation has been reported in case series [44]. Most centers refrain from transplanting the morbidly obese.

Indications for Nephrectomy Table  8.7 outlines the rare situations in which nephrectomy is indicated prior to or at the time of surgery. Common indications for nephrectomy include recurrent pain or infections, hematuria, infected reflux, suspected renal malignancy, severe and uncontrollable hypertension, severe nephritic syndrome, and space limitations. Simultaneous bilateral nephrectomy and transplantation for autosomal dominant polycystic kidney disease (ADPKD) has been reported; however, this may be associated with more complications versus a staged approach [45] such as incisional hernia, urine leak, and need for second operative procedure. Table  8.7  Indications for nephrectomy prior to transplantation ADPKD-space occupying kidneys; anorexia, nausea and vomiting, weight loss; recurrent hematuria, recurrent infections, pain Suspicious renal mass Obstructing or infected kidney stones Malignant hypertension Severe nephrotic syndrome Severe vesicoureteric reflux or hydronephrosis

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Multiorgan Transplants Renal failure complicates progressive heart and liver disease, as well as prior solid organ transplant usually as a consequence of calcineurin inhibitor nephrotoxicity [46]. Kidney transplantation confers a survival advantage in this population despite their overall increased risk of mortality and morbidity [47]. These patients may present for transplant evaluation either for consideration of a kidney or combined organ transplantation. With increased ability to accurately estimate GFR, growing awareness of the mortality contribution of decreased kidney function, and growth of nonkidney organ transplantation programs, more patients are being referred to specialists for evaluation of renal function reversibility or consideration for combined transplantation. There has also been a growing number of simultaneous liver–kidney transplants being performed in the era of MELD (Model for End-Stage Liver Disease) based liver allocation [48]. Kidney failure in advanced liver disease is common, and determining the etiology and amount of irreversible renal dysfunction can help triage kidney allocation for combined liver– kidney transplantation. Percutaneous biopsies have been suggested as being safe, and may help this decision making [49, 50]. A consensus panel concluded Regional Review Boards (RRB) should determine listing for SLK (simultaneous liver kidney transplantation), as with other MELD exceptions, with automatic approval for: (1) endstage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient ³ 10  mmHg, (2) liver failure and CKD with GFR £ 30  mL/min, (3) AKI or hepatorenal syndrome with creatinine ³ 2.0  mg/dL and dialysis ³ 8 weeks, (4) liver failure and CKD and biopsy demonstrating >30% glomerulosclerosis or 30% interstitial fibrosis [51]. As has been shown in the failed kidney transplant [47], transplantation confers a survival advantage in the solid organ transplant patient reaching ESRD compared to dialysis [52], but must be considered in the context of the patient’s overall comorbidity and survival outlook. As the survival of all transplant patients increases, transplant programs must develop a standardized approach to the evaluation and management of this ever increasing population.

R.A. Fatica et al.

Management of Lower Urinary Tract Disease It is important to remember that dialyzed patients often have a diminished urine volume, resulting in a small capacity bladder with low compliance. Such bladders will resume normal function, even 25 years later, once urine volume is restored [53]. However, small capacity bladders that are fibrotic and scarred from prior surgery, radiation, old TB, congenital anomalies (e.g., posterior urethral valves, meningomyelocele) will not recover. In these rare cases, often children, the preferred option is a bladder augmentation with bowel (ileum, stomach, colon, or dilated ureter) or a continent neobladder to produce a compliant reservoir with adequate volume [54]. Bladder augmentation is not without risk, as mucus production, residual urine, and infection often require subsequent intermittent catheterization. If the bladder is absent or destroyed, an ileal conduit can be created for transplantation [55]. It is advisable that such major reconstructions be done and healed prior to transplantation. Experience has taught that operations on a dry urinary tract, i.e., bladder neck incisions, urethral stricture repair, and prostatectomy will lead to re-stricturing and further scarring. Therefore, they should only be done when urine volume is greater than 1 L/day; or if not, delayed for about 3  months after the transplant. This includes older males who experience progressive prostatic growth absent urine output while on dialysis. These recipients may experience symptoms of prostatism or even urinary retention after the transplant, which will require treatment. During this interval for immunosuppression reduction and complete engraftment, recipients can be managed with a suprapubic tube, or preferably intermittent clean catheterization [57].

Summary and Recommendations Transplantation is no longer considered a mere lifestyle choice over remaining on dialysis and is accepted as conferring a durable survival benefit over dialysis [1]. That said, the comparison of

8  Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate

survival experiences between transplanted and dialyzed patients is not straightforward. This is because there is an intrinsic selection bias in only offering transplantation as an option to the fittest of the dialysis patients. In that regard, the waitlisted patient who has not yet received a renal transplant forms the next best comparison group. In their seminal study using the USRDS database, Wolfe et al. showed that on average, after the first 106 days posttransplantation the relative risk of death was higher for those waitlisted patients who continued to remain on dialysis [1]. This excess risk of mortality in the first 3½ months posttransplantation likely reflected the medical and surgical risk associated with the transplant procedure per se. An important caveat is that the time to equal risk of mortality observed in this study varied widely between 5 and 673  days after transplantation. As one can readily appreciate, the time to equal risk is highly variable, and the transplant physician and surgeon are essentially trying to make a judgement on this highly variable time point when the risk of transplantation is outweighed by the benefit conferred by transplantation. Furthermore, outcomes data are derived from the aggregate, and their application in the care of individuals brings in further layers of complexity to the process of candidate selection. Efforts to minimize waiting time include living donation and the use of ECD kidneys. The decision to consider use of ECD kidneys must be made after careful evaluation of the risks vs. benefits of transplantation with such a kidney with lower expected graft life and an assessment of the expected lifespan of the candidate remaining on dialysis. This decision may be further modulated by the prevalent waiting times in the donor service area that the candidate resides in. Over half the patients over the age of 60 who enter the cadaver kidney waitlist in the US will die before this kidney becomes available to them Patients at particular risk for such an outcome are diabetics. Due diligence is required in explaining the ECD process to these patients, and the pros and cons of multiple listing should be explained [56].

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Subjects with prior transplants present unique challenges. This is a growing population. The decision to offer retransplants must be individualized as the spectrum of risk and magnitude of expected benefit is broad and fraught with uncertainty.

Conclusions The transplant evaluation process represents the interface of the transplant community with the community at large. The opportunities and challenges posed by this field represent the essence of the challenge of clinical medicine. The challenges that are posed by disease and disability are constantly overcome by the determination, resilience, and courage of patients and their caregivers. Transplant centers are indeed uniquely privileged to serve patients with end stage renal disease.

References 1. 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. NEJM 1999;341(23):1725–1730. 2. Dew MA, Switzer GE, Goycoolea JM, et  al. Does transplantation produce quality of life benefits? A quantitative analysis of the literature. Transplantation 1997;64(9):1261–1273. 3. UNOS. United Network of Organ Sharing. Available at http://www.Unos.org 4. Meier-Kriesche H, Port FK, Ojo AO, et al. Deleterious effect of waiting time on renal transplant outcome. Transpl Proc 2001;33(1–2):1204–1206. 5. 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(10):726–731. 6. Augustine JJ, Poggio ED, Clemente M, et  al. Hemodialysis vintage, black ethnicity, and pretransplantation antidonor cellular immunity in kidney transplant recipients. J Am Soc Nephrol 2007;18(5): 1602–1606. 7. Nogueira JM, Haririan A, Jacobs SC, Cooper M, Weir MR. Cigarette smoking, kidney function, and mortality after live donor kidney transplant. Am J Kidney Dis 2010;55(5):817–819.

198 8. Schold JD, Srinivas TR, Kayler LK, Meier-Kriesche HU. The overlapping risk profile between dialysis patients listed and not listed for renal transplantation. Am J Transplant 2008;8(1):58–68. 9. Meier-Kriesche HU, Cibrik DM, Ojo AO, et  al. Interaction between donor and recipient age in determining the risk of chronic renal allograft failure. J Am Geriatr Soc 2002;50(1):14–17. 10. Merion RM, Ashby VB, Wolfe RA, et al. Deceaseddonor characteristics and the survival benefit of kidney transplantation. JAMA 2005;294(21):2726–2733. 11. Schold JD, Meier-Kriesche HU. Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis? Clin J Am Soc Nephrol 2006;1(3):532–538. 12. Meier-Kriesche HU, Schold JD, Srinivas TR, Reed A, Kaplan B. Kidney transplantation halts cardiovascular disease progression in patients with endstage renal disease. Am J Transplant 2004;4(10): 1662–1668. 13. Kasiske BL, Cangro CB, Hariharan S, et al. The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant 2001;1(Suppl 2):3–95. 14. Gaston RS, Danovitch GM, Adams PL, et  al. The report of a national conference on the wait list for kidney transplantation. Am J Transplant 2003;3(7): 775–785. 15. Sheashaa HA, Abbas TM, Hassan NA, et  al. Association and prognostic impact of persistent left ventricular hypertrophy after live-donor kidney transplantation: a prospective study. Clin Exp Nephrol 2010;14(1):68–74. 16. de Mattos AM, Siedlecki A, Gaston RS, et al. Systolic dysfunction portends increased mortality among those waiting for renal transplant. J Am Soc Nephrol 2008;19(6):1191–1196. 17. Issa N, Krowka MJ, Griffin MD, Hickson LJ, Stegall MD, Cosio FG. Pulmonary hypertension is associated with reduced patient survival after kidney transplantation. Transplantation 2008;86(10):1384–1388. 18. Patel AD, Abo-Auda WS, Davis JM, et al. Prognostic value of myocardial perfusion imaging in predicting outcome after renal transplantation. Am J Cardiol 2003;92(2):146–151. 19. Linares L, Cofan F, Cervera C, et al. Infection-related mortality in a large cohort of renal transplant recipients. Transplant Proc 2007;39(7):2225–2227. 20. Rahnavardi M, Hosseini Moghaddam SM, Alavian SM. Hepatitis C in hemodialysis patients: current global magnitude, natural history, diagnostic difficulties, and preventive measures. Am J Nephrol 2008; 28(4):628–640. 21. Abbott KC, Bucci JR, Matsumoto CS, et al. Hepatitis C and renal transplantation in the era of modern immunosuppression. J Am Soc Nephrol 2003;14(11): 2908–2918. 22. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Dulai G. Hepatitis C virus antibody status and survival after

R.A. Fatica et al. renal transplantation: meta-analysis of observational studies. Am J Transplant 2005;5(6):1452–1461. 23. Meier-Kriesche HU, Ojo AO, Hanson JA, Kaplan B. Hepatitis C antibody status and outcomes in renal transplant recipients. Transplantation 2001;72(2): 241–244. 24. Hartmann EL, Kitzman D, Rocco M, et al. Physical function in older candidates for renal transplantation: an impaired population. Clin J Am Soc Nephrol 2009;4(3):588–594. 25. Wong G, Chapman JR. Cancers after renal trans­ plantation. Transplant Rev (Orlando) 2008;22(2): 141–149. 26. Penn I. Evaluation of transplant candidates with ­pre-existing malignancies. Ann Transplant 1997;2(4): 14–17. 27. Secin FP, Carver B, Kattan MW, Eastham JA. Current recommendations for delaying renal transplantation after localized prostate cancer treatment: are they still appropriate? Transplantation 2004;78(5):710–712. 28. Schold J, Srinivas TR, Sehgal AR, Meier-Kriesche HU. Half of kidney transplant candidates who are older than 60 years now placed on the waiting list will die before receiving a deceased-donor transplant. Clin J Am Soc Nephrol 2009;4(7):1239–1245. 29. Meier-Kriesche HU, Srinivas TR, Kaplan B. Interaction between acute rejection and recipient age on long-term renal allograft survival. Transplant Proc 2001;33(7-8):3425–3426. 30. US Renal Data System. US Renal Data System, USRDS 2009 Annual Data Report: Atlas of EndStage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009. Available at http://www.usrds.org. Updated 2009. 31. Liani M, Salvati F, Tresca E, et  al. Arteriovenous ­fistula obstruction and expression of platelet receptors for von Willebrand factor and for fibrinogen (glycoproteins GPib and GPiib/iiia) in hemodialysis patients. Int J Artif Organs 1996;19(8):451–454. 32. Schold JD, Srinivas TR, Howard RJ, Jamieson IR, Meier-Kriesche HU. The association of candidate mortality rates with kidney transplant outcomes and center performance evaluations. Transplantation 2008;85(1):1–6. 33. Cukor D, Rosenthal DS, Jindal RM, Brown CD, Kimmel PL. Depression is an important contributor to low medication adherence in hemodialyzed patients and transplant recipients. Kidney Int 2009;75(11): 1223–1229. 34. Cibrik DM, Kaplan B, Campbell DA, Meier-Kriesche HU. Renal allograft survival in transplant recipients with focal segmental glomerulosclerosis. Am J Transplant 2003;3(1):64–67. 35. Hickson LJ, Gera M, Amer H, et  al. Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence. Transplantation 2009;87(8):1232–1239.

8  Medical and Surgical Evaluation of the Adult Kidney Transplant Candidate 3 6. Ivanyi B. A primer on recurrent and de  novo glomerulonephritis in renal allografts. Nat Clin Pract Nephrol 2008;4(8):446–457. 37. Zipfel PF, Heinen S, Jozsi M, Skerka C. Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol 2006;43(1–2):97–106. 38. Davin JC, Gracchi V, Bouts A, Groothoff J, Strain L, Goodship T. Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a CFH mutation. Am J Kidney Dis 2010;55(4):708– 711. Epub 2009 Oct 25. 39. Gallon L, Chhabra D. Anti-CD20 monoclonal antibody (rituximab) for the treatment of recurrent idiopathic membranous nephropathy in a renal transplant patient. Am J Transplant 2006;6(12):3017–3021. 40. Choy BY, Chan TM, Lai KN. Recurrent glomerulonephritis after kidney transplantation. Am J Transplant 2006;6(11):2535–2542. 41. McDonald SP, Russ GR. Recurrence of IgA nephropathy among renal allograft recipients from living donors is greater among those with zero HLA mismatches. Transplantation 2006;82(6):759–762. 42. Srinivas TR, Meier-Kriesche HU. Obesity and kidney transplantation. Contrib Nephrol 2006;151:19–41. 43. Schold JD, Srinivas TR, Guerra G, et al. A “weightlisting” paradox for candidates of renal transplantation? Am J Transplant 2007;7(3):550–559. 44. Alexander JW, Goodman H. Gastric bypass in chronic renal failure and renal transplant. Nutr Clin Pract 2007;22(1):16–21. 45. Ismail HR, Flechner SM, Kaouk JH, et  al. Simultaneous vs. sequential laparoscopic bilateral native nephrectomy and renal transplantation. Trans­ plantation 2005;80(8):1124–1127. 46. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. NEJM 2003;349(10):931–940. 47. Ojo A, Wolfe RA, Agodoa LY, et al. Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation: multivariate analy-

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ses from the United States Renal Data System. Transplantation 1998;66(12):1651–1659. 48. Thompson JA, Lake JR. The impact of MELD allocation on simultaneous liver-kidney transplantation. Curr Gastroenterol Rep 2009;11(1):76–82. 49. Wadei HM, Geiger XJ, Cortese C, et  al. Kidney ­allocation to liver transplant candidates with renal failure of undetermined etiology: role of percutaneous renal biopsy. Am J Transplant 2008;8(12): 2618–2626. 50. Tanriover B, Mejia A, Weinstein J, et al. Analysis of kidney function and biopsy results in liver failure patients with renal dysfunction: a new look to combined liver kidney allocation in the post-MELD era. Transplantation 2008;86(11):1548–1553. 51. Eason JD, Gonwa TA, Davis CL, Sung RS, Gerber D, Bloom RD. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK). Am J Transplant 2008;8(11):2243–2251. 52. Lonze BE, Warren DS, Stewart ZA, et  al. Kidney transplantation in previous heart or lung recipients. Am J Transplant 2009;9(3):578–585. 53. Serrano DP, Flechner SM, Modlin CS, Wyner LM, Novick AC. Transplantation into the long-term defunctionalized bladder. J Urol 1996;156(3): 885–888. 54. Rigamonti W, Capizzi A, Zacchello G, et al. Kidney transplantation into bladder augmentation or urinary diversion: long-term results. Transplantation 2005; 80(10):1435–1440. 55. Hatch DA, Belitsky P, Barry JM, et al. Fate of renal allografts transplanted in patients with urinary diversion. Transplantation 1993;56(4):838–842. 56. Kumar V, Julian BA, Deierhoi MH, Curtis JJ. Secondary listing for deceased-donor kidney transplantation does not increase likelihood of engraftment at a large transplant center. Am J Transplant 2009;9(7):1671–1673. 57. Flechner SM, Conley SB, Brewer ED, Benson GS, Corriere JN,Jr. Intermittent clean catheterization: an alternative to diversion in continent transplant recipients with lower urinary tract dysfunction. J Urol 1983;130:878–81.

Chapter 9

Selection and Preparation of the Pancreas Transplant Recipient Ho-Yee Tiong and  Venkatesh Krishnamurthi

Keywords  Pretransplant evaluation • Pancreas transplantation • Type 1 diabetes mellitus

Introduction Pancreas transplantation is the only treatment that can reliably establish an exogenous insulinfree, normoglycemic state in patients with diabetes mellitus (DM). It has become a mainstream transplant operation with excellent patient and graft survival. Advances in the form of newer and better immunosuppressant agents [1], as well as technical surgical refinements [2] have further facilitated the rapid growth in pancreas transplantation from 200 cases per year in 1987 to a peak of 1,472 cases a year in 2004 in the United States [3, 4]. Currently in the United States approximately 1,000–1,100 pancreas transplants are performed annually (Organ Procurement Transplantation Network [OPTN] data). Worldwide, as of 2004, nearly 23,000 pancreas transplants had been reported to the International Pancreas Transplant Registry (IPTR) [3]. To maintain good patient and graft survival, careful selection of appropriate pancreas transplant candidates is essential. As more complex patients are referred with increasing V. Krishnamurthi () Department of Urology, Glickman Urological and Kidney Institute, 9500 Euclid Avenue Q10, Cleveland, OH, 44195, USA e-mail: [email protected]

acceptance of this procedure, comprehensive evaluation of potential candidates and their careful preparation prior to transplantation will also become increasingly necessary to maintain excellent results. The focus of this chapter will be devoted to the identification of candidates for pancreas transplantation and determination of the type of procedure that is most suitable. Additionally, the clinical, laboratory, and preoperative evaluation protocol to optimize patients for pancreas transplantation will be reviewed.

Patient Selection for Pancreas Transplantation Selection of the potential pancreas transplant recipient must begin with determination of the type of diabetes mellitus (DM). Broadly, DM can be classified into two major categories, type 1 and type 2, based on the American Diabetes Association (ADA) classification system [5]. Type 1 DM can be autoimmune or idiopathic. Autoimmune type 1 DM develops from a cellmediated autoimmune destruction of the pancreatic b cells in the islets of Langerhans. These patients have low or absent insulin production and hence benefit from replacement of insulin producing pancreatic b cells. Type 1 DM has classically been considered to be present in patients with disease onset at younger than 30  years of age, with a trend to ketoacidosis, early initiation of insulin treatment,

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_9, © Springer Science+Business Media, LLC 2011

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and without excessive weight at the onset of ­disease. This is, however, an oversimplification, having overlap with other types of DM. The determination of serum levels of c-peptide has also been utilized as a measure of insulin secretion for clinical correlation to the type of DM [6]. At most transplant centers, an absent or very low c-peptide (<1 mg/mL) is required to confirm the diagnosis of Type1 diabetes. Accordingly, c-peptide deficient patients make better candidates and are the most common candidates for pancreatic transplantation [7]. However, even with detectable c-peptide levels, the distinction between type 1 and type 2 DM can be difficult in many cases. Although absent or low c-peptide levels are suggestive of the phenotype 1 DM, the presence of detectable c-peptide does not rule out the possibility of the patient having type 1 DM as c-peptide may accumulate in type 1 DM patients with renal failure [8]. Moreover, in recent years, a few centers have been performing pancreas transplantation in patients with type 2 DM with good metabolic control results [9]. Nevertheless, pancreas transplantation has been reserved for patients with established diabetic complications or extremely labile diabetes that is considered to be more life-threatening than the morbidity of the surgical procedure and the side effects of immunosuppression [10–12]. Currently, more than 50% of patients with at least 20  years of diabetes will develop severe neuropathy, retinopathy, or nephropathy. Nearly 30% of the patients developing nephropathy will progress to end stage renal failure [13]. In these patients, simultaneous transplantation of a pancreas and kidney can be a successful therapeutic option for advanced chronic kidney disease and metabolic complications from diabetes. Patients on insulin therapy, with frequent admissions for diabetic ketoacidosis or hypoglycemic unawareness, are considered by many to be absolute indications for pancreas transplantation. Documentation of medical complications from diabetes and from exogenous treatment, as well as insulin dose requirements, is important to facilitate assessment of medical eligibility. Of  note, the presence of diabetic gastroparesis  and autonomic neuropathy with postural

H.-Y. Tiong and V. Krishnamurthi

hypotension may not be immediately apparent but could have significant impact on postoperative morbidity and medical management.

Categories of Pancreas Transplantation The categories of pancreas transplantation are simultaneous pancreas kidney transplantation (SPK), sequential pancreas after kidney transplantation (PAK) and for non-uremic patients, pancreas transplant alone (PTA). The type of pancreas transplant is dependent upon the recipient kidney function. The American Diabetes Association recommended indications for ­pancreas transplantation are shown in Table 9.1 [14, 15]. The indications are continually evolving and expanding. For example, although most patients with Type 1 DM have the autoimmune or idiopathic type, pancreas transplantation has been performed successfully for patients who are insulin deficient secondary to pancreatectomy for chronic pancreatitis [16]. More recently, pancreas transplantation has been shown to reverse hepatopathy in poorly controlled type I DM patients with resultant glycogen storage disorders at our center and others [17]. Insulin allergy has also been reported as an indication for pancreas transplantation in a case report [18]. SPK should be considered in diabetic patients with imminent or established renal disease (creatinine clearance <30  mL/min) who (1) plan to have a kidney transplant, (2) meet the medical indications and criteria for kidney transplantation, and (3) have acceptable surgical risk for the dual transplant procedure [19, 20]. In these patients, the indications are relatively straightforward because the successful addition of a pancreas does not jeopardize patient survival and  will restore normoglycemia [21–23]. Furthermore, many studies have shown that SPK improves patient and kidney survival compared with kidney alone transplant, particularly in the deceased donor setting [21, 24, 25], Currently the majority of all pancreas transplants have been performed as SPK procedures [3].

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Table 9.1  Indications for pancreas transplantation Simultaneous kidney and pancreas transplant • CKD stages 4 or 5 (creatinine clearance <30 mL/min) with type 1 diabetes and with other diabetic complications • Prior renal transplant which is failing in a type 1 diabetic Pancreas after kidney transplant

• Prior functioning kidney transplant in type 1 diabetic with other diabetic complications

Pancreas transplant alone

• Hyperlabile diabetes defined by frequent acute severe metabolic complications (hypoglycemia, marked hyperglycemia, and ketoacidosis) requiring medical attention • Clinical and emotional problems with insulin therapy that are incapacitating • Consistent failure of insulin based management to prevent complications • Presence of (two or more) diabetic complications that are progressive and unresponsive to intensive insulin therapy • Early diabetic nephropathy • Proliferative retinopathy • Symptomatic peripheral or autonomic neuropathy • Vasculopathy with accelerated atherosclerosis

Approximately 25% of all pancreas t­ransplants  are PAK transplants, and for these transplants recipient selection is similar to that for SPK [3, 26]. Potential PAK recipients comprise two main categories, those with a prior kidney transplant alone and those with a prior SPK with a failed pancreas allograft [3, 27]. There is increasing interest in performing living donor kidney transplantation followed by a PAK (PALDK) [28, 29]. This has been the preferred approach at some centers for patients with potential living kidney donors, with the primary aim of minimizing the deleterious effect of waitlist time in diabetics. However, the decision as to whether a uremic diabetic patient should receive an SPK or PALDK can be difficult and controversial. Two main factors are central to this decision. One should consider the expected outcomes for each of the two scenarios for the individual patient as well as the waiting time for an SPK transplant versus an isolated pancreas transplant. Notably, although results observed for PAK are improving, the outcomes of graft and patient survival for PAK still lag behind those achieved with SPK in every era [4]. PALDK has two major benefits that arise from transplantation of a living donor kidney [27,  29, 30]. The first being that living donor transplants demonstrate the best long-term survival rates and, secondly, use of a living donor kidney does not remove a deceased donor kidney

from the pool of organs available for potential transplant recipients. In addition, the decision between the two choices may also depend on the expected waiting time for PAK versus SPK at each particular transplant center or region. In general, waiting times for PAK are generally much shorter than for SPK. Comparison of patient survival on the United Network of Organ Sharing (UNOS) waiting lists of PAK and SPK shows that the death rate on the SPK waiting list is up to two times greater due to the presence of uncorrected renal failure and by 5 years after date of listing for SPK, more than half of the patients were dead [31]. Therefore transplantation of a kidney appears to be more “valuable” in terms of improving patient survival. Hence, if the waiting time of SPK is longer than a year, patient survival can be improved by earlier living donor kidney transplantation [28, 31]. In addition, it seems that once a patient has had a kidney transplant, the time interval (longer or shorter than 4  months) between kidney and pancreas transplant is not associated with increased risks of complications or worse graft survival [32]. In all potential PAK recipients, a detailed evaluation of the renal allograft function is ­necessary. Patients with stable and adequate renal transplant function (creatinine clearance ³ 40–50  mL/min and absence of overt proteinuria) should be considered as suitable candidates

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for PAK transplantation. Patients with poor renal function may be better candidates for SPK instead due to possibility of accelerated renal graft failure from intensified calcineurin inhibitor therapy following PAK. For patients with borderline renal function or with proteinuria (>2  g/day), some centers have advocated a trial of high dose calcineurin inhibitor challenge prior to the pancreas transplant to ascertain the risk of accelerated nephropathy due to drug toxicity [33, 34]. A baseline kidney biopsy may also be useful in these patients to assess for the progression of nephropathy after PAK, but there is little data or experience in using the biopsy results to guide recipient selection. Approximately 8% of pancreas transplants are PTA in the UNOS registry, a proportion that has been stable over the last 10  years [3]. The indications as proposed by ADA are listed in Table 9.1 [15, 35]. The primary indications for PTA include two or more diabetic complications but with preserved renal function and glucose hyperlability that lead to a significantly poor quality of life or increased risk of trauma or sudden death [15]. Unlike SPK or PAK recipients, candidates for PTA do not otherwise require immunosuppression to prevent rejection of a renal allograft. Therefore the side effects and risks of immunosuppressive medications are not offset by any other potential benefit. There are also the additional surgical risks, which carry a relatively small but defined morbidity and mortality. Hence the benefits of insulin independence and potentially reversing or halting the progression of secondary end organ diseases have to be weighed against the above issues. The Diabetes Control and Complications Trial (DCCT) has clearly shown that improved glycemic control lowers the risk of secondary complications including cardiovascular events, but intensive insulin therapy is associated with three times increased risk of severe hypoglycemia [36, 37]. Despite the potential long-term benefit of pancreas transplantation at preventing end-organ complications from diabetes if performed early [38], PTA should still be reserved for patients where problems of diabetes itself are perceived

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to be more serious than the potential problems of immunosuppression and surgery.

Medical Evaluation and Preparation Pancreas transplantation is a complex operation and in order to achieve good results it is essential that transplant candidates are in an optimal state of health. As with evaluation for all solid organ transplants, the general principle is that patients should undergo careful screening and any preexisting disease should be addressed. The major objective of the pretransplant evaluation is to identify factors that increase the risk of death, graft loss, or major morbidity of pancreas transplantation. Similar to the practice at many centers, at the Cleveland Clinic we follow a multidisciplinary approach for pancreas transplant evaluation. The evaluation protocol is very similar to that for evaluation of kidney transplant recipients. The transplant surgeon and the transplant physician (nephrologist or endocrinologist) evaluate the patient through a comprehensive history, physical examination, and review of records in a combined clinic setting. Additionally, potential candidates are also interviewed by a financial counselor, transplant coordinator and transplant social worker to determine the impact of underlying illness on quality of life, assess for noncompliance or serious psychosocial problems that may arise from the burden of longstanding diabetes, and determine the potential financial impact on the patient and support network. Details of the entire transplant process are reviewed with the patient and relevant caregivers/relatives, and the potential candidates are counseled about the risks, benefits, and alternatives to pancreas transplantation. The clinical assessment is largely focused on the presentation of diabetes (age of diagnosis, immediate need for insulin therapy, insulin dose requirements), the complications of diabetes, prior cardiovascular disease, and episodes of hypoglycemic unawareness. A history of renal impairment or failure is specifically investigated. Available medical records from referring centers are

9  Selection and Preparation of the Pancreas Transplant Recipient

reviewed to highlight significant past medical and surgical problems. Risk factors that may increase the morbidity of the procedure include increasing age, obesity, adverse psychosocial factors, preexisting cardiovascular disease, chronic fungal or viral infection, chronic obstructive pulmonary disease, gastrointestinal disorders, neuropathic ulcers, osteomyelitis of the extremities, and peripheral arterial disease. From the surgical perspective the clinical assessment should aim to identify patient factors that may lead to technical complications. Examples include obesity (body mass index >30 kg/m2), a history of previous abdominal surgery or abdominal transplant, and presence and severity of peripheral vascular disease [39]. From several retrospective studies, recipient age greater than 45 years, cardiac disease (with previous myocardial infarction, coronary bypass or percutaneous angioplasty), previous pancreas transplant, and peripheral vascular disease were all independent predictors of poor patient outcomes in pancreas transplantation [40, 41], Although other studies have shown that increasing recipient age is not associated with technical complications [39], patient survival is diminished in the older ­population due to increase association of age with cardiovascular disease, infections, and malignancy. Identification of risk factors is important not only at the initial assessment, but as practiced at our center, high risk patients are also routinely reevaluated at 6- to 12-month intervals. The contraindications for pancreas transplantation are similar to that for kidney transplantation. Major categories of conditions that are considered contraindications for pancreas transplantation are shown in Table 9.2 [10–12]. The laboratory evaluation for pancreas transplant recipients is also similar to that for kidney transplant candidates. In addition to standard laboratory studies including viral serologic panels and tissue typing, c-peptide and hemoglobin A1c (HgbA1c) levels are required to document native insulin production and glucose control. For renal functional evaluation, additional testing may include native kidney biopsy, 24-h urine collection for protein and creatinine clearance,

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Table  9.2  Contraindications for pancreas transplantation • Absolute contraindications Inadequate cardiovascular reserve: − Coronary angiographic evidence of significant noncorrectable or untreatable coronary artery disease − Recent myocardial infarction − Ejection fraction below 30% − Active infection • History of recent, incompletely treated malignancy (excluding nonmelanoma skin cancer) • Positive HIV serology • Positive Hepatitis B surface antigen serology • Ongoing substance abuse • Major ongoing psychiatric illness • Recent history of noncompliance • Inability to provide informed consent • Any systemic illness that would severely limit life expectancy or compromise recovery • Significant, irreversible hepatic or pulmonary dysfunction

and/or isotopic studies to determine glomerular filtration rate. Very infrequently, pancreas transplant candidates may need evaluation of bladder function and this can be accomplished with voiding cystourethrography and urodynamic studies. Standard cancer screening guidelines should also be followed in potential kidney and pancreas transplant candidates, as the overall incidence of cancer in hemodialysis patients is higher than that seen in the general population [42]. This risk may be especially high for younger patients and for specific cancers, based on a recent published report of 800,000 patients from three continents [43]. The specific guidelines followed in our pretransplant evaluation protocol are those from major cancer preventative organizations, including American Cancer Society [44] and United States Preventative Services Task Force [45], and relate to screening for breast, cervical, colorectal, and prostate, cancers. For cervical cancer, gynecologic examination and Papanicolaou smears should be carried out at 1–2-year intervals for sexually active women 18 years of age or older [46]. Breast cancer screening comprises annual mammography for women older than 40  years of  age [47]. Colorectal cancer screening begins at  age 50 for all patients, with either an annual guaiac-based fecal occult blood test or flexible

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sigmoidoscopy and double barium enema every 5  years, or colonoscopy every 10  years [48]. Screening for prostate ­cancer involves digital rectal examination and prostate specific antigen testing for men older than 50  years of age, after appropriate counseling [49]. For patients previously treated for cancer, it would be prudent to recommend a minimum waiting period of 2  years. In the case of cancers at increased risk of recurrence, a longer waiting interval such as 5 years should be considered [42]. Radiographic evaluation of the pancreas transplant candidate can be accomplished with an abdominal and pelvic ultrasound or computed tomography (CT) scan. The primary purpose of radiographic screening is to assess for abnormal masses, gallstone disease, and native kidney pathology (renal malignancy and/or nephrolith­ iasis). A noncontrast CT scan has the additional advantage of delineating vascular calcification, which may impact the selection of targets for arterial anastomosis. A noncontrast CT in combination with pulse volume recordings (PVRs) is particularly helpful to determine the extent and severity in patients with a clinical history and/or physical exam findings of peripheral arterial disease. Given the high prevalence of coronary artery disease in diabetic (and uremic patients), car­ diovascular evaluation is essential in a high ­proportion of pancreas transplant candidates. Cardiovascular disease is the leading cause of death in diabetic uremic patient with a mortality rate of 10–20 times that of the general population [13, 37]. Currently there is no consensus on the nature of the cardiovascular evaluation in the diabetic patient with end stage kidney disease end stage renal disease. At our center, the evaluation consists of noninvasive functional assessment such as an exercise or pharmacologic (dobutamine) stress test in addition to echocardiography and electrocardiogram (EKG). It provides information on the presence of ischemia, wall motion, and ejection fraction. With a reported sensitivity and specificity of 75% and 71%, respectively for stenosis greater than 70% in ESRD patients [50], it is a useful screening test for low-risk patients in combination with

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resting EKG [51–53]. Coronary angiography should be used for ­high-risk patients with specific indications such as age over 45 years, diabetes for more than 25 years, a positive smoking history, long standing hypertension, previous major amputation due to peripheral vascular disease, or history of cerebrovascular disease [51, 54]. They should also be performed if initial noninvasive cardiac studies are abnormal, or history and examination suggest poor functional status from decreased cardiac reserve. Using this approach, patients with lesions of greater than 70% stenosis would first undergo angioplasty or coronary artery bypass surgery before being placed on the waiting list, with ultimately reported good outcomes after pancreas transplantation [55, 56]. Patients with less than 70% stenosis are approved for transplantation but must be reevaluated every 6  months to 1  year. Candidates with diffuse, inoperable disease should not be transplanted. Following evaluation of selected candidates, it is important to optimize potential pancreas transplant recipients by minimizing identified of risk factors. The American Heart Association and the International Task Force for Prevention of Coronary Heart Disease have advanced specific measures for primary prevention that should be undertaken for pancreas transplant candidates in preparation for surgery [57]. The primary measures include smoking cessation, blood pressure control, correction of hyperlipidemia, increased exercise, and weight reduction. Despite the difficulties in controlling these risk factors, counseling in these areas at the initial evaluation and subsequent reevaluations are important to ensure that candidates on the waiting list are optimized and ready for the surgery whenever they get the call.

Summary and Conclusions Pancreas transplantation can offer a significant benefit to diabetic patients with or without renal failure. The challenge in selecting the right patient for the right type of pancreas transplant is

9  Selection and Preparation of the Pancreas Transplant Recipient

based on the overall burden of comorbidity in the diabetic. Selection and preparation of the pancreas transplant recipient is best undertaken in a multidisciplinary setting with medical, ­surgical, and psychosocial input.

References 1. Singh RP, Stratta RJ. Advances in immunosuppression for pancreas transplantation. Curr Opin Organ Transplant 2008;13(1):79–84. 2. Humar A, Kandaswamy R, Granger D, Gruessner RW, Gruessner AC, Sutherland DE. Decreased surgical risks of pancreas transplantation in the modern era. Ann Surg 2000;231(2):269–275. 3. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the united network for organ sharing (UNOS) and the international pancreas transplant registry (IPTR) as of June 2004. Clin Transplant 2005;19(4):433–455. 4. Cohen DJ, St Martin L, Christensen LL, Bloom RD, Sung RS. Kidney and pancreas transplantation in the United States, 1995–2004. Am J Transplant 2006;6(5 Pt 2):1153–1169. 5. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008;31 (Suppl 1):S55–60. 6. Gjessing HJ, Matzen LE, Faber OK, Froland A. Fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and urinary C-peptide in relation to clinical type of diabetes. Diabetologia 1989;32(5):305–311. 7. Esmatjes E, Fernandez C, Rueda S, Nicolau J, Chiganer G, Ricart MJ, et al. The utility of the C-peptide in the phenotyping of patients candidates for pancreas transplantation. Clin Transplant 2007;21(3):358–362. 8. Covic AM, Schelling JR, Constantiner M, Iyengar SK, Sedor JR. Serum C-peptide concentrations poorly phenotype type 2 diabetic end-stage renal disease patients. Kidney Int 2000;58(4):1742–1750. 9. Nath DS, Gruessner AC, Kandaswamy R, Gruessner RW, Sutherland DE, Humar A. Outcomes of pancreas transplants for patients with type 2 diabetes mellitus. Clin Transplant 2005;19(6):792–797. 10. Meloche RM. Transplantation for the treatment of type 1 diabetes. World J Gastroenterol. 2007;13(47): 6347–6355. 11. Paramesh AS, Zhang R, Fonseca V, Killackey MT, Alper B, Slakey D, et al. Pancreas transplantation – a controversy in evolution. J La State Med Soc 2007; 159(6):319, 323, 325–329. 12. Dafoe DC, Vinik AI. Is pancreas transplantation for insulin-dependent diabetes mellitus worthwhile? NEJM 1990;322(22):1608–1609. 13. Nathan DM. Long-term complications of diabetes mellitus. NEJM 1993;328(23):1676–1685.

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14. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE. Pancreas and islet transplantation for patients with diabetes. Diabetes Care 2000;23(1):112–116. 15. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE, American Diabetes Association. Pancreas and islet transplantation in type 1 diabetes. Diabetes Care 2006;29(4):935. 16. Gruessner RW, Sutherland DE, Drangstveit MB, Kandaswamy R, Gruessner AC. Pancreas allotransplants in patients with a previous total pancreatectomy for chronic pancreatitis. J Am Coll Surg 2008; 206(3):458–465. 17. Fridell JA, Saxena R, Chalasani NP, Goggins WC, Powelson JA, Cummings OW. Complete reversal of glycogen hepatopathy with pancreas transplantation: two cases. Transplantation 2007;83(1):84–86. 18. Oh HK, Provenzano R, Hendrix J, el-Nachef MW. Insulin allergy resolution following pancreas transplantation alone. Clin Transplant 1998;12(6): 593–595. 19. Becker BN, Odorico JS, Becker YT, Groshek M, Werwinski C, Pirsch JD, et  al. Simultaneous pancreas-kidney and pancreas transplantation. J Am Soc Nephrol 2001;12(11):2517–2527. 20. Elkhammas EA, Henry ML, Ferguson RM, Bumgardner GL, Pelletier RP, Rajab A, et  al. Simultaneous pancreas-kidney transplantation: overview of the Ohio State experience. Yonsei Med J 2004;45(6):1095–1100. 21. Rayhill SC, D’Alessandro AM, Odorico JS, Knechtle SJ, Pirsch JD, Heisey DM, et al. Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: Is there a difference in survival? Ann Surg 2000;231(3): 417–423. 22. Bunnapradist S, Cho YW, Cecka JM, Wilkinson A, Danovitch GM. Kidney allograft and patient survival in type I diabetic recipients of cadaveric kidney alone versus simultaneous pancreas kidney transplants: a multivariate analysis of the UNOS database. J Am Soc Nephrol 2003;14(1):208–213. 23. Gutierrez P, Marrero D, Hernandez D, Vivancos S, Perez-Tamajon L, Rodriguez de Vera JM, et  al. Surgical complications and renal function after kidney alone or simultaneous pancreas-kidney transplantation: a matched comparative study. Nephrol Dial Transpl 2007;22(5):1451–1455. 24. Douzdjian V, Rice JC, Gugliuzza KK, Fish JC, Carson RW. Renal allograft and patient outcome after transplantation: Pancreas-kidney versus kidney-alone transplants in type 1 diabetic patients versus kidneyalone transplants in nondiabetic patients. Am J Kidney Dis 1996;27(1):106–116. 25. Manske CL, Wang Y, Thomas W. Mortality of cadaveric kidney transplantation versus combined kidneypancreas transplantation in diabetic patients. Lancet 1995;346(8991–8992):1658–1662. 26. United Network for Organ Sharing. 2007 U.S organ procurement and transplantation network/scientific registry of transplant recipients: Transplant data 1997–2006. 2008.

208 27. Hariharan S, Pirsch JD, Lu CY, Chan L, Pesavento TE, Alexander S, et al. Pancreas after kidney transplantation. J Am Soc Nephrol 2002;13(4):1109–1118. 28. Larson TS, Bohorquez H, Rea DJ, Nyberg SL, Prieto M, Sterioff S, et al. Pancreas-after-kidney transplantation: an increasingly attractive alternative to simultaneous pancreas-kidney transplantation. Transplantation 2004;77(6):838–843. 29. Humar A, Ramcharan T, Kandaswamy R, Matas A, Gruessner RW, Gruessner AC, et  al. Pancreas after kidney transplants. Am J Surg 2001;182(2):155–161. 30. Douzdjian V, Escobar F, Kupin WL, Venkat KK, Abouljoud MS. Cost-utility analysis of living-donor kidney transplantation followed by pancreas transplantation versus simultaneous pancreas-kidney transplantation. Clin Transplant 1999;13(1 Pt 1):51–58. 31. Gruessner RW, Sutherland DE, Gruessner AC. Mortality assessment for pancreas transplants. Am J Transplant 2004;4(12):2018–2026. 32. Humar A, Sutherland DE, Ramcharan T, Gruessner RW, Gruessner AC, Kandaswamy R. Optimal timing for a pancreas transplant after a successful kidney transplant. Transplantation 2000;70(8):1247–1250. 33. Brennan DC, Stratta RJ, Lowell JA, Miller SA, Taylor RJ. Cyclosporine challenge in the decision of combined kidney-pancreas versus solitary pancreas transplantation. Transplantation 1994;57(11):1606–1610. 34. Lane JT, Ratanasuwan T, MackShipman LR, Taylor RJ, Leone JP, Miller SA, et  al. Cyclosporine challenge test revisited: Does it predict outcome after solitary pancreas transplantation? Clin Transplant 2001;15(1):28–31. 35. Larsen JL. Pancreas transplantation: Indications and consequences. Endocr Rev 2004;25(6):919–946. 36. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. NEJM 1993;329(14):977–986. 37. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. NEJM 2005;353(25):2643–653. 38. Dean PG, Kudva YC, Stegall MD. Long-term benefits of pancreas transplantation. Curr Opin Organ Transplant 2008;13(1):85–90. 39. Humar A, Ramcharan T, Kandaswamy R, Gruessner RW, Gruessner AC, Sutherland DE. Technical failures after pancreas transplants: why grafts fail and the risk factors – a multivariate analysis. Transplantation 2004;78(8):1188–1192. 40. Gruessner RW, Dunn DL, Gruessner AC, Matas AJ, Najarian JS, Sutherland DE. Recipient risk factors have an impact on technical failure and patient and graft survival rates in bladder-drained pancreas transplants. Transplantation 1994;57(11):1598–1606. 41. Troppmann C, Gruessner AC, Dunn DL, Sutherland DE, Gruessner RW. Surgical complications requiring early relaparotomy after pancreas transplantation: A

H.-Y. Tiong and V. Krishnamurthi multivariate risk factor and economic impact analysis of the cyclosporine era. Ann Surg 1998;227(2): 255–268. 42. Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D, et  al. The evaluation of renal transplantation candidates: Clinical practice guidelines. Am J Transplant 2001;1(Suppl 2):3–95. 43. Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, et al. Cancer in patients on dialysis for end-stage renal disease: An inter­national collaborative study. Lancet 1999;354(9173):93–99. 44. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009: a review of ­current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2009;59(1):27–41. 45. Guide to clinical preventive services, 2008: Recommendations of the U.S. preventive services task force [homepage on the Internet] 2008. September 2008. Available from http://www.ahrq.gov/clinic/pocketgd08/ 46. US Preventive Services Task Force. Screening for cervical cancer: Recommendations and rationale. Am J Nurs 2003;103(11):101–102;105–106, 108–109. 47. US Preventive Services Task Force. Screening for breast cancer: recommendations and rationale. Ann Intern Med 2002;137(5 Part 1):344–346. 48. US Preventive Services Task Force. Screening for colorectal cancer: Recommendation and rationale. Ann Intern Med 2002;137(2):129–131. 49. US Preventive Services Task Force. Screening for prostate cancer: Recommendation and rationale. Ann Intern Med 2002;137(11):915–916. 50. Herzog CA, Marwick TH, Pheley AM, White CW, Rao VK, Dick CD. Dobutamine stress echocardiography for the detection of significant coronary artery disease in renal transplant candidates. Am J Kidney Dis 1999;33(6):1080–1090. 51. Manske CL, Thomas W, Wang Y, Wilson RF. Screening diabetic transplant candidates for coronary artery disease: Identification of a low risk subgroup. Kidney Int 1993;44(3):617–621. 52. Sharma R, Pellerin D, Gaze DC, Gregson H, Streather CP, Collinson PO, et al. Dobutamine stress echocardiography and the resting but not exercise electrocardiograph predict severe coronary artery disease in renal transplant candidates. Nephrol Dial Transplant 2005;20(10):2207–2214. 53. Feringa HH, Bax JJ, Schouten O, Poldermans D. Ischemic heart disease in renal transplant candidates: towards noninvasive approaches for preoperative risk stratification. Eur J Echocardiogr 2005;6(5):313–316. 54. Manske CL, Wilson RF, Wang Y, Thomas W. Prevalence of, and risk factors for, angiographically determined coronary artery disease in type I-diabetic patients with nephropathy. Arch Intern Med 1992;152(12):2450–2455. 55. Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992;340(8826):998–1002.

9  Selection and Preparation of the Pancreas Transplant Recipient 5 6. Molina JE, Sutherland DE, Wang Y, Gruessner AC, Bland BJ. Coronary bypass before simultaneous pancreas-kidney transplants for type 1 diabetics in renal failure. World J Surg 2004;28(10):1036–1039.

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57. Assmann G, Carmena R, Cullen P, Fruchart JC, Jossa F, Lewis B, et al. Coronary heart disease: Reducing the risk: a worldwide view. International Task Force for the Prevention of Coronary Heart Disease. Circulation 1999;100(18):1930–1938.

Chapter 10

Kidney Transplant Recipient Surgery Daniel A. Shoskes

Keywords  Kidney transplant • Surgical ­technique • Arterial anastomosis • Venous anastomosis • Ureteric implantation The basic principles of kidney transplant recipient surgery have remained fairly constant for the past 20 years, and the wide variation in individual surgeon practice speaks to the many routes that can give a solid technical result. The purpose of this chapter is to outline the key principles of the operation and to then provide personal pearls of technical tricks that have worked well for me, and which others may find suit their individual operative style.

Implant Location The most common location for placing a kidney transplant is in the retroperitoneal iliac fossa, with vascular anastomoses to the external or internal iliac artery and the iliac vein and ureteral anastomosis directly to the bladder. There are several practical advantages for these heterotopic choices. Staying out of the peritoneal cavity allows more rapid return of bowel function and any hemorrhage or urine leak is confined to a smaller nonabsorptive space, making diagnosis D.A. Shoskes (*) Cleveland Clinic, Glickman Urological & Kidney Institute, Q10, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]

easier and more rapid. The kidney lies just under the skin without any intervening bowel, which simplifies subsequent percutaneous biopsy. Finally, the distance to the bladder is short, allowing for use of the better vascularized proximal donor ureter for implantation. Either side can be used for either kidney, and when both sides are equally available most surgeons favor the right side because (1) the right iliac vein is usually more superficial than the left; and (2) should the iliac vessels prove unsuitable, it is easier to move up to the aorta and inferior vena cava while still remaining retroperitoneal. An alternate view is held by some surgeons who favor keeping the renal pelvis and ureter anterior (e.g., left kidney to right side, right kidney to left side) to facilitate ureteral reconstruction in the face of donor ureteral necrosis. Rarely, if the pelvis is not useable, an orthotopic transplant can be done by removing the left native kidney and anastomosing the donor vein to the recipient renal vein, the donor artery to the  splenic artery, and the donor ureter to the recipient ureter.

Preparation of Donor Kidney Typically, the donor kidney is prepared prior to implantation on a back table, which allows optimal positioning, lighting, and magnification. The kidney is kept in a basin that contains both sterile saline and ice. As long as both saline and ice are present, the temperature of the fluid should

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_10, © Springer Science+Business Media, LLC 2011

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remain between 1°C and 4°C. The degree of graft preparation could vary from minimal in the case of an open living kidney donor to significant in the case of an en bloc kidney procurement. I prefer to start by placing a mosquito clamp on the end of the ureter and holding it off to the side to prevent inadvertent transection. The renal vein and artery are then cleaned and any side branches that do not enter the kidney are ligated.

Venous Preparation The left renal vein is usually of sufficient length once the main side branches (adrenal, lumbar, and gonadal) are ligated. Note that the entire gonadal vein should be dissected away, because it can take small tributary branches from the kidney and ureter and therefore may bleed even though both ends are ligated. Because the venous drainage communicates within the kidney, small accessory renal veins may be tied off; however, when multiple veins are of similar size, they should be preserved, either by conjoining or by using a jump graft (Fig. 10.1). The right renal vein has two limitations: it is shorter than the left renal vein and is often thinner, especially posteriorly. In a living donor, a cuff of donor cava can give thicker tissue to anastomose. In a cadaveric donor, when the kidneys are split, the entire remaining cava should be sent with the right kidney. This allows the use of cava to extend the right renal vein, often to a length equal to or exceeding the right renal artery. When inspecting the donor cava, first ensure that the suprarenal portion is intact, as it may be damaged or “scalloped” during removal of the liver. The most common reconstruction technique is to cut the cava in line with the right renal vein and to then sew the superior and inferior parts of the cava with 5-0 Prolene suture (Fig.  10.2). The left renal vein orifice often remains as a convenient opening to anastomose to the recipient. If more length is required, then the cava can be rotated in line with the renal vein and only the superior opening closed with

Prolene (Fig. 10.3). The lower cava can then be anastomosed end to side directly to the recipient. Note that this requires careful ligation of all remaining lumbar venous branches coming from the cava and may result in a very wide anastomosis. After any reconstruction, testing of the vessels by irrigating with heparinized saline should show any missed branches or large gaps in the closures.

Arterial Preparation The renal artery orifice should be carefully examined for injury, especially flaps of intimal plaque or aneurysms, which may not be obvious when the artery is undistended. The artery should be cleaned a followed towards the hilum, taking care to preserve renal branches. All renal arteries are end arteries, so any branches that are ligated will result in a region of nonperfused renal parenchyma. This is especially important for lower pole branches, which often provide the entire blood supply for the donor ureter. Note that an upper pole branch may at first appear to simply be an adrenal artery. Trace its path proximally and you may discover that it takes a sharp turn into the renal parenchyma. When the renal artery does not have donor aorta attached (living donor or diseased cadaveric aorta) I prefer to make a small spatulation inferiorly, which aids in orientation later. When donor aorta is attached and healthy, a small rim of aorta can be preserved (Carrel patch), which minimizes trauma to the renal intima during anastomosis (Fig. 10.4). Multiple renal arteries can be handled by a variety of techniques, depending upon number, size, relative length, presence and health of donor aorta, and separation. With a cadaveric donor, the simplest approach is to use a patch of donor aorta that includes all the renal artery orifices (Fig. 10.3). This necessitates a longer recipient arteriotomy, and if the resultant patch is greater than 4 cm, it can be reconstructed on the back table to still allow a single recipient anastomosis but not be so long. If donor aorta is not available or too diseased, arteries can be anastomosed

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10  Kidney Transplant Recipient Surgery Fig. 10.1  Back table repair of short renal vessels. Two short renal veins were extended with the use of cadaveric iliac vein (A). The short renal artery was extended with a segment of gonadal vein (B)

Fig.  10.2  Back table preparation of a right kidney. The right renal vein has been extended with the inferior vena cava by cutting the cava in line with the vein and oversewing the superior and inferior openings (A). The

individually, but small size my increase the ­technical difficulty. If two arteries are of similar length and size, they can be brought together to form one orifice. Each artery is spatulated facing each other and then the apices stitched together with 6-0 or 7-0 Prolene. The suture line can then be run up each side of the arteries to form a single larger orifice. In the case of two renal arteries in which one is smaller than the other, an end-to-side anastomosis of the smaller to the larger can be done with running or interrupted suture. A small, metal sound positioned in the larger artery can help prevent inadvertent suturing of the back wall.

old orifice of the left renal vein can then be used to anastomose to the recipient. Note Carrel patch on renal artery, which still needs to be trimmed (B)

Ureteral Preparation Since all perfusion of the donor ureter must come from the donor renal arteries, preservation of the ureteral blood supply is essential. This is best accomplished by leaving intact the fat and adventitial tissue found in a triangle formed by the ureter, inferior pole of the kidney, and renal artery(ies). In the case of two ureters, they can be anastomosed individually or conjoined on the back table. It is my preference to keep ureters from separate renal units (e.g., pediatric en bloc kidneys) separate, but to conjoin ureters that come from the same kidney. Using the Wallace

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Fig.  10.3  Kidney with multiple vessels placed in stockinette. Stockinette is filled with iced slush and the vessels brought out through separate openings, which allows the kidney to remain cold during the recipient anastomosis. Two renal arteries kept together on a common

aortic patch (A). The two renal veins were kept on the inferior cava which was rotated in line with the vessels to provide extra length (B). A third lower pole renal artery, not identified during the organ procurement was anastomosed separately (C)

Fig. 10.4  Left kidney after back table preparation. There is a small Carrel patch on the artery (A). The renal vein has all side branches tied (B). Perinephric fat in the

“golden triangle” between the lower pole of the kidney and proximal ureter is intact to preserve ureteral blood supply (C)

technique, the ureters are spatulated, sutured together at the apex, and then the suture is run up one side of the ureteral edge.

Any suspicious solid lesions should be biopsied and sent for frozen section and any large cysts should be deroofed to ensure no internal solid components. All vessels should be flushed manually with cold heparinized saline to ensure no leaks requiring ligation or suture. It is my personal preference to place the kidney in a sterile cloth stockinette that is filled with slush. Both ends are closed with clips and the vessels brought out through a separate opening at the midpoint

Final Preparation Once the vessels and ureter are prepared, perinephric fat is removed, taking care not to cut the renal capsule, which may be adherent to the fat.

10  Kidney Transplant Recipient Surgery

(Fig.  10.3). This allows the kidney to remain cold throughout the anastomosis and makes manipulation of the kidney easier.

Recipient Surgery As mentioned, there are several implantation sites possible for the transplant kidney, but most commonly a Gibson incision with retroperitoneal exposure of the iliac vessels is used. The patient is positioned supine. It is my preference to have both arms out, for easy access to anesthesia if additional venous or arterial access is required. I place a three-way Foley catheter and attach the irrigation port to a 1 L bag of saline containing a bacitracin solution. A small volume of fluid is used to irrigate the bladder, especially if the patient is anuric. This clears debris of the bladder, which will later be opened into the retroperitoneum. Flexing the table with the break just above the pelvic brim shortens the distance between the skin and pelvic vessels, and a small degree of Trendelenburg helps keep the peritoneal contents out of the operative field. A Gibson incision starting one finger breadth above the pubis and extending two finger breadths medial to the anterior superior iliac spine is made through skin and muscle layers. I will usually ligate and transect the inferior epigastric vessels, although they may be preserved, especially if the donor kidney has a small lower pole artery which might be anastomosed to the epigastric artery. In women, the round ligament is usually transected, but in men an effort is made to preserve the cord. The cord may be transected to aid in exposure, but testicular atrophy and hydrocele may be more likely in that case. A self retaining retractor greatly aids in exposure, and I prefer a Bookwalter, typically using two lateral blades and three medial blades. The external iliac artery and vein are then mobilized, taking care to ligate any visible lymphatics. If the iliac vein is very deep, ligation and transection of the internal iliac vein can improve mobilization. Vascular occlusion during the

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anastomosis can be achieved with side-biting clamps (e.g., Satinsky, C-Clamp), bulldog clamps, Rommel tourniquets, or angled padded clamps (e.g., Fogarty). At the start of the vascular anastomosis it is worth pausing to ensure with the nurses that all suture material is ready and with anesthesia that preoperative medications (e.g., antibiotics, steroids, immunosuppressive induction drugs) have been given. I usually will give a “kidney cocktail” containing albumin, mannitol, and furosemide that runs in during the anastomosis and ask for a target mean arterial pressure of about 80 mmHg. As the vein is usually deeper, I prefer to begin with the venous anastomosis. I place a Satinsky side-biting vascular clamp and create a venotomy with a #12 hook curved scalpel blade. Because the cutting surface of this blade is superior, it minimizes the risk of perforating the iliac vessel posteriorly. The interior of the vessel is flushed with heparinized saline and the opening cut to exact size with angled scissors. I use 5-0 Prolene for the end to side anastomosis between renal vein and iliac vein, sewing and tying two double-armed sutures at each end of the anastomosis and then sewing towards the middle. At this point, some surgeons routinely place a bulldog clamp across the renal vein and remove the iliac vein clamp. This allows early detection of venous anastomotic leakage and reduces the amount of hardware in what is sometimes a tight space. The arterial clamp is then placed on the external iliac artery, usually superior to the venous anastomosis. After incising the anterior surface of the artery with a #12 scalpel blade, I prefer to complete the opening with an aortic punch, which allows for a clean opening that takes all vessel wall layers equally, even if there is plaque. For the end-to-side anastomosis, I prefer 6-0 Prolene. If a Carrel patch is available, I will again place sutures at both ends of the anastomosis and sew with each to the middle. If it is a small artery with no patch, I usually prefer to sew a single suture circumferentially. In that case, care should be taken to not cinch the suture too tightly when tying the knot (“growth factor”) so that as the arteries fill with blood the anastomosis is not narrowed.

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The venous clamp is removed first followed by the arterial. If bulldogs were used on the artery, the distal clamp is removed first to test the anastomosis. The kidney is warmed with saline poured on the surface. Anastomotic bleeding can be carefully sutured if a large gap is present, but bleeding from needle holes will typically stop with time and mild pressure. Bleeding on the renal surface can be coagulated with cautery or the Argon beam coagulator. Beware bleeding from small hilar arterial vessels which might be in spasm when the kidney is cold but will start bleeding as the kidney warms and perfuses. The kidney may pink up slowly in the face of ischemia-reperfusion injury, but if there is an anatomic line of demarcation between perfused and non-perfused kidney, immediately search for a possibly missed or transected arterial branch. To improve renal perfusion, especially in kidneys from cadaveric donors, I will inject 5 mg of verapamil into the renal artery unless the patient is heavily beta blocked, in which case the combination of a calcium channel blocker may lead to heart block. The usual preferred technique for urinary tract reconstruction is an extravesical neo-cystostomy (Lich-Gregoir) with or without the creation of an extravesical ureteral tunnel. An open intravesical tunnel (e.g., Leadbetter-Politano) is seldom necessary, requires greater ureteral length, and more likely leads to hematuria. The bladder dissection is facilitated by filling the bladder via the threeway Foley catheter and clamping the outflow. Minimal length of donor ureter that allows a tension free anastomosis should be used to minimize distal ischemia. I prefer a running anastomosis using two 5-0 Vicryl sutures. If there are two ureters, they can be inserted into the bladder individually or fist conjoined and then attached as one. If the two ureters arise from two separate renal units (e.g., pediatric en bloc transplant) I prefer separate anastomoses, in case the arterial supply to one is compromised. If the donor ureter has been damaged or if well-perfused ureter will not reach the bladder, the native ipsilateral ureter may be tied proximally, transected, and rotated up to be anastomosed to the donor ureter or renal

pelvis. The literature supports the routine use of a double J ureteral stent for reducing complication rates, realizing that for over 90% of patients they are likely unnecessary. I do use stents routinely and aim to remove them between 2 and 4 weeks postoperatively. After the ureteral anastomosis, the kidney is then reinspected for bleeding and positioned in the retroperitoneum to avoid kinking of the vessels or tension on the ureter. In the rare instance when placing the kidney laterally results in vessel occlusion in every orientation, consider placing the kidney medially, which usually requires opening the peritoneum and an intraperitoneal position. A closed suction drain may be placed in the retroperitoneum and brought out through a separate skin opening. There are many techniques for wound closure. I prefer nonabsorbable suture (Prolene) and do an inner running layer of muscle for apposition and an interrupted figure of eight outer layer for the external oblique fascia. It is important not to pull or tie the suture too tightly against the fascia. Between fluid shifts and steroids these patients will often have subsequent tissue edema and a tight closure can lead to ischemia and wound breakdown. In very obese recipients, a small drain in the subcutaneous space may be useful as well.

Pediatric En Bloc Transplant In small pediatric donors, better results are achieved by transplanting both kidneys together, still attached to the aorta and IVC (Fig. 10.5). In general, kidneys smaller than 8  cm are most commonly not separated. In preparing the kidneys on the back table, all lumber branches on the aorta and IVC are carefully ligated. The suprarenal segments of these vessels are then oversewn with Prolene. If they have been transected too close to the origin of the renal vessels, a small jump graft from the inferior part of the vessel can be attached end-to-end to the superior and then oversewn with less chance of occluding or kinking the renal vessels. These

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Fig. 10.5  Pediatric en bloc kidneys after back table preparation

kidneys often have very little hilar fat, and extra care must be taken to preserve the blood supply to both ureters. In these cases it is best to err on

the side of leaving too much fat, even though it may mean more small bleeders to coagulate or ligate after perfusion.

Chapter 11

Issues and Surgical Techniques to Expand the Pool of Kidneys Available for Transplantation Charles S. Modlin III and Charles S. Modlin Jr.

Keywords  Extended criteria donor • donation after cardiac death • dual marginal kidney transplant • pediatric en bloc kidney transplant.

Introduction This chapter reviews medical, surgical, and economic issues concerning donor selection criteria, allograft preservation, and outcome of transplantation of donor kidneys from deceased ECD donors as well as kidneys from nontraditional donors such as donors with infections, abnormal biopsies, and also discuss transplantation using “expanded living donors” (i.e., older living donors or living donor kidneys with multiple vessels, ureteral abnormalities, or stones).

The Expanded Criteria Donor Kidney transplantation affords patients with endstage renal disease (ESRD) a survival advantage over those remaining on dialysis [1]. Statistics demonstrate that patients who did not undergo transplantation have an adjusted risk of death 2.54 times higher than that of transplanted

C.S. Modlin, Jr. (*) Glickman Urological & Kidney Institute, Section of Renal Transplantation, Cleveland Clinic, Cleveland, OH, USA e-mail: [email protected]

patients of the same age, regardless of the type of allograft. The risk of death is 3.78 times higher than that for patients receiving nonexpanded (standard) criteria donor (SCD) kidneys and 2.31 times higher for patients receiving expanded ­criteria donor kidneys (ECD) [1]. Transplantation offers a significant reduction in mortality compared with dialysis in the wait-listed elderly population with ESRD, as well as in patients with kidney disease resulting from diabetes or hypertension [2]. Because of the chronic shortage of available donor kidneys for transplantation, many transplant centers have expanded their range of acceptance criteria in determining the suitability of donor kidneys for transplantation [3–19]. The suitability for donorship, in general, is related to donor age, the circumstances of death, absence of infection and malignancy, general health of the prospective donor prior to the terminal hospitalization, and status of kidney function at the time of death. Currently the only absolute exclusion criteria are human immunodeficiency virus infection (HIV), uncontrolled tumor disease, and active infections [20]. Due to the shortage of kidneys available for transplantation and the growing list of patients awaiting renal transplantation, many kidneys previously considered suboptimal for transplantation (marginal) are now transplanted routinely by many centers [21–23]. ECD kidneys are those traditionally considered to be associated with inferior graft survival, such as those from deceased donors over the age of 55 years, pediatric donors, non-heart-beating donors, donors with abnormal renal function, and kidneys with

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_11, © Springer Science+Business Media, LLC 2011

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prolonged preservation times. In addition, other donor kidneys considered “high-risk” or “suboptimal” include those from donors with hepatitis C, diabetes (DM), or hypertension (HTN), as well as other systemic disorders or findings on biopsy at time of procurement [24, 25]. Additionally, because of the increasing need for donor kidneys and increased waiting times, many transplant centers have expanded the acceptance criteria allowing donors with vascular abnormalities [26] and other anatomic abnormalities [27] and living unrelated and even living transplantation from complete strangers (altruistic donors). The current official category of “expanded criteria donors” was established by United Network for Organ Sharing (UNOS) [28, 29]. The designation of ECD kidneys now officially includes kidneys where the estimated adjusted risk of graft failure is greater than 70% (relative risk £1.70) compared to standard characteristics of transplant suitability. The donor characteristics that define an ECD kidney include any deceased donor (1) greater than age 60 years or (2) age 50 to 59 years with any two of: (a) creatinine greater than 1.5 mg/dL, (b) cerebrovascular accident cause of death, or (c) history of hypertension. The standardized definition of the ECD for kidney transplantation has facilitated modifications of the national organ allocation policies that are designed to increase procurement, improve use, decrease cold ischemia time, and lead to improved outcome [30]. The US Organ Procurement and Transplantation Network implemented in 2002 a policy allocating ECD kidneys by waiting time alone [31, 32]. In the first 18 months following policy implementation there was an 18.3% increase in ECD kidney recoveries and a 15% increase in ECD kidney transplants and the percentage of ECD kidneys with cold ischemia times of less than 12 h increased significantly. In the aggregate, recipients of ECD kidneys have improved survival compared to ESRD [33]. The current shortage of available donor kidneys coupled with the expectation that expanded criteria donor kidneys will function well is the rationale for transplanting these kidneys previously discarded [34–36].

C.S. Modlin III and C.S. Modlin Jr.

There are obvious concerns to using non-perfect donors include increased cost of hospital care [37–40], increased potential risks to the recipient in the event of poorer graft function and/or graft survival, and higher complication rates. Litigation concerns both of the hospital and the transplant center with respect to maintaining excellent patient and graft survival statistics should not be overlooked. The viability of a particular transplant center to maintain its certification to operate is dependent upon both short- and long-term outcome statistics. Some transplant centers are reluctant to “risk” their outcome ­statistics and therefore, are quite averse to accepting kidneys from ECD. The real problem is to determine the precise points at which ECD ­provide more benefit than harm.

The Recipient of an Expanded Criteria Donor Kidney: Selection Criteria As with any transplant candidate, the suitable candidate to receive an ECD kidney must undergo rigorous medical, nephrologic, and surgical clearance, which is covered elsewhere in this book. However, some unique considerations apply to which patients with ESRD should receive an ECD kidney. As mentioned, current UNOS policy for allocation of ECD kidneys allocates ECD kidneys to recipients based upon waiting time alone. In addition, transplant centers inform, identify, and place such kidneys on a separate ECD donor list as they become available in the pretransplant evaluation period during which some patients are willing to accept an ECD donor kidney for the purposes of expediting the process of allocation [41]. Pediatric patients are generally not considered candidates for ECD kidneys. Pediatric patients experience more ­surgical complications when transplanted with kidneys from pediatric donors [42, 43]. In addition, Pascual et al. performed a systematic review of kidney transplantation from ECD donors and concluded, based upon the available evidence,

11  Issues and Surgical Techniques

that patients 40 years or older, especially those with diabetic nephropathy or nondiabetic disease, but with a long expected waiting time for kidney transplantation, show better survival receiving an ECD kidney than remaining on dialysis therapy. Patients younger than 40 years of age or scheduled for kidney retransplantation should not receive an ECD kidney [44]. Sellers et  al. reported poorer outcomes of ECD transplantation in retransplanted patients receiving ECD kidneys, and cautioned against the use of ECD kidneys in the this setting [45]. Chavalitdhamrong et al. studied patient and graft survival outcomes from deceased donors age 70 years and older using the Organ Procurement Transplant Network/UNOS database (601 donors between 2000 and 2005). They found that transplants from older ECD kidneys were associated with a higher risk of graft loss and patient death, and that the risk was highest when older ECD ­kidneys were transplanted into recipients younger than 60 years old [16]. Careful and appropriate assessment of the potential recipient’s comorbidity grouped with prognostic indexes could be a useful tool in making crucial allocation decisions as to which patients should be considered candidates for an ECD kidney, given the added risks of delayed graft function (DGF) and associated complications following ECD transplantation both during the pretransplant evaluation as well as at the time of allocation and transplantation. Schold et  al. discussed which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis and evaluated the likelihood of candidates’ receiving a transplant on the basis of age and other characteristics by duration of waiting time [46]. Schold noted that increased candidate age is associated with the likelihood of not receiving a transplant during the period on the waiting list as a result of mortality and separately related to morbidity and delisting. He concluded that older and frailer candidates benefit from accepting lower quality organs early after ESRD, whereas younger and healthier patients benefit from receiving higher quality organs even with longer dialysis exposure. Many transplant centers also

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take into ­consideration the matching of nephron mass with recipient size (BMI <25 kg/m)2 and avoiding the use of ECD kidneys in recipients with a high immunologic risk [47, 48]. The question as to which recipients are most appropriately suited to be transplanted with an elderly donor kidney has been studied [49]. Kumar [50] analyzed results of transplanting 25 elderly donor kidneys into young adult recipients (ages 20–50 years). All elderly donor kidneys underwent biopsy and showed less than 20% glomerulosclerosis. Results were compared to age-matched recipients of young adult donor kidneys. Kumar noted that elderly kidneys provided suboptimal function and inferior longterm graft survival due to higher metabolic and physiologic demands which predispose to hyperfiltration adversely affecting survival, and more frequent acute rejections in younger recipients. Kumar proposed that elderly donor kidneys be transplanted into age-matched recipients. Domagala et  al. reviewed complications of transplantation of ECD donor kidneys compared to SCD kidneys and concluded that the rate of complications in recipients of ECD and SCD kidneys was comparable [51].

Clinical Evaluation of the Potential Deceased Donor The information required to evaluate the potential deceased kidney donor includes: blood type, donor age, size (body mass index, BMI), past medical history (i.e., systemic infection, serology, local infection, malignancy, etc.), current medical history (trauma, hypertension, renal disease, vasopressor requirements, other organ disease), and vital signs (hypotension, oxygen tension, urine output), laboratory tests (electrolytes, blood urea nitrogen [BUN]/creatinine, glomerular filtration rate [GFR], urinalysis, serologies, electrocardiogram [EKG], chest x-ray) [52]. Medical contraindications for organ donation include potentially transmissible infectious disease and cancer that could adversely affect recipient outcome.

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The Role of the Allograft Kidney Biopsy in Renal Transplantation

Organ Preservation and Pulsatile Perfusion

Pretransplant allograft biopsy has become standard practice with elderly donor kidneys as a means to predict kidney graft survival [25, 53, 54]. Transplant centers and organ procurement agencies have adopted differing policies dictating what donor age should automatically trigger a protocol biopsy of the renal allograft at the time of donation, but many have adopted the policy that donor kidneys above the age of 50 years undergo a wedge or needle biopsy of each kidney with frozen and permanent section readings. Many centers prefer wedge biopsies to over needle biopsies because they provide greater sampling. Prognostic information is gathered by evaluating certain renal histologic criteria, ­specifically the presence and degree of glomerular obsolescence, interstitial fibrosis, and arteriolar sclerosis [25]. Kayler et al. correlated histologic findings on preimplant biopsy with kidney graft survival and concluded donor vascular disease was an independent risk factor for suboptimal graft survival and that great caution should be exercised in the decision to transplant kidneys with moderate arterial and/or arteriolar luminal narrowing [25]. With advancing age of the donor, there is a greater likelihood of finding the above histologic changes in the donor kidney. In general, the presence of significant degrees of glomerulosclerosis (>10%) in either kidney lead many transplanting surgeons either to discard the kidney or transplant both donor kidneys into a single recipient (dual deceased renal transplantation) (Fig. 11.1) [24, 55–57]. However, Lu et al. reported on the successful transplantation of kidneys with >20% sclerosis on biopsy and concluded that such kidneys may provide excellent outcome similar to that of kidneys from donors with no glomerulosclerosis [58]. Additionally Lu reported that the degree of vasculopathy in the donor kidney did not correlate to any important donor criteria except the percent of glomerulosclerosis. Others report also that procurement biopsy provides only limited information for the decision whether or not to accept a kidney donor [25, 59].

The goals of kidney retrieval and preservation of deceased donor kidneys include maintaining structural and functional integrity of the allograft as well as providing adequate time to arrange for the logistics of kidney sharing between centers while minimizing the risk of DGF following transplantation [60–64] and reducing the discard rate of ECD kidneys [65]. Good preservation with immediate allograft function posttransplant is the goal, to reduce patient morbidity, shorten hospital stay, lower cost, and result in improved long-term graft survival [23, 26]. Johnston reported that while ECD kidneys do not appear to be more sensitive to cold ischemia time (CIT) than SCD kidneys, minimizing CIT is potentially beneficial [66]. Kidneys can be stored (cold preservation) for 48 h at 4°C; however, cold ischemia times over 24 h result in a higher incidence of DGF. An alternative to simple cold storage is pulsatile pump perfusion (PPP), whereby the deceased donor kidney is placed on a pump apparatus and mechanically perfused with a preservation solution. Longer total ischemia times can be achieved with PPP compared to simple cold storage [67–70]. Given current national sharing of organs, combination simple cold storage with PPP is common [71]. Machine preservation also provides pretransplant information in the evaluation of deceased kidneys that is not available in cold stored organs. Donor perfusion parameters can be measured (such as donor flow rates, perfusion pressures, and renal vascular resistance), in an effort to predict the possibility of posttransplant DGF. PPP is often used in cases involving kidneys from elderly donors (>50 years old) and donors with history of hypertension, vasopressor support, poor backtable flush, low urinary output, >10% glomerulosclerosis on biopsy, warm ischemia times, and donors with anticipated longer preservation times. Polyak analyzed a database of ECD kidneys undergoing PPP and concluded that perfusion characteristics (flow and resistance) are highly predictive of early graft function of ECD

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Fig. 11.1  (a) Dual deceased renal transplantation (ipsilateral implantation). (b) Dual deceased renal transplantation (contralateral implantation)

kidneys [72]. Increasing resistance is significantly correlated with posttransplant DGF as is diminished flow. Optimal pump parameters include allograft flow of greater than 100 cc/min, with calculated renal vascular resistances of less than 0.40 and perfusion pressures of less than 50 mmHg systolic. It is difficult to judge the viability of a kidney on clinical data and appearance alone. There is no clear cutoff point for warm ischemia time after which kidneys should not be used [73]. Experimental and clinical studies have shown that ischemically damaged kidneys are better preserved by hypothermic pulsatile perfusion than preservation by simple cold storage [74]. Buchanan et  al. reported on the cost saving benefit of pulsatile machine perfusion preservation of ECD kidneys because of the reduced incidence of DGF in ECD kidneys preserved with PPP [75]. In a study by Sung reviewing records of 12,536 recovered ECD kidneys, 5139 (41%) were discarded. The discard rate of pumped ECD kidneys was 29.7% vs. 43.6% for

unpumped [65]. Among pumped kidneys, those with resistances of 0.26 to 0.38 and greater than 0.38 mmHg/mL/min were discarded more than those with resistances of 0.18 to 0.25 mmHg/ mL/min. Sung concluded that biopsy findings and machine perfusion are important correlates of ECD kidney discard [65]. Others also have reported that perfusion parameters are highly predictive of early graft function and report the advantages of PPP which result in lower ECD kidney discard rates, costs reductions, lower DGF, and improved outcomes of graft survival and function and in PPP preserved ECD kidneys over those preserved with simple cold storage [76–79]. Polyak reported that the addition of prostaglandin E1 to the preservation solution during PPP (but not cold storage) improves hydrostatic perfusion parameters and reduces the incidence of DGF in ECD kidneys [80]. Use of verapamil to the preservation solution is routinely utilized at our center to decrease the peripheral vascular resistance and increase flow rates during PPP of ECD kidneys.

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The Donor Kidney with Reduced Renal Function An obvious goal of kidney donor evaluation is to avoid transplanting kidneys that will never function. Certain situations place the donor kidney at risk for nonfunction posttransplant. Donors with reduced renal function with elevated serum creatinine values or prolonged preservation times predispose to posttransplant DGF or primary allograft nonfunction [81]. However, kidneys from donors with elevated creatinines may be utilized in situations when creatinines are declining and an elevated creatinine should not be the only cause for discarding deceased donor kidneys [81–84]. Serum and urine chemistries should be used to exclude the presence of prerenal azotemia and donors aggressively rehydrated accordingly and producing urine prior to procurement [85]. Kumar reported the successful transplantation (comparable to that seen in recipients of SCD) of kidneys with donors with acute renal failure. The donors were less than 55 years of age, with a negative history of kidney disease and a negative pretransplant biopsy from chronic structural changes [86].

The Donor Kidney with Prolonged Preservation times With current mandatory nationwide sharing protocols of deceased donor kidneys, transplant centers are commonly faced with transplanting kidneys with long CIT. As mentioned previously, kidneys with extended CIT are commonly being preserved using PPP techniques. The influence of the warm ischemia time (WIT) also has been found to impact allograft outcome. Therefore, kidneys with significant WIT have traditionally been discarded by most transplant centers. WIT refers to the amount of time occurring during which the allograft is not being ­perfused in the donor (i.e., donor downtime experienced prior to initial resuscitative efforts in the field or subsequent hospitalization during

C.S. Modlin III and C.S. Modlin Jr.

which the subsequent donor kidneys are poorly perfused due to lack of adequate systemic blood pressure). Additional warm time occurs during the revascularization of the allograft itself. The revascularization time depends on a variety of donor allograft and recipient variables. Donor kidneys with anatomic abnormalities are known to require longer revascularization times. Also, recipient anatomy impacts on revascularization time, with recipients harboring atherosclerotic arteries requiring more time. Revascularization times over 1 h increase the possibility of acute tubular necrosis (ATN) and DGF, negatively affecting graft survival.

The Non-Heart Beating Donor (Donation After Cardiac Death) Many transplant centers require that only brain dead donors be used (that the heart is still beating at the time of procurement and there has been declaration of brain death), eliminating nonheart beating donors, also known as donation after cardiac death (DCD) donors, from donation. Organ donation after cessation of cardiac pump activity is referred to as non-heart beating organ donation (NHB). NHB donors can be neurologically intact; they do not fulfill the brain death criteria prior to cessation of cardiac pump activity, but brain injury is irreversible. For hospitals to participate in NHB donation, they must comply with a federal requirement for ICU patients whose deaths are considered imminent after withdrawal of life support [87, 88]. NHB donors experience greater WIT as well as instability of blood and perfusion pressure prior to organ procurement and preservation. Heartbeating donors with planned, controlled ventilatory discontinuance are preferred over uncontrolled NHB organ procurement. Several transplant centers have reported success in transplanting kidneys from NHB donors and established protocols for the retrieval of kidneys from asystolic donors [89–101]. Currently DCD donors yield 1-year and 3-year graft and patient survival rates equivalent to kidneys from brain-dead donors and

11  Issues and Surgical Techniques

account for more than 5% of all deceased donor organs [102–104]. Experience with NHB kidney donors is extensive in Japan, primarily due to the fact that until recently, deceased kidney transplantation has been limited to NHB donors. An increase in the number of kidneys by 20% to 38% has been reported [38]. Others consider NHB donors kidneys to be second-class organs secondary to warm ischemia insults [35]. Nicholson noted in a series of 30 NHB donor kidneys compared to 114 conventional deceased donor kidneys that there was a higher early graft loss in NHB donor kidneys [45]. The renal function in NHB donor kidneys at 1 and 2 years was good but slightly inferior to the conventional deceased transplants. Other studies have suggested that despite a higher incidence of DGF and greater initial utilization of hospital resources and costs following transplantation with DCD donor kidneys, comparable short-term results seen following heart-beating donors can be achieved [40, 105]. Locke reported that when the cold ischemia time was limited to under 12 h in DCD kidneys from donors under the age of 50, the rate of DGF decreased to 15% and reported also similar long-term graft survival to those from SCD, suggesting also that DCD kidneys younger than 50 years of age function like SCD kidneys and should not be viewed as marginal [106]. Rudich reported that in recipients of DCD kidneys, the most pertinent variables leading to poor outcomes were donor age, recipient transplant number, female recipient, mechanism of injury, and DGF [107].

The Elderly Deceased Donor Allograft and Dual Renal Transplantation The number of deceased donor kidneys available for transplantation has increased only slightly over the last two decades. Most of the increase in organ donation has resulted from an increased utilization of older donors [47]. From 2000 to 2005, a total of 625 dual, 7,686 single kidney ECD, and 6,044 SCD transplants from donors

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aged greater than or equal to 50 years were ­identified from the Organ Procurement and Transplantation Network/UNOS data [108]. Contradictory results have been published on the success of kidney transplantation as it relates to donor age. Some authors [50, 112–114] have shown satisfactory results with kidneys harvested from extremes of donor age when proper selection criteria exist [115–126]. The diminished graft survival of elderly donor kidneys is believed to be due to a reduced functional reserve in older donor kidneys as well as the imbalance between the number of viable nephrons supplied and the metabolic demand of the recipient [127]. Aging of the kidney starts at age 30, with an increasing incidence of sclerotic glomeruli and progressive decline in GFR [128]. The reduced functional reserve of the older ­kidney must be added to injuries from rejection and calcineurin-inhibitor toxicity. In spite of these clear-cut histologic changes in aged kidneys, the age limit of possible donors remains controversial. It seems intuitive that renal structural alterations in the aging donor kidney could influence renal function after transplantation. The donor kidney over the age of 50 should be examined for signs of impaired intrarenal perfusion. The gross appearance of the donor ­kidney and renal vasculature should be noted. A donor history of hypertensive periods and/or albuminuria portends a poorer outcome of transplantation of elderly donor kidneys. All kidneys from donors over the age of 50 years and from donors with hypertensive histories and/or anticipated or observed perfusion abnormalities should be biopsied ex situ. The glomeruli should be examined for evidence of glomerulosclerosis and/or microthrombosis, the interstitium for evidence of fibrosis, and the tubules for evidence of atrophy. Elderly donor kidneys have a reduced renal mass. According to Brenner’s hyperfiltration hypothesis, a critical reduction of nephron mass results in sclerosis of overworked nephrons [125]. Terasaki [129] proposed several situations for the occurrence of hyperfiltration of renal allografts. Risk factors for hyperfiltration include transplantation of small donor kidneys, large

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recipients, female donor kidneys transplanted into males, deceased allograft transplantation, and rejection. Feehally [130] noted that nonimmunologic factors also contribute to hyperfiltration. Therefore, elderly kidneys are at risk for hyperfiltration injury, especially if other risk factors overlap [127]. When considering transplanting kidneys from elderly donors, consideration should be given to the above risk factors. Donors over the age of 50, when carefully selected, can contribute significantly to the total number of kidneys available for transplantation. To maximize outcomes, suggestion has been made that older donor kidneys be transplanted into lightweight recipients [132]. CIT and creatinine clearance have been shown to correlate highly with graft survival when transplanting donor kidneys over the age of 60 years [25]. Collins et  al. in their study of 781 ECD recipients determined that ECD kidneys over the age of 60 years were the most significant determinant of poor outcome, whereas donor age 50 to 59 years represented in their study a category of intermediate risk [133]. A newer technique designed to maximize the number of transplanted glomeruli of elderly deceased donor kidneys involves transplanting “dual” or double allografts, whereby both kidneys from the same elderly donor are transplanted into a single, older size-matched recipient, in cases where ECD kidneys are unsuitable for single use (see Fig. 11.1) [34, 65, 66, 134–142]. Currently, not all transplant centers perform dual deceased renal transplants, but there have been reports of excellent outcomes in graft function and patient and graft survival comparable to that seen using SCD kidneys [132]. In fact, elderly donor kidneys which meet criteria for dual deceased renal transplantation are typically kidneys declined by multiple transplant centers. Often these kidneys have prolonged preservation times as a result of the amount of time required to place and export the kidneys to the accepting transplant center. The criteria and decision to perform a dual deceased renal transplant rather than transplant a single elderly deceased kidney into a recipient is based upon several observations as well as the

C.S. Modlin III and C.S. Modlin Jr.

experience of the transplanting surgeon [132]. No absolute criteria exist to determine when dual transplantation is preferred over single elderly allograft transplantation; both physiologic and structural factors help make the decision. Donor physiologic factors favoring dual deceased transplantation are when the donor’s admission creatinine clearance is less than 90 mL/min [132], terminal serum creatinine is more than 2.5 mg/dL, serial donor serum creatinines are progressively on the rise, and the donor is more than 55 years old. Structural and anatomic findings of one or both kidneys which favor dual transplantation over single transplantation include allograft biopsy findings alone or in combination of more than 10% glomerular sclerosis, vascular thickening, and interstitial fibrosis. Also small kidney size favors dual rather than single renal transplantation. A group of pathologists developed a biopsy-based scoring system to assess whether single or dual transplantation should be used [127]. In addition, much benefit can be gained by limiting the cold storage time to under 24 h [128]. Assessing renal pulsatile perfusion flow parameters may also be reviewed when deciding to transplant dual versus single elderly deceased kidneys (see section on preservation above). Recipient factors, such as the recipient’s size and the vascular anatomy (suitable vascular location for implantation), also contribute to the decision of performing dual versus single kidney implant. Lee [143] reported on early success with elderly dual deceased renal transplantation, using calculated creatinine clearance and donor age as criteria for the use of dual adult donors. Lee concluded that adequate renal mass should be transplanted to provide the recipient 50 mL/ min of creatinine clearance. Admission donor creatinine clearance equal to the sum of creatinine clearance of both kidneys was used to estimate baseline function. If a single kidney from a donor was unable to provide at least 50 mL/min of creatinine clearance, then both donor kidneys were transplanted into a single recipient. Alfrey et al. conducted a retrospective review of 152 adult deceased renal transplants, 68 being ECD donor kidneys with 20 dual transplants to

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determine under what conditions ECD kidneys should be used as single versus dual transplants [144, 145]. Recipients of single ECD kidneys had a significantly higher serum creatinine at 1 and 3 months posttransplant vs. recipients of ECD dual and non-ECD kidneys. The differences were not significant at 6 months posttransplant however. Three significant donor characteristics were found from the study to impact early graft function and outcome of dual transplants. When the donor admission creatinine clearance was less than 90 mL/min, the incidence of delayed graft function was significantly less when ECD kidneys were transplanted as dual vs. single transplants. When the donor was 59 years old or older, a 50% reduction in DGF was noted along with significantly better serum creatinine up to 3 months posttransplant when ECD kidneys were transplanted as dual vs. single kidneys. Other series have described an improvement in short-term (1-year) and longterm outcome in patients without DGF vs. those with DGF [146]. On the other hand, Harford [147] reported on single kidney transplants from donors with low estimated creatinine clearance [148]. Donors with admission creatinine clearances less than 90 mL/min were classified as marginal donors. Harford noted that the Cockcroft-Gault estimate of creatinine clearance is least accurate at either extremes of age, body size, and renal function [147]. Harford noted no difference in patient ­survival, renal function, or graft survival between recipients of elderly single vs. elderly dual deceased allografts, and therefore suggested that depressed creatinine clearance should not be used as an independent donor indicator of functional adequacy of an allograft in the recipient and that other clinical criteria should be utilized for selection of dual vs. single renal allograft transplantation. Snanoudj proposed the donor estimated GFR (eGFR) as an appropriate criterion for allocation of ECD kidneys into single or dual kidney transplantation [145]. Wolters et al. reported on using the Muenster double kidney score as an essential means for evaluation of marginal donor residual kidney function to assist in determination as to whether potential ECD

kidneys should be transplanted as single ECD kidneys, dual, or discarded [150]. As discussed under the section of immunosuppression of ECD kidneys, induction with triple maintenance calcineurin inhibitor-free immunosuppression in dual kidney transplantation from elderly donors results in lower DGF and better renal function [151].

The Pediatric Deceased Donor Kidney Contradictory results have been reported ­concerning the success of kidney transplantation in relation to donor age, with technical failure being held responsible for high graft failure rates when very young donor kidneys were used for transplantation, especially when transplanted into pediatric recipients. These kidneys may be transplanted into adult recipients either as single pediatric kidneys or as dual en bloc kidneys [152, 153].

Single-Unit Pediatric Deceased Donor Transplantation Review of 60 adult recipients of single pediatric donor deceased kidneys at the Cleveland Clinic revealed similar graft and patient survival to that of adult deceased donor transplantation [152]. This study suggested that kidneys from donors under 2 years of age are best suited to transplantation into adult recipients as dual en bloc ­kidneys rather than as single kidneys. There was no increase in technical complications, HTN, hyperfiltration nephropathy, with equivalent graft and patient survival [152].

Pediatric En Bloc Deceased Renal Transplantation Pediatric en bloc renal transplantation involves en bloc implantation of a pair (right and left) of

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young donor pediatric kidneys into only adult recipients (Fig. 11.2, 11.2a, b and c). This technique is best ­utilized for transplantation of kidneys from donors under 2 years of age [153]. Current estimates are that only about 5% of US transplant centers utilize this source of donor kidneys due to concern of increased technical complication, rejection, hyperfiltration nephropathy, and diminished allograft survival. A review at Cleveland Clinic of 33 such pediatric en bloc deceased donor kidneys demonstrated that ­successful transplantation of these young donor kidneys is in fact possible with equivalent longterm graft and patient survival [153]. Others also support the transplantation of pediatric en bloc kidneys as offering a viable option to counteract the shortage of acceptable kidney donors, but also note that surgical complications remain a significant problem, especially with younger pediatric grafts [138, 154].

Fig. 11.2  Pediatric en bloc deceased renal transplantation

C.S. Modlin III and C.S. Modlin Jr.

The Anencephalic Infant Donor Kidney Advances in transplantation have made transplantation successful in young infants. However, the paucity of organs suitable for use in small infants is a major limitation of allotransplantation. Infants with anencephaly have been considered as a potential source of solid organs for infants because of the certainty of imminent death, absence of most of the brain, accuracy of diagnosis, and desire of parents to donate their infants’ organs [155]. Peabody conducted a study of medical outcomes in 12 anencephalic infants. The serum creatinine was normal in eight of 12 infants on admission. The combined weights of both kidneys were normal in seven of nine infants in whom it was measured, and renal histologic features were normal in eight of nine infants. Despite this, no kidneys were transplanted due to

11  Issues and Surgical Techniques Fig. 11.2a  Deceased Donor Pediatric Enbloc Allograft Bench Preparation (18 month old donor allograft kidneys)

Fig. 11.2b  Reperfused Pediatric Enbloc Renal Allografts immediately following implantation depicting donor aorta and donor vena cava anastamoses

Fig. 11.2c  Reperfused Pediatric Enbloc Renal Allografts with Conjoined Ureteral Reimplantation into Bladder

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delays in declaration of brain death and restrictions of law, which rendered potentially suitable organs not suitable for transplantation and ethical issues [155, 156]. Current US law does not allow procurement of solid organs for transplantation from anencephalic infants. The only active US program removing organs from anencephalic donors was abandoned in 1989 [157].

The Deceased Donor with Hypertension Transplantation of kidneys from hypertensive deceased donors has been advocated to increase the supply of organs [158–160]. Many surgeons are reluctant to transplant these kidneys because of the potential for the presence of occult hypertensive nephropathy, as evidenced by the presence of tubular atrophy, tubular dilatation, interstitial fibrosis, and hyaline arteriolar sclerosis on biopsy. The incidence of hypertension (HTN) in the general population has been reported to be from 20% to 45% [158]. Systemic HTN may be associated with nephrosclerosis and various degrees of renal damage, and thus HTN has traditionally been considered a relative contraindication to organ donation. Smith [158] reviewed the histories of 35 heart-beating donors in New England who had hypertension and analyzed the outcomes of ­kidneys transplanted from these donors. The rate of discard and acute tubular necrosis was found to be much higher in HTN donor groups and greater with increasing duration and severity of hypertension. Discard was largely attributed to severe atherosclerotic plaque in the renal arteries and poor perfusion characteristics. The allograft function however did not differ significantly between those transplants done using donors with a history of HTN and those without HTN. The conclusion from this study was that with careful selection and thorough evaluation, organs from hypertensive donors provide an additional source of deceased kidneys. Ratner performed a retrospective review of transplantation of donors with hypertension. The use of kidneys from hypertensive deceased donors

C.S. Modlin III and C.S. Modlin Jr.

showed significantly decreased short- and longterm graft survival compared to those procured from nonhypertensive donors, in part due to a high incidence of primary nonfunction. Occult renal disease was frequently present in donor hypertensive kidneys. Renal biopsy was not predictive of eventual clinical outcome for graft survival or onset of renal function. The investigators concluded that caution should be exercised when considering the use of these ­kidneys [159, 160]

The Living Donor with Hypertension Textor et  al., indicating that the need to evaluate potential living kidney donors is more pressing than ever before, while acknowledging that the potential medical risks to individual donors presents both medical and ethical questions related to quantitative hazards of donor nephrectomy, studied the question as to what the limits are with respect to expanding criteria for living donors [161]. They noted that such conditions commonly associated with age, such as decline in glomerular filtration rate, rise in arterial pressures, and weight gain as presenting risks for living donor nephrectomy and risks following nephrectomy. They established a program to stratify acceptable medical criteria for living donation based upon age, allowing more liberal criteria for older living donors. As a result, they accept treated hypertension in white living donors, emphasizing the importance of informed consent and need for vigilant follow-up. They also concluded that since older donors are likely to have established behavioral patterns (i.e., maintaining lack of smoking, weight management, and medical follow-up care), they believe that elderly living donors make better candidates in many respects compared to younger living donors.

Contaminated Donor Kidneys and the Donor with Systemic Infection The avoidance of infection in the immunosuppressed transplant recipient is a fundamental goal. Bacteriologic surveillance of the donor and the harvested organ are done to reduce the risk of

11  Issues and Surgical Techniques

infectious disease transmission [162, 163]. Mean arterial pressures less than 70 mmHg and systemic vascular resistance less than 1,200 dyne × s/cm5 × m2 among organ donors predicted greater occurrence of septic complications and increased mortality among kidney transplant recipients [164]. Currently, most potential donors with ­suspected systemic infection or a recent history of septicemia are excluded from donation. Donors with potential bacteremia from remote infections are transplanted under appropriate antibiotic coverage and are monitored carefully in the posttransplant. Donor infections which are absolute contraindications for transplantation include the presence of HIV or AIDS [165], active viral hepatitis, Creutzfeldt-Jakob disease, malaria, or disseminated tuberculosis [79]. The donor with hepatitis is discussed further later in this chapter. Kidneys from donors with positive RPR tests or other tests for syphilis can be used with treatment of the recipient with penicillin or another antisyphilitic agent. RPR-positive donors should be monitored carefully for other risk factors for HIV infection. Donors with positive urine cultures may be utilized provided there is no evidence of acute pyelonephritis. Urine cultures should be obtained and the recipient treated with broad spectrum prophylactic antibiotics, tailoring to culture and sensitivity results when available. Patients with positive blood cultures in the absence of septic shock may also be suitable donors with recipients receiving antibiotic therapy against the infectious organism. Patients with infections in locations of the body removed from the kidneys, such as in the case of localized pneumonia, may be kidney donors. The presence of a transmissible disease does not necessarily adversely affect overall outcome. For example, organs from CMV (cytomegalovirus) or EBV (Epstein-Barr virus) positive donors to CMV or EBV negative recipients are routinely transplanted under antiviral prophylaxis despite the knowledge that some recipients will develop symptomatic CMV or EBV disease. CMV matching allocation scheme are no longer routinely practiced [166]. Donor contamination during organ retrieval (i.e., bowel perforation) was once considered an absolute contraindication to donation. Given the

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current shortage of available organs and results with antibiotics, it is no long an absolute contraindication but is still a risk in transplant recipient [167]. Cultures from the preservation fluid are obtained while the recipient is administered broad spectrum antibiotics pending finalization of culture results. Additionally, antibiotics may be administered in the organ preservation solution during cold or pulsatile perfusion storage. Infection introduced into the perfusate by a break in sterile technique or contamination of the perfusate fluid prior to use are other potential sources of infection affecting the allograft. Although microbial contamination of stored kidneys occurs commonly, it is not an important source of infection in renal transplant recipients under appropriate antibiotic coverage if only a single culture is positive or only a few colonies are counted. However, it would be wise to discard heavily contaminated kidneys if in the pretransplant period a positive report is obtained demonstrating multiple positive cultures or high colony counts. Additionally, if cultures of the perfusate are known to contain Gram-negative enteric bacilli, enterococci, B-hemolytic streptococci, or a high bacterial count of any organism use of the kidney is contraindicated. When perioperative cultures disclose organisms typically of low virulence or skin contamination and a Gram’s stain of the perfusate is negative, the ­kidneys may be transplanted safely under prophylactic antibiotics with careful monitoring of the recipient for any signs of infection [168–171]. Usually by the time a positive pretransplant culture is known, the allograft has already been transplanted. Therefore, recipients should receive prophylactic antibiotics against both gram-positive and -negative organisms until the perfusate and donor culture results are known. If the donor and/or perfusate cultures return positive, then the recipient receives antibiotics specific to the infection with careful surveillance for the development of pseudoaneurysm [171]. The clinical experience transplanting contaminated kidneys, combined with the serious shortage of deceased kidneys, argues for using all organs except those with major breaks in sterile technique. The discussion as to whether donors with pandemic influenza A/H1N1 qualify for organ

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donation has arisen. Lattes et al. reported on two kidney transplant recipients who received kidneys from the same deceased donor, in whom the diagnosis of infection by this virus became available only posttransplant. The donor had received a complete course of antiviral treatment before donation. The recipients were transplanted at two different centers and neither developed flu syndrome [172].

The Donor with Hepatitis Hepatitis B and C virus are the most common causes of chronic liver disease in renal transplant recipients and have become increasingly important late complications [173]. Morbidity and mortality (manifesting generally 8–10 years posttransplant) result from the development of chronic active hepatitis, cirrhosis, hepatic failure, hepatocellular carcinoma, and bacterial superinfections as a result of the added immunosuppressive effects of the hepatitis viruses. Hepatitis C virus is the major cause of chronic liver disease in transplant recipients because the incidence of hepatitis C in the ESRD patient population is much higher than hepatitis B. However, the rate of progression of hepatitis B-induced liver disease posttransplant is greater than that of hepatitis C. A study from the New England Organ Bank reported that in recipients of anti-hepatitis C virus positive organs, the prevalence of liver disease was 7.4 times greater. Moreover, 52% of recipients of organs from polymerase chain reaction-positive donors developed liver disease and 62% underwent seroconversion [174–176]. These facts underscore the need for screening all potential donors for hepatitis B and C [177]. Because of the likelihood of progression of viral hepatitis in the recipient after transplantation, potential donors with elevated liver enzymes with serologic evidence of active hepatitis B infection should be excluded from donation. Hepatitis B core antigen (HBcAg) is confined to hepatocyte nuclei; however, core antibody (HBcAb) usually appears in the serum 6 weeks

C.S. Modlin III and C.S. Modlin Jr.

after exposure to the virus [178, 179]. After 6 months, the initial IgM isotype converts to IgG, which then persists indefinitely [178]. The ­correlation between HBcAb and serum HBV DNA is poor. However, a window period of isolated HBcAb (IgM isotype)-positive serology has been described after an acute infection when the HBsAg has cleared from the serum but HbsAb has yet to appear. Thus, the significance of serum HBcAb-positive serology ranges from being the only serologic marker of active viral replication to resolved infection and cleared viremia [178]. Using kidneys from hepatitis B surface ­antigen (HBsAg)-positive donors is thought to place recipients at excessive risk of graft failure, morbidity, and mortality. However, the risks of using kidneys from HBsAg-negative but hepatitis B core antibody (HBcAb)-positive donors places recipients at a small risk of hepatitis B seroconversion but no excess risk of graft failure or shortterm morbidity or mortality [178], Satterthwaite [178] came to these conclusions in a study of 27 (group 1) HBcAb(−) recipients transplanted with HBsAg(−)/HBcAb(+) donors compared to the results of transplanting HBcAb(+) recipients with HBsAg(−)/HBcAb(+) donors (group 2). Neither group received hepatitis immunoglobulin therapy after transplantation and both groups received the same immunosuppression and rejection therapies as recipients of kidneys from HBcAb(−) donors. After transplantation, none of the group 1 patients became HBsAg(+), three became hepatitis B surface antibody (HBsAb)-positive, and two became HBcAb(+). Of the group 2 patients, none became newly HBsAg(+) or HBsAb(+). No patient receiving a kidney from an HBsAg(−)/ HBcAb(+) donor developed signs or symptoms of clinical hepatitis B. Graft and patient survival rates were similar in both groups and similar to the rates of the other 1,029 recipients of kidneys from HBcAb(−) donors during the study period [178]. Wachs et  al. had similar results, finding only 1 of 42 HBsAg(−)/HBcAb(+) donors resulting in seroconversion to HBsAg positivity in the recipient [171–173]. The use of kidneys from hepatitis-C positive donors is controversial. Some centers will transplant hepatitis-C positive organs only into hepatitis-C

11  Issues and Surgical Techniques

positive recipients. Matching donors and recipients for HCV genotype may minimize the risk of superinfection when using kidney from HCVpositive donors [104]. Patients should be made aware of the potential risks and benefits of receiving infected organs, even if they themselves are infected. Patients with the greatest likelihood of long-term survival (young, nondiabetics, recipient negative HCV status) should not receive a hepatitis C positive donor kidney [181].

The Donor with History of Malignancy Metastatic malignant cells in a transplanted organ can grow in the recipient and cause death of the recipient. The risk to the recipient is sufficiently great to contraindicate donation from patients with active cancer or cancer known to metastasize to the organ being transplanted. A past history of cancer judged to be surgically cured is not an absolute contraindication to donation with the possible exception of melanomas treated at a stage where there is an anticipated poor survival rate [90, 112], Donors with a past history of malignancy who are disease free for at least 2 years should be considered as potential donors depending upon the location, stage, and grade of the tumor. Patients with primary brain tumors without VP shunts and without evidence of metastasis may be used as kidney donors [182].

The Donor with Diabetes Cho, in reviewing the UNOS Scientific Renal Transplant Registry, showed that a donor history of diabetes or cigarette smoking, did not diminish graft survival [104]. Abouna et al. [15] reported on the successful transplantation of diabetic deceased donor kidneys into nondiabetic recipients, with the apparent regression of diabetic glomerulopathy [15]. It is generally accepted that carefully screened kidneys from diabetic donors should be considered for transplantation [183], particularly if donor renal function is normal,

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there is no significant proteinuria, no evidence of accelerated atherosclerosis, and the donor has had a stable intensive care unit course. Animal experiments demonstrate that when diabetic nephrosclerotic kidneys are transplanted into normal animals, the stigmata of nephropathy rapidly regress [184, 185]. Abouna suggested that the metabolic environment of the recipient determines the development and reversal of the renal lesion of diabetes rather than any sensitivity of the target organ. In Abouna’s experience transplanting diabetic kidneys into nondiabetic reci­ pients, nephropathy recurred in a patient who became diabetic, but not in a patient who remained euglycemic, suggesting that diabetic nephropathy could be prevented or early diabetic nephrosclerosis at least stabilized if the abnormal milieu can be corrected by pancreatic transplantation.

Glomerulonephritis, Lupus, Membranous Nephropathy, and Preexisting Lesions in the Donor Kidney Curschellas [186] reviewed the results of 147 zerohour biopsies of 101 donors (mean age 33, 6–64 years) investigated if preexisting lesions in renal grafts influence initial and late renal ­function of allografts under cyclosporine ­immunosuppression. An “astounding number of both specific and nonspecific findings” in these zero-hour biopsies were noted (62%). By light microscopy 38% of biopsies showed no lesions, 44% showed nonspecific, and 18% specific lesions. Nonspecific lesions comprised intimal fibrosis of small arteries in 44%, interstitial fibrosis in 8% and an arteriolar hyalinosis in 29%, and were clearly age related. Out of the 102 immunohistologically examined biopsies, 74.5% showed nonspecific IgM/C3 deposits in glomeruli and/or arterioles. An age dependent decrease of normal renal biopsies was found which was most evident in donors older than 40 years. Specific findings consisted of glomerulosclerosis (n = 4), glomerulonephritis (n = 11), intravascular coagulation (n = 10), and eclamptic kidney (n = 1). In cases of nonspecific immunohistologic findings

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and in glomerulonephritis (GN), re-biopsies showed that antigen deposits usually disappeared within 4 months. In those with nonspecific immunohistochemical changes at initial biopsy, at followup 70% of biopsies no longer showed any evidence of immune deposits. The cases of glomerulonephritis were equally distributed over different donor age groups and classified according to their immunohistological findings as follows: seven IgA nephritides (nephropathies) of minimal grade, two glomerular minimal change with specific immunohistological findings, and two lowgrade mesangioproliferative glomerulonephritides (non-IgA). In those cases with glomerulonephritis, both the preexisting deposits of immunoglobulins present at the time of transplantation usually disappeared within 4 months of transplantation. In one case, immunoglobulin deposits were no longer demonstrable as early as 2 weeks after transplantation. Independent of morphologic findings, 82% of transplant recipients had good initial and late renal function. The investigators concluded that since donor age, glomerulosclerosis, glomerulonephritis, intravascular coagulation, or eclamptic changes seem not to compromise renal function after transplantation, a more liberal choice of donors should be considered. In the case of intravascular coagulation of the donor kidney, the authors pointed out that the recipient of such a kidney should have an intact fibrinolytic system. The authors advocate performing zero-hour biopsies of all allografts as a method to help avoid misdiagnosis, e.g., glomerulonephritis as early rejection, intimal fibrosis as sclerosing transplant vasculopathy or confusing arteriolar hyalinosis with changes due to previous treatment with calcineurin-inhibitor, and to know the nature of any damage to glomeruli, tubular-interstitial space, and arterioles that already exists at the time of transplantation. Others however have also shown that immunohistological deposits cannot be used as an accurate indicator of renal function [95]. Poor renal function has been reported in some instances, in particular after transplantation of kidneys with IgA nephropathy. Reported cases have revealed occurrences of massive rejection leading to transplant nephrectomy between 4 and 1 weeks posttransplantation [187, 188].

C.S. Modlin III and C.S. Modlin Jr.

On the other hand, Tolkoff-Rubin [189] described the case of a living related donor transplant from one brother to another with end-stage IgA nephropathy. The zero-hour biopsy showed IgApositive mesangial deposits thus establishing the diagnosis of IgA nephropathy. One year later both brothers were doing well, showing no clinical signs of IgA nephropathy [189]. Schwartzman reported successful outcome of a kidney transplant of a donor with systemic lupus erythematosus and a history of remote acute renal failure but normal renal function at the time of death [190]. The harvest biopsy was unremarkable, but the zero-hour biopsy showed evidence of lupus nephritis. Sequential protocol biopsies demonstrated gradual resolution of the donor pathology, and renal function was stable. The authors concluded that preexisting mild GN may not be an absolute donor exclusion for ­candidates willing to accept ECD donors and that use of ECD kidneys should be guided by functional, biopsy, and demographic information, as no single factor alone predicts outcome. Akioka et al. reported on the case of a living related renal transplant where the donor had membranous nephropathy and the donation of the kidney did not affect the residual renal function of the donor [191].

ABO Incompatible and the Positive Cross-Match Renal Transplant In efforts to increase availability of donor organs, living donor renal transplantation from ABO incompatible donors and donors with an initial positive crossmatch have been introduced. Regarding ABO incompatible living donor transplantation, protocols which employ pretransplant antibody removal with specific immunoadsorption, immunoglobulin and anti-CD20 antibody until immunoglobulin (IgG) and isoagglutinin (IgM) antibody titers of 1/8 or lower [192] or protocols which employ recipient preconditioning using rituximab and selective immunoadsorption to obtain reduction of isoagglutinin titers less than or equal to 1:4 have reported success in outcomes of ABO incompatible transplantation [193]. With

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careful patient management, including protocols to remove or lower donor antibodies, along with stronger immunosuppression and immune monitoring, excellent results are obtainable [194–200].

The Anatomically Abnormal Allograft The national shortage of deceased donor kidneys has encouraged the occasional use of anatomically abnormal deceased or live donor kidneys, provided the imperfections do not prevent ­normal transplant function. Anatomically abnormal allografts utilized include horseshoe and ectopic kidneys, the polycystic kidney, donor kidneys with short or damaged ureters, and donor ­kidneys with complex vasculature.

The Horseshoe Deceased Kidney Donor Case reports of transplantation of horseshoe ­kidneys exist [201–206]. The incidence of horseshoe kidneys is somewhere between one in 400 worldwide and with a male to female ratio of 2:1 and is not a cause of impaired kidney function [207] in the absence of obstruction. Because of the fusion of the lower poles, the kidneys fail to rotate medially during development and the renal pelvises face anteriorly, with the ureters coursing anterior to the lower poles. Up to 80% of horseshoe kidneys have some element of hydronephrosis, either obstructive or nonobstructive. Variation in renal vasculature is the rule. The surgeon must be aware of multiple and accessory vessels of horseshoe kidneys so as not to compromise renal, renal pelvic, and ureteral blood supply leading to postoperative complications. The procuring surgeon should always remove the horseshoe kidney en bloc with a large segment of aorta and vena cava, including part of the common iliac vessels [208], to ensure safe removal of all vessels. The same procurement principles apply when one encounters other complex renal anomalies such as crossed fused or nonfused ectopic kidneys [202].

We have experience transplanting horseshoe kidneys. We usually divide them at the avascular isthmus and transplant them into two recipients. Klan reported on the successful en bloc transplantation of a horseshoe kidney which could not be divided because of a complex vascular situation [208]. The decision to divide the horseshoe kidneys is determined mainly by the vasculature. In addition, abnormalities on one side may lead to division and discarding of the unusable portion. Risks of division of the kidneys are urinary fistula and bleeding; caliceal integrity can be established with retrograde ureteral injection of methylene blue. When en bloc implantation is performed, whether cranial or caudal vessels are used, the opposite end must be carefully closed at the level of the renal vessels to prevent thrombosis in the blind ending vessel stumps [206].

The Polycystic Deceased Donor Kidney Autosomal dominant polycystic kidney disease is a systemic disorder. Kidneys typically begin to develop cystic enlargement in late adolescence or early adulthood with progression of disease to end-stage renal disease in a majority of cases over a period of decades. Hypertension, cerebral vascular accidents, cyst rupture, and hemorrhage may complicate the disease. Computed tomography and/or ultrasonography are the usual radiologic imaging modalities used establish the diagnosis of ADPCKD. In the cases of the deceased donor, the disease is most often diagnosed only intraoperati­ vely at procurement. The successful transplantation of polycystic deceased donor kidneys have been reported [210, 211]. Spees [211] reported on two such transplants with good HLA matches, normal donor renal function, and areas of preserved renal cortex. According to the authors, both of their patients had poor health prospects without a transplant and were fully informed of the abnormalities and concern that kidney function might deteriorate over time. Grafting of these kidneys was reportedly uncomplicated with posttransplant followup of 29 months and 19 months demonstrating both

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kidneys to be functioning. One allograft demonstrated shrinkage in the size of the renal cysts. Conclusions made were that carefully selected polycystic kidneys with normal function and ­ evidence of substantially preserved renal cortical mass can palliate renal failure, particularly in sedentary individuals who have shortened life expectancy and in whom a high HLA match reduces the danger of rejection of the allograft.

Fig. 11.3  (a) Bench table venous reconstruction

C.S. Modlin III and C.S. Modlin Jr.

The Donor with Multiple Arteries and Vascular Abnormalities Prior to considering transplanting deceased or living donor kidneys with multiple renal arteries or vascular abnormalities, one must be aware of commonly used bench table techniques to reconstruct the allograft vessels (Fig. 11.3a and 11.3b).

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Fig. 11.3  (continued) (b) Bench table arterial reconstruction

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Bench Table Vascular Reconstruction of the Deceased Kidney For a right donor kidney, it is necessary to ensure adequate renal venous length for transplantation, especially when it is anticipated that the recipient iliac vein is deep in the pelvis or the renal vein is short. Historically, using open donor technique for living donor transplants, a cuff of donor vena cava is usually harvested in continuity with the renal vein. However, as the majority of living donor nephrectomies are now laparoscopically, the surgeon procures as much length of the right donor renal vein close to the vena cava as safely as possible. In deceased transplantation, the vena cava is usually left attached to the right renal vein. The transplanting surgeon therefore, to lengthen the renal vein, sews the edges of the vena cava together to achieve significant renal vein extension. Several techniques have been described to refashion the attached donor vena cava to provide for renal venous extension (see Fig.  11.3a). Accessory renal veins are ligated, preserving the dominant renal vein for implantation. In cases where the donor kidney has multiple renal arteries, several techniques exist for bench arterial reconstruction prior to implantation (see Fig. 11.3b). Effort should be made to preserve all arteries, the only exception being the tenuous small upper polar artery not attached to an aortic cuff, widely separated from the main renal artery and estimated to supply less than 10% of the renal parenchyma. Lower polar arteries usually supply the transplant ureter and should be preserved whenever possible. In situations where lower polar arteries are traumatized or ligated, ureteral stents are routinely used posttransplant as the risk of urinary fistulization is heightened [212, 213]. With advancing age of donor kidneys, extensive arteriosclerosis of the renal artery is increasingly encountered. Eversion endarterectomy is a technique which may be used to treat severe arteriosclerosis of the renal artery in elderly donor kidneys previously discarded [108]. Nghiem described 34 such deceased kidneys (donor age 40–67 years), with biopsy confirmed mean

C.S. Modlin III and C.S. Modlin Jr.

glomerulosclerosis 14.7%, transplanted following eversion endarterectomy [108]. Nghiem noted that use of these endarterectomized ­kidneys was associated with graft survival and mean serum creatinine level at 4 years of 76.4% and 2.3 mg/ dL, respectively, and increased the ­number of transplants at his center by 18%. Also noted was no increased incidence of hypertension in reci­ pients of endarterectomized kidneys compared to normal kidneys. Nghiem cautioned that extreme caution be taken when multiple arteries are involved, since intimal dissection in a small vessel may be overlooked and lead to polar infarction.

The Donor Allograft with Ureteral Abnormalities One may encounter a deceased or living allograft with a complex collecting system (i.e., duplicated ureters) or compromised ureters. In order to utilize these kidneys one should be aware of available surgical options for reconstruction of the renal allograft pelvis or ureter as well as options for implantation (Fig. 11.4). When one is suspicious of the integrity or vascular supply of the collecting system, the transplant ureter should be stented at the time of ureteral implantation; however, such stenting will not prevent complications from an ischemic ureter.

Expanded Criteria Living (Old Living) Renal Donor Transplantation Elderly Living Donor Another source of ECD kidneys is utilization of donor kidneys from older living donors (OLD) (>55 years old) for older recipients (60 years or older). Gill et al. [214] studied the outcomes of kidney transplantation from older living donors to older recipients. Old transplantations were associated with inferior 3-year graft survival rates (85.7%), but similar 3-year patient survival

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Fig. 11.4  Options for ureteral implantation and reconstruction

rates (88.4%) compared with recipients of young living donors (3-year graft survival 83.4%, patient survival 87.4%) and had superior graft survival compared with all deceased donor options. Compared with OLD transplantations, ECD deceased transplants were associated with a greater risk of graft loss (hazard ratio, 2.36; 95% confidence interval, 1.18–4.74). The authors

concluded that with superior graft and patient survival in recipients of OLDs compared with standard criteria donors and ECD deceased donors, OLDs may be an important option for elderly transplantation candidates and should be considered for older patients with a willing and suitable older donor [214]. See also the section on the Elderly Living Donor with Hypertension.

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Living Unrelated Renal Transplantation, Altruistic Living Renal Transplantation, and Paired Living Donor Exchange Transplantation Although not considered to represent ECD kidneys by UNOS criteria, as sources for patients with willing living donors to bypass prolonged waiting times on the list to receive scare deceased donor allografts, kidneys from living donors who are emotionally connected but unrelated living donors (living unrelated) [215] as well as from living altruistic (unemotionally unrelated) donors are an increasing source of kidneys for transplantation [216]. Recently, several transplant centers have initiated shared paired donor exchanged programs which provide opportunities for simultaneous swapping and transplantation of living donor kidneys between patients who have incompatible living donors (i.e., positive crossmatch or ABO incompatibility) with their emotionally related or unrelated willing donor [105, 217–219] Altruistic live donor ­kidney transplantation is also increasing in frequency and results have been successful [212].

Living Kidney Donor with Stones Attitudes and practices differ between transplant centers criteria to accept kidneys from stone formers. Ennis et al. conducted a survey in 2009 of US kidney transplant programs to assess current trends in the approach to dealing with stone formers who are evaluated for kidney donation. There was a tendency toward increased acceptance of donors with a history of stones: 77% of the responding centers allowed stone formers to donate with 40% of those centers reporting a recent change in their attitudes toward accepting donors with kidney stones within the preceding 5–10 years. Ennis proposed that more studies be conducted in order to systematically examine whether appropriately selected stone formers can safely donate [220].

C.S. Modlin III and C.S. Modlin Jr.

The Radiographically Abnormal Live Donor Kidney Use of kidneys from living donors with anatomic variants has been studied and it has been concluded that kidneys with anatomic variants without pathologic significance and without the potential for the development of progressive ­disease can be used safely for transplant [221].

The Obese Living Donor Obese donors (BMI >27) have been reported as an acceptable source of living donor kidneys. The primary concerns are surgical and anesthetic risks, wound complications, and long-term risks that the donor might develop hypertension, hyperfiltration, or renal failure from reduced renal mass. The use of obese living kidney donors appears safe in the short term. They do experience more minor complications, usually related to the wound, and require slightly longer operative time. Long-term studies need to be undertaken however to assess the risks of development of diabetes and the longterm effects on the remaining solitary kidney in the obese donor [222].

Immunosuppression Issues and the Expanded Criteria Donor ECD kidneys are more susceptible to toxicity associated with calcineurin inhibitors (CNIs) [223]. Therefore, a potential strategy to improve outcomes in ECD recipients is the use of CNIfree immunosuppressive protocols. Maintenance immunosuppression with sirolimus, part of a class of drugs referred to as inhibitors of the mammalian target of rapamycin combined with prednisone and mycophenolate mofetil, triple immunosuppression with antibody induction, have been shown to offer good immunosuppressive effect with less nephrotoxicity and a low incidence of cytomegalovirus infection in recipients of ECD kidneys [223, 224]. Andres et  al. reported on the benefits of basiliximab induction

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therapy in recipients of ECD kidneys. Others have also reported on the benefit in ECD kidney recipients of CNI-free or CNI reduction immunosuppression on patient graft function and graft survival [223]. Durrbach, however, in a review on the prospective comparison of the use of sirolimus and cyclosporine in recipients of an ECD donor and reported a greater degree of DGF and no significant differences in biopsyproven acute rejection or calculated creatinine clearances between the groups, suggesting that use of sirolimus immediately after transplantation in ECD recipients is not supported.

Summary Utilization of expanded criteria donors and nontraditional donors can help lessen the current shortage of available kidneys. Transplantation using ECD kidneys has been shown to have survival advantages over the alternative of remaining on dialysis [1]. With the appropriate selection of organs from expanded donors, acceptable outcomes can be obtained. The use of older donors has accounted for a large measure of the increase in the organ donation rate. However, the most significant factors found to negatively impact transplant success have traditionally been shown to be extremes of donor age and last-hour urine output. Less significant variables affecting success rates are average systolic blood pressure, terminal serum creatinine, and days of hospitalization. Advances in the surgical techniques, organ preservation, and methods for predicting eventual long-term renal function from expanded donors will be critical in allowing precise selection criteria for kidneys for transplantation, resulting in the optimum use of a scarce and precious resource. Additionally, adaptation of immunosuppressive drug regimens in the ECD recipient, increase in nephron mass by dual kidney transplantation, pulsatile pump perfusion techniques, and improvement in the graft selection process by review of the pretransplant biopsy are currently techniques used to promote improved outcomes of transplantation of ECD kidneys and

help meet the organ donor shortage. The ongoing challenge will be to identify which donor organs previously considered suboptimal can be safely utilized to expand the organ donor pool and into whom they should be transplanted.

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246 transplantation from a non-heart beating donor. Ann R Coll Surg (Engl) 2005;87(3):W3–6. 136. Tan JC, Alfrey EJ, Dafoe DC, Milan MT, Scandling JD. Dual-kidney transplantation with organs from expanded criteria donors: a long-term follow-up. Transplantation 2004;78(5):692–696. 137. Lee RS, Miller E, Marsh CL, Kuhr CS. Intermediate outcomes of dual renal allografts: the University of Washington experience. J Urol 2003;169(3):855–888. 138. Lu AD, Carter JT, Weinstein RJ, Prapeng W, Salvatierra O, Dafoe DC, Alfrey EJ. Excellent outcome in recipients of dual kidney transplants: a report of the first 50 dual kidney transplants at Stanford University. Arch Surg 1999;134(9):971– 975, discussion 975–976. 139. Lee CM, Scandling JD, Shen GK, et al. The kidneys that nobody wanted: support for the utilization of expanded criteria donors. Transplantation 1996; 62(12):1832–1841. 140. Alfrey EJ, Lee CM, Scandling JD, et al. Expanded criteria for donor kidneys: an update on outcome in single versus dual kidney transplants. Transpl Proc 1997;29(8):3671–3673. 141. Alfrey EJ, Lee CM, Scandling JD, et  al. When should expanded criteria donor kidneys be used for single versus dual kidneys transplants? Transplantation 1997;64(8):1142–1146. 142. Carmellini M, Stefano RD, Filipponi F, et  al. Delayed graft function adversely affects one-year graft survival of deceased renal transplants. Transpl Proc 1996;28(1):359. 143. Harford AM, Gibel LJ, Eghtesad B, et al. Single kidney transplants from donors with low estimated creatinine clearance. Transpl Proc 1997;29(8):3317–3318. 144. Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: 31. 145. Snanoudj R, Rabant M, Timsit MO, Karras A, Savoye E, Tricot L, Loupy A, Hiesse C, Zuber J, Kreis H, Martinez F, Thervet E, Mejean A, Lebret T, Legendre C, Delaousse M. Donor-estimated GFR as an appropriate criterion for allocation of ECD kidneys into single or dual kidney transplantation. Am J Transpl 2009;9(11):2542–2551. 146. Wolters HH, Palmes D, Heidenreich S, August C, Brockmann J, Senninger N, Dietl KH. Long-term follow-up of double kidney transplantation using a score for evaluation of marginal donors. Transpl Int 2005;18(4):453–457. 147. Furian L, Baldan N, Margani G, Ekser B, Silvestre C, Marchini F, Bonfante L, Rossi B, Valente ML, Rigoti P. Calcineurin inhibitor-free immunosuppression in dual kidney transplantation from elderly donors. Clin Transpl 2007;21(1):57–62. 148. Drakopoulos S, Koukoulaki M, Vougas V, Apostolou T, Hadjiyannakis EI, Hadjiconstantinou V. Transplantation of pediatric kidneys to adult recipients: an analysis of 13 cases. Transpl Proc 2004;36(10):3161–3163. 149. Peabody JL, Emery JR, Ashwal S. Experience with anencephalic infants as prospective organ donors. NEJM 1989;321(6):344–350.

C.S. Modlin III and C.S. Modlin Jr. 150. Shinnar S, Arras J. Ethical issues in the use of anencephalic infants as organ donors. Neurol Clin 1989;7(4):729–743. 151. Shewmon DA, Capron AM, Peacock WJ, Schulman BL. The use of anencephalic infants as organ sources. A critique. JAMA 1989;261(12):1773–1781. 152. Smith RB, Fairchild R, Bradley JW, Cho SI. Deceased kidney donors with hypertensive histories. Trans Proc 1988;20:741–742. 153. Ratner LE, Joseph V, Zibari G, et al. Transplantation of kidneys from hypertensive donors. Trans Proc 1995;27:989–990. 154. Ratner LE, Kraus E, Magnuson T, et  al. Transplantation of kidneys from expanded criteria donors. Surgery 1996;119(4):372–377. 155. Textor S, Taler S. Expanding criteria for living kidney donors: what are the limits? Transpl Rev 2008;22(3):187–191. 156. Keating MR, Guerrero MA, Daly RC, et  al. Transmission of invasive aspergillosis from a subclinically infected donor to three differenct organ transplant recipients. Chest 1996;57:1068–1072. 157. Zukowski M, Bohatyrewicz R, Biernawska J, Kotfis K, Zengan M, Knap R, Janeczek M, Zietek Z. Risk factors for septic complications in kidney transplant recipients. Transpl Proc 2009;41(8):3043–3045. 158. Briner V, Zimmerli W, Cathomas G, Landmann J, Thiel G. HIV infection caused by kidney transplant: case report and review of 18 published cases. Schweiz Med Wochenschr 1989;119(30):1046–1052. 159. Johnson RJ, Clatworthy MR, Birch R, Hammad A, Bradley JA. CMV mismatch does not affect patient and graft survival in UK renal transplant recipients. Transplantation 2009;88(1):77–82. 160. Kumar D, Cattral MS, Robicsek A, Gaudreau C, Humar A. Outbreak of pseudomonas aeruginosa by multiple organ transplantation from a common donor. Transplantation 2003;75(7):1053–1055. 161. Odenheimer DB, Matas AJ, Tellis VA, et al. Donor cultures reported positive after transplantation: a clinical dilemma. Trans Proc 1986;18:465–466. 162. Majeski JA, Alexander JW, First MR, et  al. Transplantation of microbially contaminated deceased kidneys. Arch Surg 1982;117:221–224. 163. Harrington JC, Bradley JW, Zalneraitis B, et  al. Relevance of urine cultures in the evaluation of potential deceased kidney donors. Trans Proc 1984; 16:29–30. 164. Weber TR, Freier DT, Turcotte JG: Transplantation of infected kidneys: clinical and experimental results. Transplantation 1979;27:63–65. 165. Lattes R, Jacob N, de la Fuente J, Fragale G, Massari P. Pandemic influenza A/H1N1 and organ donation. Transpl Infect Dis 2010;Epub ahead of print. 166. Abrams J, Nathan HM, Brayman K, et al. Utilization of deceased kidneys from donors with reactive hepatitis C virus antibody or reactive hepatitis B core antibody. Transpl Proc 1997;29(8):3674–3676. 1 67. Pereira BJ. Renal transplantation in patients positive for hepatitis B or C. Transpl Proc 1998; 30(5):2070–2072.

11  Issues and Surgical Techniques 168. Roth D, Cirocco R, Zucker K, et al. The impact of hepatitis C virus (HCV) on the potential renal allograft recipient. J Am Soc Nephrol 1992;2:878. 169. First MR. Controversies in organ donation: minority donation and living unrelated renal donors. Transpl Proc 1997;29(1–2):67–69. 170. Einollahi B, Alavian SM. Hepatitis C virus infection and kidney transplantation: a review for clinicians. Iran J Kidney Dis 2010;4(1):1–8. 171. Satterthwaite R, Ozgu I, Shidban H, et al. Risks of transplanting kidneys from hepatitis B surface ­antigen-negative, hepatitis B core antibody-positive donors. Transplantation 1997;64(3):432–435. 172. Hoofnagle JH, Gerety RI, Ni L, Barker LF. Antibody to hepatitis B core Antigen. NEJM 1974;290:1336. 173. Wachs ME, Amend WJ, Ascher NL, et al. The risk of transmission of hepatitis B from HbsAg(3), HbcAb(+), HBIgM(–) organ donors. Transplantation 1995;59(2):230–234. 174. Otero J, Rodriguez M, Escudero D, et  al. Kidney transplants with positive anti-hepatitis C virus donors. Transplantation 1990;50(6):1086–1087. 175. Keung Chui AK. Transplantation of organs from primary brain tumour donors: a continuing dilemma. Transpl Rev 13(4):169–173. 176. Spees EK, et al. Successful use of deceased kidneys from diabetic donors for transplantation. Transpl Proc 1990;22:378. 177. Spees EK, Orlowski JP, Temple DM. The successful use of marginal deceased donor kidneys. Transpl Proc 1990;22(4):1382–1383. 178. Orlowski JP, Spees EK, Aberle CL, et al. Successful use of kidneys from diabetic deceased kidney donors: 67 and 44 month graft survival. Transplantation 1994;57:1133–1134. 179. Curschellas E, Landmann J, Durig M, et  al. Morphologic findings in “zero hour” biopsies of renal transplants. Clin Nephrol 1991;36(5):215–222. 180. Cerilli J, Holliday JE, Wilson CB, Sharma HM. Clinical significance of the 1-hour biopsy in renal transplantation. Transplantation 1997;26:91–91. 181. Sanfilippo F, Croker BP, Bollinger RR. Fate of four deceased donor renal allografts with mesangial IgA depots. Transplantation 1982;33:370–374. 182. Tolkoff-Rubin NE, Cosima AB, Fuller T, Rubin RH, Colvin RB. IgA nephropathy in HLA-identical siblings. Transplantation 1978;26:430. 183. Schwartzman MS, Zhang PL, Potdar S, Malek SK, Norfolk ER, Hartle JE, Weicker CA, Yahya TM, Shaw JH. Transplantation and 6-month follow-up of renal transplantation from a donor with systemic lupus erythematosus and lupus nephritis. Am J Transpl 2005;5(7):1772–1776. 184. Akioka K, Okamoto M, Ushigome H, Nobori S, Suzuki T, Sakai K, Sakamoto S, Urasaki K, Yanagisawa A, Eukatsu A, Yoshimura N. A case of living-related renal transplant from the donor with membranous nephropathy. Clin Transpl 2009;23(Suppl 20):62–66. 185. Oppenheimer F, Revuelta I, Serra N, Lozano M, Gutierrez-Dalmau A, Esforzado N, Cofan F, Ricart MJ, Torregrosa JV, Crespo M, Paredes D, Martorell J,

247 Alcaraz A, Campistol JM. ABO incompatible ­living donor kidney transplantation: a dream come true. Experience of Hospital Clinic of Barcelona. Nefrologia 2010;30(1):10–14. 186. Guthoff M, Wermet D, Steurer W, Heyne N. ABOincompatible kidney transplantation—case 13/2009. Dtsch Med Wochenschr 2009;134(50):2577. 187. Spasovski GB. First two AB-incompatible living kidney transplantations in the Balkans—should it be a procedure of choice in a developing country? Int J Artif Organs 2007;30(2):173–175. 188. Takahashi K, Saito K, Nakagawa Y, Tasaki M, Hara N, Imai N. Mechanism of acute antibodymediated rejection in ABO-incompatible kidney transplantation: which anti-A/anti-B antibodies are responsible, natural or de  novo? Transplantation 2010;89(5):635–637. 189. Thaiss F. Specific issues in living donor kidney transplantation: ABO-incompatibility. Atheroscler Suppl 2009;10(5):133–136. 190. Warren DS, Montgomery RA. Incompatible kidney transplantation: lessons from a decade of desensitization and paired kidney exchange. Immunol Res 2010. Epub ahead of print. 191. Ivanovski N, Popov Z, Masin-Spasovska J, Dimcevska AH, Kolevski P. First two ABOincompatible living renal transplantations using splenectomy, rituximab, plasmapheresis and IVIG as a preconditioning regimen: a single center experience in the Balkans. Xenotransplantation 2006;13(2):123–125. 192. Montgomery RA, Cooper M, Kraus E, Rabb H, Samaniego M, Simpkins CE, Sonnenday CJ, Ugarte RM, Warren DS, Zachary AA. Renal transplantation at the John’s Hopkins Comprehensive Transplant Center. Clin Transpl 2003;199–213. 193. Oettl T, Halter J, Bachmann A, Guerke L, Infanti L, Oertli D, Mihatsch M, Gratwohl A, Steiger J, Dickenmann M. ABO blood group-incompatible living donor kidney transplantation: a prospective, single-centre analysis including serial protocol biopsies. Nephrol Dial Transplant 2009;24(1):298– 303. Epub 2008 Aug 26. 194. Verran DJ. Transplantation of adult and pediatric horseshoe kidneys: comment. Aust NZ J Surg 1998;68(2):151. 195. Slakey DP, Patel S, Joseph V, et  al. Patient acceptance of deceased kidneys from expanded criteria donors. Transpl Proc 1997;29(1–2):116–117. 196. Shen GK, Salvatierra O Jr, Dafoe DC, et al. Use of split horseshoe kidney for transplantation. Surgery 1998;123(4):475–477. 197. Menezes de Goes G, de Campos Freire G, Borrelli M, Pompeo ACL, Wroclowski ER. Transplantation of a horseshoe kidney. J Urol 1981;126:537–538. 198. Brenner DW, Schlossbery SM, Hurwitz RL. Transplantation of horseshoe kidney into a single recipient. Urology 1990;35: 530. 199. Thomson BN, Francis DM, Millar RJ. Transplantation of adult and pediatric horseshoe kidneys. Aust NZ J Surg 1997;67(5):279–282.

248 200. Ramjumar H, Ahmed SM, Syed E, Tuazon J. Horseshoe kidney in an 80 year old with chronic kidney disease. Sci World J 2009;9:1346–1347. 201. Klan R, Hirner A, Fiedler U, et al. Transplantation of a horseshoe kidney en bloc. J Urol 1988;139:571. 202. Rosenthal JT, Khetan U. Transplantation of deceased kidneys from a donor with crossed nonfused renal ectopia. J Urol 1989;141:1184. 203. Mancini G, Comparini L, Salvadori M. Transplant of a polycystic kidney because of organ shortage. Trans Proc 1990;22(2):376. 204. Spees EK, et  al. Successful use of polycystic deceased donor kidneys. Transpl Proc 1990; 22:374. 205. Wolters HH, Schult M, Heidenreich S, Chariat M, Senninger N, Dietl KH. The anastomosis between renal polar arteries and arteria epigastrica inferior in kidney transplantation: an option to decrease the risk of ureter necrosis? Transpl Int. 2001;14(6):442–444. 206. Nghiem DD, Choi SS. Eversion endarterectomy of the deceased donor renal artery: a method to increase the use of elderly donor kidney allografts. J Urol 1992;147(3):653–656. 207. Gill J, Bunnapradist S, Danovitch GM, Gjertson D, Gill JS, Cecka M. Outcomes of kidney transplantation from older living donors to older recipients. Am J Kidney Dis 2008;52(3):541–552. 208. Gorgulu N, Caliskan Y, Yelken B, Turkmen A. Outcomes of renal transplants from spousal donors: 25 years of experience at our center. Int J Artif Organs 2010;33(1):40–44. 209. D’Alessandro AM, Pirsch JD, Knechtle SJ, Odorico JS, Van der Werf WJ, Collins BH, Becker YT, Kalayoglu M, Armbrust MJ, Sollinger HW. Living unrelated renal donation: the University of Wisconsin experience. Surgery 1998;124(4):604–610;discussion 610–611. 210. Huh KH, Kim MS, Ju MK, Chang HK, Ahn HJ, Lee SH, Lee JH, Kim SI, Kim YS, Park K. Exchange living-donor kidney transplantation: merits and limitations. Transplantation 2008;86(3):430–435. 211. Ferrari P, deKlerk M. Paired kidney donations to expand the living donor pool. J Nephrol 2009;22(6):699–707. 212. Ratner LE, Rana A, Ratner ER, Ernst V, Kelly J, Kornfeld D, Cohen D, Wiener I. The altruistic unbalanced paired kidney exchange: proof of concept and survey of potential donor and recipient attitudes. Transplantation 2010;89(1):15–22. 213. Ennis J, Kocherginsky M, Schumm LP, Worcester E, Coe FL, Josephoson MA. Trends in kidney donation among kidney stone formers: a survey of US transplant centers. Am J Nephrol 2009;30(1):12–18. Epub 2009 Jan 23.

C.S. Modlin III and C.S. Modlin Jr. 214. Walter WC, Engen DE, Stanson AW, Sterioff S, Zincke H. Use of radiographically abnormal kidneys in living-related donor renal transplantation. Nephron 1985;39(4):302–305. 215. Pesavento TE, Henry ML, Falkenhain ME, Cosio FG, Bumgardner GL, Elkhammas EA, Pellletier RP, Ferguson RM. Obese living kidney donors: shortterm results and possible implications. Transplantation 1999;68(10):1491–1496. 216. House AA, Nguan CY, Luke PP. Sirolimus use in recipients of expanded criteria donor kidneys. Drugs 2008;68(Suppl 1):41–49. 217. Rigoti P, Kahan BD. Sirolimus-based therapy for kidney transplantation from expanded criteria donors. Trahsplantation 2009;87(8 Suppl):S11–13. 218. Uslu A, Nart A, Tasli FA, Postaci H, Aykas A, Dogan M, Sahin T. Sirolimus-based triple immunosuppression with antithymocyte globulin induction in expanded criteria donor kidney transplantation. Nephrology 2008;13(1):80–86. 219. Re LS, Rial MC, Guardia OE, Galdo MT, Casadei DH. Results of a calcineurin-inhibitor-free immunosuppressive protocol in renal transplant recipients of expanded criteria deceased donors. Transpl Proc 2006;38(10):3468–3469. 220. Pallet N, Anglicheau D, Martinez F, Mamzer MF, Legendre C, Thervet E. Comparison of sequential protocol using basiliximab versus antithymocyte globulin with high-dose mycophenolate mofetil in recipients of a kidney graft from an expandedcriteria donor. Transplantation 2006;81(6):949–952. 221. Gonzalez-Martinez F, Curi L, Orihuela S, Gonzalez, G, Nunez N, Nin M. Cardiovascular disease and/or elderly donors in renal transplantation: the outcome of grafts and patients. Transpl Proc 2004;36(6):1687–1688. 222. Andres A, Marcen R, Valdes F, Plumed JS, Sola R, Errast P, Lauzurica R, Pallardo L, Bustamente J, Amenabar JJ, Plaza JJ, Gomez E, Grinyo JM, Rengel M, Puig JM, Sanz A, Asensio C, Andres I, NI2A Study Group. A randomized trial of basiliximab with three different patterns of cyclosporine A initiation in renal transplant from expanded criteria donors and at high risk of delayed graft function. J Am Soc Nephrol 2010 Jul 15. [Epub ahead of print]. 223. Durrbach A, Rostaing L, Tricot L, Ouali N, Wolf P, Pouteil-Noble C, Kessler M, Viron B, Thervet E. Prospective comparison of the use of sirolimus and cyclosporine in recipients of a kidney from an expanded criteria donor. Transplantation 2008;85(3):486–490. 224. Modlin CS, Goldfarb DA, Novick AC. The use of expanded criteria cadaver and live donor kidneys for transplantation. Urol Clin North Am 2001;28(4):687–707.

Chapter 12

Pancreas Transplantation: Surgical Techniques Alvin C. Wee and Venkatesh Krishnamurthi

Keywords  Pancreas transplantation • operative techniques • bench preparation

Background Kelly and Lillihei performed the first successful pancreas transplant in 1966 [1]. Since that initial procedure, improvements in organ preservation, immunosuppressive medications, and operative techniques have resulted in consistently high graft survival rates and enabled the procedure to become an accepted therapeutic option for the treatment of type 1 diabetes mellitus (DM1) [2–5]. About 5% of all pancreas transplants are done in patients with type 2 diabetes (DM2), and results seem to be equally good. Several groups have shown excellent glycemic control after pancreas transplantation in selected patients with DM2 [6, 7]. Other forms of diabetes such as MODY3 have also been successfully treated with pancreas transplantation [8]. To date, more than 25,000 pancreas transplants have been performed worldwide according to data from the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) [9]. Pancreas transplantation continues to remain an effective method to establish durable normoglycemia for patients with diabetes mellitus [10]. V. Krishnamurthi (*) Department of Urology, Glickman Urological & Kidney Institute, 9500 Euclid Avenue Q10, Cleveland, Ohio, USA 44195 e-mail: [email protected]

Di Carlo et  al. surveyed 121 active pancreas transplant centers to report their preferred surgical technique for pancreas transplantation [11]. Nearly two thirds of centers responded and of these, approximately 30 different surgical techniques were described. Despite this large number, the ­different surgical approaches are largely variations on the same theme and can be classified broadly according to the approaches to venous drainage and exocrine drainage. Drainage of exocrine secretions via the bladder was previously the most ­common type of exocrine drainage technique, due to the ability to monitor the graft directly by measuring urinary amylase. In initial reports urinary amylase had nearly100% sensitivity in detecting allograft dysfunction [12]. However, due to the frequent occurrence of metabolic and urologic complications, bladder drainage has been largely replaced by enteric drainage [13–15]. Based on IPTR data, of pancreas transplants done between 2000 and 2004, almost two thirds of all transplant are enterically drained [9]. In addition to the variability in exocrine drainage, differences also lie in the location of the vascular anastomoses, the types of arterial and venous reconstruction, the position of the graft, and last the use of staple versus handsewn bowel anastomosis.

Surgical Technique The focus of this chapter will be on the current operative technique utilized at the Cleveland Clinic. We divide the operation broadly into four

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_12, © Springer Science+Business Media, LLC 2011

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steps: (1) incision and exposure, (2) bench preparation, (3) revascularization, and (4) duct management.

Incision and Exposure Pancreas transplantation can be performed through a lower quadrant extraperitoneal incision or a midline intraperitoneal approach. If an extraperitoneal approach is selected, we advocate opening the peritoneum following completion of the vascular and exocrine anastomoses in order to facilitate drainage of peripancreatic secretions. In the case of a simultaneous kidney transplant, a separate incision should be made on the contralateral side. Undoubtedly the addition of another incision adds to the operative time, but one advantage of this approach is that the kidney remains extraperitoneal, which, in theory, isolates the kidney in cases of pancreas transplant-associated infections. In a large series of nearly 100 patients, Adamec and colleagues showed good results with an extraperitoneal approach to pancreas transplantation [16]. We favor an approach through a midline intraperitoneal incision, since this gives more flexibility and aids in the performance of concomitant procedures – such as simultaneous kidney transplantation, removal of peritoneal dialysis catheter, incidental appendectomy, and native nephrectomy. Postoperative pain may also be reduced since there is no division of muscle. After entering the peritoneal cavity, a Bookwalter self-retraining retractor is used to retract the abdominal wall. A medium-sized oval ring ­provides satisfactory exposure in the majority of patients. The right colon and small bowel are mobilized to expose the retroperitoneal structures. In the case of systemic drainage, the right common iliac artery and the infrarenal inferior vena cava (IVC) or the iliac veins are circumferentially dissected and isolated with vessel loops. In the case of portal venous drainage, we first isolate the superior mesenteric vein (or a large tributary) within the mesenteric root.

Bench Preparation More so than other solid organ transplants, pancreas transplantation requires protracted and meticulous preparation of the organ on the “bench.” In a broad sense, the pancreas allograft bench work consists of a splenectomy, preparation of the duodenal segment, identification and ligation of peripancreatic lymphatics and small vessels, oversewing of the mesenteric root, and vascular reconstruction.

Inspection of the Pancreas Allograft Perhaps the most important factor in the entire process of pancreas allograft preparation is to maintain the allograft in cold preservation solution. We immerse the pancreas allograft in an isolation bag containing 1 L of cold University of Wisconsin solution. The bag is then surrounded with an abundant amount of iced slush and the entire procedure is conducted within a large sterile basin. The first step in successful bench preparation is full and thorough inspection of the pancreas allograft, particularly if the procurement was completed by another surgical team. The gland color, consistency, and gross fat content should be evaluated. A satisfactory pancreas allograft is typically dull orange or pink in color (when perfused) and is easily pliable. The parenchyma and the duodenal segment should be inspected for injuries and the vasculature should be assessed for suitability for reconstruction.

Splenectomy We often perform the splenectomy first, although this can be done after reperfusion if ischemic time is extremely critical. In most cases, the splenectomy can be done within 15–20 min and is “easier” to do in a bloodless field. In performing the splenectomy, care should be taken not to injure the tail of the pancreas. We ligate perforating vessels as they are encountered with silk ties, placing the ties only on the allograft side.

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Portal Vein Mobilization The portal vein should be mobilized to the ­confluence of the splenic and superior mesenteric veins in order to provide sufficient length for implantation. This maneuver may sometimes require division of a few pancreaticoduodenal veins, most commonly the anterior superior pancreaticoduodenal vein. These veins are typically found on the right side of the portal vein, directly draining the head of the pancreas. Occasionally, the origin of the left gastric or coronary vein can be identified on the left side of the portal vein and this can be ligated and divided. We mobilize the portal vein such that when stretched, approximately 2 cm of portal vein extends from the ­surface of the gland. Only in rare, extenuating circumstances do we advocate the addition of a venous extension graft.

Reinforcement of the Mesenteric Root The root of the small bowel mesentery is divided during the pancreas procurement. This is accomplished by ligating individual vessels in the ­mesenteric root or by ligating them “en mass” with a linear stapling device. We prefer a stapling device, as this approach saves time and provides satisfactory hemostasis. Most often, unless a ­vascular staple load is used, the staple line must be reinforced to provide hemostasis. We oversew this staple line with a continuous #4 – 0 polypropylene suture. This step often ­prevents bleeding after reperfusion, as the staples may not have occluded all of the vessels in the mesenteric root.

Preparation of the Duodenal Segment Unlike the technique of bladder drainage in which the length of the allograft duodenum is important, the length of the donor duodenum is not as critical in enteric drainage, since pancreatic exocrine secretions can be absorbed by the distal bowel. On the other hand, the length of the allograft duodenum should not be redundant, since vascular compromise to the distal end of

the bowel can be catastrophic. A good “rule of thumb” is that the proximal duodenum should be at the level of the gastroduodenal artery (GDA) and the distal segment should at least 1–2 cm from the uncinate process of the pancreas. We inspect the distal duodenal staple line after reperfusing the allograft and then restaple the distal duodenum (using a GIA 80 stapler) at a visibly well-perfused level. Of note, the perfusion to the duodenal segment is based on the inferior pancreaticoduodenal artery, which arises from the SMA. The entire duodenal segment is perfused in a retrograde manner from this vessel as there is no longer antegrade flow through the superior arcade from the GDA

Arterial Reconstruction In most cases we reconstruct the arterial supply only after completion of the above mentioned steps. This sequence evolved from our practice of exploring the superior mesenteric vein for portal drainage. When performing portal venous drainage, our preferred technique of arterial reconstruction was direct anastomosis of the splenic artery to the SMA. For the last 3 years we have favored systemic venous drainage, and we most often utilize the donor iliac bifurcation or Y-graft for this technique. Both techniques and their relative advantages are discussed below. It is helpful to have facility with either technique of arterial reconstruction, since on occasion, either the donor or recipient vasculature may not allow for the initially planned approach. The superior mesenteric artery (SMA) and splenic artery are then prepared for arterial reconstruction by mobilizing the proximal ends of the arteries for approximately 5 mm. The neural and lymphatic tissue overlying the ends of these arteries should be sharply excised. Once the end of the artery is satisfactorily visible for anastomosis, the donor iliac arterial graft can be brought into the field. We also prepare the donor arterial graft by sharply removing the periadventitial tissue. The iliac bifurcation is inspected to ensure the absence of injuries and the graft is hydrodistended and any uncontrolled branches are suture ligated

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using #5-0 or #6-0 polypropylene suture. The Y graft is then oriented along the SMA and splenic arteries (Fig.  12.1). In most cases, the internal iliac or hypogastric artery matches up well to the splenic artery. The hypogastric artery is trimmed to at most 1 cm and an end-to-end anastomosis between the hypogastric and splenic arteries is done with #7–0 polypropylene. The external iliac artery is then trimmed to a similar length and an end-to-end anastomosis between it and the SMA is completed with #6–0 polypropylene. It is particularly important to keep the “limbs” of the Y graft short (<1 cm) to avoid twisting or kinking after anastomosis. Despite the initial appearance, the SMA and splenic arteries are actually in very close proximity and can, in fact, be in direct apposition by excising the surrounding neural and lymphatic tissue. Other modifications include use of an aortic patch with both SMA and the celiac axis. This can only be done in situations where the liver was not procured. One modification that we have adapted for portal venous drainage is direct end-to-side anastomosis of the splenic artery to the SMA (Fig. 12.2). This modification arose from consideration that when utilizing portal venous drainage, the donor Y graft might not have sufficient length to reach the recipient iliac artery. In these cases, an arterial extension graft was needed.

Fig. 12.1  Arterial reconstruction with donor iliac Y graft

A.C. Wee and V. Krishnamurthi

The key to direct end-to-side anastomosis of the splenic artery to the SMA is full mobilization of the SMA. Careful dissection of the neural and lymphatic around the SMA lengthens this vessel and allows it to comfortably lie adjacent to the proximal end of the splenic artery. We then fashion an elliptical arteriotomy on the side of the SMA and directly anastomose the splenic artery with a continuous #7–0 polypropylene suture. By utilizing this end-to-side arterial reconstruction, we need only one limb of the donor Y graft to provide arterial inflow to the pancreas. We most often use the external iliac artery (Fig.  12.3, inset). With this revision we can ­utilize the full length of the Y graft by ligating the internal iliac artery. The external iliac artery is then anastomosed to the SMA at the time of pancreas allograft revascularization. In contrast to the Y graft technique in which the graft is connected to the allograft pancreas, with this modification, the iliac graft is first sewn to the common iliac artery and then tunneled through the mesentery and brought adjacent to the superior mesenteric vein (SMV). Since the artery and vein now lie immediately adjacent to each other, we noted a decrease in operative time because the venous and arterial anastomoses can be done in the same operative field.

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Fig. 12.2  Direct splenic artery to SMA (end to side anastomosis)

Fig. 12.3  Arterial conduit is tunneled through the mesentery. Inset: Ligation of internal iliac artery of the donor Y graft to maximize the length of the external iliac artery

Revascularization of the Pancreas Allograft Venous Drainage The preferred method of venous drainage remains somewhat controversial, although less so than a decade ago. Based on IPTR data from 2000– 2004, systemic venous drainage was utilized for almost 80% of cases, while the remaining 20% were drained via a portal drainage technique [9]. A theoretical disadvantage of systemic venous drainage is the occurrence of systemic hyperinsulinemia. In experimental ­systems, hyperinsulinemia

has been associated with lipid metabolism disorders and premature cardiovascular problems [17– 19]. In practice, however, these problems were not observed in prospective studies [20, 21]. Moreover, Petruzzo et  al. noted lower fasting blood sugar levels following systemic drainage, possibly due to higher insulin levels.

Portal Venous Drainage Portal venous drainage, which simulates the natural physiology of insulin secretion and elimination,

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has also gained popularity after the year 2000. Most current techniques of portal venous drainage are based upon the technique description of Shokouh-Amiri [22]. This technique is done by reflecting the transverse colon cephalad and exposing the root of the mesentery. The peritoneum in the mesenteric root is incised and the superior mesenteric vein and several tributaries are dissected and isolated. We attempt to isolate 4–5 cm of this vein. We control the vein both proximally and distally and also control all significant tributaries with the aid of small bulldog clamps. We then perform an end-to-side anastomosis of the allograft portal vein to the SMV using #7–0 polypropylene suture. It is particularly important to handle this vein very delicately both during the anastomosis and subsequently since, compared to systemic veins, the SMV wall tends to very thin and fragile. Moreover, the small caliber of the SMV in this location often requires very small “bites” to avoid luminal narrowing. Some authors stress the superiority of portal venous drainage from the standpoint of decreased rejection and improved graft survival rates [23]. However, long term data show both systemic and portal venous drainage to result in similar graft survival rates [24]. Additionally, technical graft loss from thrombosis rate does not appear to differ between the two types of venous drainage.

Systemic Venous Drainage Systemic venous drainage has become the preferred technique in our center. The iliac vein or the IVC can be utilized for the anastomosis. We prefer to use the infrarenal IVC due to its larger lumen and thicker wall. In approaching the IVC for systemic drainage, the vessel should just be cleared enough to accommodate a vascular clamp. We perform an end-to-side anastomosis between the portal vein and IVC with either #5–0 or #6–0 polypropylene suture. Venous effluent from the pancreas allograft can also be drained to the iliac vein. When utilizing this approach, we favor complete mobilization of the iliac vein to allow for a more superficial anastomosis. This requires the ligation and division of several large posterior tributaries, which

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in our experience is a tedious maneuver. We have found that with the technique of implantation along the lower IVC, these steps can be eliminated (even the exposure of the vein itself), thus decreasing the overall operative time. From our experience with both approaches to venous drainage, we feel that portal venous drainage may also be preferential for deep patients, since the SMV is more superficial than the iliac vein or IVC. Both from our experience and data from large registries suggest similar outcomes with both techniques.

Arterial Revascularization Arterial revascularization is generally performed to the right common iliac artery or sometimes the external iliac artery. Use of the right iliac vessels may be technically easier than that of the left iliac vessels, due to their more superficial course. Second, placement on the left iliac vessels may require creation of a mesenteric tunnel to access the jejunum for drainage of exocrine secretions. In theory, the second reason may keep the organ in a more retroperitoneal position, which may prevent traction on the vascular anastomosis. Troppmann et al. demonstrated in a review of more than 438 pancreas transplant that left-sided implantation and arterial reconstructions other than the Y graft increases risk for graft thrombosis. A similar detrimental outcome was seen with portal vein extension grafts [25]. We favor adherence to these findings unless donor or recipient factors dictate otherwise.

Duct Management Over time enteric drainage has become the ­preferred technique of duct drainage. IPTR data from 2000–2004 showed that more than 82% of all pancreas transplants utilized enteric drainage. The primary reasons for the decrease in bladder drainage are the high frequency urological complications and the improvements in the survival of enterically-drained grafts [13].

12  Pancreas Transplantation: Surgical Techniques

Enteric drainage is most commonly done by anastomosis of the allograft duodenum to the recipient jejunum. When performing enteric drainage, reconstructive options include endto-side, or side-to-side anastomosis. Use of a Roux en Y reconstruction can, in theory, provide the advantage of isolating anastomotic complication; [26] however, this requires construction of another anastomosis (jejuno-jejunostomy) that has its own finite complication rate. Most investigators have found no significant differences between the two techniques [27, 28]. When performing bladder drainage, the graft is oriented head down, in order to facilitate sideto-side anastomosis of the allograft duodenum and the bladder. We have found that by positioning the pancreas allograft with the head up, we

Fig. 12.4  EEA staple 21 mm (American Surgical Devices)

Fig. 12.5  Technique described by De Roover et al.

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encounter less tension on the bowel anastomosis. The portal vein is then anastomosed to the IVC and the arterial Y graft is anastomosed to the right common iliac artery. After reperfusion, bleeding sites are controlled with clips and suture ligatures. Once hemostasis is satisfactory, we proceed with the bowel anastomosis, as the donor duodenum quickly becomes distended with pancreatic secretions. The enteric anastomosis can be done with either a hand-sewn or stapled technique, both of which have excellent results [29]. We have recently modified our exocrine drainage technique by performing a duodenoduodenostomy. We have used this technique with both a hand-sewn and stapled method, using the EEA 21-mm stapler (Fig. 12.4).

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Fig. 12.6  Duodeno-duodenostomy anastomosis using EEA staple. Allograft duodenum is aligned perfectly to the native duodenum after vascular anastomosis

We feel this approach to exocrine drainage provides advantages of improved accessibility for biopsy via upper gastrointestinal endoscopy. Although initially described by De Roover [30] and Hummel [31] our technique utilizes the same head up position, with the exception of the portal vein being drained systemically and the use of the circular stapler to facilitate our anastomosis. Hummel also described the advantage of this technique in monitoring graft function via gastroscopy [31]. The surgical technique of this approach is very similar. Once the vascular anastomoses are completed and the gland has been reperfused, the allograft duodenum naturally assumes a position alongside the third portion of the native duodenum. This close proximity facilitates both hand-sewn and stapled anastomoses. Another potential advantage is that by keeping the organ

in its retroperitoneal position, it may eliminate the possibility of an internal hernia.

Summary The pancreas transplant operation has undergone considerable modification since the initial procedure over 40 years ago. In addition to improvements in organ procurement and organ preservation, the details related to implantation of the pancreas allograft have been systematically analyzed and improved upon. The predominant surgical technique at present, systemic venous drainage and enteric exocrine drainage, reliably provides excellent functional outcomes in the majority of pancreas transplant cases. Knowledge of alternative reconstructive and implantation

12  Pancreas Transplantation: Surgical Techniques

techniques can be a valuable adjunct to the pancreas transplant surgeon’s skill set.

References 1. Kelly WD, Lillehei RC, Merkel FK, Idezuki Y, Goetz FC. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 1967;61(6):827–837. 2. Dieterle CD, Arbogast H, Illner WD, Schmauss S, Landgraf R. Metabolic follow-up after longterm pancreas graft survival. Eur J Endocrinol 2007;156(5):603–610. 3. Meloche RM. Transplantation for the treatment of type 1 diabetes. World J Gastroenterol 2007;13(47):6347–6355. 4. Lipshutz GS, Wilkinson AH. Pancreas-kidney and pancreas transplantation for the treatment of diabetes mellitus. Endocrinol Metab Clin North Am 2007;36(4):1015–1038; x 5. Odorico JS, Sollinger HW. Technical and immunosuppressive advances in transplantation for insulin-dependent diabetes mellitus. World J Surg 200226(2):194–211 6. Nath DS, Gruessner AC, Kandaswamy R, Gruessner RW, Sutherland DE, Humar A. Outcomes of pancreas transplants for patients with type 2 diabetes mellitus. Clin Transplant 2005;19(6):792–797. 7. Pox C, Ritzel R, Busing M, Meier JJ, Klempnauer J, Schmiegel W, et al. Combined pancreas and kidney transplantation in a lean type 2 diabetic patient. effects on insulin secretion and sensitivity. Exp Clin Endocrinol Diabetes 2002;110(8):420–424 8. Saudek F, Pruhova S, Boucek P, Lebl J, Adamec M, Ek J, et  al. Maturity-onset diabetes of the young with end-stage nephropathy: a new indication for simultaneous pancreas and kidney transplantation?. Transplantation 2004;77(8):1298–1301. 9. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for united states (US) and non-US cases as reported to the united network for organ sharing (UNOS) and the international pancreas transplant registry (IPTR) as of june 2004. Clin Transplant 2005;19(4):433–455. 10. Dean PG, Kudva YC, Stegall MD. Long-term benefits of pancreas transplantation. Curr Opin Organ Transplant 2008;13(1):85–90. 11. Di Carlo V, Castoldi R, Cristallo M, Ferrari G, Socci C, Baldi A, et al. Techniques of pancreas transplantation through the world: an IPITA center survey. Transplant Proc 1998;30(2):231–241. 12. Benedetti E, Najarian JS, Gruessner AC, Nakhleh RE, Troppmann C, Hakim NS, et  al. Correlation between cystoscopic biopsy results and hypoamylasuria in bladder-drained pancreas transplants. Surgery 1995;118(5):864–872. 13. Adamec M, Janousek L, Lipar K, Hampl F, Saudek F, Koznarova R, et al. A prospective comparison of blad-

257 der versus enteric drainage in vascularized pancreas transplantation. Transplant Proc 2004;36(4):1093–1094. 14. Orsenigo E, Castoldi R, Socci C, Cristallo M, Fiorina P, La Rocca E, et al. Advantages and disadvantages of enteric versus bladder diversion in simultaneous kidney-pancreas transplantation. Chir Ital 2002;54(4):429–436. 15. Orsenigo E, Cristallo M, Socci C, Castoldi R, Secchi A, Colombo R, et al. Urological complications after simultaneous renal and pancreatic transplantation. Eur J Surg 2002;168(11):609–613. 16. Adamec M, Janousek L, Saudek F, Tosenovsky P. 100 pancreas transplantations with extraperitoneal graft placement. Ann Transplant 2001;6(2):41–42. 17. Carpentier A, Patterson BW, Uffelman KD, Giacca A, Vranic M, Cattral MS, et al. The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism. Diabetes 2001;50(6):1402–1413. 18. Bagdade JD, Ritter MC, Kitabchi AE, Huss E, Thistlethwaite R, Gabfr O, et al. Differing effects of pancreas-kidney transplantation with systemic versus portal venous drainage on cholesteryl ester transfer in IDDM subjects. Diabetes Care 1996;19(10):1108–1112. 19. Hughes TA, Gaber AO, Amiri HS, Wang X, Elmer DS, Winsett RP, et al. Kidney-pancreas transplantation. The effect of portal versus systemic venous drainage of the pancreas on the lipoprotein composition. Transplantation 1995;60(12):1406–1412. 20. Petruzzo P, Da Silva M, Feitosa LC, Dawahra M, Lefrancois N, Dubernard JM, et  al. Simultaneous pancreas-kidney transplantation: portal versus systemic venous drainage of the pancreas allografts. Clin Transplant 2000;14(4 Pt 1):287–291. 21. Kissler HJ, Gepp H, Tannapfel A, Schwille PO. Effect of venous drainage site on insulin action after pancreas transplantation in the rat--is there insulin resistance and a risk for atherosclerosis? Metabolism 2000;49(4):458–466. 22. Shokouh-Amiri MH, Gaber AO, Gaber LW, Jensen SL, Hughes TA, Elmer D, et al. Pancreas transplantation with portal venous drainage and enteric exocrine diversion: A new technique. Transplant Proc 1992;24(3):776–777. 23. Philosophe B, Farney AC, Schweitzer EJ, Colonna JO, Jarrell BE, Krishnamurthi V, et al. Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study. Ann Surg. 2001;234(5):689–696. 24. Lo A, Stratta RJ, Hathaway DK, Egidi MF, ShokouhAmiri MH, Grewal HP, et al. Long-term outcomes in simultaneous kidney-pancreas transplant recipients with portal-enteric versus systemic-bladder drainage. Am J Kidney Dis 2001;38(1):132–143. 25. Troppmann C, Gruessner AC, Benedetti E, Papalois BE, Dunn DL, Najarian JS, et  al. Vascular graft thrombosis after pancreatic transplantation: univariate and multivariate operative and nonoperative risk factor analysis. J Am Coll Surg 1996;182(4):285–316.

258 26. Zibari GB, Aultman DF, Abreo KD, Lynn ML, Gonzalez E, McMillan RW, et al. Roux-en-Y venting jejunostomy in pancreatic transplantation: a novel approach to monitor rejection and prevent anastomotic leak. Clin Transplant 2000;14(4 Pt 2): 380–385. 27. Tyden G, Tibell A, Sandberg J, Brattstrom C, Groth CG. Improved results with a simplified technique for pancreaticoduodenal transplantation with enteric exocrine drainage. Clin Transplant 1996;10(3): 306–309. 28. Kuo PC, Johnson LB, Schweitzer EJ, Bartlett ST. Simultaneous pancreas/kidney transplantation--a comparison of enteric and bladder drainage of exo-

A.C. Wee and V. Krishnamurthi crine pancreatic secretions. Transplantation 1997; 63(2):238–243. 29. Lam VW, Wong K, Hawthorne W, Ryan B, Lau H, Robertson P, et  al. The linear cutting stapler for enteric anastomosis: a new technique in pancreas transplantation. Transpl Int 2006;19(11):915–918. 30. De Roover A, Coimbra C, Detry O, Van Kemseke C, Squifflet JP, Honore P, et al. Pancreas graft drainage in recipient duodenum: Preliminary experience. Transplantation 2007;84(6):795–797. 31. Hummel R, Langer M, Wolters HH, Senninger N, Brockmann JG. Exocrine drainage into the duodenum: A novel technique for pancreas transplantation. Transpl Int 2008;21(2):178–181.

Chapter 13

Laparoscopic Living Kidney Donation Wesley M. White and Jihad H. Kaouk

Keywords  Living kidney donation • Laparoscopy • Donor nephrectomy

Introduction End-stage renal disease (ESRD) is a principal cause of morbidity and death among Americans and constitutes a significant fiscal burden to the health care system of the United States [1]. Renal replacement therapy typically comes in the form of hemodialysis or renal transplantation. Certainly, the latter is associated with appreciably better longevity and a tangibly improved quality of life [2, 3]. Regrettably, the pervasiveness of ESRD has disproportionately exceeded the supply of available allografts [4]. Within the context of this growing shortage, the number of deceased donor renal transplants has remained relatively stable [5]. As a consequence, there exists an urgent need for improved accrual of living kidney donors. Live donor nephrectomy was traditionally performed via an open transperitoneal subcostal or extraperitoneal flank incision. While graft outcomes were outstanding with this approach, these positive outcomes came at the expense of morbidity to the donor, including significant postoperative pain, protracted convalescence,

J.H. Kaouk (*) Cleveland Clinic, Glickman Urological & Kidney Institute, Cleveland, OH, USA

and inferior cosmesis [6, 7]. Indeed, the morbidity of open donor nephrectomy was considered a disincentive to kidney donation and a barrier to its widespread use. In response to these concerns, Gill and colleagues performed the first laparoscopic donor nephrectomy in an animal model in 1994 [8]. In 1995, Ratner and Kavoussi published their experience with laparoscopic live donor nephrectomy in humans [9]. Evidencebased research over the following decade eventually established laparoscopic live donor nephrectomy as a safe, feasible, and less morbid alternative to open procurement [10, 11]. In 2007, the United Network for Organ Sharing (UNOS) reported 6,041 live donor kidney transplants, with the preponderance of these allografts procured laparoscopically [12]. Despite improvements in technique, refinements in instrumentation, and ever-growing experience, laparoscopic live donor nephrectomy remains one of the most demanding urologic procedures to perform. While the general difficulties with laparoscopic donor nephrectomy are analogous to those of laparoscopic simple and radical nephrectomy, the nature of the procedure engenders little margin for error [13]. The operating surgeon is not only culpable for the wellbeing of the donor who is altruistically undergoing an essentially elective procedure, but also for the health of the allograft that will offer the recipient an enhanced and prolonged life. Laparoscopic live donor nephrectomy demands attention to detail, technical proficiency, and a detailed understanding of the common difficulties experienced during the operation.

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_13, © Springer Science+Business Media, LLC 2011

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Preoperative Evaluation Preoperative evaluation of the live donor candidate is multi-faceted and demands close collaboration among the transplant nurses, nephrologists, and transplant and donor surgeons. Candidates must meet medical and psychological criteria as established by the American Society of Transplant Surgeons (ASTS) [14]. In general, donor candidates will go through screening at the request of the transplant center that includes a baseline laboratory profile including serum creatinine, a 24-h urine assay for protein, creatinine, and volume, and a calculated estimate of the glomerular filtration rate (GFR) with subsequent confirmation based on a GFR isotope renal function test [15]. ABO histocompatibility testing and HLA cross-matching is performed to validate the suitability and safety of the donation. The patient is screened for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) as well as hepatitis C (HCV) and other bloodborne pathogens [15]. Once baseline criteria are met, the candidate is referred to the donor surgeon for examination and consultation. The donor candidate’s history should be focused and thorough. In general, the majority of donor candidates are healthy with favorable operative characteristics. In addition to review of the patient’s past medical history, a thorough review of previous intraabdominal surgeries is imperative, as is close inspection of the abdominal wall for evidence of prior surgeries and overall body habitus. Generally, an elevated BMI is not a contraindication to laparoscopic live donor nephrectomy, but can affect the placement of ports needed for optimal exposure and visualization [16]. A prior history of intraabdominal surgeries is likewise not a contraindication for donation, but may dictate the preferred approach for procurement (retroperitoneal versus transperitoneal) [17]. Radiographic evaluation of the kidneys and renal vasculature is perhaps the most critical and relevant component of the preoperative evaluation. In the modern era, helical computed tomography of the

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kidneys with three-dimensional reconstruction (3D CT of the kidneys) offers incomparable detail and characterization of the renal vascular anatomy and demonstrates very well the presence of any pathology or anatomic anomalies (Figs.  13.1 and 13.2) [18]. In addition, volume rendering of the kidneys is performed that may dictate the appropriate kidney for donation. We cannot overemphasize the importance of personally reviewing the aforementioned imaging studies preoperatively as, in our opinion, the majority of intraoperative complications may be obviated with a thorough spatial command of the patient’s vascular anatomy. The operating surgeon should be thoroughly versed on the number and relative location of the main renal vessels, the presence of any accessory or polar vessels, and the distance to the first branch of the main renal artery. In our experience, it is helpful to inform the transplant surgeons preoperatively of early arterial branching (<1 cm), as their approach to bench preparation and implantation may be impacted by such a finding. The decision to perform a left- or rightsided laparoscopic donor nephrectomy is determined in large part by the patient’s anatomy as depicted on the 3D CT as well as the collaborative opinion of the donor and recipient surgeons. Traditionally, the left kidney has been procured given its longer renal vein [14]. However, ease of harvest and implantation should never be prioritized at the expense of the donor’s future renal function. Among patients with renal volume discordance (>20% difference in renal volume), a nuclear renal scan should be performed to establish functional equivalence [19]. If the left kidney contributes more than 60% to the overall renal function, the right kidney should be considered for procurement. Additional relative indications for right-sided donor nephrectomy include cysts in the right kidney, complex left renal vasculature, and/or an anomalous left collecting system [14, 20]. If the right kidney is chosen for procurement, adequate vein length from the edge of the vena cava (>2 cm) must be assured on 3D CT (see Fig. 13.1), and special concessions must be made intraoperatively.

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Fig. 13.1  3D CT of the kidneys demonstrating the right renal vascular anatomy and approximate length of the right renal vein

Fig. 13.2  3D CT of the kidneys demonstrating the left renal vascular anatomy and approximate length of the left renal vein. Of note, a circumaortic left renal vein is appreciated

Operative Technique Following induction in the supine position, a 16 French catheter is placed and the patient is positioned with the table break at the level of the iliac crest. The patient is converted to the full flank or modified flank position (45°) with padding under the dependent hip and axilla as well as under and between the legs (Fig. 13.3). The arms are placed on a double-arm board, padded, and taped. We flex the operating table slightly to accentuate the space

between the costal margin and iliac crest. We do not elevate the kidney rest. Once positioning is satisfactory, we secure the patient to the table with straps and 3-in. tape (see Fig. 13.2). The abdomen is prepped from the xiphoid to the pubic symphysis, laterally to the back and medially beyond the umbilicus. Drapes are secured to the patient with towel clips or a skin stapler to avoid contamination during extraction of the kidney. Prefabricated sterile drapes specifically designed for laparoscopy are employed. When appropriately used, these drapes

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Fig. 13.3  Intraoperative photograph demonstrating patient positioning during left laparoscopic donor nephrectomy. All pressure points are padded and the patient affixed to the table with adhesive tape

can provide order during the operative procedure and efficiency of instrument exchange. Appropriate port position dictates adequacy of exposure and ultimately the outcome and efficiency of the case. Following the identification of relevant landmarks, a 12-mm incision is made in the vertical plane at or just above the level of the umbilicus and in the horizontal plane approximately halfway between the umbilicus and anterior superior iliac spine (Fig. 13.4). Access to the peritoneum may be obtained with a Veress or Hasson technique. Once pneumoperitoneum is achieved at a pressure maximum of 15 mmHg, the first 12-mm trocar (right hand) is placed. The peritoneal cavity is widely inspected and the anterior abdominal wall evaluated for additional port placement. A second 12-mm port (left hand) is positioned at the subcostal margin at the lateral border of the rectus muscle. A third 12-mm port (camera port) is positioned at the level of the 12th rib again at the lateral border of the rectus muscle (Fig.  13.5). We prefer to use a 10-mm laparoscope with a 30-degree down lens. With an atraumatic small bowel grasper in the left hand and cold shears in the right hand, the descending colon is reflected off the left kidney from the upper pole to beyond the lower pole

(Fig.  13.6). It is important to identify the appropriate plane of dissection between Gerota’s fascia and the mesentery of the colon during this maneuver as dissection deeply into Gerota’s fascia will generate unnecessary bleeding and/or trauma to the allograft and failure to dissect deeply enough will compromise exposure of the renal hilum. In addition, failure to reflect the mesentery medially may make subsequent identification of the gonadal vein difficult. Additionally, it is not uncommon for the inferior mesenteric vein to be easily confused with the gonadal vein if the mesentery has not been adequately mobilized. If medial reflection of the colon remains difficult, it may be helpful to place an additional 12-mm port at the planned kidney extraction site through which a fan retractor or atraumatic grasper may be placed for additional exposure. Once the colon has been completely reflected, a plane between the upper/medial pole of the kidney and the spleen is easily identified. In most cases, the spleen may be completely mobilized and reflected off the upper pole of the kidney by incising the splenocolic ligament. Typically, this plane of dissection should allow the tail of the pancreas, colon, and the splenic vessels to be

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Fig. 13.4  Intraoperative photograph demonstrating relevant landmarks and port positioning during laparoscopic left donor nephrectomy

Fig. 13.5  Schematic detailing port positioning during left laparoscopic donor nephrectomy. A Pfannenstiel incision is made following mobilization to facilitate kidney extraction

reflected en bloc away from the concave aspect of the kidney. Again, if the mesentery was not adequately mobilized earlier, injury to these structures is a possibility. In addition, one must be aware that the dependent portion (fundus) of the stomach may sweep around the lateral aspect

of the spleen and is therefore at risk for injury when dissecting the splenophrenic attachments. The ureter and gonadal vein are identified at the lower pole of the kidney in their normal anatomic position atop the psoas muscle (Fig. 13.7). It is important not to skeletonize the ureter as its blood supply could become compromised with aggressive dissection. We find it helpful to lift but not directly manipulate the gonadal vein/ureter package anteriorly with the left hand while cleaning the psoas muscle up to and under the lower pole of the kidney with a suction/irrigator in the right hand. Perivenous and periureteral tissue should be swept anteriorly and laterally to ensure a healthy ureteral blood supply. The investments on the anterior surface of the gonadal vein may be dissected thermally with the use of a finetipped hook until the lumbar vein and main renal vein are identified (Fig.  13.8). In order to gain adequate exposure during this critical step, we find it helpful to apply static anterior traction on the vein/ureter packet while cephalad torque is applied. This maneuver allows the packet to be lifted not only out of the operative field but also places tension on the tissue that requires dissection off the gonadal vein and approaching hilum. Alternatively, a laterally positioned accessory 2- or 5-mm port may be placed to reflect the packet anteriorly while the left hand is freed to apply tension to the tissue to be dissected.

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Fig. 13.6  Intraoperative photograph demonstrating reflection of the mesentery of the descending colon away from the underlying Gerota’s fascia. A clean plane of dissection is maintained to avoid unnecessary bleeding

Fig. 13.7  Intraoperative photograph of the ureteral/gonadal vein dissection. The ureter and psoas tendon are appreciated through a thin layer of fibrous attachments

As stated, dissection of the fine fibrous attachments on the anterior surface of the gonadal vein typically affords visualization of the lateral edge of the aorta, the lumbar vein, and the inferior surface of the renal vein (Fig. 13.9). We prefer to leave the gonadal vein intact at this point, as countertraction on the gonadal vein can make dissection of the lumbar vein easier. Once the lumbar vein has been identified, we isolate and skeletonize the vessel with a 10-mm right angle dissector. Care must be taken at this juncture as

the main renal artery is typically found in the angle between the lumbar vein, aorta, and main renal vein. Once adequately isolated, the lumbar vein is doubly clipped with Hem-O-Lok clips (Weck Closure Systems, Research Triangle Park, NC) and transected. It is important to place the proximal clip several millimeters away from the origin of the vein as clip dislodgement is a potentially disastrous complication. Conversely, placement of the clip too close to the origin of the vessel may preclude secure deployment of the

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Fig. 13.8  With the ureter and gonadal vein lifted anteriorly, the psoas muscle is cleared and fine-tipped hook cautery is used to dissect along the length of the gonadal vein

Fig. 13.9  The inferior aspect of the main renal vein is appreciated. The entry of the gonadal vein into the renal vein is in its expected anatomic position

endovascular stapler during division of the main renal vein. Once the lumbar vein has been controlled and transected, the gonadal vein can typically be controlled with clips and transected (Fig.  13.10). Once the gonadal vein is divided, the renal artery and vein are generally well visualized. Following dissection and control of the gonadal and lumbar veins, the upper limit of the main renal vein should be defined and the origin of the adrenal vein identified. As before, a right angle dissector

should be carefully passed behind the adrenal vein and the vessel skeletonized. Clips should be placed proximally and distally and the vein divided (Fig. 13.11). Once the adrenal vein has been controlled, the adrenal gland may be dissected away from the kidney. As numerous perforating veins and small arterial branches are typically found in the plane between the adrenal gland and upper pole of the kidney in Gerota’s fascia, liberal use of clips, or a harmonic scalpel is advised. Care must be taken when dissecting along the upper edge of the

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Fig. 13.10  The gonadal vein has been controlled with clips and transected. A complicated renal venous anatomy is easily appreciated

Fig. 13.11  The adrenal vein has been adequately dissected and controlled with nonabsorbable clips

renal vein as the renal artery may run in a tortuous fashion and be injured in this location. Once the entire adrenal gland has been mobilized medially away from the upper pole of the kidney, the psoas muscle can generally be identified behind the upper pole. Restoring this landmark above the renal hilum tells the operating surgeon that the main renal vessels are ready to be fully skeletonized. Dissection of the renal hilum demands adequate retraction and calculated and patient dissection. Fine-tipped hook cautery and blunt dissection of superficial fibro-adipose tissue should be

employed to expose the limits of the main vessels. We find that alternating use of the suction/ irrigator and 10-mm right angle dissector aid in dissection of the vessels (Fig.  13.12). The renal vessels must be freed of all ancillary investments (lymphatic tissue, etc.) such that a right angled dissector may be easily passed from each side of the vessel with adequate clearance from the aorta (artery) and inter-aortocaval region (vein) (Fig. 13.13). We discourage extensive or aggressive dissection to the level of the renal sinus, as this may induce arterial vasospasm. Early arterial

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Fig. 13.12  A right-angled dissector is used to free all investments from the left renal artery

Fig. 13.13  The left renal artery has been adequately dissected and is ready for control and division. Again, the complex venous anatomy in this individual is visualized

branching as identified on preoperative imaging is also critical to recognize, as aggressive distal dissection may insult these branches. Once the renal artery and vein have been adequately dissected, the posterior and lateral attachments of the kidney may be taken down with blunt dissection and use of monopolar shears or hook cautery. It is often helpful to dissect posteriorly and then attempt to rotate the kidney further medially to access the remaining upper pole attachments. When performing right-sided laparoscopic donor nephrectomy, several technical qualifica-

tions merit discussion. The liver typically obscures the operative field. and we have found that the placement of an additional 5-mm trocar near the xiphoid through which a locking laparoscopic Allis clamp may be placed is helpful. It is important to position this clamp under the “notch” in the liver to maximize exposure to the upper pole of the kidney. The ascending colon and liver attachments are freed and a Kocher maneuver performed. Following identification and isolation of the renal hilum, the renal artery is dissected in the interaortocaval region, controlled with Hem-O-Lok clips and transected.

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As renal vein length is of paramount importance when performing right-sided donor nephrectomy, several concessions must be made to ensure adequate vein length. Typically, we favor incorporating a portion of the lateral wall of the vena cava in the jaws of the endovascular stapler such that vein length is maximized (Fig. 13.14). Alternative maneuvers include retroperitoneal access, hand assistance, and even control of the vena cava using a laparoscopic Satinsky clamp or through a small subcostal incision [20, 21]. In our experience, these latter maneuvers are difficult to master and may place the patient at a high level of risk. Once the recipient surgeon has confirmed their readiness for acceptance of the allograft, 12.5 mg of mannitol is administered. The ureter is divided between Hem-O-Lok clips at or below the level of the iliac bifurcation. The gonadal package is taken down with an endovascular stapler or with Hem-O- Lok clips. At this point, we prefer to make an approximate 7-cm Pfannenstiel incision which is carried down to the peritoneum (see Fig. 13.5). It is important not to violate the peritoneum at this juncture as insufflation will be compromised. Prior to division of the renal hilum, we perform a quick checklist that may avoid unnecessary complications and/or prolong the warm ischemia time. It is important to confirm that the

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CO2 tank is filled such that insufflation is not lost during pedicle division. In addition, we prefer to have two endovascular staplers and a laparoscopic Satinsky clamp ready should stapler misfire be encountered. Once ready, the kidney may be lifted laterally to place the artery and vein on slight tension. The origin of the renal artery is identified, two Hem-O-Lok clips are placed proximally, warm ischemia time is called for, and the artery is divided with laparoscopic scissors (Figs. 13.15 and 13.16). It is important to move efficiently but not haphazardly through this portion of the operation. It is preferable to spend a few extra moments clearing the operative field with the suction/irrigator as opposed to hurriedly approaching the renal vein with inadequate exposure and visualization. The endovascular stapler is next deployed across the renal vein as it crosses the aorta (Fig.  13.17). We prefer to staple and divide the caudad two thirds of the vein only. Two Hem-O-Lok clips are placed on the remaining one third of the vein, the vein is divided, and the kidney allowed to “vent.” Partial transection of the vein keeps the endovascular stapler a safe distance from the superior mesenteric artery that is often found at the superior border of the renal vein and offers a margin of safety in the setting of stapler misfire by preventing venous retraction. Once the renal hilum is transected, the peritoneum is incised and the kidney retrieved. ­A laparoscopic

Fig. 13.14  Intraoperative photograph demonstrating incorporation of lateral edge of vena cava in the endovascular stapler to maximize vein length during right laparoscopic donor nephrectomy. The right renal artery is easily visible anterior to the vein

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Fig. 13.15  The left renal artery is sequentially controlled with nonabsorbable clips. It is important to place these clips as close to the origin of the renal artery as allowable

Fig. 13.16  Following placement of no fewer than two clips on the proximal end of the artery, cold shears are used to transect the artery

retrieval bag can be used, but we prefer to retrieve the kidney with our hand under direct laparoscopic vision. We have found that the construct of many of the retrieval devices (specifically the rigid metal deployment ring) lend themselves to damage of the allograft. When the kidney is being removed, it is important to retract all ports to avoid inadvertent trauma (scraping of the kidney on the tip of the ports) to the allograft. Additionally, the upper pole of the kidney should be removed first to avoid avulsion of the ureter. Once the kidney is delivered, it should be handed

directly to the recipient surgeon and placed immediately in an ice bath. Warm ischemia time may be stopped at this point. The fascia of the Pfannenstiel incision is closed and the abdomen reinsufflated and inspected for hemostasis. Once hemostasis is confirmed, all fascial defects are closed laparoscopically using a 1-0 Vicryl suture on a Carter-Thompson needle. All skin incisions are closed using a 4-0 Monocryl or Vicryl suture in a running, subcuticular fashion. All patients are admitted to the standard nursing floor. Fluid hydration is liberal for the first 24 h.

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Fig. 13.17  An endovascular stapler is deployed across the inferior two thirds of the left renal vein. The remaining one third of the vein is controlled with clips and

transected. Although moderate bleeding is expected during this portion of the procedure, the field should be kept evacuated and the vascular anatomy visualized

Intravenous antibiotics may be administered for the first 24 h following surgery, although the benefit of doing so is controversial. The patient is mobilized the evening of surgery and ambulated on postoperative day 1. Incentive spirometry and aggressive pulmonary toilet is recommended. The Foley catheter may be removed on postoperative day 1 once the patient is ambulatory and urinary output is satisfactory. Once the patient demonstrates adequate bowel function, a clear liquid diet may be prescribed and pain control with oral narcotics may be initiated. In our experience, most patients are ready for discharge on postoperative day 2 or 3. All patients are instructed to refrain from heavy weight-bearing for 4 weeks.

References

Summary Laparoscopic live donor nephrectomy is a challenging and technically demanding procedure, but is ultimately an extremely rewarding operation to perform. In our experience, a meticulous preoperative evaluation, judicious and thoughtful intraoperative exposure, and “wisdom through experience” represent the most significant keys to success.

1. Hoyert DL, Kung HC, Smith SL. Deaths: preliminary data for 2003. In: National Vital Statistic Reports 2005;53(15). Hyattsville, MD: National Center for Health Statistics. 2. Meier-Kriesche HU, Ojo AO, Port FK, et  al. Survival improvement among patients with end-stage renal disease: trends over time for transplant recipients and waitlisted patients. J Am Soc Nephrol 2001;12:1293–1296. 3. 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. NEJM 1999;341:1725–1730. 4. U.S. Renal Data System. USRDS 2004 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, 2004. 5. Sener A, Cooper M. Live donor nephrectomy for kidney transplantation. Nat Clin Pract Urol 2008;5:203–210. 6. Barry JM. Open donor nephrectomy: current status. BJU Int 2005;95:56–58. 7. Streem SB, Novick AC, Steinmuller DR, et al. Flank donor nephrectomy: efficacy in the donor and recipient. J Urol 1989;141:1099–1101. 8. Gill IS, Carbone JM, Clayman RV, et al. Laparoscopic live donor nephrectomy. J Endourol.1994;8:143–148. 9. Ratner LE, Ciseck LJ, Moore RG, et  al. Laparo­ scopic live donor nephrectomy. Transplantation 1995;60:1047–1049. 10. Jacobs S, Cho E, Foster C, et  al. Laparoscopic live donor nephrectomy: the University of Maryland 6-year experience. J Urol 2004;171:47–51.

13  Laparoscopic Living Kidney Donation 11. Sundaram CP, Martin GL, Guise A, et al. Complications after a 5-year experience with laparoscopic donor nephrectomy: the Indiana University Experience. Surg Endosc 2007;21:724–728. 12. United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN): Donors Recovered in the U.S. by Donor Type. http://optn.transplant.hrsa.gov/. Accessed January 27, 2009. 13. Simon SD, Castle EP, Ferrigni RG, et al. Complications of Laparoscopic Nephrectomy: the Mayo Clinic Experience. J Urol 2004;171:1447–1450. 1 4. Bia MJ, Ramos EL, Danovich GM, et  al. Evaluation of living renal donors: the current practice of U.S. transplant centers. Transplantation 1995;60:322–327. 15. Kasiske BL, Cangro CB, Hariharan S, et al. The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant 2001;2(Suppl 1):3–95.

271 16. Kuo PC, Plotkin JS, Stevens S, et  al. Outcomes of laparoscopic donor nephrectomy in obese patients. Transplantation 2000;69:180–182. 17. Sundqvist P, Feuk U, Häggman M, et  al. Handassisted retroperitoneoscopic live donor nephrectomy in comparison to open and laparoscopic procedures: a prospective study on donor morbidity and kidney function. Transplantation 2004;78:147–153. 18. Pozniak MA, Lee FT. Computed tomographic angiography in the preoperative evaluation of potential renal transplant donors. Curr Opin Urol 1999;9:165–170. 19. Oh CK, Yoon SN, Lee BM, et al. Routine screening for the functional asymmetry of potential kidney donors. Transplant Proc 2006;38:1971–1973. 20. Posselt AM, Mahanty H, Kang SM, et al. Laparoscopic right donor nephrectomy: a large single center experience. Transplantation 2004;78:1665–1669. 21. Turk IA, Giessing M, Deger S, et al. Laparoscopic live right donor nephrectomy: a new technique with preservation of vascular length. Trans Proc 2003;35:838–840.

Chapter 14

Perioperative and Anesthetic Management in Kidney and Pancreas Transplantation Management Jerome F. O’Hara Jr. and Samuel A. Irefin

Keywords  Perioperative care • kidney transplantation • pancreas transplantation.

Introduction Patients who present for kidney and/or pancreatic transplantation share similar perioperative concerns (risks associated with diabetes, hypertension, vascular access, and cardiovascular disease) in performing a successful transplantation. An effort to preoperatively optimize disease states to decrease comorbidity is the first goal. Deceased donor (DD) recipient transplants proceed with urgency due to the limitations of cold ischemic time and organ viability, but should not proceed if new symptoms or signs of concern are discovered in the immediate preoperative history and physical. This chapter discusses specific anesthetic management issues related separately to kidney and pancreatic transplantation.

Kidney Transplantation Preoperative Assessment Table 14.1 lists disease states and medical issues to be considered and optimized when preparing J.F. O’Hara Jr. (*) Department of Anesthesia, Cleveland Clinic, Cleveland, OH, USA e-mail: [email protected]

an end stage renal disease (ESRD) patient for kidney transplant [1–3]. In particular, the major cause of increased morbidity and mortality in dialysis patients is cardiovascular disease and accounts for over 50% of deaths in this patient population [1, 4]. This high incidence is attributed to additional risk factors related specifically to ESRD such as volume overload, hypertension, anemia, and electrolyte abnormalities [1, 2, 5–7]. As such, careful preoperative assessment of cardiovascular fitness is important in the transplant candidate. The initiation or continued use of perioperative beta blockade for those patients determined to be of high cardiovascular risk are important. Diabetic patients in general are at increased risk for a cardiac event due to the high prevalence of clinically silent ischemic heart disease [8]. Serial functional cardiac studies should be performed to have the ESRD patient ready for a deceased or living donor kidney transplant (LDKT). Perioperative need for dialysis should be identified and patients with hyperkalemia are best dialyzed prior to the transplant in an effort to avoid immediate posttransplant dialysis. Optimal ultrafiltration is desirable. The dialysis prescription should be tailored to avoid volume depletion and hypotension. Candidates on peritoneal dialysis should have the peritoneum drained as best as possible before the operation. All members on the operative team should be cognizant of the presence and sites of arteriovenous fistulae/grafts as these can be easily compromised by inadvertent placement of constrictive restraints.

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_14, © Springer Science+Business Media, LLC 2011

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274 Table 14.1  Important preoperative considerations prior to renal transplant Cardiovascular disease Ischemic heart disease Congestive cardiac failure Hypertension Diabetes mellitus Anemia Hyperparathyroidism and elevated calcium and phosphate Dyslipidemias Infections Hepatitis B Hepatitis C Newer cardiovascular risk factors C-reactive protein Homocysteine Duration of end-stage renal disease Centre effect Reprinted from [1]. With permission

Anesthetic Management Successful kidney transplantation remains a product borne of the perioperative management of the donor (deceased or living), minimizing allograft ischemia (in  vivo and in  vitro), and stabilizing recipient physiology. The anesthesiologist is directly involved in donor patient management during allograft harvesting and recipient management during allograft implantation. Allograft warm ischemia time during harvesting and reimplantation is mainly controlled by the surgical team. Therapeutic efforts to preserve kidney function prior to the start of warm ischemia time and immediately after reperfusion are important intervals involving anesthetic management. Choice of anesthetic, invasive monitoring techniques, inhalation agents, fluid management, and renal preservation therapies can affect allograft and recipient outcomes.

Deceased Donor Kidney Management Anesthetic management may begin in the critical care setting and is centered on maintaining adequate organ perfusion and urine output while the

J. F. O’Hara Jr. and S.A. Irefin

potential donor is declared brain dead. Management continues during transport and into the operating room for organ harvesting. Anesthesia management occurs in the operating room during preparation for organ harvesting by maintaining an adequate intravascular volume and blood pressure. Retrospective data of DD management shows that the administration of vasopressors (dopamine, dobutamine, isoproterenol, or low-dose dopamine) results in a lower incidence of acute rejection and improved graft survival after transplantation [9]. This did not confirm a direct renal preservation benefit. It may be that these therapies provide an adequate cardiac output to maintain adequate renal perfusion. Recently, Schnuelle et  al. [10]. reported that DD receiving a continuous infusion of norepinephrine (£0.4 mg/kg/min) who were randomized to a treatment group with an infusion of 4 mg/kg/min of dopamine until cross clamping at harvest reduced the need for dialysis after renal allograft transplantation. Diuretic use with mannitol, dopamine, and furosemide is suggested to maintain adequate urine output to prevent tubule obstruction in the setting of previous hypotensive episodes and concern of acute tubule necrosis. Mannitol is the only diuretic with clinical ­evidence of a renal preservation benefit [11], dopamine and loop diuretics have none [12, 13]. Timing of heparinization and cooling are also important in DD management for improved allograft outcomes. In donation after cardiac death (DCD), the ­primary care team manages the donor until they enter the operating room but is not involved in the organ recovery process. Only after the patient has been declared dead by confirming asystole can the organ procurement team engage the patient to harvest organs for the planned transplantation.

Living Donor Management The donor is required to be a healthy patient in LKDT and general anesthesia is planned with large-bore intravenous access in both the laparoscopic and open approach in the event of

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unexpected blood loss. Regardless of the surgical technique, the goal is to maintain renal perfusion by inducing a moderate hypervolemic state with a minimum intravenous fluid administration of 2–3 L of a balanced crystalloid solution. Mannitol is routinely given prior to the start of allograft ischemia time in an attempt to provide a renal preservation therapy. Epidural placement for postoperative pain control in the open approach is usually considered while intravenous narcotic for the laparoscopic approach is appropriate. Explaining the risk for the donor is necessary and needs be established in the preoperative planning for LDKT. It is part of the informed consent process. A living donor is a patient who is undergoing the risk of anesthesia and surgery to benefit another individual. The donor should be informed of the incidence of significant ­morbidity (hemorrhage, bowel obstruction, or hernia) which has been reported to be as high as 1.6% with reoperation rates as high as 1% [14, 15]. In a metaanalysis of donors in LDKT when the average follow-up was at least 5 years (range 6–13 years), blood pressure was 5 mmHg higher than in the control participants [16, 17]. Another important discussion for the donor is when a high-risk recipient is involved in LKDT [16]. The donor needs to understand the potential of allograft dysfunction and recipient risk of death in patients with advanced cardiopulmonary disease.

Recipient Anesthetic Management Optimization of recipient comorbidity, dialysis coordination, and an appreciation of drug pharmacokinetic/dynamic effects are important in preparation of the recipient for anesthesia and surgery. This is critical in the setting of planned LDKT. In this setting renal transplantation is an elective surgical procedure. In the case of DD transplantation, urgency does exists for the allograft regarding increased cold ischemia time; but this should not prelude management steps to optimize a recipient for surgery. Regional anesthesia has been described as an anesthetic technique for renal transplantation,

but general anesthesia is the predominant choice [18]. The placement of an intraarterial catheter is common and central venous catheters are routine. Central venous pressure monitoring facilitates as a guide to ensure adequate intravascular volume, administer pharmacologic therapies, obtain laboratory values, and maintain postoperative intravenous access. Postoperative analgesia is usually by intravenous patient-controlled narcotics. A new novel regional technique showing success is a transverse abdominis plane approach with catheter infusion of local anesthetics [19].

Renal Preservation in Transplantation What remains as the most important strategy for successful allograft function is the focus to optimize cardiac output at the time of reestablishing renal allograft perfusion. Achieving an intravascular state of normal to hypervolemia with good arterial blood pressure should be the goal to provide adequate renal perfusion to a denervated allograft lacking normal auto regulation mechanisms. Multiple renal preservation therapies have been clinically studied and include the following.

Perioperative Fluid Management Generally, a crystalloid vs. colloid solution remains the initial volume replacement therapy in renal transplantation. A balanced crystalloid solution is preferred over saline-based fluids because they are not associated with the acid–base disturbances seen due to the high chloride load [11]. Potassium containing solutions should be used cautiously or avoided during renal transplantation due to the risk of hyperkalemia. Several observational studies have been summarized by Schnuelle [11] to suggest that volume expansion with human albumin improves the short- and long-term outcomes in renal transplantation. They comment that controlled

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studies investigating only the effect of albumin therapy in this clinical setting are not available. The question not answered is if the improved outcome of a decreased incidence of delayed graft function is a direct effect of albumin administration for renal preservation or an indirect benefit of an adequate intravascular volume status being achieved. Synthetic colloid administration has prompted discussion as to the potential of causing renal dysfunction in certain clinical settings and should be used with this consideration [20–22].

Pharmacologic Therapies Many studies have been done to evaluate the effect of diuretics, dopamine agonists, and calcium channel blockers to improve allograft function in renal transplantation. Mannitol continues to be widely used and administered to the recipient prior to allograft reperfusion. Mannitol, in doses as high as 50 g, is associated with a decreased incidence of delayed graft function and a reduced need for immediate postoperative dialysis [23–25]. Intraoperative mannitol therapy in renal transplantation did not demonstrate a long-term allograft benefit. Loop diuretics are depicted to decrease renal energy-dependent active transport systems in the ascending loop of Henle with evidence of these benefits seen in animal studies [13]. Clinical studies do not support the use of loop diuretics to shorten the duration of ARF, reduce subsequent requirements for dialysis, or improve outcomes in patients with ARF [11]. Early renal transplant clinical studies with dopamine therapy from the 1980s presented conflicting outcomes [26, 27]. Repeat studies have consistently concluded that there is no direct renal preservation benefit. Therapeutic indications for dopamine include use as an osmotic diuretic or inotrope. Calcium channel blockers were hypothesized to improve renal transplant outcomes by direct afferent arteriole dilatation and elevated cyclosporine A levels. Dawidson et  al. [28]. reported a significant improved clinical outcome when 10 mg was directly injected via the renal

J. F. O’Hara Jr. and S.A. Irefin

artery followed by a 14-day dosing schedule. After further review of calcium channel blocker studies in renal recipients, it was concluded that evidence exists that a decreased incidence of delayed graft function occurred but no long-term allograft benefit was achieved. It was not considered as a necessary therapeutic intervention, but rather to be reasonable as part of a multimodal hypertensive regiment in ESRD patients prior to renal transplantation [29]. Important in the interpretation of the study of these potential renal therapeutic agents are that most were performed in DD transplantation, each was usually not the only therapy administered, and the studies were underpowered.

Other Considerations A management consideration in caring for the DD in preparation and during organ harvesting is the concern of hyperglycemia and renal allograft ischemia-reperfusion injury. Based on animal studies, hyperglycemia prior to a renal ischemic insult resulted in severe renal injury, as evidenced by terminal serum creatinine levels and renal histology examinations [30]. Lee et al. reported profound protection against animal renal ischemic-reperfusion injury with some volatile anesthetics (isoflurane > sevoflurane, halothane, and desflurane) [31]. This may be an important consideration when choosing a volatile anesthetic for donors in LDKT.

Management in the Recovery Room In addition to optimal fluid management, the transplant recipient should be evaluated in the recovery room for evidence of surgical bleeding, volume status, oxygenation, consciousness, and metabolic stability (potassium, acidosis, and glycemic status). Based on the level of renal function obtaining after transplantation and the biochemical parameters, an assessment for need for dialysis must be made.

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Conclusion Renal transplantation is the treatment of choice for ESRD when successful and is cost effective as compared to chronic dialysis. Influencing anesthetic factors include overall intraoperative management along with fluid and pharmacologic choices. Donor and recipient anesthetic management, surgical technique, and allograft ischemic times predict renal transplantation outcome.

Pancreas Transplantation Diabetes mellitus is a common disease and a leading cause of death in USA [32]. As a systemic disease, diabetes affects every organ system. Diabetes mellitus is a syndrome characterized by chronic hyperglycemia and its associated metabolic and physiologic disturbances. Pancreas transplantation is currently reserved for patients with Type I diabetes with end-organ damage [33]. Research has clearly demonstrated that patients with Type 1 insulin-dependent diabetes mellitus benefit from improved glucose control after pancreas transplantation [34]. There was a reduced risk of developing retinopathy, albuminuria, or microalbuminuria and clinical neuropathy when compared to patients on conventional insulin therapy. Consequently, pancreatic transplantation has become a clinical option in the treatment of patients with Type 1 diabetes. There is a subgroup of patients with Type II ­disease with insulin dependency who are also considered candidates [35]. Pancreas transplantation in patients with insulin-dependent diabetes seeks to restore normal serum glucose levels and minimize or prevent secondary complications of the disease. However, as a result of alterations due to diabetes mellitus, the perioperative care of these patients is quite challenging due to associated diseases such as coronary artery ­disease, severe arterial hypertension, renal failure, autonomic and systemic neuropathy, and gastroparesis. Successful pancreas transplantation is currently the only known therapy that establishes an insulin-independent euglycemic state

with ­complete normalization of glycosylated ­hemoglobin levels [36]. As a result of improvements in organ-retrieval technology, refinements in surgical techniques, and advances in clinical immunosuppression, success rates for pancreas transplantation have greatly increased [37].

Perioperative Considerations The success of pancreas transplantation has been due to improvements in perioperative care. Advances in organ preservation, immunosuppression, and the increased experiences of surgical, anesthetic, and intensive care teams have been responsible for increased graft survival in these patients. The perioperative period demands proper care as a result of associated comorbidities of longstanding diabetes mellitus such as coronary heart disease, hypertension, renal insufficiency, autonomic and systemic neuropathy, and gastroparesis. Patient selection for pancreas transplantation is conducted by a comprehensive multidisciplinary evaluation with additional workup tailored to the individual patient as necessary. In essence, the overall evaluation should confirm the diagnosis of IDDM and the patient’s ability to undergo a major operation with little or no major postoperative complications. The cardiovascular evaluation is important and usually involves a noninvasive cardiac functional assessment, such as stress thallium imaging. Because coronary artery disease (CAD) is the leading cause of perioperative morbidity and mortality in patients with IDDM, screening for the presence of CAD is of paramount importance before transplantation [38]. Patients scheduled for transplantation should receive screening tests such as an exercise EKG, a two-dimensional echocardiography, or a thallium-dipyridamole scan. For patients with poor exercise capacity or left ventricular hypertrophy, dobutamine stress echocardiography may be useful in identifying the presence of CAD. Coronary angiography is reserved for specific indications such as known or suspected cardiovascular disease, duration of diabetes over 25 years, or history of peripheral or

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cerebrovascular disease [38]. Patients with impending or end-stage renal failure who have minimal or limited secondary complications of diabetes are optimal candidates for combined kidney-pancreas transplantation. However, a combined procedure should be considered in all IDDM patients with significant nephropathy. Combined kidney-pancreas transplantation with IDDM and end-stage renal disease provides a quality of life and long-term survival benefits that are significantly better than dialysis or insulin replacement therapy. Autonomic dysfunction as a consequence of autonomic neuropathy markedly increases the risk of untoward events in the perioperative period [39]. These patients are predisposed to severe hypotension intraoperatively and have an altered response to hypoxia, which may lead to sudden death. In addition, refractory bradycardia after neostigmine administration can occur ­presumably due to hypersensitivity of cardiac acetylcholine receptors. Neuropathy of the vagus nerve in patients with longstanding diabetes predisposes them to gastroparesis. They present with a history of heartburn, bloating, early satiety, and other gastrointestinal problems. As a consequence, aspiration prophylaxis with rapid-sequence induction should be entertained in addition to a longer period of NPO status. Airway examination is also an important aspect of managing patients who presents for pancreas transplantation. Difficult intubations that required emergency tracheostomy have been reported in this group of patients [40]. Stiff ­cervical spine, temporomandibular, and atlantooccipital joints can limit visualization of the trachea during laryngoscopy.

Anesthetic Management Pancreas transplants are cadaver organs with a limited preservation period. Therefore, they are urgent surgical procedures. Pancreas transplantation is usually performed under general anesthesia. Any intravenous induction agent can be

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used and neuromuscular blockade that does not depend on renal metabolism or excretion is usually preferred. It should be noted that some of the patients presenting for pancreas transplantation may have gastroparesis secondary to their disease process. Consequently, precautions for a full stomach at induction should be taken irrespective of NPO status. General anesthesia may be maintained with any inhalational agent. In addition all patients should receive broad spectrum antibiotics after induction and a variety of immunosuppressive agents may be required during the procedure. In addition to standard ASA monitors, central pressure monitoring to assess intravascular volume status may be required. This will also facilitate central venous access for medications, and inotropic support if needed. Arterial line placement is also necessary for frequent blood sampling. Serum glucose is monitored every half hour during pancreas transplantation, especially after allograft reperfusion both to optimize the glucose level during this critical period and help determine if the islet cells are functioning [41]. In order to ensure adequate perfusion and prevent hypotension with reperfusion, patients undergoing pancreas transplantation must have an adequate circulating blood volume when the vascular clamps are released. Blood volume can be expanded with normal saline, colloids, or packed red blood cells as necessary. Edema of the pancreas allograft after reperfusion may cause ­vascular insufficiency and graft thrombosis; therefore, fluid overload should be avoided. The major emphasis in anesthetic management is to maximize the cardiovascular performance to ensure optimum graft perfusion and recovery while avoiding myocardial ischemia. Postoperatively, most patients who are pancreas recipients can be extubated if they are alert and hemodynamically stable. Pancreas graft function is monitored with serum glucose and urinary amylase levels. They are also monitored for acute graft rejection or dysfunction. They require supplemental sodium bicarbonate infusions to treat metabolic acidosis. These patients are usually monitored closely in the intensive care unit for a few days after surgery. Correction of abnormal

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serum glucose, electrolytes, hemodynamics, and replacement of fluid losses are critical during the first 24 h after reperfusion. Dehydration, electrolyte, and acid–base abnormalities in addition to hypoglycemia or hyperglycemia can develop very quickly and jeopardize graft viability and patient survival. Principles of immunosuppression for pancreas transplantation are basically the same as for other solid organ transplantation. In conclusion, the best option for Type I diabetic patients’ remains tight glucose control and prevention of its complications. With recent advances in surgical techniques and immunosuppressive drugs, the morbidity and mortality associated with pancreas transplantation continues to decline. When performed simultaneously with kidney transplantation, pancreas transplantation provides an insulin-independent state with euglycemia, normalization of various metabolic parameters and freedom from dialysis.

References 1. SarinKapoor H, Kaur R, Kaur H. Anaesthesia for renal transplant surgery. Acta Anaesthesiol Scand 2007;51:1354–1367. 2. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32:S112–119. 3. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998;32:853–906. 4. US Renal Data System. 1998 Annual Data Report. Bethesda, MD: National Institutes of Health, National Institute of diabetes, Digestive and Kidney Diseases. Available at http://www.usrds .org/adr_1998.htm. 5. Charra B, Calemard M, Laurent G. Importance of treatment time and blood pressure control in achieving long-term survival on dialysis. Am J Nephrol 1996;16:35–44. 6. Harnett JD, Kent GM, Foley RN, et al. Cardiac function and hematocrit level. Am J Kidney Dis 1995;25:S3–7. 7. Amann K, Gross ML, London GM, et al. hyperphosphataemia—a silent killer of patients with renal failure? Nephrol Dial Transplant 1999;14:2085–2087. 8. Philipson JD, Carpenter BJ, Itzkoff J, et al. Evaluation of cardiovascular risk for renal transplantation in ­diabetic patients. Am J Med 1986;81:630–634.

279 9. Schnuelle P, Lorenz D, Mueller A, et  al. Donor ­catecholamine use reduces acute allograft rejection and improves graft survival after cadaveric renal transplantation. Kidney Int 1999;56:738–746. 10. Schnuelle P, Gottmann U, Hoeger S, et al. Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial. JAMA 2009;302:1067–1075. 11. Schnuelle P, Johannes vdW. Perioperative fluid management in renal transplantation: a narrative review of the literature. Transpl Int 2006;19:947–959. 12. Friedrich JO, Adhikari N, Herridge MS, et al. Metaanalysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005;142:510–524. 13. Ho KM, Sheridan DJ. Meta-analysis of furosemide to prevent or treat acute renal failure. BMJ 2006;333:420. 14. Matas AJ, Bartlett ST, Leichtman AB, et al. Morbidity and mortality after living kidney donation, 1999– 2001: survey of United States transplant centers. Am J Transplant 2003;3:830–834. 15. Matas AJ. Transplantation using marginal living donors. Am J Kidney Dis 2006;47:353–355. 16. Boudville N, Prasad GV, Knoll G, et  al. Metaanalysis: risk for hypertension in living kidney donors. Ann Intern Med 2006;145:185–196. 17. O’Hara JF Jr, Bramstedt K, Flechner S, et al. Ethical issues surrounding high-risk kidney recipients: implications for the living donor. Prog Transplant 2007;17:180–182. 18. Akpek E, Kayhan Z, Kaya H, et al. Epidural anesthesia for renal transplantation: a preliminary report. Transplant Proc 1999;31:3149–3150. 19. Tran TM, Ivanusic JJ, Hebbard P, et al. Determination of spread of injectate after ultrasound-guided transversus abdominis plane block: a cadaveric study. Br J Anaesth 2009;102:123–127. 20. Ragaller MJ, Theilen H, Koch T. Volume replacement in critically ill patients with acute renal failure. J Am Soc Nephrol 2001;12:S33–39. 21. Cittanova ML, Leblanc I, Legendre C, et al. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet 1996;348:1620–1622. 22. Huter L, Simon TP, Schuerholz T, et al. Hydroxyethyl starch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model. Crit Care 2009;13:R23. 23. Weimar W, Geerlings W, Bijnen AB, et  al. A controlled study on the effect of mannitol on immediate renal function after cadaver donor kidney transplantation. Transplantation 1983;35:99–101. 24. Tiggeler RG, Berden JH, Hoitsma AJ, et al. Prevention of acute tubular necrosis in cadaveric kidney transplantation by the combined use of mannitol and moderate hydration. Ann Surg 1985;201:246–251. 25. van Valenberg PL, Hoitsma AJ, Tiggeler RG, et  al. Mannitol as an indispensable constituent of an intraoperative hydration protocol for the prevention of acute

280 renal failure after renal cadaveric transplantation. Transplantation 1987;44:784–788. 26. Grundmann R, Kindler J, Meider G, et al. Dopamine treatment of human cadaver kidney graft recipients: a prospectively randomized trial. Klin Wochenschr 1982;60:193–197. 27. Walaszewski J, Rowinski W, Chmura A, et  al. Decreased incidence of acute tubular necrosis after cadaveric donor transplantation due to lidocaine donor pretreatment and low-dose dopamine infusion in the recipient. Transplant Proc 1988;20:913. 28. Dawidson I, Rooth P, Lu C, et al. Verapamil improves the outcome after cadaver renal transplantation. J Am Soc Nephrol 1991;2:983–990. 29. Shilliday IR, Sherif M. Calcium channel blockers for preventing acute tubular necrosis in kidney transplant recipients. Cochrane Database Syst Rev 2005;(2):CD003421. 30. Hirose R, Xu F, Dang K, et al. Transient hyperglycemia affects the extent of ischemia-reperfusion-induced renal injury in rats. Anesthesiology 2008;108:402–414. 31. Lee HT, Ota-Setlik A, Fu Y, et al. Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in  vivo. Anesthesiology 2004;101:1313–1324. 32. Libman I, Songer T, LaPorte R. How many people in the U.S. have IDDM? Diabetes Care 1993;16:841–842. 33. Sutherland DE. Pancreas transplants. Br J Surg 1994;81:2–4.

J. F. O’Hara Jr. and S.A. Irefin 34. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. NEJM 1993;329:977–986. 35. Light JA, Sasaki TM, Currier CB, et al. Successful longterm kidney-pancreas transplants regardless of C-peptide status or race. Transplantation 2001;71:152–154. 36. Robertson RP. Seminars in medicine of the Beth Israel Hospital, Boston. Pancreatic and islet transplantation for diabetes—cures or curiosities? NEJM 1992;327:1861–1868. 37. Sutherland DE, Gruessner RW, Gores PF, Brayman K, Wahoff D, Gruessner A. Pancreas transplantation: an update. Diabetes Metab Rev 1995;11:337–363. 38. Manske CL, Thomas W, Wang Y, et  al. Screening diabetic transplant candidates for coronary artery disease: identification of a low risk subgroup. Kidney Int 1993;44:617–621. 39. Burgos LG, Ebert TJ, Asiddao C, et al. Increased intraoperative cardiovascular morbidity in diabetics with autonomic neuropathy. Anesthesiology 1989;70:591–597. 40. Hogan K, Rusy D, Springman SR. Difficult laryngoscopy and diabetes mellitus. Anesth Analg 1988;67:1162–1165. 41. Beebe DS, Belani KG, Yoo M, et  al. Anesthetic ­considerations in pancreas transplantation. Based on a 1-year review. Surv Anesthesiol 1996;40:255.

Chapter 15

Surgical Complications after Kidney Transplantation Stuart M. Flechner

Keywords  Kidney transplant • Wound healing • Surgical complications • Lymphocele • Urine fistula • Renal artery stenosis

Surgical Complications Surgical complications following renal ­transplantation can occur at any time, and are predominantly related to the transplant wound, vascular anastomoses, or other urologic problems. Surgical complications continue to occur in about 10–20% of transplant recipients, but fortunately, are rarely the cause of allograft loss. Improvements in surgical technique and meticulous attention to both the donor and recipient operations have led to a significant decrease in the rate of surgical complications [1]. Equally important in minimizing the morbidity of transplant surgical complications is anticipation of these problems and prompt treatment when they occur. Perhaps the most significant factor that complicates the outcome of transplant surgical problems is the continuous use of immuno­suppression, needed to prevent rejection of the allograft. Therefore in principle, transplant ­surgical problems should be treated using more conservative methods, which include a more prolonged period of drainage, diversion, suture retention, and the use of nonabsorbable S.M. Flechner (*) Professor of Surgery, Glickman Urologic and Kidney Institute, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Ave/Q10, Cleveland, Ohio 44236 e-mail: [email protected]

sutures when confronted with these problems. The routine use of broad-spectrum antibiotics beginning in the operating room and the immediate perioperative period has also helped to minimize ­posttransplant wound infections [2].

The Transplant Wound The Incision The transplant incision, while usually retroperitoneal, is subject to a number of problems relating to nonhealing such as fascial or skin dehiscence, delayed incisional hernias, and rarely peritoneal entry with evisceration. In addition, prolonged fluid drainage or collections in the subcutaneous space or below the fascia may occur. Such collections can be sterile or become infected to form an abscess (Fig. 15.1). The necessary use of immunosuppression has a central role in both the development of wound problems and in causing a delay in their healing [3]. The natural course of wound healing begins by initiating many local and cellular signals that trigger inflammation. For example, corticosteroids are well known to impair the healing of surgical wounds since they impede the in-growth of inflammatory cells in wounds. In addition, corticosteroids inhibit the synthesis of collagen within fibroblasts, diminish the tensile strength of wounds, and inhibit the regeneration of capillaries, all necessary steps in wound healing [4–6]. Many transplant recipients have had prior

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_15, © Springer Science+Business Media, LLC 2011

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Fig. 15.1  Loculated wound seroma above the abdominal wall fascia in an obese kidney transplant recipient

exposure or are dependent on corticosteroids to treat their cause of renal failure or other autoimmune diseases such as lupus, inflammatory bowel disease, or rheumatoid arthritis. Other immunosuppressive agents with antiproliferative properties, in particular m-TOR inhibitors and mycophenolate mofetil, inhibit growth signals required for the proliferation of endothelial cells and fibroblasts [7]. The m-TOR inhibitors have a direct effect by downregulating production of vascular endothelial growth factor (VEGF) that is needed for inflammation and angiogenesis [8, 9]. Demographic risk factors that are commonly associated with transplant wound complications are obesity and diabetes mellitus [10]. Recipients with a BMI greater than 32 kg/m2, especially those diabetic at transplant, are at particular risk. This population may represent as many as 30–40% of the recipient population at some transplant centers. In addition, a number of recipients may become obese or develop posttransplant diabetes (PTDM) during the first year after transplant [11]. Recipients with these characteristics warrant specific attention with wound closure techniques that include the use of drains, interrupted and nonabsorbable sutures, and a longer period of suture retention in the wound (Fig. 15.2). These

same principles should be applied during the repair of a posttransplant wound dehiscence. The use of retention sutures during intraperitoneal surgery in the very obese may also be prudent.

Hernias Abdominal wall hernias that are associated with renal transplantation include, the transplant wound itself, incisions to place peritoneal dialysis catheters, umbilical hernias, inguinal hernias, native ventral hernias that can occur in very obese recipients, or those with protuberant abdomens from polycystic kidney disease. Most are detected beginning a few months to several years after the transplant. Again, immunosuppressive drugs, corticosteroids, obesity, and diabetes mellitus are significant risk factors. Recipients sometimes complain of pain in the wound or recall prolonged fluid drainage from the wound prior to the clinical presence of a hernia. They may even recall a specific event such as heavy lifting or trauma, after which the hernia became clinically evident. Depending on the size of the fascial defect and location, these hernias may contain only fat, or fat plus small and/or large intestine.

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Fig. 15.2  Wound closure in an obese (BMI 38 kg/m2) type 2 diabetic kidney transplant recipient. Closed suction drains above and below abdominal fascia, nonabsorbable fascial sutures, and skin sutures used for closure

Fig. 15.3  Abdominal CAT scan of kidney transplant recipient with large incisional hernia with bowel content

Unusual cases of sliding hernias with ovary or bladder have been reported. Interestingly, the kidney is rarely if ever part of a delayed transplant wound hernia, but can be present in the base of an early wound dehiscence. After the clinical demonstration of a posttransplant wound hernia, a CAT scan of the abdomen is helpful to confirm the presence and location of the facial defect, identify the contents of the hernia sac, and determine the proximity of the kidney,

ureter, and bladder to the defect (Fig.  15.3). Posttransplant wound hernias invariably progress, and in the majority of cases require surgical intervention. For small hernias a few centimeters in size, sac excision with a primary repair can be done. The use of interrupted and nonabsorbable sutures is preferred. For large defects, or those under any tension, the placement of nonabsorbable mesh such as PTFE is very helpful to add support and reduce the chance of recurrence [12].

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Mesh placement is also helpful when abdominal wall fascia is thin and attenuated.

(regenerative tissue matrix), which is derived from cadaveric skin [14].

The Infected Transplant Wound

Lymphocele

The infected transplant wound is a surgical emergency that should be treated on an urgent basis. The use of immunosuppression may mask the extent of the infected area, or decrease systemic symptoms and patient discomfort. The transplant recipient may also develop wound infections caused by uncommon opportunistic pathogens. An important distinction is whether the infection, abscess formation, or tissue necrosis is above or below the abdominal wall fascia. A CAT scan of the wound is indispensible in helping to define the extent of the problem. Superficial (above the fascia) infections are best treated with incision and drainage, followed by packing of the wound to allow secondary healing. Sharp debridement may be necessary to remove necrotic tissue. Appropriate parenteral antibiotics may be needed to help gain control the infection. Complete healing may take weeks or months. For large superficial wounds that would require extensive packing, the use of the vacuum assisted closure (VAC) dressing is very helpful to aid in healing and minimize patient discomfort [13]. Deep (below the fascia) fluid collections that may be infected can at times be treated with a percutaneous drain and antibiotics. These are usually isolated and amenable to radiologic drain placement. Larger below fascia abscesses usually require open exploration, culture, debridement of necrotic tissue, and vigorous washout of the wound with liters of a local antibiotic. At times a retained foreign body or a bowel or urine fistula may be identified as the source. For the latter, a primary repair is needed. In most cases the fascia can be closed, a drain placed, but the skin and subcutaneous tissues should be initially left open and packed. Secondary closure or a VAC dressing can be used after the infection is controlled and healing has been established. If the fascia does not appear healthy or is under tension, the wound defect can be bridged using AlloDerm

A lymphocele is a collection of lymph fluid formed by the retroperitoneal placement of the transplant kidney. Lymphoceles may be unilocular or multilocular or encapsulated, ranging in size from a few centimeters in diameter to a large obstructing mass containing more than 1,000 mL of lymph fluid [15]. A lymphocele is caused by lymphatic leakage from the perihilar renal lymphatics or the allograft bed. Care in ligation of perirenal lymphatics during donor nephrectomy and recipient lymphatics during preparation of the iliac fossa is important in minimizing such fluid collections. If lymph leakage is brisk prior to complete healing of the transplant wound, the fluid may exit the skin surface and form a lymphatic fistula. Severed lymphatics normally close within 48 h, and regenerate within 7–10 days. However, in transplant recipients, several factors can predispose to prolonged lymphatic leakage. These include the frequent use of corticosteroids, diuretics, and anticoagulants that increase lymph flow. Some immunosuppressants, m-TOR inhibitors in particular, have been associated with persistent lymphatic leak and lymphoceles [16, 17]. In addition, transplant rejection causing graft edema, wound hematomas, and retransplantation have been implicated in the development of lymphoceles [18]. The most common initial symptoms of a lymphocele are urinary frequency, suprapubic pressure, a palpable mass adjacent to the allograft, and edema of the ipsilateral leg and genitalia. Findings suggestive of rejection, such as hypertension, oliguria, decreased renal function, and proteinuria, may also be present. When the collection is medial and inferior to the transplant kidney radiologic imaging may reveal transplant hydronephrosis or displacement of the bladder (Fig. 15.4). Some lymphoceles surround or compress the iliac vessels, and thereby may precipitate a deep vein thrombosis in the leg or pelvis

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Fig. 15.4  Abdominal CAT scan demonstrating a large pelvic lymphocele that is surrounding the transplant ureter. A ureteral stent (arrow) is preventing obstruction with subsequent hydroureteronephrosis of the transplant kidney

Fig.  15.5  Abdominal CAT scan demonstrating large pelvic lymphocele. The collection is compressing the bladder medially. The collection is also compressing

the external iliac artery and vein (arrows), which can result in a deep venous thrombosis in the leg

(Fig. 15.5). While ultrasonography of the pelvis can identify a lymphocele, CAT scan is the diagnostic method of choice for establishing the precise location, and extent of these fluid collections. The CT scan with both oral and IV contrast also

aids in the detection of urinary extravasation and bowel proximity. Needle aspiration and determination of the creatinine and urea concentration of the fluid can also distinguish urinary extravasation from a lymphocele.

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Management of the Post Renal Transplant Lymphocele

Large Symptomatic

Small Asymptomatic Progression

Definitive Repair

Open Surgery Peritoneal Window

Laparoscopic Surgery Peritoneal Window

Percutaneous Drainage

Observation

Resolution Persistent Drainage

Sclerosis

Fibrin Glue

Fig. 15.6  Algorithm for management of a posttransplant pelvic lymphocele

The management of a postrenal transplant lymphocele is outlined in Fig. 15.6. Small, sometimes loculated, low-density perinephric fluid collections less than 5 cm are relatively common following transplantation, and can be imaged in up to 50% of recipients [19]. If the patient is clinically asymptomatic with no radiographic evidence of obstructive uropathy or urinary extravasation, no treatment is necessary. These will usually resolve over time, but may take months to disappear. When a lymphocele is enlarging over time, or causing clinical symptoms, especially renal dysfunction, a drainage procedure is indicated. Simple aspiration is usually insufficient, since most large collections will recur as the primary source of the lymphatic leak is rarely identified. Definitive repair involves the creation of a window in the peritoneum of several centimeters in length, so further lymphatic leakage will be reabsorbed by the visceral peritoneal surface. Laying some omentum into the window is also helpful for continued fluid absorption. The window can be created by open surgery through a small incision in the lower abdomen. In recent years, less

invasive laparoscopic techniques had been applied for this procedure with similar outcomes [20]. A more conservative approach is to place a percutaneous tube drain into the collection. Many collections do stop draining and close, but the length of time is unpredictable. Some investigators have reported success by injecting a sclerosing agent such as tetracycline or povidone-iodine into the tube drain to hasten closure [21]. We have closed several persistent lymphoceles by injecting fibrin glue (a mixture of calcium, cryoprecipitated plasma, and thrombin) into the cavity [22]. There are a number of considerations that may dictate the choice and timing of definitive treatment, including overall patient health, renal function, use of anticoagulation, need for rapid resolution, and patient and doctor preference. For any treatment plan it is important not to create a persistent infection in the lymphocele cavity, which would preclude intraperitoneal management options. Depending on the renal transplant population studied, anywhere from 5% to 15% of recipients will need an intervention for a lymphocele at some time after transplant. We have found that the routine ­placement of a closed

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suction drain in the ­retroperitoneal space at the time of transplant significantly reduces lymphocele formation [23], even when de  novo sirolimus is administered [24].

Vascular Problems Hemorrhage Acute postoperative hemorrhage can result from a number of sources, including an unrecognized vessel in the donor renal hilum or surface; ­disruption of the allograft vascular suture line; inadequate preparation of the graft bed with undetected or poorly ligated pelvic or epigastric vessels; or from abnormal coagulation mechanisms in the recipient. The incidence of postoperative hemorrhage may be increased when hemodialysis (accompanied by anticoagulation) is required in the immediate postoperative period. The diagnosis of postoperative hemorrhage is usually evident on clinical grounds. The patient often complains of severe pain around the kidney, in the back and flank. Acute hemorrhage may present as hypovolemic shock, and may develop rapidly. Perinephric hematoma formation can cause impairment of allograft function by compression of the renal parenchyma, renal vessels, or ureter. After volume resuscitation, emergent wound exploration is usually necessary. In rare cases when the allograft parenchyma has ruptured and reconstruction cannot be accomplished within a reasonable time, allograft nephrectomy is indicated. Once bleeding is controlled, evacuation of the hematoma and vigorous washout of the wound with a local antibiotic is important to prevent bacterial infection. Late hemorrhage, arising months or years after transplantation is extremely rare, but can occur as a result of a percutaneous needle biopsy of the transplant kidney or rupture of a pseudoaneurysm at the anastomotic site [25, 26]. The use of smaller-gauge spring-loaded needles to biopsy the transplant kidney under real-time ultrasound guidance has minimized this complication, and

many can be treated with interventional radiology techniques [25, 27]. Rupture of a mycotic aneurysm is another disastrous event that is fortunately rare [28]. It is usually the result of a deep wound infection with secondary involvement of the vascular suture line. Transplant nephrectomy with ligation of the iliac artery and drainage of the area has been reported to be an expeditious and effective procedure [29]. This may not be true in the older, diabetic, and vasculopathic recipient population of today. Salvage of the ipsilateral limb is possible with an extraanatomic revascularization procedure such as a femoralfemoral or axillofemoral bypass [30].

Renal Artery Thrombosis Arterial thrombosis is a rare (<1%) complication that may occur as a result of hyperacute rejection, postoperative hypotension (shock), faulty technical performance of the arterial anastomosis, trauma to the intima of the donor artery during organ recovery or perfusion, severe atherosclerosis in the recipient vessels, or wide disparity in the calibers of the donor and recipient vessels. Some recipients suffer from dysregulation of the normal clotting cascade and clinically manifest a hypercoagulable state [31]. These patients may report prior clotting events such as deep vein thrombosis, pulmonary emboli, or frequent thromboses of vascular access for dialysis. When such a history is evident during transplant evaluation, vascular medicine consultation is important to try to define the abnormality. The planned use of intraoperative and perioperative anticoagulation may necessary to prevent an early thrombosis and graft loss [31]. However, in the majority of cases, a technical surgical problem is the precipitating event. If the transplant recipient is anuric postoperatively or the urine output drops suddenly, imaging with a Doppler ultrasound is usually diagnostic of the absence of blood flow to the kidney. Some prefer isotopic imaging studies or even angiography, but these studies may consume valuable time. When sudden anuria occurs the first few

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days posttransplant, or if radiographic imaging is not available in a timely fashion, immediate exploration of the transplant wound may be prudent. In most cases of complete arterial thrombosis, the kidney is beyond recovery by the time the diagnosis is made, and transplant nephrectomy is the treatment of choice. Some local clots or small areas of dissection that do not progress may rarely be repaired with reanastomosis, but renal salvage after such events is uncommon [32].

Renal Vein Thrombosis Renal vein thrombosis is a rare (<1%) complication. It may result from a technical error in ­performing the venous anastomosis, ipsilateral femoroiliac thrombosis, or external compression of the iliac or renal vein by perinephric fluid ­collections or hematomas. Additional causes in pediatric recipients include extrinsic compression in the iliac fossa and kidneys from young donors less than 5 years old [33]. Similar to renal artery thrombosis patients with a history of prior thromboses or a hypercoagulable state may also be at increased risk for renal venous thrombosis [34]. Venous thrombosis should be suspected when a transplant recipient has oliguria, graft enlargement, heavy proteinuria, and ipsilateral lower extremity edema. Imaging with Doppler ultrasound will reveal the absence of renal venous blood flow; isotopic imaging demonstrates delayed uptake with little or no excretion of the isotope. Renal venography is diagnostic and is useful in delineating the extent of the thrombus if pelvic or limb involvement is suspected. If available, magnetic resonance can also be used to delineate venous involvement. Graft survival with renal vein thrombosis occurring within 1 month of transplantation has been poor. Early diagnosis and prompt thrombectomy occasionally have resulted in graft salvage, but more commonly, prolonged venous stasis will lead to a nonviable graft when surgical exploration is undertaken, and nephrectomy is then performed [35]. Renal vein thrombosis occurring more than 1 month after transplantation is best treated with

systemic anticoagulation or local thrombolysis, because by that time collateral venous channels may have been established that permit functional recovery of the graft [36].

Renal Artery Stenosis Hypertension following renal allotransplantation is common and may be secondary to rejection, ischemic allograft damage, retained native ­kidneys, steroid therapy (mineralocorticoid effect), CNI drug therapy, excess salt intake or retention, recurrence of primary renal disease in the allograft, or renal artery stenosis. The incidence of transplant renal artery stenosis has been reported to be 1–23% in single center reports, and in a recent registry analysis (voluntary reporting) of 41,867 recipients, 823 (2%) cases were identified [37]. The stenosis can occur at the site of anastomosis to the host iliac or hypogastric artery, in the donor renal artery distal to the iliac anastomosis, or in one or more branches of the allograft renal artery [38]. Currently, with a large number of recipients having diabetes and systemic atherosclerosis, significant stenotic lesions can be found in the host arterial system proximal to the kidney [39]. However, the incidence may be less in the current era with common use of a deceased donor aortic patch to facilitate anastomosis of the renal artery to the recipient iliac artery. The causes include faulty suture technique, damage to the donor arterial intima during perfusion, intimal damage from rejection, improper apposition of the donor and recipient vessels with torsion, excessive length of the renal artery leading to angulation (kinking), or atherosclerosis in the recipient artery. An increased incidence of renal artery stenosis has been observed following transplantation of small pediatric deceased donor kidneys [39]. The pathophysiology of transplant renal artery stenosis is similar to that observed in native kidneys with ischemia to the parenchyma resulting in renal dysfunction, increased renin release, and subsequent activation of angiotensin II [40]. A sudden rise in serum creatinine after the introduction of

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an ACE inhibitor is also suggests the presence of an occult renal artery stenosis. In some cases a distinct de novo systolic bruit can be heard over the kidney, but this is unusual. A duplex Doppler ultrasound study of the transplant kidney is indicated whenever a kidney recipient has severe hypertension or unexplained deterioration in renal function [41]. If the renal artery demonstrates diminished flow with high velocities suggesting a stenosis, a magnetic resonance angiogram can be obtained to identify the site of the arterial problem, although reported results of MRA have been mixed [42, 43]. If the GFR is less than 50 cc/min gadolinium is contraindicated due to the risk of nephrogenic systemic sclerosis (fibrosis), and CO2 gas can be used for contrast [44]. The standard catheter angiogram with iodinated contrast is reserved for complex cases unresolved by noninvasive imaging, or at the time of treatment. Renal vein rennin measurements and captopril renography are of limited diagnostic value in this setting. Revascularization of the allograft is indicted when arterial stenosis is considered the cause of intractable hypertension or renal dysfunction. Percutaneous transluminal angioplasty has yielded satisfactory results in the majority of patients, and has been the appropriate initial option for over 20 years [45, 46]. For some stenoses that are difficult to dilate, involve a long segment of artery, or may be associated with an intimal dissection, the placement of an intraarterial stent is needed to obtain a durable result [47, 48]. Secondary surgical revascularization is indicated if angioplasty cannot be done or is unsuccessful. A variety of techniques have been described that include segmental arterial resection with end-to-end anastomosis, saphenous vein bypass for the proximal common iliac artery or aorta, direct reimplantation into the common or external iliac artery, patch angioplasty, or anastomosis to the hypogastric artery if this vessel is available. The use of third-party deceased donor iliac vessels has also been reported [49]. These are technically complex operations due to the frequent existence of dense scar tissue around the renal artery and the renal hilum. The results of surgical revascularization in these patients are generally satisfactory, but less so than those obtained

with primary revascularization of the native or transplant kidney. These operations should be performed through a transabdominal intraperitoneal incision, which facilitates identification of the transplant renal artery and iliac vessels. It is important to first gain control of the iliac vessels above and below the transplant kidney. Of the several techniques available, a saphenous vein bypass graft from the iliac artery or aorta to the distal disease-free transplant renal artery is a versatile, and effective technique. Occasionally, with a long renal artery and a short focal area of stenosis, segmental resection with reanastomosis is a satisfactory option.

Renal Artery Pseudoaneurysm Renal arterial pseudoaneurysm formation is a potentially devastating complication of renal transplantation that occurs in less than 1% of patients. These may result from injury to the renal artery during procurement or preservation, ischemic damage from excessive stripping of the artery and its vasa vasorum, faulty suture technique, or external traumatic injury. The worst cases can result from an infected arterial anastomotic suture line from either bacterial or fungal pathogens; often termed a mycotic aneurysm [26, 28, 50, 51]. A pseudoaneurysm is caused by disruption of the arterial wall, with perforation leading to the development of a communicating sac lined by fibrous and adventitial tissue. The natural history of transplant renal artery pseudoaneurysm is not known, although it is clear that the aneurysm wall is thinner than the native ­vessel and rupture can occur at any time. Hypertension and deterioration of renal function also can result from pseudoaneurysm formation, due to turbulent flow or extrinsic compression of the renal hilar vessels. Transplant nephrectomy generally has been performed to prevent rupture, while in situ reconstruction and allograft salvage have only rarely been described [52]. An infected pseudoaneurysm may require proximal arterial bypass and extensive antibiotic treatment to resolve the problem [30, 50, 51].

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Allograft Rupture Spontaneous allograft rupture is an uncommon complication that usually occurs within the first month after transplantation [53]. Graft rupture was most often observed in transplant recipients undergoing a severe acute rejection episode accompanied by intense infiltration, edema, and hemorrhage into the graft [54]. Although this complication was formerly observed in 1–10% of patients, it is now only rarely encountered (<1%). Using modern immunosuppressive therapy and crossmatching techniques recipients do not experience severe graft enlargement during milder acute rejection episodes. Trauma, ureteral obstruction, rapid venous occlusion, and recent open renal biopsy are additional predisposing factors for graft rupture. The clinical picture includes sudden pain and swelling of the graft, a palpable flank mass, oliguria, and in some cases hypotension. Both a subcapsular and/or a perigraft hematoma can be observed on radiologic imaging. If the rupture is extensive vascular ­collapse may occur, necessitating emergency exploration. If the graft is functionally salvageable and it is technically feasible, the parenchymal defect should be repaired [55]. If the graft has been irreversibly damaged by rejection or multiple areas of rupture are found, nephrectomy provides the optimum treatment.

Urologic Problems Ureteral Fistulae Transplant ureteral fistulae occur most often in the first few months, and cause extravasated urine to collect in the transplant wound. If a fistula develops before the transplant wound is healed, urine may leak out through the incision. Clinical symptoms include pain or swelling over the allograft, deep pelvic pain, ipsilateral leg edema, or urine may leak across the peritoneum into the abdomen or dissect into the scrotum. A definitive diagnosis can be made by finding the urea

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and creatinine concentration of aspirated or ­collected wound fluid to be several times greater than the serum. It is usually important to determine the site of the fistula, which will dictate the best method of treatment. By far the most ­common site is the anastomosis of the transplant ­ureter to the host urinary tract; however, spontaneous fistulae from other sites may occur. A ureteral fistula usually results from compromised ureteral blood supply, causing necrosis and sloughing. Ureteral blood supply may be compromised by overzealous dissection or stripping of the donor ureter, overzealous electrocautery of the ureter, infection around the ureter, or faulty surgical reimplantation. Some have argued that the best preparation for a transplant ureteral fistula is prevention, and support the use of an indwelling ureteral stent for several weeks after transplant. Such stents are very well tolerated and can even help very minor ureteral fistulae to close without further intervention [56]. In a systematic worldwide review of randomized trials, The Cochrane Study Group found the routine use of ureteral stents reduced major urologic complications after kidney transplant [57]. Helpful radiographic studies to identify the site of the fistula include an isotopic renal scan, a cystogram, and a CAT scan (Fig.  15.7). When renal function is adequate, intravenous contrast can be given during CAT scanning to differentiate urine from other fluid collections. However, when renal function is compromised (GFR <40 cc/min) intravenous contrast studies become limited. We have recently used single photon emission tomography (SPECT CT) scanning as a noninvasive tool to identify small transplant ureteral fistulas [58]. SPECT uses tomographic scintigraphy for computer generated three-dimensional images of radioactive tracer, providing increases sensitivity (Fig. 15.8). The best alternative when renal function is compromised or when the patient condition is unstable, is percutaneous nephrostomy [59]. This allows early proximal diversion and provides access for an antegrade nephrostogram to delineate the site of the fistula. Small well controlled and drained fistulae may be treated conservatively with an indwelling ureteral stent, and if needed bladder drainage with a

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Fig. 15.7  MAG-3 isotopic renal scan of transplant kidney imaged at 1-min intervals. Extraurinary collection of isotope is seen to expand in the pelvis

Fig. 15.8  Single photon emission tomography (SPECT CT) imaging of the pelvis in a transplant recipient. Note the purple image of the extravasated isotope outside the urinary tract, and at the level of the skin incision

Foley catheter for 4–6 weeks [60]. When the ureter is necrotic or the urine leak persists, open operative repair is advisable. If imaging does not identify the precise site of leakage, it is helpful to administer intravenous renal excreted dye such as methylene

blue or indigo carmine to view the extravasated blue urine in the wound. For fistulae limited to the distal ureter or ureteroneocystostomy itself, a repeat ureteral reimplant can be performed over an internal ureteral stent (Fig. 15.9). If the distal transplant

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ureter appears unhealthy, the ureter is trimmed back as far as necessary to ensure that it has an adequate blood supply. When the viable ureter is short options for reconstruction include ureteroureterostomy with anastomosis of the native ureter to the proximal transplant ureter, or ureteropyelostomy (Fig. 15.10). If associated infection is a concern, external drains should be placed near the anastomosis, and in some cases, proximal nephrostomy drainage should be implemented [59]. As mentioned, in some cases percutaneous techniques can be used to avoid an operative repair.

Successful endourologic management of ureteral fistulae is likely only in select patients in whom antegrade studies suggest extravasation limited to the distal ureter and in whom contrast enters the bladder during antegrade pyelography. Proximal extravasation or failure of contrast to enter the bladder suggests extensive ureteral loss, and in such cases, percutaneous treatment will rarely prove definitive. When percutaneous management is selected, the optimal approach involves placement of a guide wire, and subsequently a stent, across the site of extravasation into the bladder.

Fig. 15.9  Techniques of surgical reconstruction in cases of transplant ureteral fistulas or obstruction. Distal ureteral lesions can be repaired with a reimplantation of the transplant ureter to the bladder or anastomosis of the native ure-

ter to the transplant ureter. This may require at times bladder mobilization to elevate the bladder and avoid tension on the anastomosis

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Fig.  15.10  Techniques of surgical reconstruction in cases of transplant ureteral fistulas or obstruction. Proximal ureteral lesions require anastomosis of the transplant renal pelvis to either the native ureter or directly

to the bladder. This may also require bladder mobilization to avoid tension on the anastomosis. The upper native kidney ureter can usually be tied off without problems; and the native kidney rarely will need nephrectomy

Percutaneous management can be continued as long as the patient remains stable clinically and serial radiographic studies show the fistula to be resolving. Separate percutaneous drainage of a urinoma should be performed to remove the extravasated urine, perform a culture, and ensure the repair remains intact. While there are a number of small series reporting success with endourologic management of transplant ureteral fistulae, one experience was less optimistic with a success rate of only 36%, even in highly selected patients [61].

renal infarction. Current vascular techniques for management of multiple renal arteries have made these uncommon. In the past repair involved open exploration with debridement, drainage, and primary closure of the involved collecting system. Unfortunately, such management was associated with high rates of graft loss [62]. The contemporary management of this uncommon complication depends on placement of percutaneous catheter for drainage at the site of extravasation, which permits closure over time. If there is any degree of distal urinary obstruction, a percutaneous nephrostomy tube and an internal stent should be placed. With adequate percutaneous drainage, calyceal fistulae should resolve without the need for open operative intervention.

Calyceal Fistulae Calyceal fistulae are a rare complication of renal transplantation that results from segmental

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Bladder Fistulae The incidence of bladder fistulae has declined dramatically with the replacement of transvesical methods of ureteral reimplantation to the extravesical Lich technique [63]. Today leakage from the bladder is most often due to a fistula from the distal transplant ureter at the site of the ureteroneocystostomy. The management of ureteral fistulae has been previously described. Most other bladder fistulae occur early after transplant, and can be readily diagnosed with a cystogram. If the bladder leak is extraperitoneal a trial of Foley catheter drainage with a separate percutaneous drain for the urinoma can be implemented. In cases of intraperitoneal bladder fistulae or when the conservative approach fails to close the leak, open exploration with debridement and repair will be necessary. In unusual cases a bladder rupture may occur after sudden urinary retention early after transplant, more likely in males than females.

Ureteral Obstruction Ureteral obstruction is generally a late complication of renal transplantation, reported in less than 5% of transplants. The diagnosis is often made during evaluation of renal dysfunction in an ­otherwise asymptomatic patient [64]. Rarely, in severe obstructions, urine volume may noticeably decrease. Ultrasound of the allograft will demonstrate hydronephrosis. If renal function is adequate, a CAT scan with intravenous contrast may identify the site of obstruction. If renal function is compromised, a percutaneous nephrostomy with antegrade pyelogram will identify the point of obstruction [59]. The most common problem is distal obstruction at the ureteroneocystostomy, usually caused by ureteral ischemia. Ureteral injury (including surgical injury), rejection, and BK viral infections are the leading causes [65]. However, longer

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segments of the upper ureter may be involved. Less common causes of ureteral obstruction include extrinsic compression by hematoma, lymphocele or abscess, pelvic lymphadenopathy, ureteral kinking, retroperitoneal fibrosis, entrapment from an inguinal hernia, or intrinsic problems such as occult ­ureteropelvic junction obstruction, a de  novo ureteral tumor, kidney stone, or a clot. Definitive operative reconstruction of transplant ureteral obstruction is dependent on the etiology and site of obstruction. If the obstruction is limited to the very distal ureter, a repeat ureteroneocystostomy over a ­ureteral stent can be performed (see Figs.  15.9 and 15.10). For long ureteral segments, the best approach is native ureter ureteropyelostomy to the transplant renal pelvis or native ureter ureteroureterostomy to the more proximal transplant ureter [66, 67]. When the native ureter is used, the proximal native ureter can be ligated and the native kidney left in situ in most instances [67]. However, in the presence of infection, native nephrectomy should be performed. If a percutaneous nephrostomy had been placed before definitive repair, this can be left indwelling during the initial postoperative period to provide temporary urinary diversion and access for postreconstructive radiographic studies. It is unwise to perform a local resection and reanastomosis of the transplant ureter, since this structure has already undergone distal division (at the time of transplant) and dividing the ureter more proximally will likely devascularize the entire segment. When the native ureter is not available or is otherwise inappropriate for use in reconstruction, a variety of salvage reconstructive procedures may be used. These include pyelovesicostomy, during which the bladder is anastomosed directly to the renal pelvis, with or without a bladder flap [68]. An alternative to pyelovesicostomy for complicated reconstruction is an ileal interposition. In extreme cases in which the transplant renal pelvis cannot be accessed either because of peripelvic fibrosis or

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an intrarenal anatomy, consideration can be given to native ureter ureterocalicostomy or vesicocalicostomy [69, 70]. If the segment of ureteral stenosis is short, it can first be managed using an endourologic approach by combining percutaneous nephrostomy drainage with transluminal ureteral balloon dilation or endoscopic incisional ureterotomy, followed by several weeks of an internal ureteral stent

(Fig. 15.11a to c) [71]. Similarly, ureteropelvic junction obstruction in the transplanted kidney, which may have been unrecognized in the kidney donor, can be treated using endourologic techniques. Balloon dilation, endoscopic pyelotomy, and ureteral stenting can resolve the problem. If the point of obstruction is due to very dense fibrotic tissue it may not dilate well, and may recur after the ureteral stent is removed. At that point an open

Fig.  15.11  Endourologic management of a transplant ureteral stricture. (a) Antegrade nephrostogram identifies a proximal ureteral structure, which is soft. Note contrast

in bladder. (b) A balloon dilator is passed across the stricture and inflated. (c) After the stricture is dilated, a double J ureteral stent is placed for 6 weeks to permit healing

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surgical approach will be needed. Reports of endourologic management of transplant ureteral stenosis suggest a 45–70% success rate, with extended periods of followup [71, 72].

Hydrocele The incidence of ipsilateral hydrocele formation after renal transplantation has been reported to be as high as 68% when the spermatic cord is transected at the time of transplantation [73]. In addition, spermatic cord transection renders the testicle ischemic due to interruption of the main blood supply, making its viability totally dependent on collateral circulation. For these reasons this practice has largely been abandoned. Traction of the spermatic cord can disrupt lymphatic drainage from the testicle and result in accumulation of hydrocele fluid. Posttransplant hydroceles also occur more frequently in recipients who have undergone periods of peritoneal dialysis, which impairs genital lymphatic return. Fortunately, the majority hydroceles after renal transplantation are asymptomatic, and only a few require treatment. Symptoms are usually related to discomfort, pain, interference with sexual activity, or embarrassment related to size. Occasionally, a urine fistula can track down into the scrotum and should be excluded. The diagnosis is usually evident on physical examination and by transillumination. Ultrasound may be used to document the size and content of the hydrocele, and to assess the testicular anatomy and blood supply. Elective scrotal hydrocelectomy can usually be done in the standard fashion, remembering that the immunosuppressed patient has a greater risk of infection, bleeding, and wound problems. If possible, operative repair should be delayed until immunosuppressive drug doses can be minimized. Aspiration of a hydrocele with tetracycline sclerotherapy is an alternative and effective treatment modality [74].

References 1. Flechner SM, Duclos A. Renal transplantation. In: Montague DK, Angermeier K, Gill IS, Ross JH (eds.). Reconstructive Urologic Surgery: Adult and Pediatric. Oxford, UK: Taylor & Francis 2008:133–142. 2. Villacian JS, Paya CV. Prevention of infections in solid organ transplant recipients. Transpl Infect Dis 1999;1(4):295–296. 3. Humar A, Ramcharan T, Denny R, et al. Are wound complications after a kidney transplant more common with modern immunosuppression? Transplantation 2001;72:1920. 4. Kihara A, Kasamaki S, Kamano T, et al. Abdominal wound dehiscence in patients receiving long-term steroid treatment. J Int Med Res 2006; 34:223–230. 5. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975; 78:71–100. 6. Ehrlich HP, Tarver H, Hunt TK. Effects of vitamin A and glucocorticoids upon inflammation and collagen synthesis. Ann Surg 1973;177:222–227. 7. Akselband Y, Harding MW, Nelson PA. Rapamycin inhibits spontaneous and fibroblast growth factor beta-stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc 1991;23(6):2833–2836. 8. Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (m-TOR)-dependent signaling. FASEB J 2002;16(8):771–780. 9. Reinders ME, Sho M, Izawa A, et al. Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J Clin Invest 2003;112(11):1655–1665. 10. Flechner SM, Zhou L, Derweesh I, et  al. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney transplant recipients. Transplantation 2003;76:1729–1734. 11. Araki M, Flechner SM, Ismail HR, Flechner LM, et al. Posttransplant diabetes mellitus (ptdm) in kidney transplant recipients receiving calcineurin or m-TOR inhibitor drugs. Transplantation 2006;81:335–341. 12. Lo Monte A, Damiano G, Maione C, et  al. Use of intraperitoneal ePTFE gore dual-mesh plus in a giant incisional hernia after kidney transplantation: a case report. Transplant Proc 2009;41:1398–1401. 13. Shrestha BM, Nathan VC, Delbridge MC, et  al. Vacuum-assisted closure (VAC) therapy in the management of wound infection following renal transplant. KUMJ 2007;5:4–7. 14. Patton JH Jr, et  al. Use of human acellular dermal matrix (AlloDerm) in complex and contaminated abdominal wall reconstructions. Am J Surg 2007;193(3):360–363. 15. Pollak R, Veremis SA, Maddux MS, et al. The natural history of and therapy for perirenal fluid collections following renal transplantation. J Urol 1988;140:716–722.

15  Surgical Complications after Kidney Transplantation 16. Goel M, Flechner SM, Zhou L, et al. The influence of various maintenance immunosuppressive drugs on lymphocele formation and treatment after kidney transplantation. J Urol 2004;171:1788–1792. 17. Huber S, Bruns CJ, Schmid G, et al. Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis. Kidney Int 2007;71(8):771–777. 18. Rashid A, Posen G, Couture R, et al. Accumulation of lymph around the transplanted kidney (lymphocele) mimicking renal allograft rejection. J Urol 1974;111:145. 19. Silver TM, Campbell D, Wicks JD, et  al. Peritransplant fluid collections. Ultrasound evaluation and clinical significance. Radiology 1981;138:145–151. 20. Gill IS, Hodge EE, Munch LC. Transperitoneal marsupialization of lymphoceles: a comparison of laparoscopic and open techniques. J Urol 1995;153:706–711. 21. Chandrasekaran D, Meyyappan RM, Rajaraman T. Instillation of povidone iodine to treat and prevent lymphocele after renal transplantation. BJU Int 2003;91:296. 22. Chin A, Ragavendra N, Hilborne L, et al. Fibrin sealant sclerotherapy for treatment of lymphoceles following renal transplantation. J Urol 2003;170:380–384. 23. Derweesh IH, Ismail HR, Goldfarb D, et  al. Intraoperative placing of drains decreases the incidence of lymphocele and deep vein thrombosis after renal transplantation. BJU Int 2008;101:1415–1419. 24. Tiong H, Flechner SM, Zhou L, et al. A systematic approach to minimizing wound problems for de novo sirolimus treated kidney transplant recipients. Transplantation 2009;87:296–302. 25. Pappas P, Constantinides C, Leonardou P, et  al. Biopsy-related hemorrhage of renal allografts treated by percutaneous superselective segmental renal artery embolization. Transplant Proc 2006;38:1375–1378. 26. Dalla Valle R, Capocasale E, Mazzoni M, et  al. Embolization of a ruptured pseudoaneurysm with massive hemorrhage following transplantation: a case report. Transplant Proc 2005;37:2275–2277. 27. Ertuk E, Rubens DJ, Panner B, et al. Automated core biopsy of renal allografts using ultrasonic guidance. Transplantation 1991;5:1311–1315. 28. Orlando G, Di Cocco P, Gravante G, et al. Fatal hemorrhage in two renal graft recipients with multi-drug resistant Pseudomonas aeruginosa infection. Transpl Infect Dis 2009;11:442–447. 29. Gorey TF, Bulkey G, Spees EK, et al. Iliac artery ligation: the relative paucity of ischemic sequelae in renal transplant patients. Ann Surg 1979;190:753–758. 30. Sienko J, Tejchman K, Cnotliwy M, et  al. Crossed bypass femoro-femoralis in patient with external iliac artery occlusion in the course of septic hemorrhage after renal graft explantation. Ann Transplant 2006;11:12–14. 31. Friedman G, Meier-Kriesche HU, Kaplan B, et al. Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of

297 renal allograft thrombosis. Transplantation 2001;72:1073–1078. 32. Subramaniam M, Edwards R, Osman HY. Revascularization of kidney allograft after renal artery occlusion secondary to angioplasty. Prog Transplant 2007;17:177–179. 33. Harmon WE, Stablein D, Alexander S, et  al. Graft thrombosis in pediatric renal transplant recipients: a report of the American Pediatric Renal Transplant Cooperative Study. Transplantation 1991;51:406–411. 34. Hausmann M, Vorobiov M, Zlotnik M, et al. Increased coagulation factor levels leading to allograft renal vein thrombosis. Clin Nephrol 2004;61:222–224. 35. Renoult E, Cormier L, Claudon M, et al. Successful surgical thrombectomy of renal allograft vein thrombosis in the early postoperative period. Am J Kidney Dis 2000;35:E21. 36. Melamed M, Kim HS, Jaar B, et al. Combined percutaneous mechanical and chemical thrombectomy for renal vein thrombosis in kidney transplant recipients. Am J Transplant 2005;5:621–626. 37. Hurst FP, Abbott KC, Neff RT, et al. Incidence, predictors and outcomes of transplant renal artery stenosis after kidney transplantation: analysis of USRDS. Am J Nephrol 2009;30:459–467. 38. Palleschi J, Novick AC, Braun W, et  al. Vascular complications of renal transplantation. Urology 1980;16:61–66. 39. Aslam S, Salifu MO, Ghali H, et  al. Common iliac artery stenosis presenting as renal allograft dysfunction in two diabetic recipients. Transplantation 2001;71:814–817. 40. Marques M, Prats D, Sanchez-Fuctuoso A, et  al. Incidence of renal artery stenosis in pediatric en bloc and adult single kidney transplants. Transplantation 2001;71:164–166. 41. Mourad G, Ribstein J, et  al. Contrasting effects of acute angiotensin converting enzyme inhibitors and calcium antagonists in transplant renal artery stenosis. Nephrol Dial Transplant 1989;4:66–70. 42. Goel M, La Perna L, Whitelaw S, et al. Current management of transplant renal artery stenosis: clinical utility of duplex Doppler ultrasonography. Urology 2005;66:59–64. 43. Bakker J, Beek FJ, Beutler J, et al. Renal artery stenosis and accessory renal arteries: accuracy of detection and visualization with gadolinium-enhanced breathhold MR angiography. Radiology 1998;207:497–504. 44. Loubeyre P, Cahen R, Grozel F, et al. Transplant renal artery stenosis. Evaluation of diagnosis with magnetic resonance angiography compared with color duplex sonography and arteriography. Transplantation 1996;62:446–450. 45. Prince MR, Zhang H, Morris M, et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology 2008;248:807–816. 46. Greenstein S, Verstandig A, McLean G, et al. Percu­ taneous transluminal angioplasty. The procedure of

298 choice in the hypertensive renal allograft recipient with renal artery stenosis. Transplantation 1987; 43:29–32. 47. Bruno S, Remuzzi G, Ruggenenti P. Transplant renal artery stenosis. J Am Soc Nephrol 2004;15:134–141. 48. Valpreda S, Messina M, Rabbia C. Stenting of transplant renal artery stenosis: outcome in a single center study. J Cardiovasc Surg 2008;49:565–570. 49. Shames B, Odorico J, D’Alessandro A, et al. Surgical repair of transplant renal artery stenosis with preserved cadaveric iliac artery grafts. Ann Surg 2003;237:116–122. 50. Osman I, Barrero R, Leon E, et al. Mycotic pseudoaneurysm following a kidney transplant: a case report and review of the literature. Pediatr Transplant 2009;13:615–19. 51. Garrido J, Lerma J, Heras M, et al. Pseudoaneurysm of the iliac artery secondary to Aspergillus infection in two recipients of kidney transplants from the same donor. Am J Kidney Dis 2003;41:488–492. 52. Sharron J, Esterl R, Washburn W, Abrahamian G. Surgical treatment of an extrarenal pseudoaneurysm after kidney transplantation. Vasc Endovascular Surg. 2009;43:317–321. 53. Azar G, Zarifian A, Frentz G, et al. Renal allograft rupture: a clinical review. Clin Transplant 1996;10:635–638. 54. Hochleitner B, Kafka R, Spechtenhauser B, et  al. Renal allograft rupture is associated with rejection or acute tubular necrosis, but not with renal vein thrombosis. Nephrol Dial Transplant 2001;16:124–127. 55. Shahrokh H, Rasouli H, et  al. Spontaneous kidney allograft rupture. Transplant Proc. 2005;37:3079–3080. 56. Regan S, Sethi A, Powelson J, et al. Symptoms related to ureteral stents in renal transplants compared with stents placed for other indications. J Endourol 2009;23:2047–2050. 57. Wilson CH, Bhatti AA, Rix DA, Manas DM. Routine intraoperative ureteric stenting for kidney transplant recipients. Cochrane Database Syst Rev. 2005;(4):CD004925. 58. Talanow R, Neumann D, Brunken R, et  al. Urinary leak after renal transplantation proven by SPECT-CT imaging. Clin Nucl Med 2009;32:883–885. 59. Saad W, Moorthy M, Ginat D. Percutaneous nephrostomy: native and transplanted kidneys. Tech Vasc Interv Radiol 2009;12:172–192.

S.M. Flechner 60. Alcaraz A, Bujons A, Pascual X, et  al. Percutaneous management of transplant ureteral fistulae is feasible in selected cases. Transplant Proc 2005;37:2111–2114. 61. Campbell S, Streem SB, Zelch M, et al. Percutaneous management of transplant ureteral fistulas: patient selection and long-term results. J Urol 1993;150:1115–1118. 62. Goldman M, Burleson R, Tilney N, et al. Calycealcutaneous fistulae in renal transplant patients. Ann Surg 1976;184:679–681. 63. Thrasher J, Temple D, Spees E. Extravesical vs. Leadbetter-Politano ureteroneocystostomy: a comparison of urological complications in 320 renal transplants. J Urol 1990;144:1105–1110. 64. Berger PM, Diamond JR. Ureteral obstruction as a complication of renal transplantation: a review. J Nephrol 1998;11:20–23. 65. Kazory A, Ducloux D. BK virus-associated urologic complications. Pediatr Transplant 2007;11:821–822. 6 6. Schiff M, Lytton B. Secondary ureteropyelo­ stomy in renal transplant recipients. J Urol 1981;126:723–726. 67. Lord RH, Pepera T, Williams G. Ureteroureterostomy and pyeloureterostomy without native nephrectomy in renal transplantation. Br J Urol 1991;67:349–351. 68. Rajfer J, Koyle M, Ehrlich R, et al. Pyelovesicostomy as a form of urinary reconstruction in renal transplantation. J Urol 1986;136–372. 69. Jarowenko M, Flechner SM. Recipient ureterocalicostomy in a renal allograft. J Urol 1985;133:844–845. 70. Von Son W, Hooykaas AP, Sloof M, et  al. Vesicocalicostomy as ultimate solution for recurrent urologic complications after cadaveric renal transplantation. J Urol 1986;136:889–890. 71. Streem SB, Novick AC, Steinmuller DR, et al. Longterm efficacy of ureteral dilation for transplant ureteral stenosis. J Urol 1988;140:32–36. 72. Benoit G, Alexander L, Moukarzed M, et  al. Percutaneous antegrade dilation of ureteral strictures in kidney transplants. J Urol 1993;150:37–41. 73. Penn I, Mackie G, Halgrimson C, et  al. Testicular complications following renal transplantation. Ann Surg 1972;176:697–699. 74. Sankari B, Boullier J, Garvin P. Sclerotherapy with tetracycline for hydroceles in renal transplant patients. J Urol 1992;148:1188–89.

Chapter 16

Urologic Complications After Kidney Transplantation Islam A. Ghoneim and Daniel A. Shoskes

Keywords  Ureteric leak • ureteral obstruction • urinary retention • erectile dysfunction

Urologic Complications after Kidney Transplantation This chapter reviews the most common urologic complications that may following renal transplantation. The recognition of these complications, their proper diagnosis, and effective management can help reduce their deleterious effect on long-term graft survival. The complications discussed include ureteral leak, ureteral obstruction, urinary calculi, urinary retention, and erectile dysfunction. The published incidence of urologic complications ranges between 1% and 15%. This wide range is in part due to the loose definition of what constitutes a urologic complication after renal transplantation such that hematuria, urinary tract infection, and urinary retention were included in some studies, where others were limited to ureteric strictures or leaks [1–4].

I.A. Ghoneim (*) Cleveland Clinic, Glickman Urological & Kidney Institute, Cleveland, OH, USA e-mail: [email protected]

Ureteral Complications Poor surgical technique and ischemia are the most common causes of ureteral complications; ureteral leak and obstruction in particular. Whereas the native ureter receives blood supply from both renal and pelvic sources, the transplant ureter relies only on descending branches from the transplant renal artery. The distal ureter is thus relatively more ischemic the farther it is from the ureteropelvic junction. Placing the graft in the pelvis allows for a shorter, better vascularized ureteric segment to be anastomosed to the bladder. Several surgical principles help ensure adequate blood supply to the ureter. Preserving the “golden triangle,” the perirenal fat between the lower pole of the kidney and the ureter, during back-table preparation helps maintain ureteral blood supply from the transplant renal artery (Fig. 16.1). These vascular twigs supply the ureter by running in the periureteral fibrofatty tissue. Avoidance of “stripping” the ureter of this tissue margin during procurement will help preserve a vascularized ureter. The early experience with laparoscopically procured kidneys was associated with high rates of urinary leaks due to ureteral skeletonization [5]. When a lower pole renal artery is encountered, it is often an end artery that gives rise to ureteric bloody supply. It is thus prudent to preserve during procurement, bench preparation, and arterial anastomosis of the graft. Preservation of accessory renal arteries is also of importance in kidneys with multiple ureters as ureteral

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_16, © Springer Science+Business Media, LLC 2011

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Fig. 16.1  Cadaveric donor kidney after bench table preparation. The tissue between the lower pole of the kidney and the ureter “the golden triangle” (circled) has been preserved as it typically harbors the blood supply to the ureter

complications are known to occur more often in such cases [6]. Upper polar arteries may supply the upper moiety ureter and should be preserved.

Ureteral Leak The incidence of urine leaks from the ureter is reported to be 1–3% [1, 4]. Ischemic necrosis and surgical technique are the most common causes. Delayed graft function and an older donor age are risk factors for ureteral necrosis [7]. An improperly constructed ureteroneocystostomy with poorly placed sutures or an anastomosis under tension are potentially avoidable surgical errors. Other causes may include bladder outflow obstruction such as that caused by a blocked Foley catheter or urinary retention ­following catheter removal. Overdistention of the bladder wall will lead to mechanical disruption of an otherwise sound ureterovesical anastomosis. Unrecognized lacerations to the renal pelvis or ureter that may occur during procurement and bench preparation may also be a cause of leakage. Ureteric stents may inadvertently pierce a calyx or protrude through the anastomotic line if not properly inserted. Though a frank urine leak may be obvious, a high index of suspicion is required to detect the

more subtle clinical presentations that may be encountered. Classically, a sudden drop in urine output, lower abdominal pain, drainage of fluid from the wound or into the surgical drain that has a creatine value several times that of the current serum creatinine are all manifestations of a urine leak. An uncommon but often overlooked sign of urine leakage is scrotal swelling, which is usually dismissed as dependant edema or related to the urinary catheter. A urine leak may be clinically difficult to distinguish in the presence of oliguric delayed graft function or when urine output is kept high by the native kidneys. Moreover, urinary leakage may insidiously occur on top of an ongoing lymph leak (from the wound or surgical drain) that has been ruled out by prior creatinine testing of the fluid. Early onset (within the first 24 h) of leakage points to a surgical error. Leaks occurring 10–14 days postoperatively are often due to ischemic necrosis and sloughing. Hence it is important to keep urine leakage part of the differential diagnosis of poor or declining urine output, fluid collections, high drain output, wound drainage, and delayed graft function. An initial approach to a suspected urine leak is to send drainage fluid or aspirated collection fluid for creatinine, and correlation of the value to that of the patient’s current serum creatinine. Imaging

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studies aid in the diagnosis and localization of the leakage site. A technetium-99m mercaptoacetyl-tri glycine (Tc99m MAG-3) renal scan is often chosen to demonstrate radiotracer outside the expected boundaries of the graft and urinary tract (Fig.  16.2). Despite the lower anatomic quality of its images, it is preferred over conventional cystography as it does not involve retrograde contrast injection in an immunosuppressed patient. Moreover, cystograms will likely show leakage from the anastomotic line, leakage occurring higher in the ureter will be demonstrated only if contrast refluxes into the ureter which may require distention of the bladder or higher pressure filling, both of which are not encouraged in the transplant patient. CT and ultrasound are highly sensitive for collections; however, they usually fail to demonstrate the source of fluid, CT being more able to identify a hematoma, but limited in differentiating urine from a seroma or lymph collection. Combination of CT scanning with a nuclear scan, the SPECT/ CT, can show both the leak and its anatomic location. Several causes and risk factors of urinary leakage are potentially avoidable. Preventive measures can reduce the incidence of this complication. Preserving ureteral blood supply as aforementioned is paramount. Good ureteral

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vascularity is evident after reperfusion by bleeding, pink edges. An ischemic ureter can often be identified during surgery. In such cases it is necessary to cut the ureter more proximally until well-perfused tissue is encountered. Should the remaining ureter be excessively short such that a tension-free anastomosis is not feasible, urinary continuity may be restored by alternative techniques. A preferred method is anastomosis of the graft ureter or renal pelvis to the ipsilateral native ureter if present (Fig. 16.3). Advantages of this technique include excellent ureteral blood supply, a large segment of native ureter that can be repositioned without tension and no compromise of bladder volume as with other methods discussed below. In oliguric ESRD patients, the proximal native ureter may be tied off safely without the need for native nephrectomy [8]. In patients producing substantial amounts of urine from their native kidneys, an end-to-side anastomosis may be necessary. An array of procedures exist to bring the bladder closer to the graft ureter (or renal pelvis), thus facilitating proper tension-free anastomosis. Simple mobilization of the lateral attachments of the bladder on the contralateral side, especially dividing the superior vesical artery, may provide 2–3 cm of length to bridge a small gap.

Fig. 16.2  Tc99m MAG-3 renal scan of patient with a urine leak. Nuclear tracer is seen outside the boundaries of the urinary bladder

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Fig.  16.3  Repair of transplant ureteral necrosis using the native ureter (uretero-ureterostomy). (a) Distal ureteral necrosis. Pooling of urine is seen in the wound. (b) After repair. The native ureter mobilized and transected.

Anastomosis to the proximal transplant ureter was end to end over an indwelling stent using running 5-0 PDS suture. The native ureter was tied proximally without native nephrectomy

A psoas hitch may also be performed. Following ­mobilization of the bladder, the bladder wall is incised perpendicular to the ureter and then reconfigured by closing the bladder incision in line with the ureter [9]. The bladder dome is hence elongated in the direction of the ureter and can be secured to the psoas minor tendon or the psoas major muscle using several absorbable sutures. The genitofemoral and the femoral nerve are close in the vicinity and care must be taken to avoid their injury when placing these sutures. A well-performed psoas hitch can bridge a gap of up to 5 cm. Raising a Boari flap is another method of bridging a longer gap of up to 10 cm. It may also be performed in addition to a psoas hitch. The end of the flap can be anastomosed to the ureter or the renal pelvis if needed (Fig. 16.4). It is important to note however that a poorly executed Boari flap can compromise bladder capacity. In addition, small or contracted fibrotic bladders of anuric patients may not have sufficient wall to allow for flap elevation. Finally, if native urothelium is not available, ileal interposition (ileal ureteric replacement) can be done to bridge the bladder and renal pelvis [10]. Totally synthetic conduit materials are an area currently under research [11]. Management of an established leak often requires intervention, whether endoscopic or surgical. Albeit, in patients with indwelling stents,

checking Foley catheter patency or placing one in, may often stop the leak. If improvement is noted on bladder drainage, the Foley should be left for 2 weeks and a cystogram showing no leakage should be obtained prior to its removal. Should high drainage continue despite adequate bladder drainage, distal ureteric necrosis should be suspected and managed promptly. In nonstented cases, a minimalist trial of stent insertion may be attempted as opposed to direct re-exploration. A nontunneled placement of the transplant ureter, its ectopic location, or simply lack of supporting periureteral tissues may present challenges to engaging the ureteric orifice and safe passage of the stent in a retrograde fashion. Success rates as high as 88% have been reported, however [12]. Antegrade stent placement via percutaneous nephrostomy is also a challenging option as there is rarely hydronephrosis, making the collecting system puncture difficult. Usually surgery is the best option for definitive repair, especially in cases of ureteric necrosis and sloughing. The site of leakage may be identified intraoperatively by intermittently filling the bladder via a three-way Foley connected to irrigation. The location and extent of ureteric necrosis often dictate the best surgical approach to repair. A clearly well-vascularized ureter with leakage at the anastomotic line due to faulty suturing may be fixed by additional interrupted

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Fig. 16.4  Boari flap repair of transplant ureteral stenosis. The bladder is mobilized and a wide based pedicle flap raised that reaches the healthy proximal ureter without tension

sutures. Extensive necrosis requires excision of the ureter back to where it is well perfused. Depending on the length of the remaining segment, simple reimplantation may be done; otherwise techniques to bridge the gap must be employed. Repair using interrupted tension-free sutures over a stent is the preferred method, as urine may have rendered the tissues edematous and friable.

Ureteral Stenosis Stenosis of the allograft ureter is reported in about 3% of transplant cases [3, 13]. External compression by a lymphocele or the spermatic cord, ureteral ischemia or intraluminal obstruction by a stone, fungal ball, sloughed renal papilla, or foreign body, are all possible causes. Stenosis of the ureter is notorious for presenting months or years after an uneventful transplant. Initial stenting of the ureter is proven to reduce the incidence of early stenosis; however, there is no demonstrated impact on later ureteral stenosis [14]. Several factors predispose to the occurrence of late stenosis; advance donor age, delayed graft function, multiple renal arteries, and (polyoma) BK viral infection [15, 16]. Cases of

u­ reteroureteral anastomosis experience a higher stricture/stenosis rate [17]. A ureteric stenosis can present differently according to its degree, location, and onset. The gradual narrowing of the ureteric lumen by a maturing fibrotic stenosis will lead to an asymptomatic decline in renal function with the incidental discovery of hydronephrosis and elevated creatinine on routine follow-up or investigation for other causes. Pain is a rare presentation and does not occur except in cases of acute, rapidly developing and high-grade obstruction. It is prudent to differentiate obstruction from dilatation of the collecting system, which may occur without impediment to urine flow. Causes of dilatation without obstruction include prior obstruction in the donor (ureteropelvic obstruction in the donor), a refluxing ureterovesical anastomosis, and loss of renal cortex due to chronic allograft nephropathy. Patients with urinary retention may develop hydronephrosis, and any new hydronephrosis should also be evaluated for urine retention and post void residual volume by ultrasound. Confirmation of hydronephrosis is possible using one of two methods: diuretic renography (using furosemide) or percutaneous puncture of the collecting system and antegrade nephrostogram [18]. The latter is less commonly performed but can serve as both a diagnostic study

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and if obstruction is proven, a guide wire can be passed through the puncture needle and a percutaneous tube placed over the wire (Fig.  16.5). Moreover, passing an antegrade stent may be attempted at this sitting, but can also be deferred until kidney function has improved and ureteric edema if present has resolved. One point to take into consideration is that while extraperitoneal placement of the kidney facilitates percutaneous access, kidneys placed intraperitoneally, such as with a simultaneous kidney pancreas transplant, may have bowel intervening between the abdominal wall and the graft. Caution must be exercised in those cases to avoid hitting bowel during localization of the kidney puncture. Diuretic renography is noninvasive, and is often performed using Tc99m MAG3. Obstruction is suggested by a prolonged t1/2 denoting slow urinary transit and/or a rising or plateau curve pattern indicating failure of clearance, especially after diuretic injection which helps to rule out a dilated

nonobstructed system [19]. False-negatives can occur in patients with poor renal function and false-positives with bladder outflow obstruction or reflux. Management of transplant ureteric strictures is best done endoscopically as surgery may be difficult months or years after the transplant. Passable strictures are accessible via the antegrade route as outlined above or in a retrograde fashion through the bladder [20]. The ureteric orifice is often located in the upper part of the posterior wall or the anterior wall and is thus ­difficult to engage. The lack of supporting tissue around the ureter renders the usual techniques of negotiating a difficult ureteric orifice less likely to succeed in this setting. Once a guide wire has been securely placed in the collecting system, several options in the management of the stricture are available. Direct stenting may be done. Failure to pass the stent may require dilatation of the stricture which can be done using balloons

Fig. 16.5  Antegrade nephrostogram showing complete ureteral obstruction

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[21], incision of the stricture with holmium laser [22], or a cold knife [23]. The initial procedure is successful in about 50–65% of cases. Stents are usually left for 6–8 weeks [22]. Recurrence of the stricture is not uncommon and is caused by inadequate primary therapy or commonly, extensive ischemia. Such cases require repeated endoscopic treatment, the use of longterm stents [24] or formal repair. Open surgical repair typically provides a durable treatment option in these cases. Identification of the stricture site may be aided by leaving a ureteric catheter just below (or above) the stricture level. The diseased segment is excised and continuity restored using any of the methods discussed above for ureteral leak (e.g., psoas hitch, Boari flap, ­ureteropyelostomy, pyelocystostomy, ileal ureter). Open surgery is successful in 83% of cases [25]. Successful treatment of transplant ureteral stenosis does reduce long-term graft loss [15].

Prophylactic Ureteral Stents The use of prophylactic double J stents placed at the time of transplantation has been a topic of debate. Metaanalysis of data from randomized controlled trials (RCTs) and case studies has shown a significant reduction in ureteric complications (9–1.5%, p < 0.0001 in RCTs and 4.8% to 3.2%, p = 0.007 in case series) [26]. Analysis of data from the Cochrane Register of Controlled Trials has revealed the relative risk of major urologic complications to be 0.24 (95% CI 0.07 to 0.77, p = 0.02) [27]. The higher occurrence of urinary tract infections in stented patients has been dramatically reduced with the addition of antibiotic prophylaxis. Stents have been found to reduce the incidence of ureteral leaks and early stenosis [14]. The presence of a stent can also make the early management of a leak easier. Not all prospective randomized trials have found a large impact [28]. The duration of stenting is often based on ­surgeon preference and experience, with the typical duration being between 2 and 6 weeks. No standard or optimal duration has been determined in

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the literature. One prudent mishap to avoid is a missed stent, which occurs when removal is forgotten due to poor documentation or patient unawareness. Calcification and stone formation will complicate such a situation and removal of the stent is difficult (Fig. 16.6). Some authors have suggested tying the stent to the Foley catheter obviating the need for cystoscopic removal [29], the major drawback to this being early removal of the stent if the Foley must be exchanged.

Urinary Calculi in Transplant Recipients The incidence of stone formation in transplant recipients is between 1% and 5% [30, 31]. Female sex and prior history of stone disease are the main risk factors for this uncommon complication. This incidence is expected to rise as more individuals with asymptomatic renal stones are being accepted as kidney donors [32], since the affected kidney is almost always used. Stones also occur if nonabsorbable sutures have been placed in the urinary tract, on missed stents, in association with chronic infections, within intestinal conduits or reservoirs, and with incomplete bladder emptying. Transplant recipients with a known history of stone disease should be evaluated for hypocitraturia, hyperparathyroidism, hypophosphatemia, and hypercalcemia [33]. The use of calcineurin inhibitors has been linked to hypocitraturia [34]. The denervated state of the allograft leads to a variable clinical presentation. Asymptomatic calculi are incidentally discovered during routine imaging or investigation of rising creatinine. Pain over the graft, hematuria, decreasing urine output, or anuria may be the initial presentation. Accordingly workup of such patients may start with the insertion of a stent or PCN in cases of acute renal failure and anuria. More often the best investigation to detect stones, their number, and location is noncontrast CT. Bladder outflow should also be evaluated in cases of bladder ­calculi. A urine culture should be performed in all cases.

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Fig. 16.6  Plain radiograph of a missed stent. Stent was placed intraoperatively. Patient subsequently moved to another country before stent was removed. Presented 2 years later with stones in kidney and bladder

Stones identified in the donor may be removed during bench preparation using ureteroscopy on the back table [35] or ultrasound-guided nephrolithotomy [32]. Small stones may be managed expectantly and many pass spontaneously. Larger, obstructing, and symptomatic stones can be managed similar to those occurring in native kidneys. Renal and ureteric stones can be treated using shockwave lithotripsy, ureteroscopy with stone extraction or fragmentation (often by laser). Rarely open surgery is needed [30]. It is to be noted that antegrade access is often easier than the retrograde route due to the ectopic position and course of the ureter. Bladder stones can be treated endoscopically by fragmentation (using laser or electrohydraulic lithotripsy) and extraction. Larger stones are better extracted using cystolithotomy.

Urinary Retention Possible causes of urinary retention after renal transplantation are bladder outflow obstruction or a neurogenic poorly contracting bladder. Bladder outflow obstruction is the most common cause seen in men and can be due to an enlarged prostate, bladder neck contracture, or a urethral stricture or less commonly a foreign body, persistent posterior urethral valves, or an ectopic ureterocele. A noncontractile bladder is usually part of dysfunctional voiding syndromes that

occur due to neurologic disorders such as multiple sclerosis, Parkinson’s disease, or the peripheral neuropathy of diabetes mellitus. The diagnosis of urinary retention is fairly straightforward. It is often more challenging to uncover its cause; particularly in anuric patients where there may be no history suggestive of voiding problems. Urodynamics can be of help in identifying bladder pathology and determining the functional state of the bladder outlet. Evaluation of post-void residual urine will help detect cases of inadequate emptying. It is important to make note of the condition of the bladder at surgery and ensure that the patient is able to void adequately after Foley catheter removal prior to discharge. Treatment is dependent on the cause. A weak bladder with failure of complete emptying may be put on a self-clean intermittent catheterization (SCIC) regimen, which has proven to be safe and effective in transplant patients [36]. Bladder outlet obstruction due to BPH can be managed by an alpha blocker (e.g., terazosin, tamsulosin, alfuzosin) which may be used in combination with a 5-alpha reductase inhibitor (e.g., finasteride, dutasteride). Patients not responding to medical treatment can also be put on SCIC, and definitive surgery is best deferred for a minimum of 3 months. Reports are available on early transurethral resection of the prostate (TURP); [37] however, significant morbidity [3, 38] and mortality [3] has been associated with this practice. Other minimally invasive treatment options for BPH

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may also be used with success (transurethral needle ablation – TUNA, and photoselective vaporization – “green light” PVP). It is worth mentioning that even when suspected preoperatively, BPH should not be surgically managed in anuric patients due to the high incidence of bladder neck and urethral strictures associated with “dry” urinary passages.

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The incidence of erectile dysfunction (ED) among male transplant recipients has been reported as high as 53% [39]. ED in the transplant population has a multifactorial etiology as it may be caused by the patient’s chronic renal failure, diabetes, hypertension (and associated medications, especially b-blockers), and vasculopathy (particularly atherosclerosis). Male ESRD patients in addition have higher prolactin production and lower clearance; [40] this in turn suppresses testosterone production causing ED. Atherosclerosis of one or both the internal iliac

arteries is a common finding especially in the older patients. Though most surgeons avoid using the internal iliac artery for renal artery anastomosis altogether, if one has been used initially, the other internal iliac should be spared, as this is associated with a 25% risk of subsequent impotence [41]. A limited workup consisting of measuring serum testosterone and prolactin may be helpful in elucidating the cause. Uremia-associated hyperprolactinemia improves following renal transplantation and is suspected to account for the improvement of ED in 20% of patients after transplant [39]. Otherwise, treatment is generally based on symptoms and is adjusted according to subjective improvement. Therapy is often initiated with an oral phosphodiesterase 5 inhibitor. Sildenafil has demonstrated good efficacy and tolerability, with no effects on calcineurin inhibitor levels [42]. Patients failing to improve on oral therapy may benefit from intracorporeal injections using prostaglandin E1 or papaverine, which have shown efficacy in renal transplant recipients [43]. Refractory cases are best managed with penile prosthesis implantation, the infection

Fig. 16.7  Plain radiograph of patient with artificial urinary sphincter. The fluid reservoir lies in the lower right pelvis where it is liable to damage during transplant

recipient dissection. A “three-part” inflatable penile prosthesis reservoir is filled with water and is radiolucent but will have a similar appearance

Erectile Dysfunction

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rate being comparable to nonimmunosuppressed patients [44]. A two-piece device is preferred over the commonly used three-piece system to avoid the need for placing a fluid reservoir in the retroperitoneum. Injury to this reservoir may occur in cases of reexploration, retransplantation or rarely with biopsy [44]. The location of the reservoir can be ascertained prior to surgery using a CT scan. This should ideally be done prior to transplanting patients with an inflatable penile prosthesis in place as the location of a reservoir, if present, may influence the decision of kidney placement. The reservoir of an artificial urinary sphincter should be dealt with likewise (Fig. 16.7).

References 1. Mangus RS, Haag BW, Carter CB. Stented LichGregoir ureteroneocystostomy: case series report and cost-effectiveness analysis. Transplant Proc 2004;36(10):2959–2961. 2. Praz V, Leisinger HJ, Pascual M, Jichlinski P. Urological complications in renal transplantation from cadaveric donor grafts: a retrospective analysis of 20 years. Urol Int 2005;75(2):144–149. 3. Shoskes DA, Hanbury D, Cranston D, Morris PJ. Urological complications in 1,000 consecutive renal transplant recipients. J Urol 1995;153(1):18–21. 4. Streeter EH, Little DM, Cranston DW, Morris PJ. The urological complications of renal transplantation: a series of 1535 patients. BJU Int 2002;90(7):627–634. 5. Philosophe B, Kuo PC, Schweitzer EJ, et  al. Laparoscopic versus open donor nephrectomy: comparing ureteral complications in the recipients and improving the laparoscopic technique. Transplantation 1999;68(4):497–502. 6. Haferkamp A, Dorsam J, Mohring K, Wiesel M, Staehler G. Ureteral complications in renal transplantation with more than one donor ureter. Nephrol Dial Transplant 1999;14(6):1521–1524. 7. Karam G, Maillet F, Parant S, Soulillou JP, GiralClasse M. Ureteral necrosis after kidney transplantation: risk factors and impact on graft and patient survival. Transplantation 2004;78(5):725–729. 8. Gallentine ML, Wright FH, Jr. Ligation of the native ureter in renal transplantation. J Urol 2002;167(1):29–30. 9. Mathews R, Marshall FF. Versatility of the adult psoas hitch ureteral reimplantation. J Urol 1997;158(6):2078–2082. 10. Shokeir AA, Shamaa MA, Bakr MA, el-Diasty TA, Ghoneim MA. Salvage of difficult transplant urinary

I.A. Ghoneim and D.A. Shoskes fistulae by ileal substitution of the ureter. Scand J Urol Nephrol 1993;27(4):537–540. 11. Andonian S, Zorn KC, Paraskevas S, Anidjar M. Artificial ureters in renal transplantation. Urology 2005;66(5):1109. 12. Sigman DB, Del Pizzo JJ, Sklar GN. Endoscopic retrograde stenting for allograft hydronephrosis. J Endourol 1999;13(1):21–25. 13. Lojanapiwat B, Mital D, Fallon L, et al. Management of ureteral stenosis after renal transplantation. J Am Coll Surg 1994;179(1):21–24. 14. Sansalone CV, Maione G, Aseni P, et al. Advantages of short-time ureteric stenting for prevention of urological complications in kidney transplantation: an 18-year experience. Transplant Proc 2005;37(6):2511–2515. 15. Karam G, Hetet JF, Maillet F, et al. Late ureteral stenosis following renal transplantation: risk factors and impact on patient and graft survival. Am J Transplant 2006;6(2):352–356. 16. Coleman DV, Mackenzie EF, Gardner SD, Poulding JM, Amer B, Russell WJ. Human polyomavirus (BK) infection and ureteric stenosis in renal allograft recipients. J Clin Pathol 1978;31(4):338–347. 17. Nie ZL, Zhang KQ, Li QS, Jin FS, Zhu FQ, Huo WQ. Urological complications in 1,223 kidney transplantations. Urol Int 2009;83(3):337–341. 18. Bach D, Grutzner G, Kniemeyer HW, Westhoff A, Grabensee B. Diagnostic value of antegrade pyelography in renal transplants: a comparison of imaging modalities. Transplant Proc 1993;25(4):2619. 19. Nankivell BJ, Cohn DA, Spicer ST, Evans SG, Chapman JR, Gruenewald SM. Diagnosis of kidney transplant obstruction using Mag3 diuretic renography. Clin Transplant 2001;15(1):11–18. 20. Basiri A, Nikoobakht MR, Simforoosh N, Hosseini Moghaddam SM. Ureteroscopic management of urological complications after renal transplantation. Scand J Urol Nephrol 2006;40(1):53–56. 21. Bachar GN, Mor E, Bartal G, Atar E, Goldberg N, Belenky A. Percutaneous balloon dilatation for the treatment of early and late ureteral strictures after renal transplantation: long-term follow-up. Cardiovasc Intervent Radiol 2004;27(4):335–338. 22. Kristo B, Phelan MW, Gritsch HA, Schulam PG. Treatment of renal transplant ureterovesical anastomotic strictures using antegrade balloon dilation with or without holmium:YAG laser endoureterotomy. Urology 2003;62(5):831–834. 23. Bhayani SB, Landman J, Slotoroff C, Figenshau RS. Transplant ureter stricture: Acucise endoureterotomy and balloon dilation are effective. J Endourol 2003;17(1):19–22. 24. Boyvat F, Aytekin C, Colak T, Firat A, Karakayali H, Haberal M. Memokath metallic stent in the treatment of transplant kidney ureter stenosis or occlusion. Cardiovasc Intervent Radiol 2005;28(3):326–330. 25. Schult M, Kuster J, Kliem V, et  al. Native pyelour­ eterostomy after kidney transplantation: experience in 48 cases. Transpl Int 2000;13(5):340–343.

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26. Mangus RS, Haag BW. Stented versus nonstented ­extravesical ureteroneocystostomy in renal transplantation: a metaanalysis. Am J Transplant 2004;4(11):1889–1896. 27. Wilson CH, Bhatti AA, Rix DA, Manas DM. Routine intraoperative stenting for renal transplant recipients. Transplantation 2005;80(7):877–882. 28. Dominguez J, Clase CM, Mahalati K, et al. Is routine ureteric stenting needed in kidney transplantation? A randomized trial. Transplantation 2000;70(4):597–601. 29. Abou-Elela A, Morsy A, Reyad I, Torky M, Meshref A, Barsoum R. Modified extravesical ureteral reimplantation technique for kidney transplants. Int Urol Nephrol 2007;39(4):1005–1009. 30. Challacombe B, Dasgupta P, Tiptaft R, et al. Multimodal management of urolithiasis in renal transplantation. BJU Int 2005;96(3):385–389. 31. Khositseth S, Gillingham KJ, Cook ME, Chavers BM. Urolithiasis after kidney transplantation in pediatric recipients: a single center report. Transplantation 2004;78(9):1319–1323. 32. Devasia A, Chacko N, Gnanaraj L, Cherian R, Gopalakrishnan G. Stone-bearing live-donor kidneys for transplantation. BJU Int 2005;95(3):394–397. 33. Harper JM, Samuell CT, Hallson PC, Wood SM, Mansell MA. Risk factors for calculus formation in patients with renal transplants. Br J Urol 1994;74(2):147–150. 34. Stapenhorst L, Sassen R, Beck B, Laube N, Hesse A, Hoppe B. Hypocitraturia as a risk factor for nephrocalcinosis after kidney transplantation. Pediatr Nephrol 2005;20(5):652–656.

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35. Rashid MG, Konnak JW, Wolf JS,Jr, et  al. Ex vivo ureteroscopic treatment of calculi in donor kidneys at renal transplantation. J Urol 2004;171(1):58–60. 36. Capizzi A, Zanon GF, Zacchello G, Rigamonti W. Kidney transplantation in children with reconstructed bladder. Transplantation 2004;77(7):1113–1116. 37. Koziolek MJ, Wolfram M, Muller GA, et al. Benign prostatic hyperplasia (BPH) requiring transurethral resection in freshly transplanted renal allograft recipients. Clin Nephrol 2004;62(1):8–13. 38. Reinberg Y, Manivel JC, Sidi AA, Ercole CJ. Transurethral resection of prostate immediately after renal transplantation. Urology 1992;39(4):319–321. 39. Russo D, Musone D, Alteri V, et al. Erectile dysfunction in kidney transplanted patients: efficacy of sildenafil. J Nephrol 2004;17(2):291–295. 40. Sievertsen GD, Lim VS, Nakawatase C, Frohman LA. Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure. J Clin Endocrinol Metab 1980;50(5):846–852. 41. Taylor RM. Impotence and the use of the internal iliac artery in renal transplantation: a survey of surgeons’ attitudes in the United Kingdom and Ireland. Transplantation 1998;65(5):745–746. 42. Zhang Y, Guan DL, Ou TW, et al. Sildenafil citrate treatment for erectile dysfunction after kidney transplantation. Transplant Proc 2005;37(5):2100–2103. 43. Lasaponara F, Paradiso M, Milan MG, et al. Erectile dysfunction after kidney transplantation: our 22 years of experience. Transplant Proc 2004;36(3):502–504. 44. Cuellar DC, Sklar GN. Penile prosthesis in the organ transplant recipient. Urology 2001;57(1):138–141.

Chapter 17

Medical Management of Kidney Transplant Recipients Vidya Vootukuru and Brian Stephany

Keywords  Kidney transplant • medical complications • posttransplant complications

Introduction Kidney and pancreas transplants confer survival advantages in well-selected recipients. These patients often have multiple comorbidities at the time of transplantation which may progress or interact with the immunosuppressive and adjunctive medical therapy that are used to maintain successful engraftment. It is not surprising then that a number of medical issues complicate the management of these patients, both early and late in the posttransplant period. Nearly half the cases of late allograft loss are due to “death with a functioning graft,” with a majority occurring as a result of cardiovascular, infectious, or malignant complications. As such, we focus in this chapter on the management of common medical complications in the posttransplant period that is essential to ensure the best outcomes possible. Of note, a separate chapter will discuss common infectious considerations and thus are not duplicated in the following.

B. Stephany (*) Department of Nephrology and Hypertension, 9500 Euclid Ave., Q7 Cleveland, OH 44195, USA e-mail: [email protected]

Cardiovascular Disease Diseases of the cardiovascular system are common in kidney transplant recipients, especially those with cumulative burden of risk factors (e.g., older age, pretransplant cardiovascular disease, diabetics, smokers, etc.). They encompass both atherosclerotic stenoses and/or occlusions of vital vascular beds (coronary artery disease, cerebrovascular disease, and peripheral vascular disease) and impaired cardiac anatomy and function leading to hypertrophy, dilation, and reduced performance. Though less so than dialysis patients, kidney transplant recipients are at a much higher risk (i.e., estimated 50-fold) of cardiovascular disease (CVD) compared to nontransplant patients [1]. In fact, by 3 years posttransplant up to 40% of patients may experience a cardiovascular event [2]. However, it is well established that transplantation abrogates the cardiovascular risk compared to other renal replacement therapies [3], and as such remains the modality of choice. The degree to which this is successful is dependent directly on both the performance of the allograft posttransplant, with patients enjoying the highest glomerular filtration rates at lowest risk, and the successful management of risk factors: tobacco cessation, avoidance of obesity, and diligent control of diabetes, dyslipidemia, and hypertension. Unfortunately, metabolic accompaniments of immunosuppression may exacerbate metabolic abnormalities and hypertension. As such, the remainder of this section will focus on these major modifiable cardiovascular risk factors in the transplant recipient.

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_17, © Springer Science+Business Media, LLC 2011

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Hypertension Epidemiology and Clinical Importance Hypertension is a common problem in renal transplant recipients. About 75–90% of patients are hypertensive using the JNC VII guidelines for hypertension (SBP >140 mmHg and DBP >90 mmHg) [1]. The risk of hypertension increases over time after transplantation and depends on the diagnostic criteria and immunosuppressive therapy. Reported incidence of hypertension in the precyclosporine era was 40–60%. Various studies have shown a prevalence ranging between 60% and 85% in cyclosporine-treated patients [4]. In general, hypertension after transplant is more common in African Americans and recipients of deceased donor kidneys compared to whites and live donor allograft recipients, respectively [5]. Hypertension is a cardiovascular risk factor and increases the risk of death and allograft failure in the transplant population. Each 10 mmgHg rise in blood pressure has been shown to increase the relative risk of death censored graft failure by 17% [6]. Unfortunately, randomized placebocontrolled clinical trials of hypertension in dedicated renal transplant patients are lacking. As such, treatment of hypertension in the transplant recipient is based on extrapolation of expected benefit observed in nontransplant populations.

Risk Factors and Pathogenesis The underlying causes of hypertension in the immediate (<3 months) and late (>3 months) posttransplant period are listed in Table  17.1. These include contributions of postoperative pain, hypervolemia, donor quality (nephron dose), level of renal function posttransplant (delayed graft function, rejection episodes, suboptimal function), recipient age, recipient race, obesity, dietary sodium, and possible contributions of native kidney disease. These factors

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interact with the type of immunosuppression employed. Both calcineurin inhibitors and corticosteroids (even at doses as low as 10 mg) contribute to hypertension. The calcineurin inhibitors, especially cyclosporine, cause afferent arteriolar vasoconstriction, activation of the sympathetic nervous system and renin angiotensin system, salt and water retention, inhibition of vasodilatory pathways (prostacyclin and nitric oxide), and increased vasoconstriction (endothelin) [7– 9]. Steroids exert a mineralocorticoid effect independent of salt intake, leading to increased body volume as well as increased cardiac output and pressor responses to epinephrine and angiotensin II. Mycophenolate mofetil (or sodium), sirolimus, azathioprine, and antilymphocyte Table  17.1  Risk factors for hypertension after renal transplant 0–2 months posttransplant Pretransplant hypertension African-American race Volume overload Withdrawal of pretransplant antihypertensive medications Immunosuppressive drugs – steroids, CNI Graft dysfunction Postoperative pain Renal artery stenosis >2 months posttransplant Donor factors: Increasing donor age African-American race Donor hypertension Recipient factors: Older recipient African-American race Male gender Obesity Diabetes Pretransplant hypertension Native kidney disease Graft related factors: Acute rejection or chronic allograft dysfunction Renal artery stenosis Recurrent or de novo glomerulonephritis Immunosuppressive medications Steroids CNI, Calcineurin inhibitors Adapted from [43]

17  Medical Management of Kidney Transplant Recipients

antibodies have not been shown to associate with hypertension. Transplant renal artery stenosis (TRAS) can present early or late and reported rates vary between 1% and 23% [10]. It can occur at the level of the iliac artery due to atherosclerosis in the recipient, at the site of anastomosis due to technical reasons or in the donor renal artery. Anastomotic stenosis is more common in living donor kidneys that are anastomosed end to side with the iliac artery as such kidneys are removed without the donor aortic cuff. The common mechanism of renovascular hypertension in these scenarios is a rise in renal vascular resistance and drop in allograft perfusion to a significant amount when luminal cross-sectional area is reduced by greater than or equal to 50%. This leads to activation of the renin-angiotensin-aldosterone axis, volume expansion, and a rise in systemic blood pressure. TRAS appears more common with deceased donor transplants compared to living donor transplants [11].

Diagnosis and Management The diagnosis of hypertension is made by regular blood pressure checks in the immediate postoperative period and subsequently during office visits. Home blood pressure measurement and ambulatory BP monitoring are encouraged. Transplant patients have been shown to have decreased nocturnal dipping and sometimes even a paradoxic rise in nocturnal blood pressure that can predispose to end-organ damage. Small studies have shown a correlation between mean 24-h ambulatory blood pressure values and left ventricular mass in the transplant population [4]. Routine screening for TRAS is not recommended in the absence of difficult to control hypertension, de  novo hypertension, worsening renal function with or without use of angiotensin converting enzyme inhibitors (ACEi), or angiotensin receptor blockers (ARB), or presence of a new bruit. It should be noted that bruits over the allograft are not specific for TRAS and can occur due to turbulence at the surgical anastomosis,

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stenosis more proximally in the aortoiliac system, or arteriovenous fistulas caused by prior allograft biopsies. In these instances prompt screening by duplex ultrasonography or magnetic resonance angiography should be performed. Increased anastomotic velocities per se in the postoperative period should not be acted upon without confirmatory studies. A parvus tardus waveform on the duplex sonogram is more specific for stenotic lesions. After consideration of the risks and benefits of an invasive procedure, confirmation by angiography (with potential opportunity to treat the lesion) can be sought.

Treatment Uncontrolled blood pressure immediately after transplant can be detrimental, resulting in stroke or bleeding. Short-acting oral or parenteral medications such as clonidine, labetalol, and hydralazine can be used for blood pressure control during this time. Diuretics are indicated in cases of concomitant volume overload. However, aggressive lowering of blood pressure during the immediate posttransplant period is not recommended given concern over compromising allograft blood flow (dysautoregulation) or decreasing perfusion in chronically damaged end organs. An acceptable blood pressure target in the first few months posttransplant should be less than 150/90. Treatment guidelines for long-term management of hypertension are based on trials in nontransplant recipients. Clinical practice guideline published by the National Kidney Foundation recommend a target blood pressure of less than 130/80, with a lower goal of less than 125/75 mmHg in proteinuric patients. As in the general population, management includes nonpharmacologic and pharmacologic treatment. Lifestyle modifications should be emphasized to all patients including weight reduction, low salt diet (<100 mEq/day), exercise, and a diet enriched in fruits and vegetables and low in fat. Alteration of immunosuppression remains an

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option for patients with hypertension refractory to medical therapy, specifically conversion from cyclosporine to tacrolimus or sirolimus or tapering of steroids. However, the risks of such strategies especially steroid withdrawal with regard to the possibility of allograft rejection need to be carefully considered. Principles of pharmacologic therapy in transplant patients are similar to those in the general population with few exceptions. Several agents have been used successfully each with its own advantages and disadvantages (Table  17.2). Concepts to be mindful of when deciding on specific antihypertensives include drug-drug interactions with patients’ immunosuppressive regimens (specifically those metabolized via the cytochrome P450 pathway), patients’ susceptibility to volume depletion, and pertinent coexisting medical conditions. Based on pathophysiologic considerations of increased calcium channel blockers (CCBs) are attractive because of their potential ability to counteract the vasoconstric-

V. Vootukuru and B. Stephany

tive effects of calcineurin inhibitors. Monotherapy with dihydropyridine CCBs should not be used. Edema is a common side effect with these agents. Use of nondihydropyridine CCBs (e.g., diltiazem, verapamil) are associated with higher exposure of CNI and corticosteroid due to their inhibition of the CYP3A4 pathway whereas dihydropyridine CCBs such as amlodipine, felodipine, and nifedipine exhibit minimal yet variable interaction Nondihydropyridine CCBs may have a synergistic antiproteinuric effect when used in conjunction with ACEi. ACEi or ARB should be used in patients with diabetes and patients who develop proteinuria after transplant. Although the cardioprotective and renoprotective properties are well known in the general population, there is limited prospective data in transplant patients. A Canadian multicenter randomized trial of ACEi use in renal transplant recipients with proteinuria and estimated GFRs between 20 and 55 mL/min/L.73 m2 is currently enrolling patients to determine their

Table 17.2  Commonly used antihypertensives – common side effects and specific indications Side effects Specific indications • Combine with other hypertensive Thiazides Volume contraction, hypokalemia, agents (vasodilators, a-blockers) hyperglycemia, hyperlipidemia, elevated creatinine • Edema • Hyperkalemia due to other drugs • Ischemic heart disease Beta blockers Blunted hypoglycemic response, bradycardia, worsened periph• Counteract tachycardia due to eral vascular disease, a-blockers or vasodilators hyperlipidemia ACEI Hyperkalemia, anemia, ARF in • Proteinuria renal artery stenosis • Coronary artery disease (CHF, post-MI) • Posttransplant erythrocytosis ARB Hyperkalemia, anemia, ARF in • Cough with ACEI renal artery stenosis • Proteinuria • Posttransplant erythrocytosis • CHF Vasodilators Reflex tachycardia, fluid retention, • Uncontrolled HTN hypertrichosis (minoxidil) Rebound hypertension, dry mouth, • Uncontrolled HTN Centrally acting drugs – clonidine orthostasis • Lower CNI dose CCB Bradycardia, edema, increased CNI levels, reflex tachycardia (dihydropyridine group) a-Blockers Orthostasis, sodium retention, reflex • Benign prostatic hypertrophy tachycardia ACEI, Angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; CSA, calcineurin inhibitors

17  Medical Management of Kidney Transplant Recipients

effect on GFR, ESRD incidence, and death [12]. In general, ACEi or ARB therapy can be initiated safely soon after transplant when stable and favorable allograft function has been achieved. Hyperkalemia, a common side effect worsened by concomitant use of CNI and trimethoprim, usually can be managed by adding a small dose of loop diuretic. Thiazide diuretics have the tendency to contribute to hypercalcemia and gout and are not encouraged in transplant recipients. An increase in serum creatinine greater than 30% soon after initiation of these drugs should raise the suspicion of TRAS. Cough occurs more frequently with use of ACEi than with an ARB. The propensity of ACEi or ARB therapy to cause anemia makes them useful in the treatment of hypertensives with posttransplant erythrocytosis. Conversely, they can also exacerbate anemia. Diuretics combined with a low salt diet are useful in the management of volume overload in the immediate posttransplant period. They also can counteract salt-retaining properties of CNI therapy, steroids, and beta blockers and increase the efficacy of other antihypertensives. However, routine use of diuretics is not encouraged as salt depletion may contribute enhanced nephrotoxicity of calcineurin inhibitors. Hypokalemia, hypomagnesemia, and volume depletion should be avoided when using diuretics. Beta blockers should be used in those with ischemic heart disease and can help blunt reflex tachycardia induced by alpha blockers, dihydropyridine CCBs and vasodilators. They should be used with caution in diabetic patients since they can blunt a hypoglycemic response. Other potential side effects include bronchoconstriction, exacerbation of peripheral vascular disease, fatigue, and bradycardia. Labetalol is often used due to combined alpha and beta blockade effects. In general, a selective beta blocker such as metoprolol along with adjunctive alpha blockade such as doxazosin may have a better side effect profile and dynamic therapeutic range. Clonidine is a useful agent particularly in the acute setting, but can cause dry mouth, orthostasis, and rebound hypertension when stopped abruptly or doses are inadvertently missed. Clonidine can be used in both acute and chronic settings. Clonidine is also

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least likely to lead to postural hypotension. Direct vasodilators such as hydralazine and minoxidil are known to cause tachycardia and fluid retention and may need to be combined with a beta blocker and diuretic. Minoxidil is generally avoided in end-stage renal disease patients, as pericardial effusions can result. Selective alpha blockers (e.g., doxazosin) can be used in those with concomitant prostatism, but typically not as monotherapy and are known to induce orthostasis and sodium retention, which may exacerbate heart failure in susceptible patients.

Management of TRAS Timely diagnosis and intervention (in the form of percutaneous angioplasty with or without stenting, or surgical correction) can potentially improve blood pressure control, reduce antihypertensive medications, and improve allograft function. These potential benefits must be weighed against potential risks, including contrast dye exposure, inadvertent arterial dissection, and peripheral cholesterol embolization in susceptible patients. In general, after percutaneous therapy restenosis occurs in approximately 30% of cases.

Diabetes Epidemiology and Clinical Importance Disordered glucose metabolism is common postkidney transplantation and can manifest as impaired fasting glucose (IFG), impaired glucose intolerance (IGT), or frank new onset diabetes after transplantation (NODAT). Similar to the general population, such transplant-associated hyperglycemia (TAH) is associated with increased risk of cardiovascular disease, microvascular and macrovascular complications, infections, allograft loss, and all-cause mortality in kidney transplant recipients [13].

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More than 20% of transplant recipients have ­preexisting diabetes at the time of transplantation [14]. A retrospective analysis of the USRDS cohort from 1996 to 2000 showed the estimated prevalence of NODAT 9.1%, 16.1%, and 24% at 3, 12, and 36 months, respectively, after transplantation [15]. Single-center prospective studies using direct testing methods and definitions demonstrated higher 1-year incidence rates of NODAT (13% and 24% using fasting blood sugar and glucose tolerance testing, respectively) and prediabetic conditions (33% and 46% incidence rate of IFG and IGT, respectively) [16, 17]. Both prediabetic conditions such as IFG and IGT, and not just NODAT, appear to affect patient survival [17–19].

Risk Factors and Pathogenesis TAH can manifest overtly immediately posttransplant or in a more insidious and asymptomatic manner. The pathogenesis of TAH includes a combination of mechanisms that decrease insulin sensitivity, decrease insulin release, and increase insulin clearance (Table  17.3). Severe hyperglycemia is not uncommon postoperatively due to surgical stress and high doses of steroids, whereas later during the first 6 months after transplant, TAH is more often attributed to medication side effects and weight gain. TAH may be transient or become persistent but complications such as DKA are rare.

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Diagnosis and Management Screening of renal transplant recipients for TAH is based on recommendations by the American Diabetes Association (Table  17.4). Fasting plasma glucose should be measured every week for the first month, then at 3-, 6-, and 12-month visits. It is prudent to perform oral glucose tolerance testing (OGTT) at 6 months posttransplant and yearly thereafter. Screening for metabolic syndrome should be conducted alongside screening for diabetes. Postoperative hyperglycemia is common and its control is critical to prevent infections. According to ADA recommendations for hospitalized noncritical patients, fasting and postprandial blood glucose levels between 90 and 130 mg/dL and less than 180 mg/dL, respectively, should be targeted. Ensuring a diabetic diet, avoiding glucose-containing fluids, limiting carbohydrate and caloric intake to a 130–180 g and 1,800–2,000 kcal/day diet, respectively, are necessary, though often not sufficient. Insulin is the mainstay of pharmacologic therapy in this period and can be initiated on a sliding scale regimen or in cases of severe hyperglycemia as an infusion. A sliding scale is administered with the addition of basal insulin such as NPH or glargine. Morning dosing of steroids can cause late hyperglycemia, a phenomenon that can be matched by the peak effect of NPH (4–10 h). If insulin requirements are low (<15–20 U) then conversion to insulin secretagogues like sulfonylureas or meglitinides could be considered. The risk of hypoglycemia is higher with some sulfonylureas due to retention

Table 17.3  Nonmodifiable and modifiable factors contributing to the development of hyperglycemia posttransplant Nonmodifiable Modifiable Decrease insulin Increasing age Hepatitis C infection sensitivity Male gender Posttransplant weight gain Nonwhite race Obesity/metabolic syndrome Family history Glucocorticoids Sirolimus Increased insulin Restored kidney function clearance post-transplant Decreased insulin Family history Tacrolimus > cyclosporine secretion ? Hepatitis C infection Adapted from [44]

17  Medical Management of Kidney Transplant Recipients Table 17.4  Diagnosis of disorders of glycemia based on revised criteria of the American Diabetes Association Random 2-Hour Fasting glucose glucose OGTT Prediabetic conditions IFG (mg/dl) 100–125 n/a n/a IGT (mg/dl) n/a n/a 140–199 Diabetes (mg/dl) ³126 ³200 ³200 From [14]

of active metabolites in the setting of impaired renal function, as in those with delayed graft function and rejection. Use of glipizide and the meglitinides (which are hepatically metabolized) are safer options in such circumstances. Long-term management of hyperglycemia includes nonpharmacologic and pharmacologic interventions. Goals of glycemic control as established by the ADA include fasting blood glucose 90–130 mg/dL, postprandial glucose levels less than 180 mg/dL and HbA1C less than 7% [20–22]. However, based on more contemporary data, targeting glycemic control to normal levels (i.e., HbA1C <6%) may be undesirable [23]. Nonpharmacologic treatment is indicated for all patients with TAH and includes dietary changes with restriction of carbohydrate load to 130–180 g/day, favoring carbohydrates with a low glycemic index, and calorie restriction and regular exercise in overweight patients to promote weight loss. Such interventions may be sufficient to maintain adequate glycemic control in patients with IFG or IGT. For those with overt NODAT, pharmacologic measures are commonly needed. Pharmacologic interventions may include use of oral hypoglycemic agents, insulin, and the modification of immunosuppression (Table 17.5). Steroids are known to cause insulin resistance, impair insulin secretion, and increase hepatic gluconeogenesis. Although the effect is dose dependent, even inclusion of low dose prednisone (i.e., 5 mg/day) compared to steroid free protocols adversely affects insulin sensitivity [24]. Although early steroid withdrawal or avoidance is an option with acceptable short-term immunologic outcomes in patients deemed at high risk for TAH, the risks of late rejection and inferior allograft survival should be kept in mind [25].

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In a randomized trial of steroid avoidance in renal transplant recipients, there was no difference in the incidence of diabetes in those on maintenance steroids vs. those off steroids except that those on steroids were more likely to need insulin. Calcineurin inhibitors are toxic to islet cells and may decrease insulin secretion and sensitivity to insulin. Tacrolimus may be more diabetogenic than cyclosporine. Conversion from CNI-based to CNI-free protocols utilizing sirolimus can result in worse glycemic control due to further reduction in insulin sensitivity and pancreatic cell function caused by that drug. As there have been no randomized controlled trials in kidney transplant recipients comparing the superiority of different pharmacologic regimens, the treatment of TAH in this population is extrapolated from such guidelines. It is important however to recognize the potential for drug interactions unique to transplant patients due to shared metabolic pathways or impaired gastric motility with the use of these agents. Hence, monitoring for hypoglycemia is critical at the time of introduction of any new agent. Commonly used hypoglycemics, actions, side effects are listed in Table  17.5. Sulfonylureas and metiglinides act by increasing insulin secretion. Sulfonylureas with the exception of glipizide (hepatic metabolism) carry a risk of hypoglycemia, particularly in those with impaired allograft function. Metiglinides have a lower risk of hypoglycemia their clearance being nonrenal. Because of their rapid onset of action, they can be taken 0.5–2 h before a meal. Metformin, an insulin sensitizer, is usually avoided because of the risk of lactic acidosis in those with allograft dysfunction. Thiazolidinediones (TZDs) also increase insulin sensitivity and are safely used in this population without the need for renal adjustment. They do however promote volume retention and should not be used in patients with heart failure. The recent controversy of adverse cardiovascular events with the use of rosiglitazone seems to be limited to this drug and use of pioglitazone appears to be safe. Incretin mimetics (GLP-1 receptor agonists) such as exenatide promote GLP-1 induced postprandial insulin secretion

Sulfonylurea

1.0–2.0

0.5–1.0

500–2550 mg/day

Acarbose 25–100 mg with meals

Replacement

Increase insulin sensitivity Increase insulin secretion

Incretin mimetics Increase postprandial 5–10 mg twice daily prior to (Byetta) insulin release meals DPP-IV inhibitors Increase postprandial 25–100 mg once daily (sitagliptin) insulin release a TZD, Thiazolidinediones b Sulfonylureas are second-generation drugs only c Drug information: Lexicomp Adapted from [45] and [46].

Insulin

Meglitinides

TZDb

GI side effects

0.5–1.0 05–0.8

Edema, weight gain, hepatotoxicity Hypoglycemia, weight gain

Flatulence, weight gain

Hypoglycemia, weight gain GI upset, lactic acidosis

Weight gain, hypoglycemia Nausea

Rosiglitazone 4–8 mg/day 0.5–1.0 Pioglitazone 7.5–45 mg/day Nateglinide 60–120 mg before 1.0–2.0 meals Repaglinide 0.5–4.0 mg before meals Varies with formulation 1.5–3.5

1.0–2.0

Glipizide 2.5–40 mg/day Glyburide 1.25–20 mg/day

Increase insulin secretion

Decreased hepatic glucose production Increased peripheral glucose utilization Alpha-glycosidase Delay GI absorption inhibitors of carbohydrates

Biguanides (metformin)

b

Reductiona in HbA1C Common side effects

Dose rangea,c

Mechanism

Table 17.5  Commonly used hypoglycemic agents

Glipizide-not used if GFR < 10 mL/min Glyburide not used if GFR < 50 mL/ min Do not use if Cr >1.5 mg/dL

Glipizide 2–5 h Glyburide 4–10 h

1–1.5 h

12 h

Adjustment required with reduced GFR

Requirements may change based on renal function Not recommended if GFR < 30 mL/min

Adjustment may be needed

2–4 h

Varies with formulation 2.4 h

Not recommended if SCr > 2, accumulated when GFR < 25 mL/ min No adjustment necessary

~2 h

4–9 h

GFR adjustmentc

t1/2c

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and blunt the hyperglycemic response. Although there have been no trials in the kidney transplant population, it has been used safely though it should be avoided with a glomerular filtration rates less than 30 ml/min. An additional benefit is weight loss due to appetite suppression induced by this agent. Inhibitors of DPP-1V, which is an enzyme that degrades GLP-1, such as sitagliptin increase endogenous GLP-1 and lower fasting and postprandial glucose and have the advantage of being administered orally. Renal adjustment is required and there is no published data on pertinent drug interactions at this time. Short-acting meal time insulin like Lispro or Apidra and longacting basal insulin such as glargine or detemir can be used safely. There are no currently known drug interactions between insulin and immunosuppressive medications, although impairment in allograft function could increase insulin levels via impaired renal clearance.

Hyperlipidemia Epidemiology and Clinical Importance Dyslipidemia occurs in approximately 40–60% of renal transplant recipients [26]. The exact prevalence varies with the immunosuppressive agents employed, being twice as common with cyclosporine compared to tacrolimus-based regimens. Hypertriglyceridemia predominates in sirolimus treated patients. The direct impact of hyperlipidemia on transplant outcome is not clear and it is treated with a view to prevent cardiovascular morbidity in transplant recipients.

Risk Factors and Pathogenesis Aside from traditional risk factors such as age, genetic predisposition, and obesity, several drugs commonly used in the transplant patient contribute to hyperlipidemia (Table  17.6).

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Table 17.6  Risk factors contributing to hyperlipidemia in the renal transplant recipient Advancing age Weight gain/obesity/metabolic syndrome Hypothyroidism Proteinuria Diabetes Alcohol abuse Liver disease Medications Immunosuppressive medications – steroids, calcineurin inhibitors, sirolimus Nonimmunosuppressive medications – beta-blockers, diuretics, anticonvulsants, oral contraceptives

Steroids induce insulin resistance with increased total cholesterol and triglycerides (TG). The hyperlipidemic effect of the calcineurin inhibitors may relate to their effect on LDL receptors, with reduced negative hepatic feedback on LDL or bile acid synthesis. Tacrolimus may have a better lipid profile compared to cyclosporine and switching from cyclosporine to tacrolimus can improve lipid profiles. Sirolimus increases triglycerides and total cholesterol levels via reduced lipoprotein lipase activity and decreased metabolism of apoB100-containing lipoproteins. The effect of sirolimus seems to be dose dependent and is potentiated by use of cyclosporine [27].

Diagnosis and Monitoring Guidelines put forth by NKF-KDOQI closely mirror the ATP III guidelines for the general population with a few differences. These include the inclusion of transplant patients in the highest risk category for cardiovascular risk and more frequent monitoring of lipid profile. Goals of lipid-lowering therapy in the transplant recipient are listed in Table  17.7. A fasting lipid profile should be checked within 3–6 months posttransplant, at 1 year posttransplant, and at least yearly thereafter. Additionally repeat lipid panels should be obtained 2–3 months after a change in antilipemic drug, introductions of medications

320 Table  17.7  Goals of dyslipidemia according to the NKF-KDOQI guidelines Definition Goal TG >500 TG <500 LDL 100–129 LDL <100 LDL >130 LDL <100 If TG >200, then calculate non-HDL IF Non HDL >130 Non-HDL <130 Adapted from [26] and [47]

known to cause dyslipidemia, and with changes in proteinuria and renal function [26]. Secondary causes of dyslipidemia should be ruled out [26]. A LDL goal of less than 100 mg/dl is suggested by KDOQI-NKF guidelines, but a target less than 70 mg/dL may be applicable to those with diabetes and previous CVD. Three months of therapeutic lifestyle changes can be considered in those with LDL 100–129 mg/dL before initiating of drug therapy. In patients with very high triglycerides (>500), the goal of therapy is to prevent pancreatitis using lifestyle changes and drug therapy with fibrates or niacin in those who cannot tolerate fibrates. Both these drugs are known to reduce TG by about 20–50%. The rationale for statins as first-line agents for total and LDL cholesterol lowering is extrapolated mostly from the cardiovascular protective quality of this class of medications in nontransplant patients, as few data exist specifically in this population. The sole lipid-lowering trial in renal transplantation, ALERT randomized 2,102 renal transplant recipients to fluvastatin (40 and 80 mg) vs. placebo [28]. Those randomized to active therapy showed a reduction in LDL by 32%. Although the incidence of the primary composite end point of cardiac death, nonfatal MI, or coronary revascularization was not different in the two groups, a secondary endpoint of cardiac death and nonfatal MI was significantly lower in the statin group. Post hoc analyses also demonstrated that earlier initiation resulted in greater cardiovascular event reduction (64% risk reduction when enrolled within 4 years compared to 19% when enrolled >10 years after transplant).

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Though generally well tolerated, adverse effects of statins and fibrates such as myopathy is higher with older age, smaller body frame, and concomitant use with certain drugs (i.e., fibrates, niacin, cyclosporine, azole antifungals, macrolide antibiotics, nondihydropyridine calcium channel blockers, and amiodarone) [26]. Most statins (simvastatin, atorvastatin, lovastatin) are metabolized by the same pathway as cyclosporine (CYP3A4), and hence coadministration can lead to higher statin levels and a higher risk of myopathy. It is thus recommended that statins metabolized through CYP3A4/5 be administered at half the dose used in the normal population. Fluvastatin, however, is metabolized by the CYP 2C9 enzyme pathway and Pravastatin via sulfation. As a result these drugs may be better tolerated but are less potent. Regardless, it is prudent to decrease the dose of statin when used in a cyclosporine- or tacrolimus-treated patient, with slow uptitration to achieve the target cholesterol levels while minimizing side effects. Symptoms with either normal or mild elevation of CK should lead to lowering the dose and close monitoring. Baseline liver function tests are useful [26]. For those who cannot tolerate a statin, niacin can be considered. Niacin is also used in those who cannot achieve LDL goal on a statin alone. Its use is limited by hyperglycemia and flushing. It is also contraindicated in liver disease, gout, and active peptic ulcer disease. Bile acid sequestrants lower exposure of mycophenolic acid and calcineurin inhibitors. Treatment of severe hypertriglyceridemia (TG >500 mg/dL) involves treatment of reversible causes and drug therapy. Fibrates are first-line agents, but should be used cautiously in those taking cyclosporine or statins due to increased risk of rhabdomyolysis. These agents can cause elevated creatinine when used with cyclosporine and renal adjustment is suggested for most fibrates. Niacin may be used as a second-line agent for uncontrolled TG or for those who cannot tolerate fibrates. Fish oil can be used as an adjunct but is not recommended as monotherapy. There are no data on the use of ezetimibe in this population and is not recommended for monotherapy.

17  Medical Management of Kidney Transplant Recipients

Cancer Cancer is the third most common cause of death in renal transplant recipients, after cardiovascular disease and infections, being responsible for 9–12% of deaths. The overall incidence of malignancies increases the longer one survives after their transplant surgery, up to 33% at 30 years posttransplant for non-skin malignancies. This increased risk applies to de novo cancers as well as recurrent malignancies from the pretransplant period that had been thought cured – recurrences that may have occurred earlier than if no transplant had occurred in the first place. Analysis of large registries shows a recurrence rate of preexisting cancers as high as 22% [29]. Given this finding, significant attention is paid to age-appropriate cancer screening and ample wait times after their treatment and presumed cure prior to transplantation to avoid as best possible transplanting patients otherwise destined to develop malignancies early posttransplant. Malignant transformation of cells due to DNA damage (e.g., skin cells from sun exposure or direct toxin mediated damage of resident lung cells from smoking) along with unintended consequences of immunosuppressive medications employed to prevent rejection – suppression of normal immune surveillance, direct induction of transforming growth factor beta (TGFb)-related cellular effects by calcineurin inhibitors (CNIs), and mutations in antioncogenes (e.g., p53) – are all pathogenetic mechanisms believed to contribute to this higher risk. The time posttransplant when malignancies present vary widely, but can manifest very early (e.g., EBV-associated posttransplant lymphoproliferative disorder, PTLD). Lack of proper studies related to cancer screening in the transplant population has led to the extrapolation of screening recommendations from the general population. There are obvious potential problems with such a practice. Given competing mortality risks beyond malignancies and a lower overall life expectancy in transplant recipients, cancer screening as performed in the general population with the potential psychological risks of false-positives and testing- or treatment-associated

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Table 17.8  Risk factors for posttransplant bone disease Pretransplant factors Preexisting bone disease Osteitis fibrosa Mixed bone disease Adynamic bone disease Osteomalacia Posttransplantation factors Immunosuppressive drugs PTH status Hypophosphatemia Renal function Others Older age Diabetes Postmenopausal status Adapted from [30]

complications may not accomplish the ultimate goal of a cost-effective increase in quality of life years. That being said, screening nihilism is also not advisable, as many transplant patients clearly benefit from early detection of cancers that allow timely and successful treatment. Once identified, timely referral to an appropriate specialist is prudent. Additionally, immunosuppression reduction and/or withdrawal at the time of diagnosis may be warranted, but one universal recommendation regarding such practice is not possible and should be based on weighing the risks of allograft rejection as well as the natural history, stage, and severity of the malignancy after consultation with an oncologist. Recommendations for screening as suggested by European Best Practice Guidelines on Renal Transplantation, the American Society of Transplantation, and the KDIGO (Kidney Disease Improving Global Outcomes) clinical practice guidelines are listed in Table  17.8. Below is ­further discussion on selected malignancies.

Nonmelanomatous Skin and Lip Cancers Skin cancers account for 40–53% of all malignancies among kidney transplant recipients [4]. In contrast to the general population where

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the occurrence of basal cell carcinoma is approximately fivefold higher than squamous cell carcinoma, the latter is the most common nonmelanomatous skin cancer in kidney transplant recipients compared to basal cell carcinomas by a factor of nearly two. In general, these skin malignancies tend to be clinically more aggressive in this population, resulting in approximately a twofold risk of death compared to the general population. They attend to occur at a relatively younger age, are more likely to metastasize to lymph nodes, and may result in more local destruction and disfigurement. In addition to traditional risk factors for nonmelanomatous skin cancer, including ultraviolet sunlight exposure which varies by geographic area, and smoking (especially for lip cancer), human papilloma viral infection with or without a history of viral warts appears to increase one’s risk. We recommend that all patients should avoid excessive sun exposure, use protective clothing and appropriate sunscreen, and if a concerning lesion is noted we refer to a dermatologist for biopsy.

Malignant Melanoma Malignant melanoma is two to four times more common in transplant recipients compared to the general population and accounts for the greatest proportion of skin cancer-related death posttransplant. Additionally, malignant melanomas have the dubious distinction of being the most common inadvertently donor transmitted malignancy.

Cancers Associated with Viral Infections Owing to the increased susceptibility to viral infections as a consequence of immunosuppression posttransplant, it is not surprising that patients are also at increased risk of malignancies

which certain viruses may play a causal role: HIV and/or HHV8 associated Kaposi’s sarcoma, anogenital cancers caused by HPV (i.e., cervical, vulvovaginal, anal and perianal, penile, and scrotal), hepatocellular carcinomas induced by hepatitis B and C viruses, and posttransplant lymphoproliferative disorders (PTLD) associated with EBV. Kaposi’s sarcoma and EBVassociated PTLD occur earlier posttransplant than other malignancies, perhaps as a result of their viral origin, which may be inadvertently enhanced by the higher degree of early immunosuppression. Anogenital cancers are more common in women than men and typically present at a younger age than in the general population.

Colorectal Cancer Data from large registries suggest a two- to fourfold increased risk of colon cancer in kidney transplant recipients compared to a nontransplant population, where the risk becomes significantly different after extended followup beyond 10 years posttransplant. There is some evidence that colon cancer may occur at a younger age in kidney transplant patients, but once diagnosed the prognosis may not be significantly different.

Breast Cancer The risk of developing breast cancer appears to be similar to the general population, and indeed may even be lower soon after transplant either as a result of some unknown consequence of the transplant process itself or more plainly a result of selection bias due to pretransplant screening. Both benign adenomas and breast calcifications can occur in dialysis and transplant recipients and confound mammographic screening, leading to false-positives and subsequently more invasive procedures.

17  Medical Management of Kidney Transplant Recipients

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as a result of limitations in the utility of bone mineral density tests in a patient population with CKD [30]. Within 3 years of transplant, the risk There is controversy in the general population of hip fracture is increased by 34% compared to over the benefits vs. risks of prostate cancer dialysis patients, especially in diabetics [31]. screening using prostate specific antigen testing Despite the potential limitations of bone density and digital rectal examination. Though the incimeasurements in this patient population, given dence does not appear to be greater in transplant these higher risks guidelines as published by the recipients compared to the general population, National Kidney Foundation still recommend as the number of older male renal transplant bone density testing at the time of transplant and recipients grows, the incidence of prostate canevery 1 to 2 years thereafter. cer is expected to increase. As such in the As alluded to earlier, both pretransplant and absence of more robust data, transplant profesposttransplant factors contribute to bone disease, sional societies have recommended screening and it almost always is due to effects of various practices that mirror those of nontransplant factors (see Table 17.8). In the first few months organizations. after transplant, a dramatic decrease in PTH ­levels in those with mild preexisting secondary hyperparathyroidism, combined with preexisting adynamic bone disease and high doses of glucoBone Disease corticoids lead to decreased mineralization and low bone turnover. Over the long term, though Epidemiology and Pathogenesis not as well characterized, most studies imply low turnover, decreased bone formation, and Factors contributing to bone disease in transplant delayed mineralization with persistent resorppatients are listed in Table 17.8. Increased risk for tion as the main mechanism of continued bone bone loss and fractures in the transplant popula- pathology. However, up to 30–50% of transplant tion contribute to morbidity and is a challenging patients demonstrate persistent high PTH levels problem in the medical management of these due to parathyroid hyperplasia, even after restopatients. Given most transplant recipients had pre- ration of renal function or continued secondary existing chronic kidney disease (CKD) metabolic hyperparathyroidism due to suboptimal graft bone disease usually is present at the time of function. Consequently, this may lead to high transplant. After transplantation, patients often turnover bone disease in some patients. remain with some degree of impaired glomerular Glucocorticoids decrease osteoblastic activity filtration rate and metabolic bone disease factors and osteoblast apoptosis and decreased intestinal may persist. Finally, factors posttransplant such as calcium absorption resulting in increased PTH. medications, aging, menopause, and the develop- Osteonecrosis, a serious complication of glucoment of diabetes can lead to a further decline in corticoid use, is usually multifocal involving bone health. Loss of bone mineral density (BMD) more than one joint in 50–70% of patients. The is most pronounced within the first 6 to 12 months most common presentation is collapse of the after transplant and occurs to a greater degree in femoral head. This complication is fortunately the lumbar spine compared to the femoral neck. less frequent with decreasing cumulative steroid Up to 60% of patients may develop osteoporosis exposure given the availability of other immunoduring this early period after kidney transplanta- suppressive agents [30]. Hypophosphatemia, which commonly occurs tion. A major determinant is glucocorticoid exposure that directly leads to osteopenia, the degree posttransplant is an important contributor to low bone turnover by inducing increased apoptosis dictated by length of exposure and dose. Data regarding long-term bone health post-­ and decreased activity of osteoblasts. Etiology of kidney transplant are less congruous, probably this may be due to impaired intestinal absorption

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or enhanced phosphaturia delayed normalization of hyperparathyroidism as a result of parathyroid hyperplasia and/or hyperphosphatonism (e.g., FGF-23) despite improvement in kidney function, and potentially also glucocorticoid use. Hypercalcemia can result from persistently elevated PTH secretion for hyperplastic glands in about 10–20% of transplant patients within the first 2 years of transplant. Parathyroid gland hypertrophy may not resolve even after establishment of normal renal function, and glandular involution may take years. Clinical effects of symptomatic hypercalcemia from persistent hyperparathyroidism may include renal failure from afferent arteriole vasoconstriction, soft ­tissue calcification, and bone demineralization. About 1–5% of patients may require parathyroidectomy for persistent symptomatic hyperparathyroidism posttransplant [30]. Cinacalcet, a calcimimetic that acts on the calcium-sensing receptor in the parathyroid gland, can reduce PTH in such cases of tertiary hyperparathyroidism posttransplant, thus avoiding a surgical procedure. It should be cautioned however that there are limited studies showing its efficacy in this population, especially compared to the definitive surgical treatment.

Treatment in Early Posttransplant Period Serum calcium, phosphorus, and bicarbonate should be monitored frequently early posttransplant. Additionally, we recommend routine surveillance of intact PTH and vitamin D levels within 3 months of transplant and at least every 12 months thereafter, or more frequently for those with impaired graft function. We also ­recommend the use of daily calcium supplements (1,000 mg for men, 1,500 mg for women) and replenishment of vitamin D stores as appropriate. Indeed randomized trials have shown that early initiation of calcium and vitamin D preparations after transplant can attenuate the degree of bone loss within the first year in those on ­steroid containing regimens. For those patients with reasonable allograft

function (i.e., >30 mL/min) after 3 months posttransplant on steroid-containing regimens and/or those with other pretransplant risk factors for osteoporosis (extrapolated from the general population), we recommend bone mineral density testing within the first year, with the caveat that interpretation of bone mineral density testing is complicated in patients with preexisting kidney disease. That being said, use of bisphosphonates in the early transplant period has been shown to offset loss of bone density within the first year of transplant, but at a higher risk of adynamic bone disease. The effect of the latter finding on longterm bone health remains unanswered and as such, indiscriminate use of these agents should be avoided.

Treatment in the Late Posttransplant Period Several agents have been studied to treatment of established low bone density later on posttransplant, but again no data exist on their effects on fracture risk and thus should be interpreted with caution. Calcitriol, intranasal calcitonin, and various bisphosphonates in combination with calcium supplements have all been shown to attenuate long-term decline in, or indeed improve, the bone density in patients. Bisphosphonates are generally well tolerated in this population, and higher incidence of renal dysfunction or mortality has not been reported. Whether or not the effect on bone density translates into a decrease in fracture risk is still unknown.

Anemia Epidemiology and Background Posttransplantation anemia (PTA) often complicates the management of kidney transplant recipients. PTA is defined as hemoglobin less than 12 g/ dL or 13 g/dL in women and men, respectively.

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Depending on the time posttransplant and exact definition of anemia employed, the prevalence of PTA ranges between 7% and 75% [32].

Risk Factors and Pathogenesis Factors contributing to PTA are listed in Table  17.9. Early PTA is usually attributed to surgical blood loss, the effects of delayed or sluggish graft function on erythropoiesis, and the marrow suppressive effects of immunosuppression and the inflammatory milieu of dialysis or CKD. A certain resistance to erythropoiesis stimulating agents (ESA) exists in this immediate posttransplant period as a result of cytokine activation and the immunologic response. There is a bimodal response to endogenous erythropoietin (EPO) production following kidney transplantation. First there is an early peak that precedes allograft function recovery as a fall out of renal ischemia during the harvest of the organ. Later, there is a more sustained yet smaller Table 17.9  Causes of posttransplant anemia Recipient/donor factors Recipient age Donor age Gender Transplant factors Early—within 6 months • Surgical blood loss • DGF • Acute rejection • Induction agents • Hemolysis • Inflammation from dialysis/CKD or cytokine/ immunologic response after transplant Infections Late – after 6 months • Graft dysfunction – acute or chronic • Iron deficiency • Hyperparathyroidism • Infections • Malignancy • Medications – RAAS agents, mycophenolate, azathioprine, tacrolimus, sirolimus, bactrim, ganciclovir Adapted from [33]

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increase in EPO as allograft function improves. This upregulation of endogenous EPO production may explain the relative resistance to ESAs seen in this early period, whereby pharmacologic administration does not augment further a hemoglobin response [33]. The second peak in EPO production is also adversely affected by sustained DGF and/or acute rejection, the latter occurring in part due to downregulation of genes for erythropoiesis [34]. PTA prevalence decreases at 12 months posttransplant when most of the above factors have resolved in the absence of graft dysfunction. Late causes of PTA after this time period may include new graft dysfunction, iron deficiency, and GI blood loss. Chronic allograft dysfunction is a major determinant of anemia after the first year of transplant and tends to occur at higher GFR that in the native CKD population. Drugs including mycophenolate mofetil, azathioprine, and thymoglobulin lead to PTA via direct bone marrow suppression. Tacrolimus may also rarely cause autoimmune hemolytic anemia. Sirolimus can cause severe anemia, presumably by decreasing EPO production and/or decreased iron utilization. RAAS blockers are known to cause suppression of erythropoietin production, the mechanism of which remains unclear. A potentially serious cause of PTA is hemolysis as part of the hemolytic-uremic syndrome, potentially caused by transplant immunosuppression. However, this hemolysis is typically accompanied by progressive thrombocytopenia and very often, graft dysfunction which aids in its distinction from other causes. Finally, viral infections (CMV, EBV, HHV 6, HSV, Hepatitis B and C) can all cause varying degrees of anemia. Particularly, there is an association between parvovirus B19 and resistant PTA, at its worst leading to pure red cell aplasia.

Diagnosis and Management There is no substitute for frequent hemoglobin checks to monitor for worsening anemia, especially early posttransplant. The initial evaluation

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should include checking reticulocyte index, iron and ferritin, folate, vitamin B12, and testing for occult fecal blood loss and hemolysis, including haptoglobin levels, direct and indirect Combs’ assays, and examination of red blood cell morphology. Therapy is then initiated based on these initial test results. The indication of blood transfusions is dictated on a case-by-case basis, taking into consideration the severity of anemia, along with the presence of symptoms and comorbid conditions (particularly coronary atherosclerosis) that make a patient’s tolerance of anemia less. The efficacy of ESAs in raising hemoglobin levels has been shown in the kidney transplant population. However, use of ESAs is low, being only 20–25% in those with severe anemia. Studies on the consequences of PTA and its effect on cardiovascular, all-cause mortality, allograft, and patient survival in nontransplant CKD patients are conflicting at best, with a suggestion of harm in those randomized to higher hemoglobin levels [35, 36]. Hence, indiscriminate use of these agents should be avoided and lower hemoglobin levels should be targeted (i.e., <12 g/dL) when prescribed.

Posttransplant Erythrocytosis (PTE) PTE, defined as a Hgb greater than 17–18 g/dL, varies in prevalence across studies due to variable definitions and duration of erythrocytosis, but is approximately 10–25% [4]. It occurs between 8 and 24 months after transplant and one fourth of cases resolve spontaneously within 2 years of onset [37]. Several risk factors that have been described include male gender, a wellfunctioning allograft, presence of native kidneys, and smoking. The pathogenesis of PTE may be multifactorial, including upregulation of EPO production from native kidneys, enhanced EPO production by the allograft (potentially mediated via angiotensin receptor activity), and increased EPO responsiveness in the bone marrow. About two thirds of patients with PTE are symptomatic with headaches, lethargy, and plethora. About 10–30% patients can have thromboembolic

events, and 1–2% die from such events [37]. Management includes avoiding a volumedepleted state, phlebotomy if HCT is greater than 55% or 50% if symptomatic or with peripheral or cerebrovascular disease, and institution of RAAS blockers (either ACEI or ARBs), which typically leads to a decrease in hemoglobin levels in the first month in a dose-dependent fashion, reaches a nadir at three months. Discontinuation of RAAS blockade could lead to recurrence within 3 months.

Pregnancy Introduction End-stage renal disease (ESRD) is known to affect gonadal function and disrupts fertility and conception. This is at least partially reversed after successful kidney transplantation and there have been several reports of successful pregnancies posttransplantation. The overall prevalence of successful conception and pregnancy is hard to determine because of underreporting, and most rates are obtained from voluntary reporting registries that ultimately lead to selection bias: approximately 1,500 outcomes in female and 1,000 outcomes in male recipients entered since 1991 in the United States National Transplantation Registry (NTPR) [38]. Given that the design of this study was not dependent on voluntary reporting, it has added greatly to the available literature. However, it is likely that the available published data still represent only a minority of pregnancies, and this problem emphasizes the need for better registry and transplant center reporting for outcome data as well as large-scale prospective trials.

Infertility and Sexual Dysfunction General factors leading to infertility in both sexes include hormonal imbalances, decreased libido, vasomotor disturbances, medications, and

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psychological factors [38]. In the female recipient, alteration in the hypothalamic-pituitary-ovarian axis with increased FSH, LH, and prolactin and menstrual disturbances (anovulatory cycles, amenorrhea) has been described in chronic ­kidney disease (CKD) patients. These findings are more pronounced with progression to ESRD and contribute overall to reduced fertility rates. Additionally, patients with CKD are known to have early menopause on average 4.5 years earlier than non-CKD women [39]. Interestingly, though not universal such hormonal imbalances can normalize within 6 months of successful kidney transplantation [40]. Male infertility in uremia is commonly due to impaired gonadal function and disturbances in the hypothalamic pituitary axis with decreased testosterone, high FSH, LH, and prolactin, decreased libido and erectile dysfunction. Some men with CKD have demonstrated histologic changes in the testes with destruction of seminiferous tubules and germinal aplasia [38]. Improvement in sperm motility but not sperm count or morphology has been shown after renal transplantation. Pregnancies fathered by transplant patients appear not to associate with fetal malformations. The independent effect of immunosuppressive medications on male infertility is less clear, but appears minimal.

Optimal Timing and Contraception The optimal timing of pregnancy in the transplant patient is of utmost importance. All female recipients of childbearing age should be counseled about the risks of pregnancy, risks of transmission in case of hereditary kidney disease, risks of rejection, preterm delivery, and long-term graft prognosis. Pregnancy in the peritransplant period is not advised because of the use of potentially teratogenic and fetotoxic medications as well as need for intense immunosuppression in the first few months posttransplant. Contraception should, therefore, start before transplant since with a wellfunctioning allograft, ovulatory cycles can return within 1–2 months of transplantation. Barrier

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methods (potential for contraception failure) and IUDs (need intact immune system for action and carry risk of infection) are not considered optimal contraceptive methods by The American Society of Transplantation Consensus Conference report. Progestin-only or low-dose estrogen-progestin pills are acceptable for use, although hypertension and thromboembolic complications, especially when used with cyclosporine, need to be kept in mind. Use of long-acting subcutaneous hormone preparations in the transplant population is not proven and these need to be used under close supervision. Previous recommendations to wait 2 years after transplant have been replaced by the American Society of Transplantation Consensus Opinion that as long as graft function is adequate and stable (defined as creatinine less than 1.5 mg/dl with less than 500 mg/24-hr protein excretion), no recent rejection, no fetotoxic infections are present, no teratogenic drugs are being used, immunosuppression is stable, the patient can proceed with pregnancy after the first year of transplantation [41].

Antenatal Period We recommend pregnancies in a kidney transplant population be comanaged by a transplant physician and a high-risk obstetrician. The goals are to maximize the chance of stable allograft function, optimize maternal health, manage complications such as hyperglycemia very aggressively, delay preterm delivery to maximize fetal growth as possible, and avoid preeclampsia. Recommendations for the monitoring of the pregnant transplant patient are listed in Table 17.10.

Risks of Pregnancy to the Mother Preexisting impairment in allograft function is a large determinant of maternal risk, as a low glomerular filtration rate is an independent risk

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Table 17.10  Antenatal monitoring of renal transplant recipients Test/visit When/minimal interval Rationale Prepregnancy evaluation Before transplantation Live virus vaccine; do not administer after Rubella transplantation RH compatibility of Before pregnancy If the patient is RH negative and the transplant is RH patient and transplant positive, then theoretically the patient may become sensitized to RH, which may pose a problem only if the baby is RH positive Before pregnancy Counsel regarding risks before pregnancy and the risks Hepatitis B and C, HSV, for transmission; hepatitis B vaccine can be given; CMV, HIV, toxoplasreduce HIV transmission; check cervical cultures is mosis, and rubella HSV positive Pregnancy evaluation BP Daily Patient can monitor and report High risk pregnancy with likelihood of preterm delivery Clinic visits Every 2–3 week up to 20 week; every 2 week until 28 week; every week thereafter Routine labs Pyuria and urine culture Each visit Risk for ascending asymptomatic bacteriuria and pyelonephritis CBC Every 2–6 week Decreased WBC count may predict neutropenia and thrombocytopenia in the newborn; if anemia is present, then an ESA may be useful if not iron deficient or other reversible causes of anemia are ruled out Every 2–4 week Rejection and preeclampsia are difficult to diagnose Serum BUN, Cr, calculated creatinine clearance and proteinuria Calcium, phosphorus Monitor at start and as Transplant patients may have tertiary hyperparathyroidneeded ism or have had subtotal parathyroidectomy CNI Every 2–4 week Levels may vary throughout gestation Liver function tests Every 6 week Gravid liver may be more sensitive to azathioprine hepatotoxicity Glucose tolerance test Each trimester Many patients are taking steroids and CNI Testing specific to pregnancy IgM to toxoplasmosis Each trimester if Risk for congenital infection seronegative IgM to CMV Each trimester if Risk for congenital infection seronegative More invasive Testing Kidney biopsy Unexplained decrease in Hard to appreciate graft dysfunction and to allograft function distinguish acute rejection from CNI toxicity, preeclampsia, pyelonephritis Adapted from McKay et. al. [38]

factor for preeclampsia, prematurity, low birth weight, and neonatal death. Additionally, pregnancy itself may worsen pre-gravid renal dysfunction. Studies in non-transplant CKD women show those with mild dysfunction (SCr <1.3 mg/ dL) do not have an increased risk of decline in renal function during gestation, but those with

moderate (1.3–1.9 mg/dL) or severe (>1.9 mg/ dL) renal dysfunction have an increased risk of accelerated irreversible decline in maternal kidney function to ESRD, hypertension, and proteinuria [42]. The AST consensus conference considers a Cr greater than 1.5 mg/dL and proteinuria greater than 500 mg/24 h as high risk for irreversible

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graft loss due to pregnancy. In addition, due to changes in blood volume, there is a significant variability in levels of immunosuppressive drugs and difficulty in maintaining therapeutic levels, and therefore, a risk for graft rejection. The AST recommends that immunosuppressive dosing should be maintained at prepregnancy doses, but followed with closer monitoring of drug levels. Detection of rejection based on serum creatinine can be challenging due to a natural decline in serum creatinine due to hyperfiltration during pregnancy, which may otherwise mask a rejection-associated rise in creatinine. If needed, a renal biopsy can be safely performed under ultrasound guidance. If rejection occurs, it can be safely treated with steroids. Hypertension can occur either as an exacerbation of preexisting hypertension or develop de  novo during pregnancy. The prevalence of hypertension in the pregnant transplant patients has been estimated at 73% [38]. Blood pressure should be maintained closer to normal, which differs from guidelines in nontransplant pregnant women with chronic hypertension. Acceptable agents include labetalol, hydralazine, nifedipine, and methyldopa. Atenolol should be avoided due to concern about fetal growth. ACE inhibitors and angiotensin receptor blockers are contraindicated due to their teratogenic effects. Preeclampsia is an important complication which if unrecognized can cause significant maternal and fetal morbidity. It is more common in the hypertensive transplant recipient than normotensive mothers (15–25% vs. 5%) and is characterized by development of hypertension and proteinuria after 20 weeks [38]. This may be difficult to diagnose in the transplant population because of preexisting hypertension, proteinuria, and even hyperuricemia and edema associated with this disorder. Complications in the mother include renal dysfunction, liver failure, HELLP syndrome, seizures, stroke, and death. Pregnant transplant recipients are at high risk of developing gestational diabetes and urinary tract infections and screening recommendations for both these are in Table 17.1. Infections such as CMV, HIV, Hepatitis B and C, HSV, toxoplasmosis, and rubella can be transmitted through a

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transplacental route and/or breastfeeding, and patients should be screened for these prenatally. CMV is known to cause mental retardation, as well as hearing and visual defects in the fetus, and maternal immunity does not completely protect from transmission; women should be counseled against conception in the event of a recent episode of CMV disease. Vaginal delivery is preferred unless there is an indication for cesarean section for other obstetric reasons. Care should be taken to protect the transplanted ureter if cesarean is undertaken. If patients have been chronically on prednisone, peripartum stress dose steroids should be administered and graft function should be closely monitored for at least 3 months after delivery.

Risks to Fetus Risks to the fetus are determined by medical and infectious complications in the mother and effect of immunosuppressive agents on organogenesis. Preterm delivery (<37 weeks) is very common (mean, 34 weeks), reported to be about 50% in the U.S and European registries [38]. Causes of preterm labor include maternal and fetal distress, premature rupture of membranes, pyelonephritis, and allograft rejection. Low birth weight (<2,500 g) is common in up to 50% of cases in the UK and US registries [38]. Intrauterine growth retardation (IUGR, i.e., <10th percentile of weight for gestational age) is seen in approximately 50% in transplant recipients and is thought to be due to preexisting hypertension, renal dysfunction, and tendency to develop preeclampsia [38]. Regular sonographic monitoring is needed to detect IUGR in transplant recipients. Since preterm delivery is so common, any sign of fetal distress should alert the physician and steroids should be administered (28–34 weeks) to promote lung maturity [38]. All immunosuppressive medications commonly used in transplantation pass through the maternal fetal circulation. It is hard to discern the degree of fetal exposure to these drugs due to a paucity of data on pharmacokinetics and

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pharmacodynamics, alterations in drug bioavailability, drug elimination, and the activity of the drug transporters within the placenta and fetus. Table 17.11 shows that absolute safety can never be guaranteed with any of the drugs. The degree of transfer to the fetal circulation depends on the pharmacokinetics of individual drugs. Prednisone is thought to be metabolized by the placenta and very small amounts are detectable in the fetus. Cyclosporine is transferred freely across the placenta and studies have shown an inhibition of fetal T cells to a similar degree as in the mother. However, there are no reported malformations in animal or human studies with calcineurin inhibitors and these appear to be safe in pregnancy. Cyclosporine has been reported to be associated with IUGR possibly due to sustained vasoconstriction. Azathioprine, a prodrug, is metabolized to 6-mercaptopurine, which crosses the placenta freely, but this does not get converted to its active form thioinosinic acid in the fetus due to the relative lack of fetal inosine pyrophosphorylase enzyme. At doses of 2 mg/kg or less, no anomalies have been reported in humans with azathioTable  17.11  Pregnancy risk category of various immunosuppressive agents Immunosuppressive medication FDA category CNI Cyclosporine (Neoral, C Sandimmune, Gengraf) Tacrolimus, FK 506 C (Prograf) Antiproliferative agents Mycophenolate mofetil D (CellCept, Myfortic) Azathioprine (Imuran) D Rapamycin, sirolimus C (Rapamune) Leflunomide (Arava) X Corticosteroids Prednisone (Deltasone) B Antirejection agents Methylprednisolone C Muromonab-CD3 C (Orthoclone OKT3) C Anti-thymocyte globulin (Thymoglobulin, ATGAM) Adapted from [38]

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prine. Placental transport of MMF and sirolimus is not well characterized. The incidence of major malformations at birth has not been shown to be much higher than in the general population in the US registry. The drug that should be mentioned in this context is mycophenolate mofetil (and presumably entericcoated mycophenolate), the former having been associated with severe malformations (most notably cleft lip and palate, microtia, and absence of external auditory canals) [38]. Data on sirolimus are limited. The incidence of subtle defects is unclear given limited prospective data on children of transplant recipients. The choice of immunosuppressive agents in a pregnant transplant patient is a difficult one given the lack of randomized controlled trials, which likely will never be performed due to ethical considerations. As such, data on safety are extrapolated from data in nonpregnant patients along with retrospective analyses of safety and adverse event rates in patients who happen to become pregnant. Given mycophenolate has now been associated with fetal malformations, patients who are planning to become pregnant should be converted to a non-mycophenolate regimen (preferably at least 6 weeks prior to conception), usually by substituting it with azathioprine as this agent has a longer track record of safety in pregnant transplant recipients despite its similar category D rating. Though this is a low-risk maneuver in theory, any alteration in the immunosuppression of a patient with stable allograft function carries with it some risk of rejection, and patients should be counseled on this matter. Despite its category C rating, scant data exist regarding m-TOR inhibitors and pregnancy, and as such we recommend conversion to a calcineurin inhibitor-based regimen when pregnancy is being planned. We usually increase steroid doses by a factor of 1.5 and cover the puerperium at that dose to stave off the increased risk of rejection in that time frame. Breastfeeding can contribute to fetal exposure of immunosuppressive medications. Data on breast milk concentrations of MMF and sirolimus are lacking. Prednisone and azathioprine are detected in breast milk in small amounts, and

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both cyclosporine and tacrolimus are detected in concentrations similar to those in maternal serum. The American Society of Pediatrics ­recommends breastfeeding for mothers on prednisone but not for those taking cyclosporine. There are no recommendations for those on ­tacrolimus or azathioprine. It is unclear if the risks of exposure to medications outweigh the benefits of breastfeeding. Until more information is available, breastfeeding need not be considered as an absolute contraindication.

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agents or digoxin, rhabdomyolysis, or hemolysis), or impaired renal excretion (i.e., low GFR, type 4 renal tubular acidosis physiology as a consequence of calcineurin inhibitor tubular toxicity). Acute treatment of hyperkalemia (i.e., calcium, glucose/insulin, bicarbonate, dialysis) follows that typical in nontransplant patients and is dictated both by the clinical scenario, including the presence or absence of EKG changes, the absolute level of potassium, and current renal and bowel function. Chronic management includes optimization of allograft function as best possible, use of potassium-wasting agents where appropriate (i.e., diuretics or resin binders), and minimization or complete withdrawal of CNIs in the worst of cases.

Hypophosphatemia This is multifactorial as noted above and may manifest as proximal muscle weakness, ileus or hemolysis, and rarely respiratory failure. This is best managed with IV supplemental phosphorus for levels less than 1.0 mmol/L or with oral supplements otherwise.

Hypomagnesemia This is usually common in CNI-treated patients and reflects direct tubular effects of those drugs which lead to renal magnesium wasting. It may manifest as arrhythmias or as seizures when severe. Hypocalcemia may accompany hypomagnesaemia, the former typically not correcting until the latter is treated.

Hyperkalemia This is almost always multifactorial in etiology posttransplant, but classically can be due to a problem of ingestion (i.e., dietary loads, inappropriate supplementation), shift from intracellular to extracellular compartment (i.e., uncontrolled diabetes, metabolic acidosis, use of beta-blocking

References 1. Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation 2006;82(5):603–611. 2. Available from: www.usrds.org/. 3. Meier-Kriesche HU, et  al. Kidney transplantation halts cardiovascular disease progression in patients with end-stage renal disease. Am J Transplant 2004;4(10):1662–1668. 4. Kasiske BL, et al. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol 2000;11(Suppl 15):S1–86. 5. Cosio FG, et al. Relationships between arterial hypertension and renal allograft survival in African-American patients. Am J Kidney Dis 1997;29(3):419–427. 6. Kasiske BL, et  al. Hypertension after kidney transplantation. Am J Kidney Dis 2004;43(6):1071–1081. 7. Andoh TF, Gardner MP, Bennett WM. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation 1997;64(9):1236–1240. 8. Benigni A, et al. Nature and mediators of renal lesions in kidney transplant patients given cyclosporine for more than one year. Kidney Int 1999;55(2):674–685. 9. Huang LQ, Whitworth JA, Chesterman CN. Effects of cyclosporin A and dexamethasone on haemostatic and vasoactive functions of vascular endothelial cells. Blood Coagul Fibrinolysis 1995;6(5):438–445. 10. Fervenza FC, et  al. Renal artery stenosis in kidney transplants. Am J Kidney Dis 1998;31(1):142–148. 11. Sankari BR, et al. Post-transplant renal artery stenosis: impact of therapy on long-term kidney function and blood pressure control. J Urol 1996;155(6):1860–1864.

332 12. Knoll GA, et al. The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in ­kidney transplantation—study design. Nephrol Dial Transplant 2008;23(1):354–358. 13. Crutchlow MF, Bloom RD. Transplant-associated hyperglycemia: a new look at an old problem. Clin J Am Soc Nephrol 2007;2(2):343–355. 14. Shirali AC, Bia MJ. Management of cardiovascular disease in renal transplant recipients. Clin J Am Soc Nephrol 2008;3(2):491–504. 15. Kasiske BL, et  al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3(2):178–185. 16. Nam JH, et al. Beta-cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus. Transplantation 2001;71(10):1417–1423. 17. Cosio FG, et  al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 2005;67(6):2415–2421. 18. Selvin E, et al. Glycemic control and coronary heart disease risk in persons with and without diabetes: the atherosclerosis risk in communities study. Arch Intern Med 2005;165(16):1910–1916. 19. Khaw KT, et  al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004;141(6):413–420. 20. Wilkinson A, et al. Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant 2005;19(3):291–298. 21. Nathan DM, et  al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. NEJM 2005;353(25):2643–2653. 22. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854–865. 23. Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. NEJM 2008;358(24):2545–2559. 24. Midtvedt K, et  al. Insulin resistance after renal transplantation: the effect of steroid dose reduction and withdrawal. J Am Soc Nephrol 2004;15(12):3233–3239. 25. Srinivas TR, Meier-Kriesche HU. Minimizing immunosuppression, an alternative approach to reducing side effects: objectives and interim result. Clin J Am Soc Nephrol 2008;3(Suppl 2):S101–116. 26. Kasiske B, et  al. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant 2004;4(Suppl 7):13–53. 27. Chueh SC, Kahan BD. Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen: incidence, risk factors, progression, and prognosis. Transplantation 2003;76(2):375–382.

V. Vootukuru and B. Stephany 28. Holdaas, H., et  al., Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361(9374):2024–2031. 29. Penn I. Effect of immunosuppression on preexisting cancers. Transplant Proc 1993;25(1 Pt 2):1380–1382. 30. Weisinger JR, et al. Bone disease after renal transplantation. Clin J Am Soc Nephrol 2006;1(6):1300–1313. 31. Ball AM, et al. Risk of hip fracture among dialysis and renal transplant recipients. JAMA 2002;288(23):3014–3018. 32. Yorgin PD, et al. Late post-transplant anemia in adult renal transplant recipients. An under-recognized problem? Am J Transplant 2002;2(5):429–435. 33. Winkelmayer WC, Chandraker A. Pottransplantation anemia: management and rationale. Clin J Am Soc Nephrol 2008;3(Suppl 2):S49–55. 34. Besarab A, et al. Dynamics of erythropoiesis following renal transplantation. Kidney Int 1987;32(4):526–536. 35. Drueke TB, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. NEJM 2006;355(20):2071–2084. 36. Singh AK, et al. Correction of anemia with epoetin alfa in chronic kidney disease. NEJM 2006;355(20):2085–2098. 37. Vlahakos DV, et  al. Posttransplant erythrocytosis. Kidney Int 2003;63(4):1187–1194. 38. McKay DB, Josephson MA. Pregnancy after kidney transplantation. Clin J Am Soc Nephrol 2008;3(Suppl 2):S117–125. 39. Holley JL, et  al. Gynecologic and reproductive issues in women on dialysis. Am J Kidney Dis 1997;29(5):685–690. 40. Saha MT, et al. Time course of serum prolactin and sex hormones following successful renal transplantation. Nephron 2002;92(3):735–737. 41. McKay DB, et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005;5(7):1592–1599. 42. Fischer MJ. Chronic kidney disease and pregnancy: maternal and fetal outcomes. Adv Chronic Kidney Dis 2007;14(2):132–145. 43. Cosio FG. In: Weir M (ed.). Medical Management of Kidney Transplantation, Philadelphia: Lippincott Williams & Wilkins, 2004. 44. Bloom RD, Crutchlow MF. New-onset diabetes mellitus in the kidney recipient: diagnosis and management strategies. Clin J Am Soc Nephrol 2008;3(Suppl 2):S38–48. 45. Weir M. Medical Management of Kidney Transplantation. Philadelphia: Lippincott Williams & Wilkins, 2004. 46. Nathan DM, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32(1):193–203. 47. Gill JS. Cardiovascular disease in transplant recipients: current and future treatment strategies. Clin J Am Soc Nephrol 2008;3(Suppl 2):S29–37.

Chapter 18

Infectious Complications: Prevention and Management Robin K. Avery, Michelle Lard, and Titte R. Srinivas

Keywords  Posttransplant infection • Transplant complications • Cytomegalovirus • Opportunistic infection

Introduction Infections have traditionally been a major source of complications in the posttransplant period [1, 2]. A preventive approach can reduce the morbidity of CMV, BKV, and other infections. Bacterial and candidal infections, most commonly from an intraabdominal source, remain a problem in pancreas recipients despite advances in surgical techniques and prophylaxis. This chapter reviews practical approaches to pretransplant screening of donor and recipient, and management of posttransplant bacterial, viral, fungal, and parasitic infections with an emphasis on ­prevention and early detection. Recent devel­opments include increasing antimicrobial resistance, which poses a challenge for antibiotic management. In addition, suggestions for immunizations and avoiding environmental exposures are presented. Guidelines for the prevention and management of infections after solid organ transplantation have been published by the American Society of Transplantation (AST ID Guidelines), and the

R.K. Avery (*) Department of Infections Disease, Medicine Institute, The Cleveland Clinic, USA e-mail: [email protected]

reader is encouraged to consult these guidelines for more detail about individual pathogens.

Pretransplant Screening of Donor and Recipient, and Donor-Derived Infections The pretransplant evaluation is an excellent time to review any infectious complications the transplant candidate may have had in the past [3]. Information on previous episodes of urinary tract  infection, pneumonia, sinusitis, cellulitis, wound infections after previous surgery, bloodstream infections (BSI) or sepsis, catheter-related infections (including dialysis catheters or PD catheters), and other infections should be recorded. It is important to make sure these infections have been fully treated and have resolved clinically, microbiologically, and radiographically before proceeding to transplant. Recurrent or persistent infections in a particular organ system deserve special attention in this regard. A current area of debate is the safety of transplanting patients who have had infections with multi-drug resistant bacteria and who may still be colonized with these. Further data on outcomes in such patients would be very helpful to clinicians. Evaluation of prospective living donors should also include an assessment of any recent or active infections, and testing to insure that these have completely resolved. A serologic panel is performed as part of pretransplant screening for both donor and

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_18, © Springer Science+Business Media, LLC 2011

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recipient. This generally includes serologies for CMV, Epstein-Barr virus (EBV), hepatitis B and C, HIV, HTLV–I/II, RPR (serologic test for syphilis), and sometimes other infectious agents including Strongyloides, Toxoplasma, endemic mycoses, and others. Results of this serologic panel may disqualify some donors (e.g., HIV or HBsAg positivity), or may restrict the donors to certain subgroups (e.g., HCV). Prophylactic strategies may be adjusted depending on the results (CMV, EBV, hepatitis B core antibody). Similarly, the results of the serologic panel for the recipient may also alter posttransplant management. A thorough exposure history including travel, geographic areas of residence, pets, employment, and hobbies should be obtained from the transplant candidate. Individuals with extensive histories of gardening, farming, landscaping, construction work, marijuana smoking, and other such exposures to plants and the outdoors may be more likely to be colonized with fungal organisms. A PPD skin test to detect latent TB infection (LTBI), or more recently an INFg release assay (IGRA) for LTBI, should be performed [3, 4]. Many centers initiate isoniazid prophylaxis for LTBI prior to transplantation but may complete the 9- to 12-course posttransplant. For patients from tropical countries or the southeastern US, a serologic test for Strongyloides, and treatment with ivermectin pretransplant if positive, can prevent devastating posttransplant disseminated strongyloidiasis. In parts of Central and South America, donor and recipient screening may include Trypanosoma cruzi serology (the agent of Chagas’ disease). The pretransplant evaluation is also an opportunity to initiate and complete all needed vaccinations, which are more effective before than after transplant. In fact, immunization early on in chronic kidney disease is more effective than waiting until end-stage renal disease has developed. Immunization against hepatitis B is offered by dialysis centers, but dialysis patients often require an enhanced-potency hepatitis B vaccine and/or booster doses in order to achieve seroconversion. Pneumococcal vaccine should be administered if it has not been given within 5  years.

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If a tetanus vaccine has not been administered within 10  years, a Tdap (tetanus-diphtheria-­ acellular pertussis) vaccine should be given. Seasonal influenza vaccine should be administered yearly. The H1N1 influenza vaccine is now incorporated into the seasonal influenza vaccine as of the 2010-11 flu season, so it is not necessary to administer 2 different flu immunizations as was done in the 2009-10 flu season.”. Despite thorough evaluation, donor-derived infections may still occur. In recent years, the highprofile transmissions of West Nile virus, rabies, and lymphocytic choriomeningitis virus [5]. have sparked a debate regarding which additional measures should be added to donor screening. The availability of rapid molecular testing has also prompted some organ procurement organizations to perform NAT (nucleic acid amplification) testing for HIV, HBV, and HCV on donors with highrisk social histories, in order to try to detect those who are in the “window period” after viral infection but before antibody seroconversion [158].

Posttransplant Infections: Overview The paradigm of three posttransplant periods of infection risk, articulated by Robert Rubin over 2 decades ago [1, 6], still has validity with modifications. In this paradigm, the first month posttransplantischaracterizedbyprimarilypostoperative infections, including surgical site infections and deep abdominal infections; catheter-related bloodstream infections; pneumonias, and urinary tract infections. The second time period (months 2–6) is characterized by the opportunistic infections which are classically associated with transplantation, including CMV, EBV-PTLD, fungal infections, Pneumocystis jiroveci, etc. Then in the third and final time period, patients are divided into three groups: (1) those that have done well and have had immunosuppression tapered; (2) those that have had intensified immunosuppression and remain susceptible to all of the opportunistic infections seen in the second time period; and (3) those in whom long-term viruses cause late adverse outcomes, including BK polyomavirus,

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hepatitis B and C, “late CMV,” and human papillomavirus. This conceptual framework has been expanded and modified by large registry and other studies of timing and risk factors for posttransplant infections. Dharnidharka and colleagues examined risk factors for hospitalization for bacterial infection and for viral infection in renal transplant recipients by analyzing USRDS data [7]. In this study of 28,924 recipients, risk factors for viral infection included recipient age less than 18 years and donor CMV positivity. For bacterial infections, delayed graft function, primary renal diagnosis of chronic pyelonephritis, pretransplant diabetes, and female gender were identified as risk factors [7]. Among pediatric recipients, hospitalizations for infection now exceed those for acute rejection [8], and younger age and antibody induction increase risks for infection overall [9]. Trends over time (1995– 2003) were examined in a study by Snyder et al., in which CMV infection was found to have declined significantly, hepatitis C increased, and other infections decreased slightly during that time period [10]. The decline in symptomatic CMV infection is likely related to the use of either prophylactic or preemptive therapy as effective CMV prevention strategies. Similarly a study by Linares et  al. of 1,218 renal showed decreased mortality over time from viral infections; increased mortality related to fungal infections, and unchanged mortality related to bacterial infections [11]. The “net state of immunosuppression” is a composite factor comprised of exogenously administered immunosuppressive agents, the effects of the underlying renal disease, metabolic and nutritional factors, age, neutropenia, breaks in mucosal defenses, humoral immunodeficiencies, and other conditions affecting immune function [1, 2, 6]. Knowing the environmental exposures of the patient, the net state of immunosuppression, the time posttransplant and the prophylactic and antirejection agents administered, the clinician can deduce risk for particular types of infections. Quantitative correlates of this net state of immunosuppression are being developed in the form of assays such as the ATP

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immune function assay (a measure of global ­cellular immune function, in which low T cell responses correlate with higher infection risk) [12] and quantitative immunoglobulins [13, 14], as hypogammaglobulinemia increases risk for posttransplant infection. Recent research has focused on genetic predispositions to infection, in the form of mannose binding lectin levels [14, 15] and cytokine polymorphisms [16]. In the future, it may be possible to have a more individualized approach both to immunosuppression and infection prophylaxis. Certain immunosuppressive agents have been associated with unique profiles of infection risk. Antilymphocyte therapy for steroid-resistant rejection is associated with increased risk of viral infections, particularly CMV, EBV/PTLD, and BK virus [17]. By contrast, sirolimus and related agents are associated with an increased risk of bacterial infections, but decreased risk of symptomatic CMV disease [18, 19]. Late introduction of MMF may be associated with an increase in infection risk [20].

Posttransplant Infections: Surgical Site and Intraabdominal Infections Since the early days of organ transplantation, surgical site infections have been a concern. This is particularly true of pancreas transplantation, in which deep intraabdominal infections are more common than with other organ transplants [21], and can be associated with decreased graft [22] and patient survival [21] (although not in all studies) [23]. The Spanish RESITRA research network studied 1,400 kidney recipients and found that 55 patients (4%) developed 63 episodes of incisional surgical site infection, at a median time of 20  days posttransplant (range, 2–76  days). Organisms included Escherichia coli (31.7%), Pseudomonas aeruginosa (13.3%), Enterococcus faecalis, Enterobacter spp., and coagulase-negative staphylococci [24]. In this study, patients with diabetes and those receiving sirolimus-based immunosuppression were at increased risk of

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incisional infections [24]. Menezes et  al. studied 1939 ­kidney recipients in Brazil and found that reoperation, chronic glomerulonephritis, acute rejection, delayed graft function, diabetes, and high body mass index were ass­ ociated with increased risk for surgical site infections [25]. The overall infection rate in pancreas transplant recipients remains high (46% in one study) even with modern immunosuppression and antimicrobial prophylaxis [26]. Deep intraabdominal infection occurs in 12–27.5% of all pancreas transplant recipients [27–31], and may be a cause of graft loss, relaparotomy, and retransplantation [27, 28, 30–32]. These infections are often polymicrobial and may involve bacterial species, yeast, or both. Some authors have concluded that a deep wound infection should prompt allograft removal; [28] however Steurer et  al. found that 5/11 patients with deep intraabdominal infection required graft pancreatectomy, whereas the other six were managed with debridement and abscess drainage without graft removal [31]. In a study by Everett et  al., 69/197 patients (33%) had wound infections, of which 21 (10%) were superficial and the others deep or combined superficial and deep [28]. Coagulase-negative staphylococci and Candida spp. were the most common isolates [28]. Risk factors that have been identified for intraabdominal infection after pancreas transplantation include elevated donor body weight [33], recipient body mass index [33], peak recipient serum amylase in the first week [33], positive donor duodenal swabs for Candida spp [21]. prolonged operative time [28], older donors [28], acute tubular necrosis [34], posttransplant fistula [34], and graft rejection [34]. Obesity appears to  predispose to infections as well as other ­complications following pancreas transplantation (including intraabdominal infection, enteric leaks, and necrotizing fasciitis) [35]. In one study by Benedetti et al., 12/13 pancreas retransplantations performed due to previous infection were again complicated by infection, in 10/13 cases with the same organism identified 1–5 years earlier [32]. This suggests that persistence of infecting organisms in the vicinity of the explanted graft site can be a

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clinically significant problem. The authors ­concluded that prolonged posttransplant prophylaxis with an agent effective against the previous infecting organisms is appropriate [32]. There is some controversy as to whether mode of pretransplant dialysis affects risk for posttransplant infections. Kim et  al. reported that peritoneal dialysis, compared with hemodialysis, does not increase risk for intraabdominal infections after transplant [23]. Jimenez et  al. found similar rates of intraabdominal infection but significantly higher risk of graft pancreatectomy in patients with previous peritoneal dialysis as compared with hemodialysis [36]. Papolois et  al. found no difference in infection rates between patients who had had peritoneal dialysis versus hemodialysis pretransplant, but found that any type of dialysis pretransplant was associated with an increased infection rate posttransplant [27]. Type of pancreas transplantation (enteric vs bladder-drained) influences risk for infection. In one study by Pirsch et  al., enteric drainage was associated with significantly less risk for opportunistic infections (12% vs 31%, p = 0.002), CMV and fungal infection rates, and urinary tract infections (20% vs 63% by 1 year, p = 0.0001) [37]. However in the study by Everett et  al., enteric drainage was associated with a higher wound infection rate [28]. An alarming development in the last few years has been the increase in antimicrobial-resistant bacterial and fungal species [38, 39]. These include not only MRSA and VRE, but quinoloneresistant and multidrug-resistant (MDR) Gramnegative organisms including extended-spectrum beta-lactamase-producing (ESBL) organisms, carbapenem-resistant Acinetobacter baumannii (CRAb), and Klebsiella pneumoniae (KPC). Administration of broad-spectrum antibiotics, a longer ICU stay, and a complex course appear to be risk factors for acquisition of these organisms, which are frequently resistant to all agents except antibiotics such as colistin and tigecycline. Linares et al. found that for multiresistant organisms in general, risk factors included age greater than 50  years, HCV infection, SPK transplant (vs kidney-alone), post-transplant hemodialysis, reoperation, and requirement for nephrostomy [38].

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For infection with MDR Gram-negative organisms, particularly ESBL-producing organisms in kidney and pancreas recipients, this group identified SPK transplant, previous use of antibiotics, posttransplant dialysis, and posttransplant urinary obstruction as risk factors [39].

Postoperative Infections: Bloodstream Infections Bloodstream infections (BSI) after kidney and pancreas transplantation fall into several categories. Those BSI that are early posttransplant are often associated with intraabdominal infection, and late posttransplant BSI are associated with urinary tract infection and transplant pyelonephritis. The nature of the organism should give a clue as to the source, and if the source is not obvious (e.g., if the organism is a Gram-negative that is not growing in the urine), further imaging such as renal transplant ultrasound and abdominal CT scanning may be necessary in order to exclude an abscess, perinephric collection, peripancreatic collection, or other potential source that may require further management. Catheter-related infections are a risk, particularly in patients with long-term indwelling IV catheters or short-term central venous catheters. Catheter-related infections are most frequently Gram-positive (coagulase-negative staphylococci or Staphylococcus aureus) although Gramnegative bacilli, Candida spp., Bacillus spp., and diphtheroids can cause these infections as well. The reader is referred to the Infectious Diseases Society of America (IDSA) Guidelines for catheterrelated infection for further details [159]. Removal of the catheter is important if tunnel infection, septic thrombophlebitis, or persistent bacteremia is present; or if the organism is Candida spp., S.  aureus, a multidrug-resistant Gram-negative bacillus or Enterococcus. If the organism is coagulase-negative Staphylococcus without tunnel infection or septic thrombophlebitis, and blood cultures clear rapidly, an attempt can be made to clear the infection with the catheter in place, using a combination of IV antibi-

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otic therapy and vancomycin lock therapy. If such a strategy is employed, “proof-of-cure” blood ­cultures after completion of antibiotics are important. If cultures are persistently positive, the catheter should be removed. A study of Gram-negative bloodstream infection by Al-Hasan et al. identified 223/3367 solid organ transplant recipients with these infections [40]. The highest overall incidence was in the first month posttransplant, as would be expected given anatomic issues, early postoperative complications, and ICU stays. Interestingly, however, kidney recipients were more likely than liver recipients to develop Gram-negative BSI after 12 months following transplantation, which may reflect the ongoing importance of urinary tract infections [40]. The 28-day all-cause mortality was 4.9% overall and was lower, 1.6%, in kidney recipients [40]. Another study of bloodstream infection in enteric-drained pancreas transplant recipients identified 46 episodes in 35 recipients (16% of 217 total recipients), despite prophylaxis with piperacillin-tazobactam, ciprofloxacin, and fluconazole [22]. Median onset was day 12 posttransplant, and the source was thought to be intraabdominal infection in 21, central venous catheter in 10, wound infection in 5, urinary tract infection in 2, and donor-transmitted in 2. Grampositive cocci were identified in 77% of these cultures (include coagulase-negative staphylococci in 43%, S. aureus in 17%, and Enterococcus spp. in 14%) while Gram-negative rods were found in 18%. Graft survival, but not patient survival, was significantly decreased in the group with bloodstream infections [22].

Postoperative Infections: Urinary Tract Infections Urinary tract infections are particularly important in kidney and kidney–pancreas transplant recipients because of their complications, which can include transplant pyelonephritis, bacteremia or candidemia, full-blown sepsis, and allograft dysfunction. Age, gender, kidney function,

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comorbidity, immunosuppression, urologic instrumentation, and time posttransplant are some of the factors involved in determining risk for UTIs [41]. UTIs may be lower or upper tract, with the latter including the allograft and sometimes the native kidneys [42]. Pretransplant UTIs may be a risk factor for post-transplant UTIs [43], and tagged WBC scanning may be helpful in detecting occult cyst infection in polycystic kidneys that have not been removed [44]. Longterm posttransplant antimicrobial prophylaxis is increasingly controversial as resistance has become a major issue [42]. Intriguing recent evidence suggests that specific bacterial virulence factors may be associated with an increased risk of allograft dysfunction in UTIs [45]. Rice et  al. found that 40% of renal recipients with E. coli UTIs had pyelonephritis, and 82% of these had acute allograft injury defined as a greater than 20% increase in SCr. The patterns of E. coli adherence factors in strains cultured from these patients were analyzed and found to be different from previous reports; P fimbriae expression was associated with allograft injury in 62%, whereas strains not expressing P fimbriae were associated with allograft injury in only 29% [45]. Thus, strainspecific factors may affect allograft outcomes in UTIs. Further information of this nature might lead to novel preventative strategies based on neutralizing or antagonizing such virulence factors. UTIs are an important complication in SPK as well as kidney-alone transplants. In one series of 200 consecutive SPK transplants, UTIs (n = 344) were the most common infection noted, of 678 total infections [46]. In bladder-drained pancreas transplantation, UTIs are particularly common. One study by Pirsch et  al. found that 63% of bladder-drained as compared with 20% of entericdrained pancreas recipients had developed a UTI by 1 year posttransplant (p = 0.0001) [37]. In pediatric kidney recipients, USRDS data shows that the risk for graft loss after early UTI, but not late UTI, is elevated. UTI is not an independent predictor of posttransplantation death [47]. Boys aged 2–5 (vs age 13 £ 18) are at higher risk for UTIs, whereas girls in the age category of 0–1 are at higher risk [47].

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The evaluation of the transplant recipient with recurrent UTI involves first a determination of whether the same or multiple organisms are involved in different episodes. Isolation of the same organism on different occasions suggests a persistent or partially treated focus, such as a foreign body nidus (e.g., a stent or stone) or a deep tissue focus within the allograft or native kidney. When the latter is the case, sometimes a protracted course of an appropriate oral or intravenous antimicrobial agent may eradicate this focus. When a foreign body is present, often removal is necessary in order to definitively eradicate infection. Isolation of different organisms on different occasions suggests predisposing factors such as anatomic or functional abnormalities (incomplete bladder emptying, partial or complete obstruction), in addition to the effects of immunosuppression. Strategies to prevent recurrent UTIs in the era of antimicrobial resistance include the identification and management of any anatomic issues such as hydronephrosis; removal of foreign bodies to the extent possible; attention to culture and susceptibility information rather than prescribing empiric quinolone therapy; and sometimes the use of protracted culture-driven courses of antibiotic therapy. Even with these measures, some patients will still develop recurrent transplant pyelonephritis and urosepsis with little or no warning in terms of lower-tract symptoms such as dysuria. In such patients, some clinicians perform surveillance urine cultures at set time intervals, on analogy to preemptive therapy for viral infection, though more data regarding the success of such a strategy would be welcome.

Viral Infections: CMV, EBV, and Other Herpesviruses Cytomegalovirus (CMV) remains a significant pathogen in kidney and pancreas transplantation, although prophylactic and preemptive therapy have led to improved CMV control over time [48–51]. The impact of CMV is illustrated in a study of 1,424 kidney transplant and SPK

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recipients, in whom symptomatic CMV infection or CMV disease increased risk for development of rejection (p = 0.003) and non-CMV infection (p = 0.001) [52]. Thus, the goal of CMV prevention strategies is not only to prevent direct infectious syndromes due to CMV, but also to prevent the “indirect” effects on the allograft and mitigate the risk of other opportunistic infections that can occur in the aftermath of CMV infection [1]. CMV infections in renal transplant recipients may present as asymptomatic viremia detected on screening; or with a systemic syndrome including fever, fatigue, leukopenia, and thrombocytopenia; or with tissue-invasive disease including esophagitis, gastritis, colitis, hepatitis, pneumonitis, or meningoencephalitis. PCRs for CMV may be negative with gastrointestinal CMV disease and suspicion of CMV disease demands histologic confirmation. CMV infection in the kidney is rare in the current era of CMV prophylaxis. Pancreas transplant recipients may manifest allograft pancreatitis or present with perforation of the duodenal segment of the pancreas allograft. Most centers utilize either prophylaxis or preemptive therapy for CMV prevention, or a combination of these. Prophylaxis refers to the administration of antiviral therapy to an entire group at risk, whereas preemptive therapy limits antiviral treatment to those who develop evidence of CMV viremia on a sensitive early detection test. Prophylaxis, usually with ganciclovir derivatives such as valganciclovir, has been associated with improvement in direct infectious syndromes and also indirect effects of CMV such as predisposition to other infections and to allograft dysfunction [48]. Symptomatic CMV disease and tissue-invasive disease associated with high viral loads may still occur as “late CMV” after prophylaxis [53], though use of preemptive therapy either as a primary prevention strategy or as an adjunct to prophylaxis may allow for earlier detection of potential “late CMV.” [53, 54] A randomized trial by Khoury et  al. of prophylactic vs. preemptive valganciclovir therapy in renal transplant recipients showed that both strategies were effective in

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CMV ­prevention, but there was more CMV DNAemia (as anticipated) overall in the preemptive group, and “late CMV” (>100  days posttransplant) was seen only in the prophylaxis group [55]. The donor seropositive, recipient seronegative (D+/R–) group remains the most challenging, in that these patients receive a viral load from the donor without antecedent virus-specific cellular immunity to control initial viral replication. These CMV D+/R– patients are most at risk for high viral loads, tissue-invasive CMV disease, recurrences, and development of ganciclovir resistance (often after multiple courses of therapy). Although many centers use 3-month courses of prophylaxis, some extend this to 6 months, particularly in the highest-risk group. Lo et al. studied 75 SPK recipients and found a 44% incidence of CMV infection in the D+/R– group (as compared with 17% in other groups) even using 6 months of ganciclovir prophylaxis, and this group had worse kidney graft survival and event-free survival compared with the D–/R– group at low risk for CMV [56]. The PV16000 study, a randomized trial comparing oral ganciclovir versus valganciclovir prophylaxis for 100  days, involved 364 D+/R– kidney, liver, heart, and pancreas transplant recipients [57]. Although rates of viremia were similar at the end of the first year (48.5% vs 48.8%), there was more complete suppression of viral replication on valganciclovir (2.9% vs 10.4% viremia on prophylaxis with oral ganciclovir vs valganciclovir), and no development of ganciclovir resistance in the valganciclovir group [57]. However, other studies have described resistance occurring in valganciclovir-treated patients [58–60]. The optimal CMV prevention strategy has yet to be defined, but may turn out to involve both prophylactic and preemptive therapy as well as measures of virus-specific cellular immunity over time. In the last several years, there has also been a shift in treatment of active CMV viremia from IV ganciclovir to oral valganciclovir. The VICTOR study, a multinational, multicenter ­randomized trial of IV ganciclovir vs. oral valganciclovir therapy in 321 solid organ transplant

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recipients with CMV viremia (including some with tissue-invasive CMV), legitimized the use of valganciclovir for treatment of active CMV [61]. The treatment period was 21 days, followed by a 28-day period of valganciclovir maintenance. The success rate for viremia elimination was similar at 21 days (48.4% for IV ganciclovir vs 45.1% for valganciclovir) [61]. Many clinicians still favor IV therapy for the most severely ill patients and those with extremely high viral loads or gastrointestinal absorption issues. In addition, this study established that patients frequently still have detectable viral loads at day 21, contrary to general belief [61]. A followup to this study showed no differences in late recurrences between the groups, while a detectable viral load at day 21 was a risk factor for recurrence [62]. Ganciclovir resistance developed in eight patients, with no difference between the groups [62]. These results underscore the importance of eradicating viremia before discontinuation of treatment doses of antiviral medication, and should prompt ongoing virologic monitoring, particularly in those patients who fail to clear CMV viremia rapidly.

Practical Management of CMV Infection and Viremia The usual regimen for prophylaxis against CMV is valganciclovir 450–900 mg once daily adjusted appropriately for renal function. Oral ganciclovir has inferior bioavailability and is used at a dose of 1,000 mg three times daily. Close monitoring of the neutrophil count is advised. Salient drug interactions include a risk of seizure and encephalopathy, especially in the setting of renal dysfunction and concomitant therapy with neurotoxic drugs such as imipenem. Additive bone marrow toxicity may present when concomitant therapy with azathioprine, leflunomide, mycophenolate mofetil, or sirolimus. It is our practice to use valganciclovir prophylaxis for 3 months after transplantation in all but the donor CMV negative-recipient CMV negative group. Regardless of what CMV prevention method is chosen, some patients will develop

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CMV viremia. If the center is using prophylaxis rather than preemptive therapy as their major ­preventive modality, it may still be useful to add preemptive monitoring in order to capture “late CMV” episodes early, particularly in high-risk D+/R– patients. One such strategy involves monitoring of quantitative CMV DNA viral load every 1–2  weeks for the first year in all patients or at least the D+/R– subgroup. When the viral load is higher than some cutoff point (e.g., >1,000 copies/mL), therapy can be instituted generally with valganciclovir 900  mg orally twice daily (or adjusted for renal function), although many clinicians still prefer to use IV ganciclovir (5 mg/kg IV twice daily, or adjusted for renal function) for patients with extremely high viral loads (e.g., >100,000 copies/mL), highly symptomatic disease, or inability to tolerate oral medications. The length of therapy should be at least until the CMV DNA is undetectable (monitored generally once a week during therapy) and some experts feel two consecutive CMV DNA determinations should be negative before stopping therapy. At the end of therapy of a CMV episode, the decision point is to resume monitoring (to catch any recurrence early) or to use suppressive valganciclovir therapy for 1–3 months (as in the VICTOR study) to prevent recurrences. This decision will be based on a number of factors, including the net state of immunosuppression of the patient, the degree of toxicity from prior ganciclovir or valganciclovir courses of therapy (particularly neutropenia), and (in the real world) whether the patient’s insurance fully covers valganciclovir which is an expensive medication. In any case, the time that is most likely for recurrences to occur is within the 1–2 months after discontinuation of antiviral therapy, and secondary preemptive monitoring of CMV DNA during this time period allows for early detection and treatment. Tissue invasive CMV disease demands a full 3  weeks of antiviral therapy by oral or intravenous routes depending on the clinical circumstances. Therapy should be monitored using serial CMV PCR. Close monitoring of blood counts is mandatory. The dose of antiproliferatives is usually halved. Prophylaxis with valganciclovir for a full 3  months after an episode of

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CMV infection is recommended. All patients receiving therapy with depleting anti-T-cell antibody for rejection treatment should receive CMV prophylaxis just as if they are being transplanted de novo.

Epstein-Barr Virus EBV is a known cause of posttransplant lymphoproliferative disorder (PTLD). As with CMV, the EBV D+/R– group is at highest risk. Since most adults are seropositive for EBV, more high-risk recipients are found in the pediatric transplant group. EBV DNA monitoring has been successfully utilized to predict risk for PTLD in high-risk populations [63], and may lead to interventions such as reduction of immunosuppression or institution of antiviral therapy with ganciclovir derivatives [64]. The use of antilymphocyte therapy for rejection is associated with increased risk for both symptomatic CMV and EBV/PTLD in kidney and kidney– pancreas recipients [65–67]. Institution of antiviral prophylaxis during and after such therapy can decrease the risk of symptomatic CMV [68]. The role of antiviral therapy in the prevention of PTLD has been more difficult to demonstrate, but several lines of indirect evidence suggest an effect. Keay et al. found a high incidence of PTLD in a group of pancreas recipients who were not receiving antiviral prophylaxis as they were CMV D–/R– [67]. Funch et al. performed a multicenter case control study to assess the impact of antiviral prophylaxis on PTLD risk, and found an up to 83% reduction in PTLD with antiviral therapy, particularly ganciclovir [69]. With every 30  days of ganciclovir therapy, the risk of PTLD was decreased by 38% during the first year [69]. The cornerstone of PTLD prevention, however, remains careful modulation of immunosuppression in patients at risk, with immunosuppression reduction, to the extent possible, when significant EBV DNAemia is detected. Other members of the herpesvirus family – herpes simplex virus (HSV), varicella-zoster

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virus (VZV), human herpesvirus 6, 7, and 8 (HHV-6, 7, 8) can cause clinically significant disease particularly by reactivation in the recipient. HSV mucosal reactivation is common in the early posttransplant period and can cause painful oral and perineal ulcerations; patients who are not already receiving a ganciclovir derivative for CMV prophylaxis will frequently receive acyclovir prophylaxis for the first 1–3  months for HSV prevention. VZV can cause dermatomal zoster by reactivation, or disseminated zoster in the severely immunocompromised patient. The latter can include zoster hepatitis, pneumonitis, meningoencephalitis, and/or “rashless” zoster (a difficult diagnosis to make; it should be suspected in the patient with abdominal pain and cryptic liver function test elevation). HHV-6 and 7, the roseoloviruses, are very common in the general population and can reactivate 2–4  weeks posttransplant, either asymptomatically or in association with pneumonitis, meningoencephalitis, hepatitis, or pancytopenia [70]. HHV-8, the agent of Kaposi’s sarcoma, has been associated with KS developing after transplantation. Prophylaxis with ganciclovir derivatives may decrease the reactivation rate of HHV-6, EBV, and VZV, but not HHV-7 [71].

BK Virus and Polyomavirus Allograft Nephropathy The polyomaviruses BK (and less commonly JC virus) have been recognized to cause interstitial nephritis in renal allograft recipients, and also ureteral stenosis. BKV is a virus with specific tropism for cells of the urinary tract. It causes a “silent” chronic infection, usually without constitutional or systemic symptoms, which leads to allograft dysfunction and ultimately graft loss in 1–10% of all renal recipients over time (BKVAN or PVAN), with 35–67% of infected patients progressing to graft loss over 1 year if no interventions are pursued [72–74]. Although viral activation is frequently detectable within a few months after transplant, the process can progress gradually over months to years. Quantitative

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measurements of viral load can provide an ­indication of activity of this infection and a means of gauging response to therapy [75]. Risk factors include intensified immunosuppression, particularly depleting antilymphocyte therapy with antithymocyte globulin. Patients on a sirolimusbased regimen may have a lower incidence but can still develop BKVAN [76]. BKVAN has also been described in kidney–pancreas transplant recipients in whom it may be difficult to treat because of requirement to maintain higher levels of immunosuppression [76, 77]. Pancreas graft function may be preserved in those who lose renal graft function [76]. BKVAN is also an important complication in pediatric renal transplantation, occurring in 4.6% of children in an NAPRTCS study, which also identified polyclonal induction therapy and zero HLA DR mismatch as risk factors [78]. The advent of periodic screening of either blood or urine (for quantitative BKV DNA in blood or urine; urine VP-1 mRNA, or urine decoy cells) has reduced graft loss considerably at many centers by affording an opportunity for early intervention [74, 79, 80]. Screening protocols vary from one center to another, but one protocol recommended by an expert panel consists of screening every 3  months for the first 2  years, when allograft dysfunction occurs, or when a biopsy is performed [81]. Positive results should be confirmed by a quantitative molecular test [81]. Diagnosis of full-blown PVAN requires allograft biopsy [81]. However, measures to control BKV may be instituted on the basis of elevated viral load, before (or in the absence of) a biopsy [79]. When BKV is detected above a threshold level (e.g., 10,000 copies/mL in blood), the first intervention is usually reduction of immunosuppression, if possible. This generally takes the form of reduction of the MMF dose less than 1  g/day and/or lowering the tacrolimus target level to less than 6 ng/mL or cyclosporine level less than 150  ng/mL [82]. This intervention is more difficult if the patient has had rejection recently treated with intensified immuno­ suppression, in which case a pulsed steroid therapy with rapid taper is advocated, rather than

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r­ emaining on intensified immunosuppression long term [82]. Reduction of immunosuppression allows for the development of BKV-specific cellular immunity, which appears to be key in controlling this chronic infection and preventing progression to graft loss [83]. If the BKV level has failed to improve or has risen despite reduction of immunosuppression for at least 4 weeks, patients may be considered for one of several therapies. As yet no randomized trials have compared these strategies headto-head although case series exist for each treatment. Leflunomide [72], cidofovir [75], intravenous immunoglobulin (IVIg) [84], and fluoroquinolones (ciprofloxacin) [85] are the most commonly used drugs, either alone or in combination [86]. Leflunomide, a drug approved for therapy of rheumatoid arthritis, has both antirejection and anti-BKV activity [72] and can replace MMF in an immunosuppressive regimen. Josephson et al. used leflunomide alone in 17 patients and leflunomide plus cidofovir in nine patients, and found that blood and urine BKV levels decreased and SCr stabilized in the 22 patients who were able to maintain blood levels of the active metabolite of greater than 50,000 ng/m [72]. Rates of response to leflunomide in other series have varied [87].

Practical Management of BK Virus Infection At many centers, leflunomide is the first anti-BK therapy employed after reduction of immunosuppression when the viral load continues to rise, while ciprofloxacin appears to be most effective at lower viral loads. There are no strict guidelines for the use of leflunomide. Some use a loading dose followed by a maintenance dose ranging between 20 and 60 mg/day. Blood levels of teriflunomide, a metabolite may be monitored but are not always readily available. Toxicities of leflunomide include cytopenias, hepatitis, peripheral neuropathy, diarrhea, and alopecia. When initial therapy does not lead to a decrease in viral load, either cidofovir (nephrotoxic) or

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IVIg or both may be added. The decision to add an agent (combination therapy) versus switching will depend upon the severity of BKV disease, the viral load, and toxicities the patient has experienced with previous therapy. There is a growing anecdotal experience with combination therapy, but ideally future clinical trials would assess its efficacy in comparison with single agents. When progression to graft loss occurs despite reduction of immunosuppression and antiviral therapy, retransplantation is an option which has been successful in most reported cases [88, 89]. Allograft explantation does not appear to be ­necessary for retransplantation in this setting, but a period of time (e.g., 1 year) off all immunosuppression is helpful to allow the patient to develop robust BKV-specific cellular immunity [83, 88]. Measurement of virus-specific cellular immune function may become helpful as a guide to timing of retransplantation in the future.

Hepatitis Viruses in Renal and Pancreatic Transplantation The topic of hepatitis viruses in the renal transplant candidate and recipient is a large one, and only a brief summary will be presented here. Considerations include: (1) preexisting chronic hepatitis B or C infection in the transplant ­candidate; (2) differential risks of de novo donorderived hepatitis infection from an HBcAbpositive or HCV-positive donor; (3) clinical outcomes in HCV D+/R + renal transplant recipients; and (4) risk of non-donor-derived nosocomial or community-acquired hepatitis infection acquired posttransplant. Preexisting chronic HBV infection in the form of HBsAg positivity was more common in an earlier era before HBV vaccination of dialysis patients became widespread. Progression of preexisting hepatitis B may be early and fulminant or chronic and gradually progressive under transplant immunosuppression. Antiviral therapy has ameliorated outcomes in recent years. Drug resistance is an issue; lamivudine resistance is

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becoming more widespread, and entecavir ­therapy for lamivudine- and adefovir-resistant HBV in kidney recipients has been described [90]. Surprisingly, some long-term (>20  years) survivors of kidney transplantation with functioning allografts have detectable viral loads of HBV and HCV without progression to cirrhosis, although this group has a higher incidence of diabetes and a higher mortality than those not infected with hepatitis viruses [91]. Patients with preexisting HCV may have poorer posttransplant outcomes than HCVnegative kidney recipients, but still better longterm outcomes than if they had remained on dialysis [92]. Pereira et  al. found that kidney recipients who were HCV-positive had a relative risk of death of 1.41 (compared with those who were HCV-negative), and a relative risk of death from infection or liver disease of 2.39 [92]. Long-term relative risk of death was lower in transplanted HCV-positive patients compared with remaining on dialysis [92]. Thus, HCV seropositivity is not a contraindication to transplantation, but such patients may benefit from careful modulation of immunosuppression and attentive monitoring for early detection of infection. The risk of donor-derived transmission from an HBsAg-positive donor is high, and these donors are generally not used [93] except in hyperendemic areas such as Taiwan [94]. However, risk of the HBcAb-positive, HBsAgnegative (“core-positive”) donor resulting in HBsAg-positivity in a naïve kidney recipient is quite low, approximately 1 in 40 or less (in contrast to liver transplantation where the risk is 50% without prophylaxis) [95, 96]. This risk can be further reduced by effective vaccination of the candidate pretransplant, and by posttransplant prophylaxis with HBIg and/or lamivudine [97]. These donors should thus not be declined on the basis of their core-positive HBV serology. Immunization of the potential transplant candidate early on in disease is helpful, since endstage organ disease is associated with poorer rates of seroconversion and dialysis patients may require enhanced potency vaccine doses or additional booster doses.

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The risk of HCV transmission from an ­HCV-positive donor to a naïve recipient is high, in comparison to the HBcAb-positive donor. Initiatives to increase the donor pool have included recommendations for use of HCVpositive donors [98]. Receiving a transplant from an HCV-positive donor was associated with improved survival compared with staying on dialysis on the waiting list, in a USRDSbased study by Abbott et  al. of over 38,000 patients in whom 52% of the patients who received transplants from HCV-positive donors were themselves HCV-positive [99]. However, use of an HCV-positive donor (as compared to a HCV-negative donor) has been associated with an increased risk of mortality (adjusted hazard ratio 2.12), primarily from infection, in another large study by Abbott et al. [100]. This held true regardless of the age or HCV status of the recipient [100]. Posttransplant diabetes appears to contribute to this increased risk of death in patients with posttransplant HCV [101]. There is also a theoretical concern about superinfection with a genotype 1 HCV strain in a patient with non-genotype-1 HCV since genotype 1 is less likely to respond to drug therapy. However, in one study, genotype did not have an effect on survival in transplant candidates with ESRD [102]. The role of pretransplant and posttransplant antiviral therapy for HCV is debated [103]. Goals of pretransplant therapy are to prevent progression of liver disease prior to transplant and prevent progression after transplant, as well as to control HCV-related renal disease [104]. Some studies have reported good results with pegylated interferon prior to transplant [105], but others have emphasized suboptimal response rates and poor tolerability of anti-HCV therapy in patients with renal disease [103, 104]. Ribavirin is contraindicated in patients with renal failure [104]. Posttransplant, the use of interferon is concerning for possible triggering of rejection [104, 105], but therapy may be undertaken in specific circumstances such as prevention of progression of HCV glomerulopathy or advanced liver disease [104]. Ribavirin may be used as part of combination therapy when renal function has been restored posttransplant [104].

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Although nosocomial HCV transmission in dialysis units was common in the past, stringent infection control measures including adherence to universal precautions, attention to hygiene, sterilization of machines and equipment, serologic testing, and other measures have reduced this risk of transmission considerably [106– 108]. Nosocomial HCV transmission to transplant recipients has also been described in settings other than dialysis units, and again, meticulous infection control practices prevent transmission.

Practical Approach to Hepatitis C in the Transplant Candidate and Recipient The pretransplant evaluation starts with routine HCV serology. If Anti-HCV is positive, a quantitative HCV RNA is obtained and a hepatology consultation and liver biopsy are sought. Biopsy findings of stage I and II mild chronic hepatitis do not contraindicate transplantation. Consid­ eration should also be given to the possibility of pretransplant treatment of Hepatitis C with ribavirin and interferon. The genotype of HCV predicts prognosis. Higher viral loads and lower response rates to treatment are associated with genotype 1 infections as compared to infections with genotypes 2 and 3. Such therapies may achieve a sustained virologic response and improvement in liver histology as reflected in preserved architecture and improved fibrosis. The correlates of sustained virologic response and improvement in hepatic fibrosis include the HCV genotype, degree of elevation of AST and ALT, and the degree of fibrosis noted on biopsy. Pretransplant treatment of HCV is critical as posttransplant treatment of HCV is fraught with risk in the context of currently available regimens, as interferon often precipitates rejection and ribavirin may cause hemolytic anemia. Patients with HCV who have sustained virologic and histologic remission with antiviral treatment may then proceed to renal transplantation. If the liver biopsy reveals cirrhosis, further

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evaluation for combined liver–kidney transplantation should be undertaken, as patients with hepatitis C and cirrhosis are at great risk for posttransplant hepatic failure and a poor overall outcome. A subset of patients may have liver disease that is ­sufficiently advanced to preclude solitary kidney transplant, but the degree of hepatic insufficiency and portal hypertension may not warrant liver transplantation. In this instance, consideration should be given to careful follow-up for progression of liver disease during dialysis and reevaluation with a view to simultaneous liver– kidney transplant as hepatic disease progresses. After successful renal transplantation, routine posttransplant surveillance of AST and ALT is recommended. At a minimum, annual quantitative HCV RNA should be obtained to monitor progression of hepatic disease. We recommend that patients with hepatitis C be followed in close liaison with a hepatologist. Recently, hepatitis E virus was described as an emerging cause of chronic hepatitis in transplant recipients [109, 110]. Although previously thought to be a cause of acute self-limited hepatitis, this virus has been described as causing progression to chronic liver disease and cirrhosis in kidney and kidney–pancreas recipients [111]. Therapy and prevention measures have not yet been defined.

Other Viral Infections There is now a robust and growing experience with kidney transplantation in HIV-positive ­individuals, who experience patient and graft survival similar to that of HIV-negative renal transplant recipients [112]. Careful selection of candidates and meticulous management of antiretroviral therapy are important for long-term outcomes and maintaining suppression of HIV viral load. Drug interactions with transplant medications, particularly calcineurin inhibitors, make the role of the transplant pharmacokineticist extremely important. Community-acquired respiratory viruses can cause a spectrum of disease including clinically

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severe syndromes in transplant recipients. In particular, influenza, respiratory syncytial virus (RSV), parainfluenza virus, and adenovirus can cause lower respiratory tract infection and may necessitate ICU admission and mechanical ventilation. Both seasonal influenza and novel H1N1 influenza can cause highly symptomatic infection. Antiviral therapy for influenza should follow the guidelines from the Centers for Disease Control (CDC) for the particular year in question, since antiviral resistance is rapidly changing. In the 2009–2010 influenza season, novel H1N1 “swine” influenza is still largely suscep­tible to oseltamivir and zanamivir, whereas ­seasonal influenza is expected to be largely oseltamivir-resistant. No antivirals are universally accepted for treatment of the other respiratory viruses mentioned above, although many centers use inhaled ribavirin for treatment of lower respiratory tract infection due to RSV [113], and some use palivizumab (RSV-specific monoclonal antibody). Adenoviruses, in addition to respiratory infection, can cause severe nephritis and graft dysfunction, with or without concomitant hepatitis [114]. Mathur et al. described a case of adenovirus infection of the renal allograft with tubular necrosis and granulomatous reaction, but sparing of the pancreatic allograft [115]. Human papillomavirus infection is a cause of some skin cancers and much of cervical and perianal neoplasia. Cervical intraepithelial lesions are more common in the posttransplant population, and frequent screening is recommended [116]. Parvovirus B19 has been recognized to cause severe anemia in some transplant recipients, which generally responds to therapy with IVIg [117]. It has recently been recognized that mild anemia may also be associated with parvovirus infection, and the latter is more common than previously suspected in the transplant population [118]. The best tests for diagnosis are parvovirus PCR and/or bone marrow biopsy, rather than parvovirus IgG/IgM; IgG will be positive in most adult patients and IgM may be falsely negative in the immunosuppressed patient. Recently, norovirus (Norwalk agent) has been described as a cause of chronic diarrhea in renal

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transplant recipients [119]. Westhoff et  al. described two patients who showed persistent viral excretion for greater than 7  months and 3 months, one with a syndrome of fever, diarrhea, and abdominal discomfort that only resolved with reduction of immunosuppression [119]. West Nile Virus (WNV) has been found to be a seasonal risk primarily in the summer and early fall in some geographic areas. It is a mosquitoborne virus that can cause manifestations ­ranging from mild flulike illness to meningoencephalitis, flaccid paralysis, and coma. Transplant recipients are at higher risk of neurologic complications [120]. There are no licensed antivirals for WNV and prevention focuses on avoiding ­mosquito bites in high-risk times and areas (see below).

Pneumocystis and Fungal Infections P. jiroveci (formerly P. carinii), now categorized with the fungi, remains an important pathogen in transplant recipients. The pneumonia associated with this organism can cause significant morbidity and mortality and a lengthy recovery phase. Patients who are not sulfa-allergic generally receive trimethoprim-sulfa prophylaxis for at least 6–12 months and in some cases long-term (with the additional benefits of prophylaxis vs Nocardia, Listeria, Toxoplasma, and some bacterial respiratory and urinary tract pathogens.) Treatment of rejection and CMV infection are risk factors for developing Pneumocystis infection [121], so resumption of anti-Pneumocystis prophylaxis should be considered after these events if the patient is not currently receiving it. Treatment of Pneumocystis is with high-dose trimethoprim and sulfamethoxazole or with pentamidine in those who are allergic to sulfonamides. Atovaquone is an alternative agent. Posttransplant fungal infections include candidiasis, aspergillosis, cryptococcosis, endemic mycoses (especially histoplasmosis and coccidioidomycosis), and non-Aspergillus mycelial fungi such as Scedosporium, Paecilomyces, etc. Candidiasis is most frequently seen in the early

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posttransplant period in the form of mucosal infection (particularly oropharyngeal, esophageal, or perineal), urinary tract infection, deep abdominal infection, or candidemia related to central venous catheters. Intraabdominal infection is discussed above. Oral mucosal yeast ­prophylaxis with either nystatin or clotrimazole troches is almost universal for at least the first month posttransplant, and may be reinstated ­during periods of intensified immunosuppression. Urinary tract candidal colonization or infection may progress to upper-tract infection involving the allograft, sometimes with dissemination, urinary tract obstruction due to fungus balls, and candidemia. Prophylaxis with fluconazole has been used at some centers in the early posttransplant period, but a recent case–control study by Safdar et  al. revealed that 51% of ­candiduria was caused by C. glabrata which frequently has reduced susceptibility to fluconazole [122]. Donor-derived candidal infection [123] or positive preservation fluid cultures [124] may lead to the devastating complication of mycotic aneurysm and arteritis. Early and vigorous antifungal therapy in the recipient may help to ­prevent this complication [125]. Aspergillosis most often takes the form of pulmonary or sino-orbital infection in patients with environmental exposures such as extensive pretransplant gardening, landscaping, farming, construction, or marijuana smoking. Posttransplant nosocomial exposures including hospital construction may be a factor. Cryptococcosis often occurs in the period greater than 6  months posttransplant and is associated with meningitis, central nervous system lesions, and elevated CSF pressure, which may require ventriculostomy and/or shunting. An immune reconstitution syndrome may occur [126], which is associated with a high risk of subsequent allograft loss [127]. Intriguing recent work suggests a synergistic antifungal effect in patients on calcineurin-­inhibitor-based regimens [128]. The endemic mycoses histoplasmosis and coccidioidomycosis are found primarily in certain regions of the USA (the Midwest and Southwest, respectively). Reactivation of remote, dormant infection appears to be the main source

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of clinically apparent disease. Posttransplant ­histoplasmosis occurred at a median of 17 months posttransplant with an incidence of 1 in 1,000 person/years in an endemic area in a series by Cuellar-Rodriguez et  al. [129]. Disseminated disease was frequent, but transplant recipients frequently did well with protracted therapy [129]. Coccidioidomycosis, by contrast, carries a much higher mortality risk (28%), although the incidence has declined from 7% to 9% in earlier years to 1–2% with targeted azole prophylaxis [130]. Diagnosis of coccidioidomycosis can be challenging as false-negative serologic testing may occur, and the clinician should have a high index of suspicion in patients who currently or previously resided in endemic areas [131]. Recent years have seen the rise of nonAspergillus mold infections in solid organ transplant recipients, including infections due to Zygomycetes, Scedosporium spp., and other agents [132]. These infections are more likely to be disseminated, to involve the central nervous system, and confer higher mortality risk than those due to Aspergillus spp [132]. Cryptococcal infections can occur at any time after transplantation but are most common after the first 1–6 months have elapsed after transplantation. Cryptococcosis can present as meningitis, space-occupying brain lesions, pneumonia, pulmonary nodules, or skin nodules. Highly immunosuppressed patients may present with mere weight loss and failure to thrive. The most common manifestation of cryptococcosis is meningitis. This can present with remarkably few symptoms or meningismus or headache and may be mistaken for global confusion due to drug toxicity or depression. Photophobia should always trigger suspicion for a meningitic process. As cryptococcal infection produces basal meningitis, obstructive hydrocephalus, cranial nerve palsies, and blindness can result. Prompt diagnosis and institution of appropriate therapy can prevent neurologic sequelae. Unfortunately, even with such treatment, residual neurologic deficits can ensue from scarring and mortality risk is high. The diagnosis is based on serum and CSF cryptococcal antigen (quantitative titers),

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CSF India ink preparation, and the usual ­treatment is amphotericin B or its liposomal ­analogue (to mitigate nephrotoxicity) and flucytosine. Maintenance therapy can then shift to ­fluconazole. Given the life-threatening nature of this entity, it is common practice to stop calcineurin inhibitors and antiproliferatives with cryptococcal meningitis. Serial brain imaging may be needed to follow the course of hydrocephalus and ventriculoperitoneal shunts may be needed to prevent neurologic sequelae. Therapy of fungal infections has been altered by newer azoles, lipid amphotericin preparations, and echinocandins. Fluconazole is active against Candida spp., although C. krusei is resistant and C. glabrata frequently has reduced susceptibility to fluconazole. Widespread use of fluconazole has been associated with a shift to non-C. albicans spp [122]. Voriconazole and posaconazole have joined itraconazole as mold-active agents with powerful activity against Aspergillus spp. and many other molds (except that voriconazole does not have activity against Zygomycetes, whereas posaconazole does). Voriconazole is now considered the agent of choice for invasive aspergillosis; [133] although it may be used as a single agent, combination therapy with voriconazole plus caspofungin (an echinocandin) was associated with improved outcomes in a retrospective study of solid organ transplant patients by Singh et  al. [134]. Echinocandins (caspofungin, micafungin, anidulafungin) have broad activity against yeasts, including many fluconazole-resistant yeasts, but not Cryptococcus or Histoplasma. Liposomal preparations of amphotericin are less nephrotoxic than standard amphotericin B, but still may be associated with nephrotoxicity, electrolyte abnormalities, and infusion-related reactions. Recent years have seen a shift away from amphotericin B and toward newer azoles such as voriconazole and posaconazole, with or ­without combination therapy with an echino­ candin. However liposomal amphotericin is ­particularly useful for treating infections with Zygomycetes.

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Practical Approach to Fungal Infections When an invasive fungal infection is suspected (e.g., pulmonary nodules, especially with cavitation; sino-orbital disease; hepatic and splenic lesions), diagnostic microbiology is extremely important, as fungi may look alike histopathologically but may require different therapies. Bronchoalveolar lavage should be accompanied by transbronchial biopsy whenever possible, and open-lung biopsy should be considered when other tests are nondiagnostic. Suspected sino-orbital or intracranial fungal infection should prompt emergent ENT and/or neurosurgery evaluation since early aggressive surgical debridement may be lifesaving. Screening with antigen tests such as cryptococcal antigen and galactomannan is most helpful. There should be a low threshold for lumbar puncture in the event of CNS symptoms so that cryptococcal infections can be diagnosed promptly and treated.

Other Bacterial Infections: Clostridium difficile, Mycobacterium, Legionella, Nocardia, Listeria, Rhodococcus spp. C. difficile-associated diarrhea (CDAD) has become a major concern particularly since the advent of the epidemic strain of C. difficile in 2005. Hospital-acquired infection has become more common, and the epidemic strain is associated with more severe disease, treatment failures, recurrences, and colectomies than the classic strain. C. difficile is an important pathogen in transplant recipients as they are frequently receiving multiple antibacterial agents which may predispose to C. difficile overgrowth, and may have long hospital and ICU stays with opportunity for nosocomial acquisition of the organism. A review by Riddle and Dubberke emphasized the importance of rigorous infection control practices in transplant recipients and also a high index of suspicion [135]. C. difficile infection may present

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with fever, leukocytosis, and abdominal distention in the absence of diarrhea, and should be suspected in such situations. The occurrence of ileus is a risk factor for colonic dilatation and perforation, and close followup with abdominal radiography and colorectal surgical consultation may prevent life-threatening complications. Either metronidazole or oral vancomycin may be used for therapy of mildly symptomatic disease, but more clinically severe disease should be treated with oral vancomycin [135]. For patients with ileus who cannot take oral vancomycin, intravenous metronidazole may be used. Reactivation of Mycobacterium tuberculosis can be devastating posttransplant, and is associated with increased risk of disseminated disease and mortality as compared with the nontransplant population [136]. Median time of onset can be greater than 1 year posttransplant [137]. Even when therapy is successful, allograft loss associated with rejection due to low calcineurin levels in patients on rifampin-containing regimens frequently occurs, and successful therapy with rifampin-sparing regimens has been described [138], although some studies have shown that rifampin can be safely used with careful monitoring [137, 139]. In a review by Singh and Paterson, dissemination occurred in 33% of those with posttransplant TB, and previous antilymphocyte therapy was a risk factor for disseminated disease [136]. Mortality rate among 499 SOT patients was 29%; disseminated infection, prior rejection, and antilymphocyte therapy were predictors of mortality [136]. In renal transplant recipients, isoniazid hepatotoxicity occurred in only 2.5% [136]. Treatment of latent TB infection with isoniazid prophylaxis may help to prevent later TB reactivation, and is generally well tolerated in the renal transplant population [136, 140]. However, neither the optimal time to start prophylaxis nor the criteria for prophylaxis have been fully defined. PPD skin testing has been a standard part of pretransplant screening for many years, but may be falsely negative in ESRD patients due to anergy. Recently, the INFg release assay (IGRA) for TB has been utilized as a ­pretransplant screening tool [141], but indeterminate results may occur in

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patients with end-stage organ disease [141]. INH, rifampin and rifabutin are potent inducers of CYP3A4/5 and levels of CNI can be expected to fall. As such, close monitoring of CNI levels and dose adjustments are mandatory. Corticosteroid doses should also be increased by a factor of 1.5 for the same reasons. Nontuberculous mycobacterial infection, most commonly due to M. avium–intracellulare (MAI) complex, M. chelonae, or M. abscessus, may occur posttransplant [142, 143]. These infections may be localized to skin, soft tissue, tendons, joints, or lung; or may be disseminated, presenting with fever of unknown origin, leukopenia, abnormal liver function tests, and/or pulmonary nodules. Mycobacterial isolator cultures of blood, BAL fluid, bone marrow, or tissue biopsies may be necessary to make the diagnosis. Legionellosis is probably an underdiagnosed infectious complication in transplant recipients [144]. It can cause a variety of clinical manifestations including a rapidly progressive multilobar pneumonia, and transmission has been associated with hospital water supply at some centers [144]. The most common species is Legionella pneumophila, but other species such as L. micdadei may occur and may present in atypical fashion; the urinary antigen test detects only L. pneumophila type 1. Nocardia spp. are causes of nodular pulmonary infiltrates, central nervous system infection, and occasionally infection in other organ systems including skin, soft tissue, and joint infection. Risk factors include intensified immunosuppression [145], previous CMV infection [145], and hypogammaglobulinemia [146]. Trimethoprimsulfamethoxazole prophylaxis may be partially protective against development of nocardiosis [147], but breakthrough infections occur; two thirds of patients with nocardiosis in one case– control study were receiving TMP-SMX prophylaxis [145]. Different Nocardia species have different antimicrobial susceptibility patterns and therapy should ideally be guided by susceptibility testing information. Treatment is often with TMP-SMX at highdose and in some cases, with other agents or combinations such as imipenem, linezolid, azithromycin.

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Rhodococcus equi is a cause of nodular ­pulmonary infection in immunosuppressed hosts [148–150] and may be associated with horses and farm exposures. Cultures of this organism may be misidentified as “diphtheroids” so clinicians should maintain a high index of suspicion [148]. Listeria monocytogenes is a foodborne pathogen causing meningitis, bacteremia, and occasionally other infections in elderly, very young, pregnant, or immunocompromised patients. Nonpasteurized dairy products, soft cheeses, hot dogs, deli meats, and many other foods have been cited as sources of listeriosis. Careful attention to food preparation, reheating of any leftovers to steaming hot, and care in selection of dining venues outside the household can help in preventing listeriosis. Given the proclivity of the immunocompromised subject to Listeria, empiric coverage should include that pathogen, e.g. ampicillin as part of a meningitis regimen along with vancomycin and ceftriaxone.

A Practical Approach to the Febrile Transplant Recipient In evaluating a febrile transplant recipient, the clinician should assess the patient in the framework of the timetable of posttransplant infection and the net state of immunosuppression (see above). Antimicrobial prophylaxis, past infections, travel, pets, construction, and other environmental exposures should be carefully recorded and current community outbreaks (such as influenza and RSV) should be considered. Physical examination should particularly emphasize sino-orbital, nasal, or pharyngeal abnormalities (fungal infection, PTLD, or complicated bacterial sinusitis); chest exam; cardiac exam; abdominal exam (tenderness, hepatosplenomegaly, wounds, and incisions); extremities (swelling, ulcerations); skin (lesions, rashes, or nodules that might be amenable to biopsy); focal neurologic findings or meningismus (an emergency), and indwelling catheter sites. Depending on the clinical presentation and the time posttransplant, microbiologic studies might include blood, urine, wound, and sputum

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cultures; nasopharyngeal swab for respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, and adenovirus); stool for C. difficile, stool culture, and parasites; CMV DNA, EBV DNA, HHV-6 PCR, cryptococcal antigen (serum or CSF), bacterial/fungal/AFB cultures and stains on CSF or other body fluids; PCR on CSF for HSV, VZV, CMV, EBV, HHV6, JC virus; fungal antibody panel; urine or blood Histoplasma antigen and Cryptococcus antigen, urine Legionella antigen, Aspergillus galactomannan antigen, and isolator blood ­cultures for fungi or mycobacteria. Depending on clinical or radiographic findings, procedures such as CT-guided abscess drainage, LP, thoracentesis, paracentesis may be indicated with microbiologic studies as above. Any abnormality on chest radiograph should prompt consideration of chest CT scanning, for better visualization of nodules, cavities, and other abnormalities. CT scan of the abdomen and pelvis is helpful for detecting abscesses and other perigraft collections as well as lymphadenopathy that may suggest PTLD. Pulmonary infiltrates may be diffuse (suggesting viral, PCP, or overwhelming bacterial etiology); patchy or lobar (more commonly bacterial); or nodular (fungal, AFB, Nocardia), but there is considerable overlap between these categories. Nasopharyngeal swabs for respiratory viruses should be promptly obtained in the setting of community outbreaks or compatible presentations. Transplant recipients may not have diagnostic sputum cultures and often ­benefit from early bronchoalveolar lavage and transbronchial biopsy; cultures from the “ID-BAL” should be sent for, e.g., routine bacterial, Legionella, fungal, AFB, Nocardia stains and cultures; PCP stain; and viral cultures or PCR for CMV, HSV, and community respiratory viruses. Open lung biopsy may be helpful for patients with rapidly progressive infiltrates and hypoxemia in whom other testing has been diagnostic; this may also help narrow and focus the antibiotic coverage which otherwise would be multiagent with attendant risks of toxicity. Empiric antimicrobial therapy should be directed by the likely pathogens from the

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a­ ssessment above, and the severity of the patient’s ­illness. If influenza is suspected, current CDC ­recommendations for influenza therapy should be followed, since antiviral resistance patterns are  rapidly changing. Pulmonary infiltrates should  prompt broader coverage than that for community-acquired pneumonia in the general population (unless the patient is on minimal immunosuppression and >1 year posttransplant). For a severe pneumonia, coverage for MRSA ­(linezolid or vancomycin), Gram-negative organisms including Pseudomonas (e.g., piperacillintazobactam or imipenem) and azithromycin (for Legionella, Mycoplasma, Chlamydia, etc.) is one possible regimen, with consideration of ganciclovir, antiinfluenza agents, and an antifungal if the clinical situation suggests it. Alternatively a respiratory quinolone (levofloxacin or moxifloxacin) plus MRSA coverage could be used, but increasing quinolone resistance in enteric Gramnegative bacteria and Pseudomonas in this population should prompt a rapid switch if response is not immediate. In a septic patient, particularly one who has been recently hospitalized or in the ICU, consideration should be given to empiric coverage for nosocomial organisms at that ­particular center (such as multidrug-resistant Acinetobacter, Pseu­domonas, or Stenotro­ phomonas, or carbapenem-resistant K. pneumo­ niae). A particular consideration is adequate empiric coverage for Listeria when meningitis is suspected. The institution of antifungal therapy will depend on the presentation, particularly chest radiography and chest CT, and presence or absence of neutropenia. Pancytopenia should prompt discontinuation of agents such as MMF and azathioprine, and filgrastim should be administered to maintain an absolute neutrophil count above 1,000 cells/mL. Pancytopenia suggests CMV, EBV, HHV-6, or disseminated fungal or mycobacterial infection. If a recent test for CMV viremia has not been performed, empiric therapy with ganciclovir is appropriate while awaiting results. The above recommendations are general and must be tailored to each patient’s specific situation or known colonizing pathogens.

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Preventing Infections in the Transplant Population: Exposures, Immunizations In addition to prophylactic and preemptive strategies described above, transplant recipients can themselves be taught to minimize risks of infection exposures. Please see the section of the AST Guidelines entitled “Strategies for safe living following solid organ transplantation” for a full discussion of these issues [3, 151]. Kidney and kidney–pancreas transplant recipients who wish to go back to work in fields where there is risk for infectious exposures such as health care, landscaping, construction, etc., may benefit from individualized counseling and protective measures. Within the hospital, meticulous hand hygiene and stringent infection control practices should be followed to prevent the spread of respiratory viruses, tuberculosis, C. difficile, multiresistant bacterial organisms, and other agents. The CDC has issued an updated set of guidelines in 2007 for isolation precautions for various diseases [152], although there is some latitude for interpretation and different centers may have slightly different protocols. The basic universal theme is “standard precautions” and above that, there are disease-specific precautions based on the mode of spread of the particular organism. In addition, 2002 guidelines for hand hygiene have been published [153], constituting one of the most important measures in preventing transmission of pathogens by healthcare workers. Immunizations remain a cornerstone of prevention in pretransplant candidates and posttransplant recipients. The reader is referred to the AST ID Guidelines [3, 154] and other reviews for full details [155–157]. The pretransplant evaluation is an ideal time for updating of immunization status [3]. Posttransplant, live vaccines are generally avoided, although small studies in pediatric transplant recipients have suggested safety of some live vaccines such as varicella vaccine in some groups. Larger studies have not corroborated any link between immunizations and rejection [155]. Yearly injected (nonlive) influenza vaccine is important for transplant recipients although

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seroconversion rates may be less than in the ­general population. Creating a “circle of protection” around the transplant recipient by immunizing household contacts and healthcare workers is an important preventive measure.

Conclusion Clinical prevention strategies, preemptive monitoring, molecular diagnostic assays, and newer antimicrobial agents have improved the outlook for posttransplant infections. However, many challenges remain, such as increasing antimicrobial resistance in bacteria and fungi; rise of more virulent strains of some organisms such as C. difficile; and inability to prevent allograft loss in some transplant recipients with polyomavirus infection. More multicenter collaborative studies would be welcome since it is often difficult to discern the best modes of treatment and prevention based on single-center studies. Finally, education of the patient and their family members, awareness of environmental exposures, and implementation of timely immunization protocols, can help prevent infectious complications and help maintain good long-term health in the transplant recipient.

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354 73. Hariharan S. BK virus nephritis after renal transplantation. Kidney Int 2006;69(4):655–662. 74. Ramos E, et  al. The decade of polyomavirus BK-associated nephropathy: state of affairs. Transplantation 2009;87(5):621–630. 75. Vats A, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virusassociated nephropathy in children and adults. Transplantation 2003;75(1):105–112. 76. Benavides CA, et al. BK virus-associated nephropathy in sirolimus-treated renal transplant patients: incidence, course, and clinical outcomes. Transplantation 2007;84(1):83–88. 77. Duclos AJ, et  al. Prevalence and clinical course of BK virus nephropathy in pancreas after kidney transplant patients. Transplant Proc 2006;38(10): 3666–3672. 78. Smith JM, et  al. BK virus nephropathy in pediatric renal transplant recipients: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry. Clin J Am Soc Nephrol 2007;2(5):1037–1042. 79. Ramos E, et  al. BK virus nephropathy diagnosis and treatment: experience at the University of Maryland Renal Transplant Program. Clin Transpl 2002:143–153. 80. Hirsch HH, et al. Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management. Adv Exp Med Biol 2006;577: 160–173. 81. Hirsch HH, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005;79(10): 1277–1286. 82. Trofe J, Hirsch HH, Ramos E. Polyomavirusassociated nephropathy: update of clinical management in kidney transplant patients. Transpl Infect Dis 2006;8(2):76–85. 83. Comoli P, Hirsch HH, Ginevri F. Cellular immune responses to BK virus. Curr Opin Organ Transplant 2008;13(6):569–574. 84. Sener A, et  al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: oneyear follow-up of renal allograft recipients. Transplantation 2006;81(1):117–120. 85. Randhawa PS. Anti-BK virus activity of ciprofloxacin and related antibiotics. Clin Infect Dis 2005;41(9):1366–1367; author reply 1367. 86. Josephson MA, et al. Polyomavirus-associated nephropathy: update on antiviral strategies. Transpl Infect Dis 2006;8(2):95–101. 87. Faguer S, et al. Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation. Transpl Int 2007;20(11):962–969. 88. Hirsch HH, Ramos E. Retransplantation after polyomavirus-associated nephropathy: just do it? Am J Transplant 2006;6(1):7–9. 89. Ramos E, et  al. Retransplantation in patients with graft loss caused by polyoma virus nephropathy. Transplantation 2004;77(1):131–133.

R.K. Avery et al. 90. Kamar N, et al. Entecavir therapy for adefovir-resistant hepatitis B virus infection in kidney and liver allograft recipients. Transplantation 2008;86(4): 611–614. 91. Younossi ZM, et  al. Chronic viral hepatitis in renal transplant recipients with allografts functioning for more than 20 years. Transplantation 1999;67(2): 272–275. 92. Pereira BJ, et al. Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1998;53(5):1374–1381. 93. Natov SN, Pereira BJ. Transmission of viral hepatitis by kidney transplantation: donor evaluation and transplant policies (Part 1: hepatitis B virus). Transpl Infect Dis 2002;4(3):117–123. 94. Wei HK, et al. HBsAg(+) donor as a kidney transplantation deceased donor. Transplant Proc 2008; 40(7):2097–2099. 95. Wachs ME, et al. The risk of transmission of hepatitis B from HBsAg(–), HBcAb(+), HBIgM(–) organ donors. Transplantation 1995;59(2):230–234. 96. Madayag RM, et  al. Use of renal allografts from donors positive for hepatitis B core antibody confers minimal risk for subsequent development of clinical hepatitis B virus disease. Transplantation 1997;64 (12):1781–1786. 97. Chung RT, Feng S, Delmonico FL. Approach to the management of allograft recipients following the detection of hepatitis B virus in the prospective organ donor. Am J Transplant 2001;1(2):185–191. 98. Rosengard BR, 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. 99. Abbott KC, et al. The impact of transplantation with deceased donor hepatitis c-positive kidneys on survival in wait-listed long-term dialysis patients. Am J Transplant 2004;4(12):2032–2037. 100. Abbott KC, et al. Hepatitis C and renal transplantation in the era of modern immunosuppression. J Am Soc Nephrol 2003;14(11):2908–2918. 101. Abbott KC, et  al. Impact of diabetes and hepatitis after kidney transplantation on patients who are affected by hepatitis C virus. J Am Soc Nephrol 2004;15(12):3166–3174. 102. Natov SN, et al. Hepatitis C virus genotype does not affect patient survival among renal transplant candidates. The New England Organ Bank Hepatitis C Study Group. Kidney Int 1999;56(2):700–706. 103. Berenguer M. Treatment of chronic hepatitis C in hemodialysis patients. Hepatology 2008;48(5): 1690–1699. 104. Terrault NA, Adey DB. The kidney transplant recipient with hepatitis C infection: pre- and posttransplantation treatment. Clin J Am Soc Nephrol 2007;2(3):563–575. 105. Martin P, Fabrizi F. Hepatitis C virus and kidney disease. J Hepatol 2008;49(4):613–624.

18  Infectious Complications: Prevention and Management 106. Gallego E, et al. Effect of isolation measures on the incidence and prevalence of hepatitis C virus infection in hemodialysis. Nephron Clin Pract 2006; 104(1):c1–6. 107. Natov SN, Pereira BJ. Hepatitis C virus in chronic dialysis patients. Minerva Urol Nefrol 2005; 57(3):175–197. 108. Jadoul M, Cornu C, van Ypersele de Strihou C. Universal precautions prevent hepatitis C virus transmission: a 54 month follow-up of the Belgian Multicenter Study. The Universitaires Cliniques St-Luc (UCL) Collaborative Group. Kidney Int 1998;53(4):1022–1025. 109. Gerolami R, et al. Hepatitis E virus as an emerging cause of chronic liver disease in organ transplant recipients. J Hepatol 2009;50(3):622–624. 110. Aggarwal R. Hepatitis E: does it cause chronic hepatitis? Hepatology 2008;48(4):1328–1330. 111. Kamar N, et al. Hepatitis E virus-related cirrhosis in kidney- and kidney-pancreas-transplant recipients. Am J Transplant 2008;8(8):1744–1748. 112. Roland ME, et  al. HIV-infected liver and kidney transplant recipients: 1- and 3-year outcomes. Am J Transplant 2008;8(2):355–365. 113. Krinzman S, et al. Respiratory syncytial virus-associated infections in adult recipients of solid organ transplants. J Heart Lung Transplant 1998;17(2):202–210. 114. Emovon OE, et al. Refractory adenovirus infection after simultaneous kidney-pancreas transplantation: successful treatment with intravenous ribavirin and pooled human intravenous immunoglobulin. Nephrol Dial Transplant 2003;18(11):2436–2438. 115. Mathur SC, et al. Adenovirus infection of the renal allograft with sparing of pancreas graft function in the recipient of a combined kidney-pancreas transplant. Transplantation 1998;65(1):138–141. 116. Paternoster DM, et al. Human papilloma virus infection and cervical intraepithelial neoplasia in transplanted patients. Transplant Proc 2008;40(6): 1877–1880. 117. Beckhoff A, et al. Relapsing severe anaemia due to primary parvovirus B19 infection after renal transplantation: a case report and review of the literature. Nephrol Dial Transplant 2007;22(12):3660–3663. 118. Ki CS, et  al. Incidence and clinical significance of human parvovirus B19 infection in kidney transplant recipients. Clin Transplant 2005;19(6):751–755. 119. Westhoff TH, et al. Chronic norovirus infection in renal transplant recipients. Nephrol Dial Transplant 2009;24(3):1051–1053. 120. Kumar D, et  al. Community-acquired West Nile virus infection in solid-organ transplant recipients. Transplantation 2004;77(3):399–402. 121. Arend SM, et al. Rejection treatment and cytomegalovirus infection as risk factors for Pneumocystis carinii pneumonia in renal transplant recipients. Clin Infect Dis 1996;22(6):920–925. 122. Safdar N, et al. Predictors and outcomes of candiduria in renal transplant recipients. Clin Infect Dis 2005;40(10):1413–1421.

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123. Battaglia M, et al. True mycotic arteritis by Candida albicans in 2 kidney transplant recipients from the same donor. J Urol 2000;163(4):1236–1237. 124. Mai H, et al. Candida albicans arteritis transmitted by conservative liquid after renal transplantation: a report of four cases and review of the literature. Transplantation 2006;82(9):1163–1167. 125. Matignon M, et al. Outcome of renal transplantation in eight patients with Candida sp. contamination of preservation fluid. Am J Transplant 2008; 8(3):697–700. 126. Singh N, et al. An immune reconstitution syndromelike illness associated with Cryptococcus neofor­ mans infection in organ transplant recipients. Clin Infect Dis 2005;40(12):1756–1761. 127. Singh N, et  al. Allograft loss in renal transplant recipients with Cryptococcus neoformans associated immune reconstitution syndrome. Transplantation 2005;80(8):1131–1133. 128. Kontoyiannis DP, et al. Calcineurin inhibitor agents interact synergistically with antifungal agents in vitro against Cryptococcus neoformans isolates: correlation with outcome in solid organ transplant recipients with cryptococcosis. Antimicrob Agents Chemother 2008;52(2):735–738. 129. Cuellar-Rodriguez J, et  al. Histoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area. Clin Infect Dis 2009;49(5):710–716. 130. Blair JE. Coccidioidomycosis in patients who have undergone transplantation. Ann NY Acad Sci 2007; 1111:365–376. 131. Blair JE. Approach to the solid organ transplant patient with latent infection and disease caused by Coccidioides species. Curr Opin Infect Dis 2008; 21(4):415–420. 132. Husain S, et al. Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin Infect Dis 2003;37(2):221–229. 133. Walsh TJ, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46(3):327–360. 134. Singh N, et  al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006;81(3):320–326. 135. Riddle DJ, Dubberke ER. Clostridium difficile infection in solid organ transplant recipients. Curr Opin Organ Transplant 2008;13(6):592–600. 136. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998;27(5):1266–1277. 137. Lattes R, et  al. Tuberculosis in renal transplant recipients. Transpl Infect Dis 1999;1(2):98–104. 138. Vachharajani TJ, et al. Tuberculosis in renal transplant recipients: rifampicin sparing treatment protocol. Int Urol Nephrol 2002;34(4):551–553.

356 139. Park YS, et al. Clinical outcomes of tuberculosis in renal transplant recipients. Yonsei Med J 2004;45 (5):865–872. 140. Antony SJ, Ynares C, Dummer JS. Isoniazid hepatotoxicity in renal transplant recipients. Clin Transplant 1997;11(1):34–37. 141. Manuel O, et  al. Comparison of quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation. Am J Transplant 2007;7(12):2797–2801. 142. Patel R, et  al. Infections due to nontuberculous mycobacteria in kidney, heart, and liver transplant recipients. Clin Infect Dis 1994;19(2):263–273. 143. Jie T, et  al. Mycobacterial infections after kidney transplant. Transplant Proc 2005;37(2):937–939. 144. Chow JW, Yu VL. Legionella: a major opportunistic pathogen in transplant recipients. Semin Respir Infect 1998;13(2):132–139. 145. Peleg AY, et al. Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis 2007;44(10):1307–1314. 146. Poonyagariyagorn HK, et al. Challenges in the diagnosis and management of Nocardia infections in lung transplant recipients. Transpl Infect Dis 2008;10(6):403–408. 147. Wilson JP, et al. Nocardial infections in renal transplant recipients. Medicine (Baltimore) 1989;68(1):38–57. 148. Perez MG, Vassilev T, Kemmerly SA. Rhodococcus equi infection in transplant recipients: a case of mistaken identity and review of the literature. Transpl Infect Dis 2002;4(1):52–56. 149. Lo A, et al. Rhodococcus equi pulmonary infection in a pancreas-alone transplant recipient: consequence of intense immunosuppression. Transpl Infect Dis 2002;4(1):46–51. 150. Munoz P, et al. Rhodococcus equi infection in transplant recipients: case report and review of the literature. Transplantation 1998;65(3):449–453.

R.K. Avery et al. 151. Strategies for safe living following solid organ transplantation. Am J Transplant 2004;4(Suppl 10):156–159. 152. Siegel JD, et al. 2007 Guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control 2007;35(10 Suppl 2):S65–164. 153. Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Society for Healthcare Epidemiology of America/Association for Professionals in Infection Control/Infectious Diseases Society of America. MMWR Recomm Rep 2002;51(RR-16):1–45, quiz CE1-4. 154. Guidelines for vaccination of solid organ transplant candidates and recipients. Am J Transplant 2004;4(Suppl 10):160–163. 155. Avery RK, Michaels M. Update on immunizations in solid organ transplant recipients: what clinicians need to know. Am J Transplant 2008; 8(1):9–14. 156. Burroughs M, Moscona A. Immunization of pediatric solid organ transplant candidates and recipients. Clin Infect Dis 2000;30(6):857–869. 157. Pirofski LA, Casadevall A. Use of licensed vaccines for active immunization of the immunocompromised host. Clin Microbiol Rev 1998; 11(1):1–26. 158. Humar A, Morris M, Blumberg E, et al. Nucleic acid testing (NAT) of organ donors: is the “best” test the right test? A consensus conference report. Am J Transplant 2010;10:889–99. 159. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:1–45.

Chapter 19

Living Kidney Donation: Pre- and Postdonation Evaluation and Management Jonathan Taliercio and Emilio D. Poggio

Keywords  Living kidney donor • living donor evaluation • outcomes • Living donation • kidney transplantation

Introduction Over 500,000 people in the United States suffer from end stage renal disease (ESRD), with an estimated mortality of approximately 15–20% during the first year on dialysis. Despite this high mortality rate, the prevalence of patients with ESRD is rising, likely attributable to improvement in the medical care of this patient population. Kidney transplantation is considered to be the best treatment option for patients with ESRD because of the improved patient survival and quality of life [1]. Unfortunately, the limitation to kidney transplantation is organ shortage that far exceeds the needs. Living kidney donation has from the early years of clinical kidney transplantation been a major source of transplant organs, a fact that is still true 50 years after the first living donation. Dr. Joseph Murray performed the first living kidney donor transplantation on December 23, 1954 between two identical siblings, Richard and Ronald Herrick,

E.D. Poggio (*) Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Eluclid Avenue Cleveland, OH 44195, USA e-mail: [email protected]

at Peter Bent Brigham’s Hospital in Boston. Richard developed acute renal failure from an unspecified glomerular etiology at age 23. Ronald donated his kidney in order to save Richard’s life. The brothers were monozygotic twins and shared a perfectly matched HLA type, which omitted the need for immunosuppression. Richard died 8  years later from unspecified causes. Dr. Joseph Murray later went on to win the Nobel Prize in 1990 for his contributions to medicine. Since this time there have been numerous advances in transplantation medicine including tissue typing, organ procurement, and immunosuppression, which has led to an increase in the number of living donor kidney transplantation procedures performed worldwide. In 2009 living kidney donation represented approximately 46% of all kidney transplants performed in the US. While there is no international registry capturing the number of living donor kidney transplantation procedures performed globally, Hovart et  al. [2] reported that living donation is currently performed in at least 69 countries. The number and ratio between deceased donor and living donor transplantation is highly variable depending on the country, but it is estimated that approximately 27,000 living donor transplantations were performed legally worldwide in 2006, representing 39% of all kidney transplants. The shortage of available organs has forced clinicians to consider an older person with a small burden of disease as a viable candidate for donation. Fortunately, medical and surgical advancements have allowed practitioners to

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_19, © Springer Science+Business Media, LLC 2011

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accept these candidates to donate without exceeding minimal risk. For example, until the early 1990s, most living donors were 18–34 years old. More recently, the majority of donors are 35–49 years of age. This past year in the USA, there were 1,360 kidneys donated from people 50–64  years old and 65 donated from the age group of 64 and older. This trend, whereby an increasing number of donors are now older, is often the result of transplant centers responding to disparities between organ supply and demand. However, the long-term success of living kidney transplantation is sustained by the fundamental premise of “do no harm” to the donor. Therefore, the primary goal of the transplant physician is to ensure the safety of the donor, and then decide if the person would be a good candidate for the intended recipient. Many transplant centers will accept a donor with some relative contraindications if the donor will derive emotional benefit from donating. For example, the benefit a living related donor might derive from donating their organ to a loved one (spouse or offspring) may outweigh the risk of relative contraindications. This consideration is a recurrent theme when discussing many of the relative contraindications encountered in the sections ahead and should be considered on an individual basis. Consensus guidelines for kidney transplant donation were established by the Amsterdam Forum in 2004. This forum was comprised of 100 experts in the field of transplant medicine representing over 40 countries [3, 4]. The primary role of the forum was to develop a set of guidelines to help transplant centers evaluate living donor candidates to ensure their safety and optimize outcomes. Many transplant programs use the Amsterdam Forum as a guideline. However, there is significant variability among centers. As a result, potential organ donors might be able to donate a kidney at one center, but be excluded from another. This article will review some of the more contentious aspects of living kidney donor evaluation and specifically address the impact of the donor characteristics on recipient graft outcomes. We will also discuss the shortand long-term complications to the donor associated with living kidney donation.

Donor Evaluation The evaluation of prospective donors should be conducted by a nonpartisan third party (i.e., a healthcare professional not taking care of the intended recipient) in order to avoid any potential conflicts of interest among the caring physician, organ donor, and intended recipient. The evaluation process should begin by performing a screening questionnaire that would immediately disqualify a prospective living donor based on absolute medical contraindications to donor nephrectomy. Following this initial screening, all living donor evaluations should begin with a thorough history and physical exam as well as a social and psychological evaluation. Historical emphasis includes, but is not limited to, hypertension, diabetes, infections, nephrolithiasis, cancer, family history of kidney disease, hypertension and diabetes mellitus, and motivation for donation. Age-appropriate cancer screening is recommended, especially given the increasing prevalence of older prospective donors. Significant medical conditions impacting donation are summarized in Table  19.1. A typical laboratory workup of the living donor candidate is presented in Table 19.2. We present absolute and relative contraindications to living donation in Table  19.3. The following sections cover ­relevant issues in the living donor evaluation in greater detail.

Donor Age The United States requires that all organ transplant donors be 18 years or older. At this age, the individual is considered to have completed adolescence and full biologic development, and is considered a legal adult. A very important aspect to discuss with a prospective young donor relates to the impact of nephrectomy on their active lives, including plans for family development such as pregnancy in females (discussed further) or education/work-related matters that might be temporarily interrupted. A full understanding by the prospective donor of what is involved in organ

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Table  19.1  Selected medical conditions impacting living donation (From Abridged 2004 Amsterdam Forum Guidelines [Adapted from [3]) Hypertension • BP >140/90 by ambulatory blood pressure monitoring is generally not acceptable. • Donors with easily controlled hypertension who are >50 years, normal GFR for age and gender or greater than 80 mL/min/1.73 m2, and urinary albumin excretion <30 mg/day may be acceptable after a thorough evaluation and on a case-by-case consideration. Obesity • Patients with a BMI >35 kg/m2 should be encouraged to loose weight, targeting a BMI of <30 kg/m2, especially in the presence of other comorbid conditions. • All obese or overweight patients should be encouraged to lose weight, targeting a normal BMI, and maintain it following donation. Dyslipidemia • Dyslipidemia alone does not exclude a person from donation, but must be considered as a risk factor in conjunction with other comorbid conditions. Initiation of treatment when indicated should be encouraged. Pregnancy after live donation • Delay pregnancy for a minimum of 12 months after donor nephrectomy. • Closer follow up during pregnancy may be indicated in women who donated a kidney. Glomerular filtration rate (GFR) • GFR >80 mL/min/1.73 m2 is required to be eligible for donation; however, interpretation of GFR in the context of gender and age may be more appropriate. Proteinuria • Random urine albumin to creatinine ratio should be performed initially. Acceptable values are considered as follows: − <10 mg albumin/g creatinine is optimal. − Between 10 and 30 mg albumin/g creatinine may be acceptable but should be verified by a 24-h albumin excretion. − >30 mg/g is high, corresponds to what is generally regarded as albuminuria (microalbuminuria or macroalbuminuria), and is not generally acceptable. Some studies use sex-specific cut-off levels of >17 mg/g for women and >25 mg/g for men as high. • An abnormal random albumin-to-creatinine ratio should be confirmed with a 24-h urine collection. Any level of proteinuria should be considered a contraindication to donation. Hematuria • Isolated hematuria (defined as >3–5 RBCs/HPF) should prompt against donation unless urine cytology and urologic and nephrologic workup is negative. • Kidney biopsy may be indicated to assess for intrinsic renal pathology if nephrolithiasis and malignancy are excluded. Diabetes • Patients who have a history of diabetes or a fasting blood glucose ³ 26 mg/dL measured on two separate occasions (or an oral glucose tolerant test ³ 200 mg/dL are excluded from donation. Stone disease • An asymptomatic donor with a history of a simple kidney stone may still be a candidate if he/she has a normal stone workup including a 24-h urine collection and absence of multiple stones and nephrocalcinosis on imaging studies. • Asymptomatic potential donor with single stone may be a donor candidate if: − The donor meets the previous criteria, and the current stone is <1.5 cm in size or potentially removable during transplant. − Donors should be excluded if the type of stone: − Has a high reoccurrence rate (cystine, struvite, stones associated with systemic or inherited disease). − Is difficult to prevent. Malignancy • Donors are excluded for donation if they have a history of: − Melanoma, testicular, renal cell carcinoma, choriocarcinoma, hematologic malignancy, bronchial cancer breast cancer, or monoclonal gammopathy. (continued)

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Table 19.1  (continued) • Donation is acceptable in a prior history of malignancy if: − Previous treatment of malignancy does not place donor at risk for ESRD. − The cancer is curable and transmission of cancer can be excluded. Urinary tract infections • Donors need to have sterile urine before donation and asymptomatic bacteriuria should be treated prior to donation. • Unexplained hematuria and pyuria requires evaluation for adenovirus, tuberculosis, and cancer. Other infections • Negative serology for HIV, Hepatitis B and C, TB and syphilis should be confirmed.

Table 19.2  Laboratory testing and predonation workup – Complete blood count – Comprehensive metabolic panel including a fasting glucose – Coagulation studies – Lipid profile – Cytomegalovirus serology – Epstein-Barr virus serology – HSV and HHV8 – Hepatitis B and C serology – HIV – Syphilis testing – Urinalysis – Random albumin/creatinine ratio and/or 24-h urine collection – Protein/albumin quantification – Creatinine clearance or isotope GFR testing – ABO, HLA testing – Crossmatch test – Electrocardiogram – Chest roentography – Renal imaging preferably using computer tomography or magnetic resonance imaging – PPD in endemic areas or suggestive history – Urine hCG in all pre- or perimenopausal females – Pap smear testing in women £ 65 years old – Mammogram in women ³ 40 years old – PSA testing for Caucasian men older than 50 years or African-American older than 45 years – Colonoscopy ³ 50 years old or earlier if higher risk – Prospective donors with high risk for cardiovascular disease (males >45 year old, females >55 years old, hypertension, EKG abnormalities, hyperlipidemia, smoker, or peripheral arterial disease), consider cardiac stress testing – Prospective donors who are current or previous smoker, consider pulmonary function tests and chest computer tomography

donation is paramount for its success. While age 18 is a widely accepted cut off, there is no con-

cise agreement as to the age in which a person should no longer be considered a candidate for donation. The consensus guidelines established by the Amsterdam Forum [3] do not address this issue, because it is the overall health status of an individual that may be more important in determining candidacy rather than the biologic age. Some transplant programs have clear biologic age restrictions, while other programs consider older donors if they are highly functional and have a low disease burden. Age in a healthy individual is a determinant factor of kidney function. It has long been known that glomerular filtration rate (GFR), the best index of kidney function, decreases almost linearly with age. Emerging evidence shows various degrees of histologic damage normally occurring in the healthy aging individual prospective kidney donor. It is a matter of debate whether this is a physiologic or a pathologic process. Recently, investigators have also begun to focus on living donor age and its impact on recipient graft outcomes. Naumovic et  al. [5] evaluated 273 living donor kidney transplant recipients and divided them on the basis of donor age into two groups: recipients whose donors were younger than 60 years old (age 34–59) versus donors older than 60 years old (age 60–85). Recipients of grafts from each group had similar acute rejection rates; however, the older donor group was found to have lower graft function following transplantation, increased risk of chronic renal allograft dysfunction in the first year, and decreased graft survival over the 5-year study period. In a prospective study, Oien et al. [6] followed 739 first-time living kidney transplant

19  Living Kidney Donation: Pre- and Postdonation Evaluation and Management Table  19.3  Absolute and relative contraindications to donation Absolute contraindications Uncontrolled hypertension Diabetes mellitus GFR < 80 mL/min/1.73 m2 or kidney disease A 24-h urine protein >300 mg/day Age <18 years old Pregnancy Cognitive impairment or failed psychiatric testing Active infection Infection Stone disease or nephrocalcinosis, bilateral stone disease, stones >1.5 cm, potential for recurrent stone disease with presence (hypercalcuria, hyperuricemia, cystinuria, hyperoxaluria, struvite stones, and metabolic acidosis) Parenchymal kidney disease Polycystic kidney disease, Alport’s disease, IgA nephropathy Active malignancy History of melanoma, testicular, renal cell carcinoma, choriocarcinoma, hematologic malignancy, bronchial cancer, breast cancer, or monoclonal gammopathy Hepatitis B and C infections HIV Relative contraindications Age >65 years old Well controlled hypertension on only one blood pressure medication Body mass index ³ 35 kg/m2 Multiple dysmetabolic risk factors Dyslipidemia Increased risk of hypertension Increase risk of diabetes mellitus Obesity Microscopic hematuria in which urine cytology, urologic and nephrologic workup is negative Stone disease: • A single episode of asymptomatic unilateral stone disease • Stone <1.5 cm Thin basement disease Remote malignancy Remote hepatitis B and C Substance abuse

recipients over 55 months. Multivariate analysis showed that recipients whose donors were at least 65 years old had an increase in episodes of acute rejection as well as a decrease in graft survival compared to younger donors. Investigators

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at Mayo Clinic studied 103 recipients with living donors younger than 50 years old and compared them to 52 recipients with living donors 50 years old and older [7]. Their analysis showed no difference between short term graft survival but there was a significant reduction in GFR after 24 months in recipients of older donors. Poggio et al. [8] examined 104 living kidney donors and divided them into two cohorts. Two years after kidney donation, recipients of donors younger than 45 years old had a statistically significant higher estimated GFR compared to those above 45 years of age. Issa et al. [9] also showed that donor age is an independent determinant of recipient’s graft function in a larger cohort of living donor kidney transplant recipients. Therefore, analogous to what is observed in deceased donor transplantation and as shown by Iordanous et al. [10] in a systematic review of the published literature, there is now sufficient evidence suggesting that donor age is an independent factor determining graft outcomes in living donation.

Cardiovascular and Pulmonary Evaluation All candidates should undergo preoperative cardiac evaluation and testing for noncardiac surgery as defined by the 2007 American College of Cardiology and American Heart Association Task Force or individual transplant center guidelines if they have significant risk factors for cardiovascular disease [11]. Because most prospective donors are relatively young and have minimal comorbidities, specific cardiac testing is not commonly needed. It is prudent that those donors with advanced age, smoking history, or cardiovascular risk factors such as dyslipidemia undergo noninvasive stress testing. Individuals with a history of significant smoking should also have chest roentography and pulmonary function tests. There is a higher risk of postoperative pulmonary complications (pneumonia, failure to wean) with an FEV1 or FVC less than 70% predicted or FEV1/FVC less than 65%

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p­ redicted [12]. Current smokers are advised to stop permanently but if unable, encouraged to stop 4 weeks prior to surgery.

Hypertension The 2003 Joint National Committee defines hypertension as a systolic blood pressure (SBP) greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg on at least two separate occasions. Ambulatory blood pressure monitoring defines hypertension as a 24-h average BP greater than 135/85 mmHg, awake (daytime) average blood pressure (BP) greater than 140/90  mmHg, or nighttime (asleep) average greater than 125/75  mmHg. Many centers only screen patients using clinic BP readings, despite the inaccuracies of the technique. Ambulatory BP monitoring is vital in distinguishing prospective donors who have white coat hypertension versus essential hypertension that would exclude people from donation. In one study, 62% of patients who were diagnosed with clinic hypertension had a change in their diagnosis to white coat hypertension after 24-h ambulatory BP monitoring and were eligible to donate. Seventeen percent of normotensive donors by clinic BP readings were actually found to have masked hypertension and were excluded for donation. A Mayo Clinic study confirmed the previous results showing that only 11% of the original 36% prospective donors who were diagnosed with hypertension from clinic BP actually had hypertension as measured by ambulatory BP monitoring [13]. Therefore, we recommend that when possible 24-h or daytime ambulatory BP monitoring be used to confirm hypertension when clinic hypertension is diagnosed or if the donor has a strong familial history of hypertension and other risks factors such as obesity, so to expose occult disease. Traditionally, hypertension has been a contraindication to donation, but in recent years some centers began to consider prospective donors with well-controlled hypertension. Additionally, it is unclear if there is a difference between African American and Caucasian living

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donors with respect to subsequent risk of ­developing hypertension. Textor et al. evaluated 148 Caucasian living kidney donors and measured their blood pressures, microalbuminuria, and measured GFR at predonation, 6  months, and 12  months postnephrectomy. Twenty four patients were found to be hypertensive as defined by an awake ambulatory BP measurement greater than 135/85 mmHg or a BP measurement taken in the clinic of more than 140/90  mmHg. Hypertensive patients were placed on a restricted sodium diet and initiated on an angiotensin receptor inhibitor with or without a thiazide diuretic. Patients who were started on pharmacotherapy returned to the clinic for followup prior to donation. Donation proceeded in those in which hypertension was controlled. At 6 and 12 months postnephrectomy, 86% of the patients in the hypertensive group remained normotensive by clinic BP criteria and 54.1% by ambulatory BP measurement criteria. After correction for age, there was no significant difference between the normotensive and hypertensive donor group in regard to measured GFR and albuminuria at 1  year postdonation. There was also no difference in kidney recipients of these organs with respect to GFR and proteinuria at 1  year of follow up. The study concluded that Caucasian living kidney donor candidates who have moderate hypertension controlled with one medication could be acceptable kidney donor candidates [14]. Notably, this study may not be applicable to African American living donor candidates whom are known to have higher rates of hypertension, chronic kidney disease, and ESRD compared with other ethnic groups [15, 16]. A recent study demonstrated that African Americans donors have a higher risk than Caucasians of hypertension postdonation [17]. Moreover, a recent analysis by Segev et  al. of living donor data from the UNOS registry and matched healthy subjects obtained from the NHANES database showed that hypertensive African American males were at the highest risk for early postdonation mortality. [18] Therefore, evaluation of hypertension in the context of racial differences should be considered when attempting to risk stratify prospective donors.

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Metabolic Derangements Living kidney donor evaluation attempts to risk stratify candidates in order to minimize short and long-term complications. Metabolic derangements including dyslipidemia, impaired fasting glucose (IFG), and increased body mass index (BMI) are all risk factors for progression of chronic kidney disease or cardiovascular disease. The presence of one metabolic derangement conveys additional risk but individually is typically not an absolute contraindication to donation. Unfortunately, many of these metabolic derangements coexist and cluster, and thus can be additive in the total risk to the donor. Studies evaluating individual metabolic derangements and donor and or recipient allograft outcomes are limited. The sections ahead will review ­general practice guidelines regarding metabolic derangements and highlight the limited literature regarding outcomes.

Dyslipidemia Approximately 30% of all Americans have hyperlipidemia [19]. The prevalence of hyperlipidemia in donors at time of nephrectomy is not well studied. Dyslipidemia is not a contraindication to donation, but must be considered along with other risk factors when assessing donation. One study evaluated pre-operative and postoperative cholesterol in 121 living kidney donors and compared them to 81 healthy subject controls. Both groups had similar preoperative lipids levels, however at 52  months follow up, the donors had statistical significant increases in total cholesterol, low density lipoprotein, triglycerides, and weight gain [20]. Contrary to this study, Ibrahim et  al. showed that living kidney donors had lower total cholesterol and triglycerides after 12  years after donation compared to matched controls [21]. Hyperlipidemia in the donor, in conjunction with other metabolic derangements, has been shown to have a potential negative impact of long-term graft function. A retrospective study

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by Issa et al. [9] evaluated 248 live kidney donors and analyzed variables associated with progression of kidney disease in the transplanted recipient. Approximately 50% of the donors had a cholesterol level greater than 200 mg/dL, which in multivariable analysis was independently associated with poor graft function, along with higher donor blood pressure and older donors. Interestingly, the study created a model using four variables (donor age greater than 45, GFR less than 110  mL/min, total cholesterol greater than 200  mg/dL, and SBP greater than 120  mmHg) and showed a linear correlation between the presence of these individual factors and graft outcome 2 years posttransplantation.

Impaired Fasting Glucose Diabetes mellitus (DM), defined as a fasting blood glucose greater than 125 or ³126 mg/dL on two separate occasions, is an absolute contraindication for donation. Controversy exists with respect to prospective donors with an impaired fasting glucose (IFG) or history of gestational diabetes (GDM). Approximately 23% of all people in the United States have IFG, defined as plasma blood glucose between 100 and 125 mg/dL [22]. Twenty-five percent of individuals with an IFG will develop DM in 3–5 years [23]. Some transplant centers discourage donations from patients with a family history of DM or prior history of GDM alone because of the future risk to the donor of developing DM [24]. Studies indicate conversion from GDM to DM ranges between 6% and 92%, depending on race, diagnostic criteria, and duration of follow up [25]. Patients with risk factors for diabetes such as obesity, positive family history, or GDM should be screened using fasting plasma glucose or a 2-h oral glucose tolerance test. Patients with an impaired fasting glucose should proceed forward with an oral glucose tolerance test. There is a paucity of data regarding risk stratification of donors with a history of IFG or GDM with respect to donor and graft outcomes, mostly because in clinical practice these disorders preclude donation.

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Increased Body Mass Index and Obesity The National Health and Nutrition Examination Survey (NHANES) reported that approximately 70% of Americans are either overweight or obese as defined by a BMI of greater than 25 and 30 kg/ m2, respectively [26]. Evaluation of the overweight prospective donors can be challenging because obesity increases the risk of stroke, diabetes, hypertension, and cardiovascular disease in the nondonor population [27]. Epidemiologic evidence indicates that obesity is strongly associated with the progression of chronic kidney ­disease in the absence of diabetes [28] as well as the development of nephrolithaisis. A recent study by Segev et al. using the UNOS database showed that 63% of living donors had a BMI ³ 25  kg/m2. Interestingly, there was no increase in mortality when donors were stratified by BMI [18]. Patients with a BMI greater than 35 kg/m2 are generally discouraged from donating, especially in the presence of other risk factors; however, clinical practice varies at each transplant center. The integrity of allografts harvested from overweight donors has become a recent focus of attention. Obesity-related nephropathy (glomerulomegaly, thickening of the basement membrane, and perimesangial deposition) might not be appreciated during an evaluation, as it can exist in the absence of microalbuminuria [29]. Other histologic changes seen in protocol biopsies from kidneys of normotensive obese donors include increased tubular dilatation and arterial hyalinosis [30]. An elevated BMI predonation is an independent risk factor for renal function impairment 2 months after nephrectomy [31, 32]. Maintenance of the functional reserve capacity, which is necessary to preserve postdonation GFR, was absent in all obese donors during dynamic testing and was shown to have a large impact on younger donors [31]. Moreover, Espinoza et  al. demonstrated that kidney recipients of obese donors (BMI greater than 30  kg/m2) have a decreased estimated graft GFR and an increase in episodes of acute rejection 50  months after transplantation compared to nonobese donors [33]. It is recommended

that appropriate weight loss is attempted prior to donation whenever it is indicated.

Nephrolithiasis The prevalence of nephrolithiasis in the general population is between 8% and 12%, with approximately 50% of individuals being asymptomatic [34, 35]. A similar rate has recently been reported in prospective living donors by the Mayo Clinic group [36]. Since the risk of stone formation increases with age, the transplant physician will undoubtedly encounter the prospective aging donor candidate with a history of stone disease. Kidney stones have been shown to be a risk factor for the development of chronic kidney disease, and therefore the evaluating physician needs to proceed with caution [37]. More importantly, the risk of urinary obstruction due to nephrolithiasis is of concern in subjects with a single kidney. Therefore, patients with a history of nephrolithiasis need a 24-h urine analysis evaluating for hypercalcuria, hyperoxaluria, hypocitraturia, and hypercysteinuria as well as serology for serum parathyroid hormone, serum calcium, bicarbonate, albumin, hyperuricemia, and vitamin D levels. Not uncommonly, a candidate will have an asymptomatic stone incidentally identified during routine donor work up (intravenous pyelograms, CT angiography, and radionuclide scintigraphy). Renal imaging is always recommended to help identify potential problems not appreciated by history and physical exam such as renal cell carcinoma, cystic disease, and anatomical abnormalities. A recent study indicated that 26% of all prospective donors were rejected due to radiographic evidence reported on helical CT angiography leading to medical exclusions [38]. Due to the increased sensitivity and specificity of helical CT scans, more incidental defects will be appreciated and invariably create more clinical dilemmas. Many transplant institutions address the issue of prospective living donors with nephrolithiasis differently. The Amsterdam guidelines recommend that candidates who have

19  Living Kidney Donation: Pre- and Postdonation Evaluation and Management

a history of a single asymptomatic stone with a normal 24-h urine analysis are eligible to donate as long as there are no risks for recurrent stone formation. Any patient with recurrent or bilateral nephrolithiasis, nephrocalcinosis, and stones greater than 1.5 cm should not be considered for donation.

Hematuria Identification of asymptomatic kidney disease in a prospective living donor is a crucial component of the evaluation process to ensure the safety of the donor and the recipient. Routine urinalysis and sediment examination is a primary component of the initial visit. Persistent microscopic hematuria occurs in 2.7% of the general population. The presence of persistent microscopic hematuria requires further investigation [39]. Evaluating physicians should expect to encounter a higher prevalence of microscopic hematuria in the clinic, if the donor is related to the intended recipient who has a genetically transmissible renal disease. A thorough history assessing for symptoms of urinary tract infections, nephrolithiasis, smoking, and family history of kidney disease should be obtained. A workup including a urine culture, urine cytology, CT urogram, and cystoscopy might be warranted. If less invasive tests are negative, then renal biopsy might be indicated if the prospective donor is resolute on donation. Persistent isolated hematuria is often seen in intrinsic renal diseases, once anatomic abnormalities and malignancy has been excluded. One study reported ten prospective donors who underwent kidney biopsy for persistent microscopic hematuria. Six patients had thin basement membrane disease or a variant, two patients had glomerulosclerosis, and two patients had normal parenchyma. Interestingly, two out of the four patients who had pure thin basement membrane disease donated, and after 15 months the donor had not developed proteinuria, azotemia, or hypertension [39]. There is significant debate

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regarding the eligibility of donation in candidates who have IgA and thin basement disease [40]. Historically, thin basement membrane disease has a benign course; [41] however, case series have reported that this might not be such an indolent condition [42]. IgA nephropathy has a variable pathogenic course, but 20–30% of patients with the disease have progressed to ESRD [43, 44]. Other parenchymal pathologies such as Alport’s disease and polycystic kidney disease in which the only clinical manifestation is hematuria are less controversial. Six heterozygous mothers with microscopic hematuria donated their kidney to their affected child with Alport’s disease. After 6  years of follow up, 50% of donors developed new onset hypertension and 33% developed proteinuria [45]. In our opinion, all prospective donors with a family history of Alport’s disease, IgA nephropathy and microscopic hematuria should not donate. Donors with biopsy-proven thin basement membrane who still desire to donate need to be considered on an individual basis and thoroughly educated on the potential long-term risks of donation.

Renal Mass and Function Glomerular filtration rate is considered the best measure of kidney function [46]. Inulin is the most accurate method for measuring GFR. Unfortunately, because of its cost and difficult application, this approach is prohibitive. Many creatinine-based GFR equations have been developed in order to provide a noninvasive and inexpensive estimate of GFR; however, these equations are not precise and accurate enough to warrant their use in the evaluation of living donor kidney function. Traditionally, transplant facilities perform a 24-h urine collection to estimate creatinine clearance and simultaneously quantify albuminuria/proteinuria excretion. It is important to remark that accurately assessing GFR from a urine collection is fraught with many potential technical problems including collection errors, variable tubular creatinine

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secretion rates (overestimating GFR), and the inability to account for gender and age differences. However, this method is the most commonly used in the evaluation of kidney function of prospective living donors by most transplant centers when other alternatives such as isotopic (“hot”) or nonisotopic (“cold”) clearances of renal markers are not available. Radioisotope testing is considered the new “gold standard” for measuring GFR. Radioisotope testing was found to be superior to both 24-h urine collections and creatinine-based estimated GFR equations [47]. Various isotopes in clinical use are freely filtered by the kidney without being secreted by the tubules, thus reflecting a more accurate GFR [48]. An estimated GFR greater than 80  mL/min/1.73  m2 is considered appropriate for donation. However, it is now becoming more evident that using cutoffs specific for age and gender to determine normal kidney function in donors would be more appropriate [49, 50]. Patients who have marginal 24-h urine creatinine clearance or estimated GFR-based creatinine clearances should undergo radioisotope testing when possible. In the setting of health, renal mass as a surrogate marker of nephron load relates directly to renal function [8]. At the same time, renal mass relates to the size of a particular individual and consequently to gender as female are in general smaller than male. Using registry data, Kayler et al. [51] showed a significant adjusted graft survival advantage for male recipients of male donor kidneys compared with any other gender combination.InvestigatorsusingtheCollaborativeTransplant Registry identified 124,911 kidney transplant recipients. After adjusting for variables, the group showed that there was inferior graft outcomes and recipient survival when the donor was female irrespective of the recipient gender. Recipients of male donated kidneys regardless of gender had lower creatinine at 1, 3, and 10  years posttransplantation. Acute rejection was higher in male recipients who received a female kidney compared to male donated organ [52]. A confounding factor when comparing allograft survival and glomerular filtration rates is the size disparity between kidneys whose

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donor is a different gender from the recipient. The presumption is that males have larger kidneys, and therefore a larger nephron dose transplanted, which will result in an improved GFR. In one study, transplant recipients receiving a larger renal volume adjusted for recipient body size had a significantly higher GFR compared to those who received a smaller renal mass [8]. On the other hand, in a different study researchers have proposed that renal volume is not the only cause for the discrepancy in graft outcomes between genders, and proposed that the metabolic requirements of the recipient is an important contributor as well [53, 54]. In summary, female donors may have a negative effect on long-term recipient GFR if transplanted to larger patients; however, the biologic cause of this observational finding is not known and recommendations cannot be mode used on these epide miological associators.

Potential Risks Associated with Donor Nephrectomy Even prospective donors who have endured the most stringent donor evaluation will experience complications. Potential risks can be divided into immediate and late complications.

Immediate Complications Immediate complications are the usual perioperative risks associated with abdominal surgeries. Complications rates have also been influenced by the evolution from the classic open nephrectomy to the laparoscopic nephrectomy. The mortality rate for donor nephrectomies has been estimated between 0.03% and 0.04% [55, 56] and has remained stable over decades. Segev et  al. analyzed living donors from the UNOS registry and compared them to matched controls from the NHANES database over a 15-year period that incorporated the transition between

19  Living Kidney Donation: Pre- and Postdonation Evaluation and Management

open to laparoscopic nephrectomy. The group noted that there was no difference in surgical mortality between groups, and the incidence was comparable to laparoscopic cholecystectomy. However, in subgroup analysis there was a ­significant increase in perioperative mortality (within 90  days of surgery) in males, African Americans, and hypertensive donors [18]. In a separate registry study involving 1,022 donors, major complications occurred in 3% of cases [56]. Major complications included: wound infections, perforated viscous, hematomas, bleeding, hernias, and pneumothorax. Wound infection was the most common complication comprising of 40% of all major complications, which required debridement. Minor complications occurred more frequently in 18% of the cases of which urinary tract infections accounted for 56%. Other minor complications included pneumonia, urinary retention, blood transfusion, arrhythmia, deep vein thrombosis, and pneumothorax.

Late-Term Complications Maternal and Fetal Complications following Donation As the donor pool has expanded, more women of childbearing age are being considered as candidates, and the issue of the potential effects of donation on maternity and newborns has gained more attention. In a normal healthy pregnancy, there is an increase in obligate demands of the kidneys such as an increase in GFR and renal plasma flow by 50% and 25%, respectively [56]. These effects and others have been shown to result in deterioration of pre-gestational renal disease [57, 58]. There is a limited body of literature addressing this issue, and most of the available data derives form early case series in female donors and more recently from observational studies. The early case series showed that kidney donation was not associated with an increase risk for maternal or fetal complications [57, 58].

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However, these initial series involved only 56 women and 83 pregnancies and represented ­single-center experiences. In more recent reports and larger studies such as the one by Reisaeter et al. [59], the investigators identified 620 women who were pregnant prior to donation. They compared them to 106 women who became pregnant after donation, against a random population from the Medical Birth Registry of Norway assessing for pregnancy and birth outcomes. The authors found that postdonation pregnancies were associated with a significantly increased risk of preeclampsia but a nonsignificant increase in stillbirths when compared to predonation pregnancies. The risk for preeclampsia was estimated at 5.5% versus 2.6% and for stillbirths at 2.8 ­versus 1.1%. These increases were not statistically different when compared to the same outcomes in the general population. A second observational study by Ibrahim et  al. included pregnancy outcomes in 1,085 donors [21]. In this study, women were compared if they were pregnant before donation (n = 2,723), and after donation (n = 490). Interestingly, postdonation pregnancies were associated with increased risk for gestational diabetes (0.7 vs 2.7%), gestational hypertension (0.6 vs 5.7%), preeclampsia (0.8 vs 5.5%), prematurity (4.0 vs 7.1%), and fetal loss (11.3 vs 19.2%). However, as in the Reisaeter et al. study, the postdonation complications were similar to the rates observed in the general population. Therefore, there is a small but measurable increase risk for maternal and fetal complications for pregnancies after donation, however, the risks are not higher than in the general population. Disclosure of any potential risk to the prospective donor should be addressed.

Late -Term Outcomes and Implications for Subsequent Kidney Disease and Overall Survival Donor nephrectomy represents the sudden loss of approximately 50% of nephron mass, with an immediate and corresponding decrease in GFR. However, the remaining contralateral healthy

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renal parenchyma has the ability to recover a significant percentage of lost function within a ­relatively short period of time. Since the early years of kidney donation, several investigators have shown that in healthy individuals unilateral nephrectomy is followed by a compensatory increase in functional capacity of the contralateral kidney by approximately 20–40% [60–63]. Velosa et al. [63], among others, showed that as early as 1-week postnephrectomy, renal function has recovered to levels slightly lower than those achieved at 6 months post-nephrectomy. Similarly, others showed that the GFR at 1 year postdonation was essentially the same as the one achieved as early as 1 week postdonation [60, 64]. During the past decade, the National Kidney Foundation has provided the framework for a new approach to the diagnosis, staging, and management of kidney disease. Estimation of GFR plays a pivotal role in not only defining but also classifying kidney disease. However, the definition of ­kidney disease does not take into consideration the underlying pathologic process that determines the degree of kidney dysfunction. Therefore, evidence of parenchymal kidney damage is not required to establish the diagnosis of stage 3 CKD as long as the estimated GFR is less than 60 mL/min/1.72 m2 – a level that could be seen in former donors. Whether an isolated decreased GFR in an otherwise healthy subject (e.g., former kidney donors) should be considered “chronic disease” remains a matter of debate [65]. The question that the transplant community now faces is whether the current approach to CKD is applicable to living kidney donors. Prospective studies to specifically address this matter are not available yet, although singlecenter experiences with long-term follow up indirectly provide reassuring results. Perhaps more important is whether any decrease in GFR (with or without albuminuria) negatively impacts the long-term quality and extent of life following donation. Although there have been reports of the need for renal replacement therapy in kidney donors, the preponderance of evidence continues to indicate that kidney donors live at least as long as the general population [21, 66–71]. Despite the fact that mild hypertension, decreased GFR, and low

l­evels of proteinuria are commonly reported in these cohorts [72], the rates of ESRD and/or mortality are similar or lower than what is expected in the general population. Some have hypothesized that the outcomes in donors should be better than those in the general population because the latter includes subjects with undiagnosed medical and renal disease. However, this opinion may be debatable because, while donors are screened for disease prior to donation, they are not exempted from developing medical ­conditions that could lead to kidney disease ­following donation. In the study by Segev et al., in which donors were matched to subjects of the general population, the long-term mortality rates once again were found to be lower than those observed in the general population [18]. Moreover, causes of death appear to be similar to those observed in the general population, with cardiovascular events and malignancies being the most frequently reported. Factors found to be associated with renal dysfunction, albuminuria, and/or hypertension have been: time since transplantation (i.e., younger donors), female gender, and increased body weight in one study [21]. However, in a study using the UNOS registry, young male African American donors had a higher risk of needing kidney transplantation [71]. Finally, in the few studies where quality of life was assessed, former donors report superior scores when compared to those observed in the general population [21, 73].

Conclusion Living donor kidney transplantation is a wellaccepted practice for the treatment of ESRD and is a significant source of transplant organs worldwide. The overall continued success of living organ donation depends on securing the shortand long-term safety of the prospective donor, and a thorough evaluation process and subsequent follow up are paramount for its success. Prospective donors should be informed of all potential short and long-term risks. As the field evolves and the prospective donor criteria is chal-

19  Living Kidney Donation: Pre- and Postdonation Evaluation and Management

lenged, it is imperative that the transplantation community continue to place emphasis on ­understanding of the biologic, emotional, ethical, and legal implications of living donation.

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12. Gass GD, Olsen GN. Preoperative pulmonary function testing to predict postoperative morbidity and mortality. Chest 1986;89:127–135. 13. Textor SC, Taler SJ, Larson TS, Prieto M, et al. Blood pressure evaluation among older living kidney donors. J Am Soc Nephrol 2003;14:2159–2167. 14. Textor SC, Taler SJ, Driscoll N, Larson TS, et  al. Blood pressure and renal function after kidney donation from hypertensive living donors. Transplantation 2004;78:276–282. 15. Tarver-Carr ME, Powe NR, Eberhardt MS, LaVeist TA, et  al. Excess risk of chronic kidney disease among African-American versus white subjects in the United States: a population-based study of potential explanatory factors. J Am Soc Nephrol 2002;13:2363–2370. 16. Choi AI, Rodriguez RA, Bacchetti P, Bertenthal D, et al. White/black racial differences in risk of end-stage renal disease and death. Am J Med 2009;122:672–678. 17. Nogueira JM, Weir MR, Jacobs S, Haririan A, et al. A study of renal outcomes in African American living kidney donors. Transplantation 2009;88:1371–1376. 18. Segev DL, Muzaale AD, Caffo BS, Mehta SH, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA 2010;303: 959–966. 19. Goff DC, Jr., Bertoni AG, Kramer H, Bonds D, et al. Dyslipidemia prevalence, treatment, and control in the Multi-Ethnic Study of Atherosclerosis (MESA): gender, ethnicity, and coronary artery calcium. Circulation 2006;113:647–656. 20. Demir E, Balal M, Paydas S, Sertdemir Y, et  al. Dyslipidemia and weight gain secondary to lifestyle changes in living renal transplant donors. Transplant Proc 2005;37:4176–4179. 21. Ibrahim HN, Foley R, Tan L, Rogers T, et al. Longterm consequences of kidney donation. NEJM 2009;360:459–469. 22. Thorpe LE, Upadhyay UD, Chamany S, Garg R, et al. Prevalence and control of diabetes and impaired fasting glucose in New York City. Diabetes care 2009;32:57–62. 23. Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 2007;30:753–759. 24. Lumsdaine JA, Wigmore SJ, Forsythe JL. Live kidney donor assessment in the UK and Ireland. Br J Surg 1999;86:877–881. 25. Kaaja RJ, Greer IA. Manifestations of chronic disease during pregnancy. JAMA 2005;294:2751–2757. 26. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999–2008. JAMA 2010;303:235–241. 27. Malnick SD, Knobler H. The medical complications of obesity. QJM 2006;99:565–579. 28. Ejerblad E, Fored CM, Lindblad P, Fryzek J, et  al. Obesity and risk for chronic renal failure. J Am Soc Nephrol 2006;17:1695–1702.

370 29. Goumenos DS, Kawar B, El Nahas M, Conti S, et al. Early histological changes in the kidney of people with morbid obesity. Nephrol Dial Transplant 2009;24:3732–3738. 30. Rea DJ, Heimbach JK, Grande JP, Textor SC, et al. Glomerular volume and renal histology in obese and non-obese living kidney donors. Kidney Int 2006;70:1636–1641. 31. Rook M, Bosma RJ, van Son WJ, Hofker HS, et al. Nephrectomy elicits impact of age and BMI on renal hemodynamics: lower postdonation reserve capacity in older or overweight kidney donors. Am J Transplant 2008;8:2077–2085. 32. Rook M, Hofker HS, van Son WJ, Homan van der Heide JJ, et  al. Predictive capacity of pre-donation GFR and renal reserve capacity for donor renal function after living kidney donation. Am J Transplant 2006;6:1653–1659. 33. Espinoza R, Gracida C, Cancino J, Ibarra A. Effect of obese living donors on the outcome and metabolic features in recipients of kidney transplantation. Transplant Proc 2006;38:888–889. 34. Bansal AD, Hui J, Goldfarb DS. Asymptomatic nephrolithiasis detected by ultrasound. Clin J Am Soc Nephrol 2009;4:680–684. 35. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, et  al. Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int 2003;63:1817–1823. 36. Lorenz EC, Vrtiska TJ, Lieske JC, Dillon JJ, et  al. Prevalence of renal artery and kidney abnormalities by computed tomography among healthy adults. Clin J Am Soc Nephrol 2010;5(3):431–438. 37. Rule AD, Bergstralh EJ, Melton LJ, 3 rd, Li X, et al. Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 2009;4:804–811. 38. Strang AM, Lockhart ME, Kenney PJ, Amling CL, et  al. Computerized tomographic angiography for renal donor evaluation leads to a higher exclusion rate. J Urol 2007;177:1826–1829. 39. Koushik R, Garvey C, Manivel JC, Matas AJ, et al. Persistent, asymptomatic, microscopic hematuria in prospective kidney donors. Transplantation 2005;80:1425–1429. 40. Steiner RW, Spital A. Evaluating living kidney donor candidates with minor medical abnormalities. Kidney Int 2007;72:378; author reply 378. 41. Sue YM, Huang JJ, Hsieh RY, Chen FF. Clinical features of thin basement membrane disease and associated glomerulopathies. Nephrology (Carlton) 2004;9:14–18. 42. Frasca GM, Onetti-Muda A, Mari F, Longo I, et al. Thin glomerular basement membrane disease: clinical significance of a morphological diagnosis – a collaborative study of the Italian Renal Immunopathology Group. Nephrol Dial Transplant 2005;20:545–551. 43. Clarkson AR, Woodroffe AJ, Aarons IA, Thompson T, et al. Therapeutic options in IgA nephropathy. Am J Kidney Dis 1988;12:443–448. 44. Donadio JV, Grande JP. IgA nephropathy. NEJM 2002;347:738–748.

J. Taliercio and E.D. Poggio 45. Gross O, Weber M, Fries JW, Muller GA. Living donor kidney transplantation from relatives with mild urinary abnormalities in Alport syndrome: long-term risk, benefit and outcome. Nephrol Dial Transplant 2009;24:1626–1630. 46. Levey AS. Measurement of renal function in chronic renal disease. Kidney Int 1990;38:167–184. 47. Issa N, Meyer KH, Arrigain S, Choure G, et  al. Evaluation of creatinine-based estimates of glomerular filtration rate in a large cohort of living kidney donors. Transplantation 2008;86:223–230. 48. Agarwal R. Ambulatory GFR measurement with cold iothalamate in adults with chronic kidney disease. Am J Kidney Dis 2003;41:752–759. 49. Poggio ED, Braun WE, Davis C. The science of Stewardship: due diligence for kidney donors and kidney function in living kidney donation – evaluation, determinants, and implications for outcomes. Clin J Am Soc Nephrol 2009;4:1677–1684. 50. Poggio ED, Rule AD, Tanchanco R, Arrigain S, et al. Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors. Kidney Int 2009;75:1075–1087. 51. Kayler LK, Rasmussen CS, Dykstra DM, Ojo AO, et al. Gender imbalance and outcomes in living donor renal transplantation in the United States. Am J Transplant 2003;3:452–458. 52. Zeier M, Dohler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13:2570–2576. 53. Oh CK, Jeon KO, Kim HJ, Kim SI, et al. Metabolic demand and renal mass supply affecting the early graft function after living donor kidney transplantation. Kidney Int 2005;67:744–749. 54. Oh CK, Lee BM, Jeon KO, Kim HJ, et al. Genderrelated differences of renal mass supply and metabolic demand after living donor kidney transplantation. Clin Transpl 2006;20:163–170. 55. 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. 56. Mjoen G, Oyen O, Holdaas H, Midtvedt K, et  al. Morbidity and mortality in 1022 consecutive living donor nephrectomies: benefits of a living donor registry. Transplantation 2009;88:1273–1279. 57. Buszta C, Steinmuller DR, Novick AC, Schreiber MJ, et al. Pregnancy after donor nephrectomy. Transplantation 1985;40:651–654. 58. Wrenshall LE, McHugh L, Felton P, Dunn DL, et al. Pregnancy after donor nephrectomy. Transplantation 1996;62:1934–1936. 59. Reisaeter AV, Roislien J, Henriksen T, Irgens LM, et al. Pregnancy and birth after kidney donation: the Norwegian experience. Am J Transplant 2009;9:820–824. 60. Boner G, Shelp WD, Newton M, Rieselbach RE. Factors influencing the increase in glomerular filtration rate in the remaining kidney of transplant donors. Am J Med 1973;55:169–174. 61. Edgren J, Laasonen L, Kock B, Brotherus JW, et al. Kidney function and compensatory growth of the kid-

19  Living Kidney Donation: Pre- and Postdonation Evaluation and Management ney in living kidney donors. Scand J Urol Nephrol 1976;10:134–136. 62. Saxena AB, Myers BD, Derby G, Blouch KL, et al. Adaptive hyperfiltration in the aging kidney after contralateral nephrectomy. Am J Physiol Renal Physiol 2006;291:F629–634. 63. Velosa JA, Offord KP, Schroeder DR. Effect of age, sex, and glomerular filtration rate on renal function outcome of living kidney donors. Transplantation 1995;60:1618–1621. 64. Bock HA, Bachofen M, Landmann J, Thiel G. Glomerular hyperfiltration after unilateral nephrectomy in living kidney donors. Transpl Int 1992;5(Suppl 1):S156–159. 65. Poggio ED, Rule AD. A critical evaluation of chronic kidney disease – should isolated reduced estimated glomerular filtration rate be considered a “disease”? Nephrol Dial Transplant 2009;24:698–700. 66. Fehrman-Ekholm I, Duner F, Brink B, Tyden G, et al. No evidence of accelerated loss of kidney function in living kidney donors: results from a cross-sectional follow-up. Transplantation 2001;72:444–449. 67. Fehrman-Ekholm I, Elinder CG, Stenbeck M, Tyden G, et al. Kidney donors live longer. Transplantation 1997;64:976–978.

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68. Gossmann J, Wilhelm A, Kachel HG, Jordan J, et al. Longterm consequences of live kidney donation follow-up in 93% of living kidney donors in a single transplant center. Am J Transplant 2005;5:2417–2424. 69. Narkun-Burgess DM, Nolan CR, Norman JE, Page WF, et al. Forty-five year follow-up after uninephrectomy. Kidney Int 1993;43:1110–1115. 70. Ellison MD, McBride MA, Taranto SE, Delmonico FL, et al. Living kidney donors in need of kidney transplants: a report from the organ procurement and transplantation network. Transplantation 2002;74:1349–1351. 71. Gibney EM, Parikh CR, Garg AX. Age, gender, race, and associations with kidney failure following ­living  kidney donation. Transplant Proc 2008; 40:1337–1340. 72. Garg AX, Muirhead N, Knoll G, Yang RC, et  al. Proteinuria and reduced kidney function in living kidney donors: a systematic review, meta-analysis, and meta-regression. Kidney Int 2006;70:1801–1810. 73. Fehrman-Ekholm I, Brink B, Ericsson C, Elinder CG, et  al. Kidney donors don’t regret: follow-up of 370 donors in Stockholm since 1964. Transplantation 2000;69:2067–2071.

Chapter 20

Psychology, Quality of Life, and Rehabilitation After Kidney and Pancreas Transplantation Kathy L. Coffman

Keywords  Psychosocial evaluation • Kidney transplant • Psychiatric complications

Introduction The psychosocial burden that accompanies chronic disease is a challenging clinical issue that needs to be dealt with through all phases of ESRD from dialysis initiation to successful transplantation.

Psychological Aspects of ESRD End-stage renal disease and its attendant psychosocial burden have a complex bidirectional relationship. The psychological impact of kidney disease depends on the phase of life when the disease begins. Chronic kidney disease (CKD) affects both the kidney transplant candidate and the transplant recipient regarding their ability to care for themselves and their interactions with society. Some of the clinically important factors impacting the psychosocial burden in end-stage renal disease are enumerated in Table 20.1 The

K.L. Coffman (*) Cleveland Clinic Foundation, 9500 Elucid Ave/P-57, Cleveland, Ohio 44195, USA e-mail: [email protected]

following examples illustrate these points. Diabetics with ESRD may have sequelae of long-standing diabetes such as amputations, blindness, cardiac disease, cerebrovascular accidents, and erectile dysfunction, that compromise quality of life and may lead to depression. Diabetic patients with childhood onset often have difficulty adhering to diet and fluid restrictions and in an attempt to assert their independence, may take a rebellious stance as adolescents. Older patients with polycystic kidney disease (PKD) may have witnessed the demise of a parent from PKD and have a foreshortened view of their own life. They may have concerns about passing this genetic condition to 50% of their children. These factors may particularly impact their quest for living donors. Similar considerations are also relevant in African Americans who are prone to hypertensive kidney disease.

Psychological Adjustment to Dialysis Dialysis disrupts normal life. Patients may experience denial resulting in disregard for dietary and fluid restrictions or skipping dialysis sessions, resulting in severe fluid overload, hyperkalemia, and arrhythmias. Some patients regress on dialysis and try to regain control by manipulating dialysis staff about who puts them on the machine and how long they are connected. Patients with antisocial personality disorder, borderline personality disorder, obsessive

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_20, © Springer Science+Business Media, LLC 2011

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374 Table 20.1  Factors that impact psychosocial morbidity in ESRD Adherence to medical regimen Age of onset of kidney failure Body image Comorbidity Corticosteroids Disease burden Gender Growth curve Hereditary illness Side effects of medications Symptoms of uremia

compulsive disorder (OCD) traits or OCD are prone to acting out through confrontation with dialysis staff. Anger management, cognitive behavioral therapy, coping skills training, relaxation techniques, and treatment of anxiety and depression may be helpful. Patients with panic disorder and agoraphobia may require a selective serotonin uptake inhibitor (SSRI) and benzodiazepines to be able to tolerate dialysis. Restless legs syndrome (RLS) can make it difficult for patients to remain connected to the machine. Underlying iron deficiency must be treated, and ropinirole or L-dopa may diminish symptoms. Other constructive coping methods include: listening to music, reading, watching television, or sleeping during dialysis. ESRD may decrease motivation for work and household chores through anemia and uremia, causing slowed thinking, fatigue, and confusion, recent challenges that persist into adulthood. Despite many challenges, children with ESRD show remarkable adjustment, and many become employed and productive adults [1].

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Quality of life in ESRD patients is rated as less than good in two thirds of patients. Comorbidity is high in ESRD, as only 9% are free of significant comorbid conditions. Successful transplantation alleviates many of the mediators of poor quality of life in ESRD patients on dialysis. Underdialysis in the dialyzed patient or symptomatic uremia may be manifest in the transplant candidate as anorexia, mild cognitive dysfunction, hypoactive delirium, fatigue, headache, lassitude, tiredness, excessive somnolence, nausea and vomiting, or pruritus [3]. One controversial question centers on whether simultaneous K/P transplantation results in better health-related quality of life (HRQL) than kidney transplant alone. One sizable study found that HRQL was the same with either simultaneous kidney-pancreas transplant (SKPT) or kidney transplant alone (KTA) [4], whereas the majority of studies showed that HRQL was better with SPKT than KTA [5–9]. Patients after K/P transplantation with functioning kidney and pancreas, or functioning kidney that required insulin both reported better quality of life (QOL) than pretransplant patients and posttransplant recipients on dialysis who had rejected the pancreas [10]. Bentdal suggested that pancreas transplantation be considered earlier before onset of diabetic complications to improve QOL and to prevent blindness, erectile dysfunction, and other end-organ damage [11]. Although survival does not exceed that on dialysis until 1 year after transplant in those aged 60–70 years old, the procedure is still more cost effective than hemodialysis (HD). With the current prolonged waiting times, many elderly become unsuitable candidates while waiting or die [2,12].

Quality of Life in ESRD and Transplantation Quality of life in kidney and kidney/pancreas (K/P) and other categories of pancreas transplants should be considered during all stages of the transplant process. Joseph et al. provide an exhaustive overview of the many quality of life studies in kidney transplant and K/P transplant recipients [2].

Psychiatric Referral in Patients with ESRD Roughly 10% of ESRD patients have been hospitalized with a psychiatric diagnosis. Principal indications for psychiatric referral in the context

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Table  20.2  Reasons for psychiatric referral of ESRD patients

Table  20.4  Absolute psychiatric contraindications to kidney–pancreas transplantation

Transplant evaluation Adherence issues Capacity evaluation Delirium Anger and aggression Alcohol or drug abuse Insomnia Restless legs syndrome Sexual dysfunction

Active psychotic disorder Active substance abuse Extreme non-adherence to the medical regimen Mental retardation without adequate social support Severe personality disorders Suicide attempt within the past year

Absolute psychiatric contraindications to transplantation are presented in Table 20.4.

Table 20.3  Psychiatric assessment for kidney–pancreas transplantation   1. General knowledge of transplantation and capacity to give informed consent   2. Adherence to the current medical regimen   3. Social supports including having an identified caregiver   4. Attitude towards incorporation of the organs   5. Coping strategies   6. Difficulties with previous surgeries or procedures – such as dialysis   7. Past psychiatric treatment   8. Substance abuse history   9. Religious beliefs that would affect the transplant process 10. Documentation of baseline mental status examination

of end stage renal disease and transplantation are enumerated in Table 20.2. Depression appears to be undertreated, as 44% of ESRD patients scored 15 on the Beck Depression Inventory, but only 16% received antidepressants [13]. A useful approach includes describing the symptoms of depression, and asking directly whether the patient has these symptoms. Assessment for risk of suicide is essential. The suicide rate is higher in ESRD patients than in the general population, usually resulting from major depression or substance abuse, but can also occur without demonstrable psychiatric illness [14]. The challenge in the pretransplant evaluation is to make a good psychiatric assessment and analyze whether these problems will be ameliorated or exacerbated by transplantation [15]. Table 20.3 summarizes the key elements of pretransplant psychological and psychiatric evaluation in kidney and pancreas transplant candidates.

Nonadherence with the Medical Regimen A large multi-center study confirmed that noncompliance leads to worse outcomes. Nonadherence with the medical regimen is not uncommon in HD patients, and reportedly is more likely in those with financial problems precluding access to care and medications, hostility towards authority, and impaired memory. Nondiabetics and younger patients may be ­particularly prone to nonadherence [16]. Nonadherence with the medical regimen can be targeted with educational programs emphasizing the importance of attendance at dialysis, effects of diet on potassium and phosphorus, and effects of fluid overload on electrolyte levels and heart rhythm. Specific goals can be set with behavioral contracting and reinforcement through weekly telephone contacts. Group therapy in the HD unit decreases distress and weight gain between HD sessions [17].

Selection for Transplantation Most ESRD patients generally know their daily fluid restriction. They should be able to discuss problem areas of adherence with the renal diet. Very compliant patients gain between 2 and 3 kg between dialysis sessions. Excessive weight gain between HD sessions causes cramping. Blood

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pressure, glucose, phosphorous, or potassium should be well controlled. Peritoneal dialysis (PD) patients should know about sterile technique and how often they have had peritonitis. Nonadherent patients can be educated with goals for improvement over a 3–6 month period prior to listing for transplantation.

Rehabilitation Posttransplantation If patients are not participating in physical therapy or self-care, they may need psychiatric assessment for anxiety, depression, delirium, pain management, or steroid psychosis or effects of calcineurin inhibitors and other medications, dyselecrolytemias, and dysglycemia. Medication, supportive therapy from the social worker and psychiatrist, peer support, and behavioral interventions may help mobilize patients that are ­falling behind in recuperation. A pathways approach may be beneficial. Pathways to posttransplant rehabilitation are depicted in Table  20.5. Recipients who were unemployed before the transplant may feel illprepared to reenter the work force, due to outdated job skills, or loss of disability income if they obtain employment at an entry level salary. Loss of private insurance may force patients to spend down assets to qualify for state medical insurance, leaving those on a fixed income no financial cushion. Benefits of returning to work include: lower rates of depression, more motivation to maintain health, increased self-esteem, and better quality of relationships. However, remaining “sick” to ensure financial solvency may well prevent some recipients from seeking work. Several programs address this issue. The Health Insurance Portability Table  20.5  Pathways approach to rehabilitation posttransplant Early mobilization Education on self-administration of medications Expectations are set preoperatively for self-care Physical therapy to return to full mobility and increase endurance Nutritionist consultation if malnourished due to: CMV colitis, gastroparesis, pancreatitis, duodenal leakage, or uremic cachexia

Table 20.6  Barriers to employment Age discrimination Concentration problems Depressed mood from steroids Diarrhea from CellCept Difficulty multitasking Discrimination due to previous medical problems Memory problems from steroids Painful extremities from diabetic neuropathy Peripheral vascular disease limiting mobility Poor stamina from muscle weakness from corticosteroids Tremor from high levels of Tacrolimus or cyclosporine Unemployment and disability before the transplant Unrealistic fear of infection due to immunosuppression Visual impairment from irreversible diabetic retinopathy

and Accountability Act of 1996 ensures that insurance cannot be denied once the employee meets any preexisting conditions stipulations. Of kidney recipients employed at the time of transplant, 89.6% returned to work. Return to work rate among K/P recipients was 75% if employed at the time of transplant, versus 50% in those not working at the time of transplant. Return to work rates for pancreas transplant patients working at the time of transplant were 100% versus 42.8% for those not working at the time of transplant [18]. In summary, clinicians must take an objective approach to evaluating physical and psychiatric disability posttransplant. Because kidney and pancreas transplant recipients face numerous barriers to employment, the push for universal employment may not be realistic (Table 20.6).

Psychiatric Symptoms and Disorders in Kidney–Pancreas Recipients, and Adaptation to Transplantation Pretransplant Psychological Issues Diagnosis of kidney failure generally occurs months or years before transplant and most patients recall being told they would eventually need a

20  Psychology, Quality of Life, and Rehabilitation After Kidney and Pancreas Transplantation Table 20.7  Instruments for transplant assessment Psychosocial Assessment of Candidates for Transplantation (PACT), Transplant Evaluating Rating Scale (TERS) Psychosocial Levels System (PLS) Short Form Health Survey (SF-36 or SF-12) Sickness Impact Profile (SIP) Nottingham Health Profile (NHP) Beck Depression Inventory (BDI) Brief Symptoms Inventory (BSI) Symptom Checklist (SCL-90-R) Long-Term Medication Behavior Self-Efficacy Scale Kidney Transplant Questionnaire (KTQ) Kidney Disease Questionnaire (KDQ) Kidney Disease–Quality of Life (KDQOL) ESRD Symptom Checklist

transplant. Nevertheless, the decision to seek ­transplant evaluation can bring anticipatory anxiety and sleeplessness while awaiting approval for listing. Some worry that past behavior will preclude their candidacy. A few engage in acting out behavior to provoke rejection by the transplant team, because they are unable to cope with the prospect of transplantation. Generally the waiting period after listing is the hardest. Patients should be reevaluated during the waiting period to see whether medical or psychological issues have arisen that could jeopardize transplantation. Patients may witness others die on dialysis, leading to high anxiety on dialysis, posttraumatic stress disorder (PTDS), or bereavement. Dialysis patients may regress and become depressed. Reliance on immature defenses to cope including idealization/devaluation, projection, blaming, and splitting may result in termination and referral to another dialysis center. The same pattern of mistrust and poor therapeutic alliance may recur with the transplant team. These patterns should be sought and addressed in the pretransplant evaluation. Useful tools that can be employed in the pretransplant psychiatric evaluation are summarized in Table 20.7.

Posttransplant Psychological Issues Patients may feel euphoric the first few days posttransplant from the high steroid dose, relief at having survived until transplant, and anticipating

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a more liberal diet, fuller life, and improved sexual functioning. The steroid taper may cause irritability and tearfulness. A low-dose neuroleptic may help irritability. Those with a history of depression may relapse on steroids. Patients may feel overwhelmed by decreased sleep from steroids, and learning the medication regimen. Rejection causes anxiety and depression. Thoughts of the donor’s death arise toward the end of the first week. Patients often feel guilty and state, “someone had to die for me to live.” Recipients may have magical thinking, fearing that their wish for an organ caused harm to another person. Pointing out that the organ is a gift that either the donor or the donor’s family chose to give ahead of time may help recipients. Donor families experience comfort knowing their donation gave renewed life. Without adequate ­discussion patients may have survivor’s guilt and poor self care, as they can feel unworthy of the gift. Some fantasize about meeting the donor ­family, and are disappointed if the donor family does not write back. Portrayals by the media f­oster this idea, since meetings between recipients and donor families are not common. Postoperatively, some patients become delirious. Steroid psychosis rapidly responds to neuroleptics. Steroids should not be discontinued for psychosis alone as rejection will usually ensue. Common causes of delirium include altered electrolytes, antihistamines, benzodiazepines, cyclosporine A (CYA) or tacrolimus (FK506) toxicity, pneumonia, pain medications, uremia, and urinary tract infections. Primary nonfunction and graft loss may prompt depression and grief, a sense of unfairness, anger, or a loss of faith. Decreased appetite or social withdrawal with cytomegaloviral infection or esophageal candidiasis may be misinterpreted as depression. In the first 2 weeks after transplantation, biopsies, intravenous lines, phlebotomy, and side effects of medications such as tremor from tacrolimus and cyclosporine may cause anxiety or misinterpreted as such. Dopamineblocking drugs such as metoclopramide and prochlorperazine may cause akathisia, which can cause desperation and suicidality in some patients. Complications causing a long hospital stay or frequent readmissions can lead to ­separation

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anxiety, financial issues, and demoralization. The sense of being a burden to family may arise, especially if the transplant fails and the patient returns to dialysis. Changes in body image and incorporation of the organ are challenges in the first few months after surgery. Patients may resent steroid effects, which can prompt medication nonadherence. Fantasies about the donor may be fueled by any information the team discloses, such as age, sex, religion, or ethnicity. Patients may grieve for the donor, especially if the donor’s age is close to a child or grandchild. Given these considerations, information about the donor should be kept secured in a separate chart. Adjustments in family dynamics after transplant are challenging. Some patients are comfortable in the sick role and family members may reinforce this role. Fear of losing disability checks may cause patients to consider cessation of immunosuppression to return to dialysis, rather than risk unemployment, loss of medical coverage, and foreclosure. PTSD may be seen in the first month after transplant – often expressed in nightmares symbolic of the illness. As can be seen from the foregoing discussion, myriad conditions can affect quality of life after transplantation, and the clinically salient conditions that the treating physician should be on the alert for are summarized in Table 20.8.

Table 20.8  Factors that decrease quality of life in kidney transplant recipients Emotional problems Diabetes Gingival hyperplasia (CYA) Hair loss (FK506) Headaches from high levels (CYA, FK506) Hirsutism (CYA) Neurotoxicity (FK506) Older age Multiple medical comorbidities Race – African American Sex – Female Sex drive decreased Tremor (CYA, FK506) Weight gain from steroids Refs [12,19,20]

K.L. Coffman

Posttransplant Adherence to the Medication Regimen There are three basic types of nonadherent patients. The largest group (47%) are the forgetful, ­accidental noncompliers. Use of a 7-day pillbox with notebook or personal digital assistant and watch with an alarm may help patients remember their medications. Education about the basic concepts of rejection can help the 28% of patients who are “invulnerables,” who believe taking immunosuppressants on schedule is unnecessary. Education also helps the “decisive noncompliers” (25%) who make their own judgments about which drugs they will take or not take. Factors that may predict non-adherence include: demographics, poor social support, psychiatric disorders, substance abuse, and pretransplant compliance [21]. Renal transplant patients insured through Medicaid return to dialysis at double the rate at 1 year (36% vs 17%) and 5 years (26% vs 10%) than those privately insured. Figures were similar for return to dialysis in patients attending less than 85% of follow-up visits in the first 2 years, namely 1 year (35% vs 16%) and 5 years (26% vs 11%). These observations were not dependent on age, sex, delayed graft function, diabetes mellitus, education, history of prior transplant, race, distance from the medical center, sensitization, tissue mismatch, substance abuse or urban residence [22].

Psychiatric Disorders in Kidney and Pancreas Transplant Recipients Depression is a strong factor in immunosuppressant medication noncompliance in kidney transplant recipients [23]. Rates of psychosis are comparable for patients after renal transplantation, 7.5/1,000 person-years versus those on chronic dialysis, 7.2/1,000 person-years. Noncompliance resulted in graft loss in 9% of recipients with psychosis as compared with 3.7% in those without psychosis. Psychosis is also

20  Psychology, Quality of Life, and Rehabilitation After Kidney and Pancreas Transplantation

s­ ignificantly associated with increased risk of death [24].

Alcohol and Substance Abuse in Kidney and Pancreas Transplant Patients Some have stated that alcohol use is less prevalent in renal transplant recipients and ESRD patients than the general population. However, a more recent review revealed increased graft loss and patient death in alcoholic males [25,26]. Carbohydrate-deficient transferrin (CDT) has been used to diagnose and monitor chronic alcohol abuse, detecting drinking in excess of 6 drinks daily. However, more than 50% of kidney– pancreas transplant recipients have increased carbohydrate-deficient isotransferrins causing false positive results, whereas kidney transplant alone (KTA) and diabetic outpatients had normal results [27]. There is little published on marijuana use in ESRD or kidney transplantation, mostly with emphasis on risk of infection with Acinetobacter, aspergillus, and other agents [28]. Serial quantitative THC levels, preferably on urine samples, can help determine whether patients have ceased marijuana abuse. THC is stored in fatty tissue and slowly released, so with long-term heavy use, toxicology screening may be positive for up to 1 month after cessation. With only occasional use, patients will test negative within 5 days of use [29]. Morbidly obese patients may take up to 11 months to clear THC after ceasing daily marijuana use. Daily users generally will run THC levels of around 200 ng/mL [30]. Cocaine can cause renal failure due to rhabdomyolysis. Smoking tobacco has been linked to myocardial infarction, peripheral vascular events, and death after renal transplantation [31]. Since cardiovascular disease is the prime cause of mortality in kidney transplant recipients, smoking cessation programs are essential [32]. Early detection of risk factors, treatment, and followup can reduce cardiovascular mortality in renal

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transplant patients from 40–55% to 15% over an average followup of 10 years [33]. Smoking after kidney transplantation fell from 38% prior to 1990 to 13% of the cohort with transplants after 2000, but was strongly associated with vascular intimal fibrosis [31]. Tobacco use is associated with increased complications, comorbidity, graft loss, and death, and is a relative contraindication to transplantation [34]. Tobacco use was also associated with squamous cell cancer in kidney transplant recipients.

Sleep Disorders Sleep disorders are frequent in ESRD patients. Sleep apnea should be sought and treated especially in obese subjects. Restless legs syndrome may occur in 20–30% of ESRD patients. The incidence of RLS in the general population is 3–15%. RLS occurs in roughly 6.6–62% in longterm dialysis patients. Addressing iron-deficiency anemia, hyperphosphatemia, and psychological factors, and minimizing drugs that worsen RLS such as dopamine (DA) antagonists (metoclopramide, prochlorperazine, and amiodarone), lithium, SSRIs, and TCAs is essential. Proposed RLS treatments include benzodiazepines, carbamazepine, clonidine, DA agonists, gabapentin, and opioids. RLS usually remits within weeks of kidney transplantation [35].

Pain Pain in ESRD patients and K/P transplant recipients is not well studied. Some assert that a majority of ESRD patients have pain, especially diabetics due to diabetic neuropathy [36]. Chronic analgesic abuse may cause ESRD in those with chronic pain, i.e., migraine headaches. Alternatives such as gabapentin and topiramate have decreased renal clearance, and topiramate promotes kidney stones and glaucoma. We have seen

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withdrawal in two kidney transplant recipients when gabapentin dosage was abruptly decreased, with tremulousness, emotional lability, diarrhea, and extreme rebound pain, as well as tachycardia and hypertension. Withdrawal symptoms and pain control rapidly improved with return to the previous gabapentin dosage [37]. The pharmacokinetics of analgesics and metabolites may change when glomerular filtration rate is low. Pain medications exacerbate cognitive impairment, constipation, emesis, fatigue, and orthostatic hypotension. More research is needed to maximize pain relief while avoiding polypharmacy in patients with multiple comorbid conditions [15].

Table  20.10  Adverse effects of antidepressants and anxiolytics in ESRD Drug

Adverse Effect

Amitriptyline Amoxapine

Acute eosinophilic pneumonia NMS (Neuroleptic Malignant Syndrome), death Not removed by dialysis Delirium or sedation may result Reduce dosage to 150 mg every 3 days, as metabolites accumulate with low GFR If GFR < 10 mL/min, cut dose 50–75% or an active metabolite can accumulate Reversible ARF-drug-induced interstitial nephritis Reversible Guillian-Barré-like weakness Conjugated 10-hydroxynortriptyline elevated 10–20-fold Parent drug not removed by dialysis Acute eosinophilic pneumonia in overdose Parkinsonian symptoms

Benzodiazepine Bupropion SR

Buspirone

Clomipramine

Nortriptyline

Antidepressant and Antipsychotic Drugs in ESRD Clinically important considerations pertinent to antidepressants, antipsychotics, neuroleptics and anxiolytics are summarized in Tables 20.9–20.12. The neuropsychiatric side effects of immunosuppressants are summarized in Table  20.13. In ESRD patients, citalopram and fluoxetine appear to be the safest and do not require dose modification [38–40]. On dialysis, steady-state levels of fluvoxamine were reached after 8 days [41]. Previously, the psychiatric literature suggested that tricyclic antidepressants (TCAs) were generally not removed by HD so no adjustment in ­dosage was needed. Several papers refuted this finding, showing that secondary and tertiary TCAs and the hydroxylated metabolites are not Table 20.9  Antidepressants in ESRD Medication

dosing modification

Citalopram Fluoxetine Fluvoxamine

None None Increase by 20% (levels reduced 22% after dialysis) (decreased t½ with hypoalbuminemia) Reduce by ¼–½ (increased t½ from 24 h to 42–92 h)

Sertraline

Trazodone

Refs [37,41,61–65]

Table 20.11  Mood stabilizers in ESRD Drug

Dosage adjustment with Dialysis

Carbamazepine Lamotrigine

None; doubled clearance, but long t½ Significantly reduced renal clearance Give 600 mg postdialysis for level 0.6–0.8 mg/mL Dependant on renal clearance for elimination Decrease dosage if GFR < 60 mL/ min Significantly decreased level postdialysis May increase seizure risk

Lithium carbonate Oxcarbazepine

Valproate

Refs [49–53]

removed by dialysis, but glucuronidated metabolites are removed. The conjugated hydroxylated metabolites are elevated up to 500–1,000% normal, and may explain the hypersensitivity of ESRD patients to adverse effects of TCAs [42]. For example, the pharmacokinetics of nortriptyline are unchanged, but one metabolite, conjugated 10-hydroxynortriptyline, had concentrations 10–20 times higher in ESRD patients, and only

20  Psychology, Quality of Life, and Rehabilitation After Kidney and Pancreas Transplantation Table  20.12  Antidepressants and Interactions with Calcineurin inhibitors Drug

Effect

Mechanism

Fluoxetine

Rare Parkinsonian symptoms High CNI levels High CNI levels Rare Parkinsonian symptoms Rare serotonin syndrome

Dopaminergic

Fluvoxamine Nefazadone Sertraline Venlafaxine

CYP3A4 CYP3A4 Dopaminergic p-glycoprotein High desmethylvenlafaxine level

Table 20.13  Neurotoxicity of calcineurin inhibitors Symptoms Ataxia Confusion Dysarthria Grand mal Seizure Loss of consciousness Paralysis MRI findings Children – Gray and white matter changes Adults – Reversible posterior leukoencephalopathy Edema of posterior cortical and subcortical white matter

43% was removed by a 10-h dialysis session. Since nortriptyline and unconjugated 10-hydroxynortriptyline are not readily removed by dialysis, HD will not remedy toxicity in overdose situations [43]. Bupropion SR dosage should be reduced, as there is accumulation of metabolites hydroxybupropion and threohydrobupropion in patients with low GFR [44]. Benzodiazepines are not removed by dialysis and may cause sedation or delirium in patients on dialysis. Buspirone is removed by dialysis until GFR less than 10 mL/min, then dosage should be cut 50–75%, as an active metabolite can accumulate [45]. There is little information on many of the neuroleptic drugs in the setting of renal failure. Clinically, chlorpromazine has increased peritoneal clearance in continuous ambulatory peritoneal dialysis (CAPD). Delirious ESRD patients treated with haloperidol may require higher

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doses than previously thought for efficacy, in the range of 12–24 mg orally or IV total daily [46]. There was one case of hypothermia in a dialysis patient on olanzapine monotherapy [47]. Reportedly there is no need to adjust the dosage of ziprasidone, as drug levels are not affected by dialysis [48]. Since this drug causes prolonged QT on the EKG, caution would be the better part of valor in ESRD patients. There is no data available in ESRD patients for aripiprazole, but this drug may be useful in patients with prolonged QT segment, as Abilify (aripiprazole) effectively shortens the QT interval (Table 20.11) [49–54]. Posttransplant drug interactions between psychotropic medications and immunosuppressant drugs generally involve P450 3A4. Nefazodone and fluvoxamine are both metabolized via P450 3A4, so they may cause toxic levels of tacrolimus or cyclosporine. Drugs such as erythromycin, fluconazole, and HAART may also cause drug-drug interactions via P450 3A4. The anxiolytics alprazolam, midazolam, and triazolam are all 3A4 substrates and may interact with the calcineurin inhibitors in theory [55]. Serotonin syndrome is a risk if tramadol is prescribed for postoperative pain for a patients on SSRIs, SNRIs, or TCAs [56]. There is a misconception that the synthetic opioid tramadol is not addictive, but withdrawal has been observed. In one eighth of patients, atypical withdrawal included: anxiety and panic, hallucinations, paranoia, and numbness and tingling in the extremities [57]. Serotonin syndrome has resulted from combining linezolid and SSRIs [58]. Serotonin syndrome may be mistaken for the neurotoxicity of CNIs, or hepatic encephalopathy. Venlafaxine may interact with CNIs and cause serotonin syndrome, probably due to a p-glycoprotein interaction. The metabolite desmethylvenlafaxine may be doubled, though the parent drug levels are normal. Use of venlafaxine or desmethylvenlafaxine in patients with liver failure may result in fatality from serotonin syndrome [59]. Use of St. John’s wort for depression decreases calcineurin inhibitor levels by 50%, increasing the risk of rejection and cost of treatment [60].

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Summary and Conclusions Careful and comprehensive evaluation of the psychosocial milieu is an integral part of ESRD care, transplant evaluation, and the posttransplant followup of kidney and pancreas transplant recipients. Psychosocial stressors and psychiatric stressors influence the outcome of kidney and pancreas transplantation. Close involvement of personnel skilled in the management of psychosocial aspects of ESRD and transplantation through the continuum of care in the transplant process is essential to ensure durable graft and patient outcomes.

References 1. Krmar RT, Eymann A, Ramirez JA, Ferraris JR. Quality of life after kidney transplantation in children. Transplantation 1997;64(3):540–541. 2. Joseph JT, Baines LS, Morris MC, Jindal RM. Quality of life after kidney and pancreas transplantation: A review. Am J Kidney Dis 2003;42(3):431–445. 3. Tzamaloukas AH, Agaba EI. Neurological manifestations of uraemia and chronic dialysis. Niger J Med 2004;13(2):98–105. 4. Humar A, Kerr SR, Ramcharan T, Gillingham KJ, Matas AJ. Peri-operative cardiac morbidity in kidney transplant recipients: Incidence and risk factors. Clin Transplant 2001;15(3):154–158. 5. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 2001;233(4):463–501. 6. Lo A, Stratta RJ, Hathaway DK, et al. Long-term outcomes in simultaneous kidney-pancreas transplant recipients with portal-enteric versus systemic-bladder drainage. Am J Kidney Dis 2001;38(1):132–143. 7. Gross CR, Limwattananon C, Matthees B, Zehrer JL, Savik K. Impact of transplantation on quality of life in patients with diabetes and renal dysfunction. Transplantation 2000;70(12):1736–1746. 8. Adang EM, Engel GL, van Hooff JP, Kootstra G. Comparison before and after transplantation of pancreas-kidney and pancreas-kidney with loss of pancreas—a prospective controlled quality of life study. Transplantation 1996;62(6):754–758. 9. Brons IG, Calne RY, Jamieson NV, Rolles K, Williams PF, Evans DB. Results with combined kidney and paratopic segmental-pancreas transplantation. Diabetes 1989;38(Suppl 1):18–20. 10. Piehlmeier W, Bullinger M, Nusser J, et al. Quality of life in type 1 (insulin-dependent) diabetic patients prior to and after pancreas and kidney transplantation in

K.L. Coffman r­ elation to organ function. Diabetologia 1991;34(Suppl 1):S150–157. 11. Bentdal OH, Fauchald P, Brekke IB, Holdaas H, Hartmann A. Rehabilitation and quality of life in diabetic patients after successful pancreas-kidney transplantation. Diabetologia 1991;34(Suppl 1):S158–159. 12. Jofre R, Lopez-Gomez JM, Moreno F, Sanz-Guajardo D, Valderrabano F. Changes in quality of life after renal transplantation. Am J Kidney Dis 1998;32(1):93–100. 13. Moss MA, Schwartz M. Improving fluid compliance in the hemodialysis population. Nephrol News Issues 1999;13(11):81–82. 14. Kurella M, Kimmel PL, Young BS, Chertow GM. Suicide in the United States end-stage renal disease program. J Am Soc Nephrol 2005;16(3):774–781. 15. Kurella M, Bennett WM, Chertow GM. Analgesia in patients with ESRD: A review of available evidence. Am J Kidney Dis 2003;42(2):217–228. 16. Auslander GK, Buchs A. Evaluating an activity intervention with hemodialysis patients in Israel. Soc Work Health Care 2002;35(1–2):407–423. 17. Shrestha A, Shrestha A, Vallance C, McKane WS, Shrestha BM, Raftery AT. Quality of life of living kidney donors: A single-center experience. Transplant Proc 2008;40(5):1375–1377. 18. Carter JM, Winsett RP, Rager D, Hathaway DK. A center-based approach to a transplant employment program. Prog Transplant 2000;10(4):204–208. 19. Matas AJ, McHugh L, Payne WD, et al. Long-term quality of life after kidney and simultaneous pancreas-kidney transplantation. Clin Transplant 1998;12(3):233–242. 20. Johnson CD, Wicks MN, Milstead J, Hartwig M, Hathaway DK. Racial and gender differences in quality of life following kidney transplantation. Image J Nurs Sch 1998;30(2):125–130. 21. Rapisarda F, Tarantino A. Non compliance predictive factors in renal transplantation. G Ital Nefrol 2004;21(1):51–56. 22. Kalil RS, Heim-Duthoy KL, Kasiske BL. Patients with a low income have reduced renal allograft survival. Am J Kidney Dis 1992;20(1):63–69. 23. Cukor D, Newville H, Jindal R. Depression and immunosuppressive medication adherence in kidney transplant patients. Gen Hosp Psychiatry 2008;30(4):386–387. 24. Abbott KC, Agodoa LY, O’Malley PG. Hospitalized psychoses after renal transplantation in the United States: Incidence, risk factors, and prognosis. J Am Soc Nephrol 2003;14(6):1628–1635. 25. Fierz K, Steiger J, Denhaerynck K, Dobbels F, Bock A, De Geest S. Prevalence, severity and correlates of alcohol use in adult renal transplant recipients. Clin Transplant 2006;20(2):171–178. 26. Gueye AS, Chelamcharla M, Baird BC, et  al. The association between recipient alcohol dependency and long-term graft and recipient survival. Nephrol Dial Transplant 2007;22(3):891–898. 27. Arndt T, Hackler R, Muller T, Kleine TO, Gressner AM. Increased serum concentration of carbohydrate-deficient transferrin in patients with combined pancreas and kidney transplantation. Clin Chem 1997;43(2):344–351.

20  Psychology, Quality of Life, and Rehabilitation After Kidney and Pancreas Transplantation 28. Coffman KL. The debate about marijuana usage in transplant candidates: Recent medical evidence on marijuana health effects. Curr Opin Organ Transplant 2008;13(2):189–195. 29. Schwartz RH. Urine testing in the detection of drugs of abuse. Arch Intern Med 1988;148(11):2407–2412. 30. de Mattos AM, Prather J, Olyaei AJ, et  al. Cardiovascular events following renal transplantation: Role of traditional and transplant-specific risk factors. Kidney Int 2006;70(4):757–764. 31. Ehlers SL, Rodrigue JR, Patton PR, Lloyd-Turner J, Kaplan B, Howard RJ. Treating tobacco use and dependence in kidney transplant recipients: Development and implementation of a program. Prog Transplant 2006;16(1):33–37. 32. Ostovan MA, Fazelzadeh A, Mehdizadeh AR, Razmkon A, Malek-Hosseini SA. How to decrease cardiovascular mortality in renal transplant recipients. Transplant Proc 2006;38(9):2887–2892. 33. Zitt N, Kollerits B, Neyer U, et al. Cigarette smoking and chronic allograft nephropathy. Nephrol Dial Transplant 2007;22(10):3034–3039. 34. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis 2000;36(1):167–176. 35. Micozkadioglu H, Ozdemir FN, Kut A, Sezer S, Saatci U, Haberal M. Gabapentin versus levodopa for the treatment of restless legs syndrome in hemodialysis patients: An open-label study. Ren Fail 2004;26(4):393–397. 36. Innis J. Pain assessment and management for a dialysis patient with diabetic peripheral neuropathy. CANNT J 2006;16(2):12–7, 20–6; quiz 18–9, 27–8. 37. Coffman KL. (Personal Observation). 38. Blumenfield M, Levy NB, Spinowitz B, et  al. Fluoxetine in depressed patients on dialysis. Int J Psychiatry Med 1997;27(1):71–80. 39. Bergstrom RF, Beasley CM, Jr, Levy NB, Blumenfield M, Lemberger L. The effects of renal and hepatic disease on the pharmacokinetics, renal tolerance, and risk-benefit profile of fluoxetine. Int Clin Psychopharmacol 1993;8(4):261–266. 40. SchwenkMH,VergaMA,WagnerJD.Hemodialyzability of sertraline. Clin Nephrol 1995;44(2):121–124. 41. Kamo T, Horikawa N, Tsuruta Y, Miyasita M, Hatakeyama H, Maebashi Y. Efficacy and pharmacokinetics of fluvoxamine maleate in patients with mild depression undergoing hemodialysis. Psychiatry Clin Neurosci 2004;58(2):133–137. 42. Lieberman JA, Cooper TB, Suckow RF, et al. Tricyclic antidepressant and metabolite levels in chronic renal failure. Clin Pharmacol Ther 1985;37(3):301–307. 43. Dawling S, Lynn K, Rosser R, Braithwaite R. Nortriptyline metabolism in chronic renal failure: Metabolite elimination. Clin Pharmacol Ther 1982;32(3):322–329. 44. Worrall SP, Almond MK, Dhillon S. Pharmacokinetics of bupropion and its metabolites in haemodialysis patients who smoke. A single dose study. Nephron Clin Pract 2004;97(3):c83–89.

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45. Bennett WM, Singer I, Coggins CJ. A guide to drug therapy in renal failure. JAMA 1974;230(11):1544–1553. 46. Sanga M, Shigemura J. Pharmacokinetics of haloperidol in patients on hemodialysis. Nihon Shinkei Seishin Yakurigaku Zasshi 1998;18(2):45–47. 47. Fukunishi I, Sato Y, Kino K, Shirai T, Kitaoka T. Hypothermia in a hemodialysis patient treated with olanzapine monotherapy. J Clin Psychopharmacol 2003;23(3):314. 48. Aweeka F, Jayesekara D, Horton M, et al. The pharmacokinetics of ziprasidone in subjects with normal and impaired renal function. Br J Clin Pharmacol 2000;49(Suppl 1):27S–33S. 49. Procci WR. Mania during maintenance hemodialysis successfully treated with oral lithium carbonate. J Nerv Ment Dis 1977;164(5):355–358. 50. Gubensek J, Buturovic-Ponikvar J, Ponikvar R, Cebular B. Hemodiafiltration and high-flux hemodialysis significantly reduce serum valproate levels inducing epileptic seizures: case report. Blood Purif 2008;26(4):379–380. 51. Fillastre JP, Taburet AM, Fialaire A, Etienne I, Bidault R, Singlas E. Pharmacokinetics of lamotrigine in patients with renal impairment: Influence of haemodialysis. Drugs Exp Clin Res 1993;19(1):25–32. 52. Lee CS, Wang LH, Marbury TC, Bruni J, Perchalski RJ. Hemodialysis clearance and total body elimination of carbamazepine during chronic hemodialysis. Clin Toxicol 1980;17(3):429–438. 53. Maia J, Almeida L, Falcao A, et al. Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther 2008;46(3):119–130. 54. Goodnick PJ, Jerry J, Parra F. Psychotropic drugs and the ECG: Focus on the QTc interval. Expert Opin Pharmacother 2002;3(5):479–498. 55. Fireman M, DiMartini AF, Armstrong SC, Cozza KL. Immunosuppr Psychosom 2004;45(4):354–360. 56. Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997;31(2):175–177. 57. Senay EC, Adams EH, Geller A, et  al. Physical dependence on ultram (tramadol hydrochloride): Both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003;69(3):233–241. 58. Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake inhibitors: Case report involving sertraline and review of the literature. Pharmacotherapy 2006;26(2):269–276. 59. Newey C, Khawam E, Coffman K. Not provided. Not provided. 2009 or 2010, in press. 60. Beer AM, Ostermann T. St. John ‘s wort: interaction with cyclosporine increases risk of rejection for the kidney transplant and raises daily cost of medication. Med Klin (Munich) 2001;96(8):480–483. 61. Kunishima Y, Masumori N, Kadono M, Tsukamoto T. A case of neuroleptic malignant syndrome in a patient with hemodialysis. Int J Urol 2000;7(2):62–64. 62. Fukunishi I, Kitaoka T, Shirai T, Kino K, Kanematsu E, Sato Y. A hemodialysis patient with trazodone-induced parkinsonism. Nephron 2002;90(2):222–223.

384 63. Onishi A, Yamamoto H, Akimoto T, et al. Reversible acute renal failure associated with clomipramineinduced interstitial nephritis. Clin Exp Nephrol 2007;11(3):241–243. 64. Noh H, Lee YK, Kan SW, Choi KH, Ha DS, Lee HY. Acute eosinophilic pneumonia associated with ami-

K.L. Coffman triptyline in a hemodialysis patient. Yonsei Med J 2001;42(3):357–359. 65. Salerno SM, Strong JS, Roth BJ, Sakata V. Eosinophilic pneumonia and respiratory failure associated with a trazodone overdose. Am J Respir Crit Care Med 1995;152(6 Pt 1):2170–2172.

Chapter 21

Kidney Allocation System for Deceased Donor Kidneys in the United States Islam A. Ghoneim and David A. Goldfarb

Keywords  Cadaveric kidneys • allocation • organ procurement

Introduction The inadequate supply of organs in relationship to those in need is the driving force behind allocation [1]. To allocate is to apportion for a specific purpose or to particular persons scarce and limited resources according to a specific plan. Organ allocation is a major undertaking that requires sharing of critical information pertaining to both donors and recipients among the involved medical parties as well as the physical process of organ procurement and delivery.

What Is the National Infrastructure for Organ Allocation? The US government created the Organ Procurement and Transplantation Network (OPTN) in 1984 to link the medical professionals involved in the process of organ transplantation on both the donor and recipient ends [2]. The major goal of OPTN was to efficiently and effectively allow for organ sharing on the national scale. I.A. Ghoneim (*) Cleveland Clinic, Glickman Urological & Kidney Institute – Q10, 9500 Euclid Avenue, Cleveland, OH, USA, 44195 e-mail: [email protected]

The US government has chosen to delegate, under federal contract, the day to day operation and management of OPTN to a private, nonprofit organization. This organization has the responsibilities of • Establishing an organ sharing process that maximizes the efficient use of deceased donor organs • Ensuring the fair and timely allocation of donor organs • Establishing a patient waiting list system that allows for the collection, storage, analysis of patient data thus facilitating organ matching, and transplantation • Providing information, consultation and guidance to persons and organizations concerned with human organ transplantation in order to increase the number of organs available for transplantation The current organization appointed to the management of OPTN is the United Network for Organ Sharing (UNOS) based in Richmond, Virginia [3]. UNOS has been managing the OPTN since its inception and has been awarded five successive contract renewals. Most of the current policies and bylaws that operate within OPTN have been proposed and adopted by UNOS.

Ethical Issues in Organ Allocation Any organ allocation system aims to provide the sharing of organs, a scare and lifesaving form of therapy, by balancing two major ethical principles:

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_21, © Springer Science+Business Media, LLC 2011

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equity and utility. Equity implies the fair distribution of organs such that an equal chance exists for every potential recipient to receive each potential organ. Utility involves providing as much benefit out of each potential organ, which can be measured by maximizing patient survival, graft (kidney) survival, quality of life, and years added to life (compared with the alternative, dialysis). Utility emphasizes the efficient use of a scarce resource. Both principles on their own are insufficient to provide an adequate compressive system that caters for the specifics of the patients on the waiting list [1]. Other ethical and moral principles must be factored into the process, such as prioritarianism, which favors those that are sicker, worst-off, or are younger. A complex system incorporating ethical and medical factors forms the basis for organ allocation.

The Current Organ Allocation System OPTN divides the USA into 58 donation service areas (DSAs). Each DSA is locally operated by an independent organ procurement organization (OPO) that implements UNOS policies and procedures and functions in conjunction with local donor hospitals and transplant programs. Hospitals within a DSA are required by the Center for Medicare and Medicaid Services (CMS) to notify their OPO of any deaths likely to occur in the hospital setting such that organ donation may be contemplated in those cases. Several criteria allow hospitals to identify potential donors; the most commonly used is the Glasgow Coma Scale. Patients with acute brain injury, a Glasgow coma scale less than 5, and dependency on mechanical ventilation are medically reviewed as potential donors [4]. Once brain death is declared, medical suitability is confirmed, and consent is obtained for donation, a list of potential candidates is generated from the national waiting list [5]. Priority for allocation of kidneys is given first to local patients (the local OPO list). Provided the kidneys are suitable and matched with local waitlist candidates, the kidneys remain with transplant centers in the DSA so that logistically they can be transplanted as quickly as possible. If the kidneys are

turned down locally for medical concerns or there are no suitable local candidates, then priority for the offer goes to a regional list, and finally to a national list. (See later for zero mismatch mandatory national sharing.) The final decision on the recipient of the organ among that group of candidates is the prerogative of the transplant surgeon and should be based on sound medical issues. In 1999 UNOS launched UNet, a secure, Internetbased transplant database system for all organ matching and management of transplant data that allows the rapid and confidential sharing of pertinent medical and social information related to potential organ donors. UNet  also displays the highest scoring candidates on the waiting list who are potential recipients for these organs. An elaborate system exists that allows selection of candidates for every potential organ from the national waiting list. Until 2007, the process of notifying centers of organ offers was done by phone contact. In 2007, UNOS released DonorNet, which is an electronic system for notification of potential donors and the candidate match list [6]. This system is able to accommodate more simultaneous offers to transplant centers than would otherwise be feasible through a system of phone contact. OPO coordinators enter pertinent medical information in the field regarding the donor offer. A preliminary offer is then sent to the transplant center designee. If the donor meets the center’s acceptance criteria, then appropriate candidates can be entered into the computer for provisional acceptance. When the organs are procured, they are accepted for the first medically suitable candidate in points order on the match run. All of this is now done by the secure, Internet-based system DonorNet. OPOs and centers then arrange the logistics for transplantation of the organ. The match list run involves a “point system algorithm” run by a central computer that assigns each recipient points based on the following factors:

Wait Time This is simply the time the patient has been on the waiting list. One point is added for every year from the time of listing and activation.

21  Kidney Allocation System for Deceased Donor Kidneys in the United States

Wait time is the largest determinant of ranking order when a suitable organ is offered. It fulfills the “first come, first served” principle of equity and fairness.

HLA Matching HLA matching is known to improve long-term outcomes [7]. In the era of modern immunosuppression, the impact of HLA matching on outcome and the decision-making process has declined. Class I HLA antigens A and B have been shown to play a lesser role in determining short-term outcome, and their effect on the long term outcome is questionable. In addition, HLA-B matching can result in racial disparity [8]. HLA-DR matching has been shown to have the highest impact on graft survival. The current UNOS point system has undergone several modifications in this area to accommodate the evolving outcomes data. The system now allocates 2 points for a DR zero mismatch and 1 point for one DR mismatch. Outcome optimization through HLA matching improves organ utilization.

Zero Mismatch (0MM) Sharing In accordance with the principle of utility, 0MM organs (HLA-ABDR) are mandatorily shared [9]. This is based on the improved outcomes associated with these kidneys. Notwithstanding, there may be circumstances where nonimmunologic donor quality issues may outweigh the purported immunological advantage of the 0MM. For example, the offer of a 66-year-old 0MM donor with diabetes, hypertension, and an elevated creatinine may not be appropriate for an 18-year-old recipient based on adverse predictors of graft longevity. It is the prerogative of the receiving center whether to accept such an offer. The procuring OPO will offer a 0MM kidney to the appropriate matching patient regardless of the geographic location of the recipient. A 0MM kidney identified in New York is shared with a patient in Seattle as determined by the national list. Note that 0MM kidneys will first be offered

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to local candidates, then to regional, and finally national candidates. This obligatory organ sharing mandates a payback organ from the receiving OPO. This policy has created a situation where some OPOs are disproportionate exporters or importers of mandatory shared kidneys. Some OPOs have had to create local regulatory governances to prevent a kidney debt from getting out of control. The 0MM policy has been modified in 2009 to allow more organs to remain locally within an OPO to avoid a constant drain of organs through either obligatory sharing or payback. The system currently requires sharing of 0MM organs to matching recipients only if the recipient is sensitized and has a calculated panel reactive antibody or CPRA of 20% or more.

Degree of Sensitization Panel reactive antibody (PRA) is a measure how sensitized a candidate is. Actual PRA measurement represents the percentage of a standard HLA typed panel that is reactive with the candidate’s serum. It is taken as a surrogate for how difficult it is to find a cross-match negative organ for this patient. PRA has now been replaced by calculated panel reactive antibody (CPRA), which is the percentage of deceased organ donors that will be crossmatch incompatible for a candidate [10]. This involves entering unacceptable antigens which the patient has, based on more sensitive contemporary tissue typing methods, as part of their profile on the waiting list. Though fewer organs will be offered to such patients as a result of a high CPRA, the organs that are offered will have a higher likelihood of a negative crossmatch. Candidates with a CPRA 80% or greater receive 4 points.

Younger Age Transplant candidates who are 11 years of age or younger are assigned 4 points and those 11–18 years old are given 3 points for zero mismatch offers. Candidates 18 years old or younger

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are given priority for organs that are from donors 35 years old or younger. They are offered organs second only to those with a 0MM.

Prior Organ Donation Candidates who have been prior living donors are granted 4 points and are prioritized for matching after those with a zero mismatch.

Strengths and Weaknesses of the Current Kidney Allocation System The current system identifies two main types of donors; the standard criteria donor (SCD) and the expanded criteria donor (ECD). This separation was based on donor characteristics that have been shown to affect outcome. ECD kidneys, by definition, have a relative risk of graft failure of 1.7 or greater compared to a reference range of donors between 18 and 39 years [11]. The ECD donors are over 50 years old, died of cerebrovascular accident, and have a history of hypertension or abnormal creatinine at procurement. Any donor over 60 years old is automatically an ECD donor. The allocation of these organs is based on wait time alone (except priority for 0MM). The purpose of this designation was to facilitate placement of lower quality organs into patients unlikely to sustain the wait time for a standard criteria kidney. This two category model does not always predict the actual recipient outcomes because there is considerable overlap in the donor quality between ECD and SCD kidneys [12]. HLA matching for only DR loci has allowed better outcomes; however, it has lead to a more limited role for HLA matching in the point system. This in turn has allowed wait time to take the more determinant role for prioritizing candidates. Despite the fairness of a system driven by waiting time, it does not give importance to those of more medical urgency such as those with

I.A. Ghoneim and D.A. Goldfarb

limited vascular access for dialysis or those with multiple comorbidities that are adversely affected by a long time on dialysis. Any such exceptions to prioritize patients based on medical need must be agreed upon between centers within a DSA. This is where kidney allocation becomes different from liver or lung allocation. In kidney there is no priority score based on medical need. In liver the MELD score predicts waitlist mortality and in lung transplantation the LAS score incorporates medical need and patient benefit. The present allocation system has created some paradoxical dilemmas. Given the importance of wait time to prioritizing patients, older recipients (with relatively lower life expectancy compared to younger recipients) may receive young donor organs with the potential for very long graft survival. Since death with a functioning graft is still common, the loss of graft life potential in this setting represents a potential inefficient use of the organ [13]. Equally of concern is allocating a poor quality organ to a younger patient who may predictably outlive the lifespan of the graft. The zero mismatch system, while allowing maximum utilization of organs, has maintained the racial disparity gap such that minorities are less likely to receive a zero mismatched kidney and will be offered fewer local organs when their local OPO is obliged to share optimum organs for payback.

Additional Considerations for a New Allocation System Several concepts are currently under evaluation by UNOS in an attempt to devise a more comprehensive approach to organ allocation. Life years from transplant (LYFT), the donor profile index, and dialysis time are the factors being studied; the ultimate goal being the integration of these factors into a formula to derive a Kidney Allocation Score (KAS). Such a system represents a new approach to balancing equity and utility as the disparity

21  Kidney Allocation System for Deceased Donor Kidneys in the United States

between the number of candidates and organs becomes greater.

Life Years from Transplant LYFT is defined as the difference between a ­candidate’s median projected survival after transplantation minus their waitlist survival should they remain indefinitely on dialysis [14]. This formula for LYFT calculation is: LYFT = (estimated survival with transplant from available donor) − (estimated survival on dialysis) × 0.8 The estimated survival on dialysis is adjusted for the lower quality of life by a factor of 0.8 based on surveys of candidates on the waiting list on dialysis. Several variables of clinical importance and statistical significance are incorporated in calculating LYFT; they are shown in Table 21.1. LYFT is designed based on data that is derived objectively, is reproducible across transplant centers, is readily available, and is of good quality (i.e., properly obtained and recorded). In general, it provides for placing organs with a longer anticipated graft life into younger patients and those with lower anticipated graft survival into older recipients with

Table 21.1  Factors used to calculate LFYT Factor used to calculate LYFT Candidate age at offer Zero antigen mismatch Degree of mismatch at the HLA-DR loci Candidate and donor located in same donor service area Donor after cardiac death Donor age Donor cause of death Donor CMV serology Donor hypertension Donor weight Candidate years on dialysis at offer Candidate BMI Candidate albumin Candidate diabetes status Candidate previous transplant Candidate CPRA Candidate diagnosis of polycystic disease

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Table 21.2  Factors used to calculate DPI Age Gender Race Height Weight Creatinine History of smoking Donor after cardiac death Current ECD definition Hepatitis C virus History of hypertension History of diabetes Cause of death (i.e., anoxia, stroke, central nervous system tumor, other)

a calculated shorter life expectancy. It is designed to optimize utility in an allocation system. It has been criticized because of the adverse impact it may have on the older candidate population.

Donor Profile Index The classification of deceased donor kidneys into two discrete categories (SCD and ECD) has been shown not to precisely correlate with the true clinical performance of these kidneys in their recipients [12, 15]. The quality of an organ is best depicted as a spectrum that can only be represented by a continuous measure; the Donor Profile Index. The DPI includes more variables than the current system (Table 21.2). The intended designation will be a DPI of zero for those kidneys with the best performance and survival potential and a DPI of one for those with the worst. DPI will provide more donor information that is hoped to ultimately lead to a greater and more appropriate utilization of organs.

Dialysis Time Disparities in the timing of referral may be out of the control of patients. In order to “level the playing field,” normalizing the waitlist to the

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initiation of dialysis may be a new mechanism to incorporate equity that is based on medical need into the allocation algorithm.

Sensitization Calculated Panel Reactive Antibody (CPRA) is the calculated percentage of donors having one or more HLA antigens that would not be compatible for a specific transplant candidate. The new system will continue to include CPRA to allow for prioritization of highly sensitized individuals. Currently only those with a CPRA greater than 80% are given priority (get 4 points). The new system will allocate 0–4.5 points in a sliding scale fashion in linear correspondence with the CPRA. This allows those with a CPRA of, e.g., 30% to still get points as they truly experience barriers to transplant. Incorporation of the above factors allows the inherent disadvantages of each one to be compensated for by the others. LYFT may be disadvantageous to elderly candidates with several comorbidities. This is balanced by other factors such as time on dialysis and CPRA.

Summary Allocation is a complex endeavor. It is the system that designates the utilization of a scarce resource, which in this case is the donor kidney. It ultimately reflects the value system of the organization that creates it, and strives to balance the ethical notions of equity, justice, and utility. The kidney committee of UNOS is looking at new ways to allocate kidneys that may incorporate some of the concepts elaborated above, including LYFT, donor profile indexing, and dialysis time.

I.A. Ghoneim and D.A. Goldfarb

References 1. Persad G, Wertheimer A, Emanuel EJ. Principles for allocation of scarce medical interventions. Lancet 2009;373:423–431. 2. HRSA - OPTN history. (Accessed at http://optn. transplant.hrsa.gov/optn/history.asp.) 3. United Network for Organ Sharing Website. (Accessed at http://www.unos.org/.) 4. Shafer TJ, Wagner D, Chessare J, et  al. US organ donation breakthrough collaborative increases organ donation. Crit Care Nurs Q 2008;31:190–210. 5. O’Connor K, Delmonico, F. Donation after cardiac death and the science of organ donation. In: Cecka and Terasaki E (ed.). Clinical Transplants 2005. Los Angeles: UCLA Immunogenetics Center, 2005:229–234. 6. Massie AB, Zeger SL, Montgomery RA, Segev DL. The effects of DonorNet 2007 on kidney distribution equity and efficiency. Am J Transplant 2009;9:1550–1557. 7. Goes N, Chandraker A. Human leukocyte antigen matching in renal transplantation: An update. Curr Opin Nephrol Hypertens 2000;9:683–687. 8. Ting A, Edwards LB. Human leukocyte antigen in the allocation of kidneys from cadaveric donors in the United States. Transplantation 2004;77:610–614. 9. Organ procurement, distribution and alternative systems for organ distribution and allocation. http://optn. transplant.hrsa.gov/PoliciesandBylaws2/policies/ pdfs/policy_7.pdf 10. Cecka JM. Calculated PRA (CPRA): The new measure of sensitization for transplant candidates. Am J Transplant 2010;10:26–29. 11. Delmonico FL, Sheehy E, Marks WH, Baliga P, McGowan JJ, Magee JC. Organ donation and utilization in the United States, 2004. Am J Transplant 2005;5:862–873. 12. Schold JD, Kaplan B, Baliga RS, Meier-Kriesche HU. The broad spectrum of quality in deceased donor kidneys. Am J Transplant 2005;5:757–765. 13. Meier-Kriesche HU, Schold JD, Gaston RS, Wadstrom J, Kaplan B. Kidneys from deceased donors: maximizing the value of a scarce resource. Am J Transplant 2005;5:1725–1730. 14. Wolfe RA, McCullough KP, Schaubel DE, et  al. Calculating life years from transplant (LYFT): Methods for kidney and kidney-pancreas candidates. Am J Transplant 2008;8:997–1011. 15. Rao PS, Schaubel DE, Guidinger MK, et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation 2009;88:231–236.

Chapter 22

Ethics of Transplantation David A. Goldfarb and Jerome F. O’Hara Jr.

Keywords  Ethical principles • transplant tourism • brain death

Introduction Judgments based on ethical principles are part of the daily routine of transplant professionals. This is driven by the unique circumstances in transplantation where vital human organs are removed from one person and placed into a second human being. The inherent conflicts engendered by this activity are resolved into accepted standards of behavior through the study of ethics. As a consequence of ethical discussions, rules and policies are drafted that provide a template for standards of practice. Additionally, transplantation is limited by the supply of organs. For example, there are approximately 83,000 perspective waitlist patients in USA and only 16,500 transplants were performed in 2008 (the last year with complete information). The scarcity of organs as a resource also creates its own ethical concerns, particularly regarding allocation. The range of ethical concerns and questions is large. These include such topics as establishing brain death, donation by cardiac death, presumed consent for

D.A. Goldfarb (*) Cleveland Clinic, Glickman Urological & Kidney Institute – Q10, 9500 Euclid Avenue, Cleveland, OH USA, 44195 e-mail: [email protected]

donation, allocation policy, standards for living donation, payment for organs, transplant tourism, paired donation, solicitation for organs, donor quality, and informed consent. In this chapter we will highlight a few basic ethical issues.

Brain Death Donors must be dead in order to recover their organs for the purpose of transplantation. This is what is commonly known as the “dead donor rule,” and is a widely accepted. This is based on the ethical principle that it is wrong to kill an innocent person to save the life of another. It is acceptable to retrieve organs from someone who has already died of an independent cause. The ethical dilemmas arise in defining the criteria for death, how to identify such patients, obtaining consent for organ donation, and the logistics of performing organ procurement. Some background is important to understand this issue. The moment of death is extremely difficult to precisely define. Is it with cessation of brain function? or of heart beat? or of spontaneous respirations? Traditionally, the time of death has been associated with the cessation of spontaneous respiration or heartbeat. Brain death was not recognized until recently. As transplantation emerged as a viable therapeutic option in the 1960s, there was not universal acceptance for cessation of brain function (with a beating heart) to be the basis for declaration of death. In most circumstances, donation was limited to what we

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_22, © Springer Science+Business Media, LLC 2011

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now call donation by cardiac death protocols, even for brain-dead patients. The success of improved life-sustaining technology, such as reliable mechanical ventilation, lead to prolonged survival in patients with severe neurological injury. Absence of total brain function (cortical and brainstem) would lead to loss of integrative body function and spontaneous cessation of respiratory and cardiac function without mechanical life support. In 1968, a report of the Ad Hoc Committee of the Harvard Medical School to examine the definition of brain death was published [1]. This paper changed the landscape in transplantation. The authors defined irreversible coma (or brain death) as a new criterion to define death for two reasons: first, to facilitate withdrawal of care in patients with no hope of meaningful neurologic recovery, in order to avoid protracted futile care and family suffering. Second, it would standardize the death criteria to avoid controversy in obtaining organs for transplantation. These lead to the establishment of brain death laws, and the general acceptance of brain-dead patients as a source of human organ donors. Organ procurement could be conducted on heart beating, brain-dead donors with legal legitimacy, subject to the consent of the patient (advanced directive) or surrogate. Not only did this improve the number and quality of organs transplanted but it also paved the way for multi­ organ transplantation.

Consent for Brain Dead Donors Coupled with the establishment of death, organ procurement can only proceed with consent of the donors or their appointed representative (medical power of attorney). This is consistent with the notion of preservation of patient autonomy. In the USA, consent for organ donation can be given by the patient in the form of advance directive or by a legal surrogate. Some states, such as Ohio, now have registries that establish a priori permission for organ donation and are legally binding. In some areas of the world such as

D. A. Goldfarb and J.F. O’Hara Jr.

Western Europe, there is an alternative process known as presumed consent. Organ harvesting from cadaveric donors is permissible if the deceased did not make known his refusal during his lifetime (this may be recorded in a national registry set up for this purpose) [2, 3]. The adoption of this approach in Spain has been offered as partial explanation of why that country has the highest donation rates in Western Europe. In the absence of a registered refusal, patients are presumed to give consent to organ donation. This “opt out” system has not gained favor in the USA. The argument against its adoption has been concern that this may limit patient autonomy. One has to actively “opt out,” the default position is participation in donation. Some have argued that presumed consent does not limit autonomy, since people are given the choice not to participate, though they must actively choose this. It is important to recognize that in order to proceed with deceased donation there must be an established diagnosis of death either by neurologic or cardiac definition and the patient or their legal surrogate must give express permission for organ donation.

Donation After Cardiac Death Donation after cardiac death (DCD) has evolved into an ethically accepted practice with defined parameters and recent awareness to the process in an attempt to increase organ procurement. Reich et  al. describe controlled DCD as being able to offer the patient and family an opportunity to donate when criteria for brain death declaration will not have been met prior to cardiac death [4]. They further emphasized it must be recognized that the patient who is considered for DCD is not dead and not a donor unless and until he or she should die, and the transplant community has no say in whether or when support will be withdrawn. These issues become critical in managing the logistics of DCD procurement. In a review of organ donation, Steinbrook reported that the most rapid increase in the rate

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of organ recovery from deceased persons has occurred in the category of donation after “cardiac death” – that is, a death declared on the basis of cardiopulmonary criteria (irreversible cessation of circulatory and respiratory function) rather than the neurologic criteria used to declare “brain death” (irreversible loss of all functions of the entire brain, including the brain stem) [5]. In July 2007, the Organ Procurement and Transplantation Network and the United Network for Organ Sharing (OPTN/UNOS) required all 257 transplant hospitals and 58 organ-procurement organizations in the USA to generate protocols to facilitate organ recovery in DCD. With this focus, DCD donors currently represent the greatest percentage increase category to harvest deceased donor organs for transplantation. Organs were recovered from 793 (~10%) deceased donors after cardiac death in 2007 and a 772% increase was reported over the last 10 years [6]. This current trend and the requirement for all transplant hospitals to have protocols in place for DCD makes it mandatory for those involved to understand the elements necessary to protect the rights of the donor, optimize allograft harvesting, and avoid medicolegal issues.

Criteria DCD donor death occurs when respiration and circulation have ceased with cardiopulmonary function and do not resume spontaneously. Electrocardiographic silence is not required for the determination of death. The criterion for determining death is the absence of circulation. The period of observation necessary to determine that circulation will not recur spontaneously after removal of life sustaining therapies has been reviewed by many organizations [4, 7]. Guidelines require waiting for greater than 2 min but generally less than 5 min of pulselessness before pronouncing a patient dead in the context of DCD. This 2–5-min time interval takes into consideration that there is no evidence

in the literature of “auto-resuscitation” of the heart following 2  min of cardiac arrest and observing an end-point of 5 min will minimize warm ischemic damage to perfusable organs. This practice is in accordance with recommendations from the Institute of Medicine, American College of Critical Care Medicine, Society of Critical Care Medicine, and Canadian Council on Organ Donation [5]. Although heparin administration has been discussed as part of the standard of care at the time when life-sustaining treatment is being withdrawn in anticipation of death, femoral catheters and other pharmacological agents are not [4]. All protocols developed need to list the specifics of such plans in DCD and be detailed in the informed consent. The following are “model elements” that protocols are required to address. They are adopted by the OPTN/UNOS and presented as previously report by Steinbrook [5].

Donors “A patient who has a non-recoverable and irreversible neurological injury resulting in ventilator dependency but not fulfilling brain death criteria may be a suitable candidate for donation after cardiac death. Other conditions may include end stage musculoskeletal disease, pulmonary disease, and high spinal cord injury.” “The decision to withdraw life-sustaining measures must be made by the hospital’s patient care team and legal next of kin, and documented in the patient chart.” Depending on the circumstances, the “legal next of kin” may be a relative, a designated health care representative, or an appropriate surrogate. The assessment of potential donors “should be conducted in collaboration with the local organ procurement organization and the patient’s primary health care team.” The medical director of the organ-procurement organization and transplant-center teams should be consulted. “An assessment should be made as to whether death is likely to occur after the

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withdrawal of life-sustaining measures within a predictable time frame that allows for organ donation.”

Withdrawal of Life-Sustaining Measures “A surgical time out is recommended prior to the initiation of the withdrawal of life-sustaining measures.” The intent is to verify patient identification and the roles and responsibilities of the various personnel. The following are critical. “No member of the transplant team shall be present for the withdrawal of life-sustaining measures,” such as removal of an endotracheal tube or termination of medications for bloodpressure support. “No member of the organ recovery team or organ procurement organization staff may participate in the guidance or administration of palliative care, or the declaration of death.” From an ethical perspective there needs to be clear separation of the role of the transplant team until death is declared. This is so that there is no real or perceived conflict of interest regarding care of the perspective donor. This is the only way to preserve public trust in such a system. The time for declaration of death in DCD has been debated, and varies from at least 2–5 min after cessation of a pulse. The dilemma is the balance of cessation of life with no expected auto resuscitation, yet a time frame that will permit viable procurement of allografts. The time from the onset of asystole – the absence of sufficient cardiac activity to generate a pulse or blood flow to the declaration of death is generally about 5 min, but it may be as short as 2  min [8]. The limited data available suggest that circulation does not spontaneously return after the heart has stopped beating for 2  min [9]. If a patient does not die quickly enough to permit the recovery of organs, endof-life care continues and any planned donation is canceled. It has been reported to occur in up to 20% of cases [5].

D. A. Goldfarb and J.F. O’Hara Jr.

Medicolegal Challenges There have been medicolegal issues and felony charges against transplant physicians who facilitate the death in DCD by administering narcotics and benzodiazepines or ordering a patient to be extubated to begin the process of proceeding with DCD. DCD guidelines make it clear that “zero tolerance” exists in having the organ harvesting surgical transplant team involved with the process of deescalation of care for that patient. This phase of the process is the sole responsibility of the DCD patient’s primary care physician and follows through the time of declaring the patient dead. The surgical team is required not to be in the presence of the patient during this time period. Controversy remains from the recent report describing the harvesting of pediatric DCD hearts when asystole occurred for only 75 s [10]. This action defied existing guidelines and is an active topic among the transplant medical community in providing an ongoing ethical debate regarding this decision. Efforts by national transplant organizations to promote the deceased donor option of DCD are in place in an attempt to increase transplants to waiting recipients. Delineation of the medical/ surgical team’s role and timing of participation in DCD needs to be very clear to everyone involved. Understanding individual roles is important to properly care for the DCD patient, respect the family in their time of grieving, and remain within the medicolegal parameters.

Living Donor Issues Ethical judgments regarding living donation (LD) must balance the conflicting principles of beneficence to the recipient with the donor’s right of autonomy and the notion of nonmaleficence for the donor (do no harm). For the recipient, one must establish the benefits that accrue to ­living donation from a specific donor. In general, this will be favorable for recipients. With an LD, the recipients have a shorter wait time, the

22  Ethics of Transplantation

opportunity to optimize health status, improved tissue quality with an LD kidney, potential for improved HLA matching if genetically related, and improved reliability of early renal function after transplant. The short- and long-term graft survivals are improved compared to deceased donor transplantation. From the perspective of the recipient it almost always looks favorable. Ethical dilemmas can arise in the setting of highly co-morbid recipients where there may be serious debate regarding the level of beneficence achieved through a transplant [11]. The comorbid burden may predispose to either early graft loss or patient mortality. Ultimately transplant centers need to determine the value of transplantation to the patient. There are no precise predictive tools to assess this although some have been developed [12]. Most centers have created a recipient selection committee comprised of nephrologists, surgeons, nurse coordinators, social workers, psychiatrists, and ethicists with special transplantation experience. Final decisions regarding transplant candidacy by such committees are uniquely crafted, taking into account individual needs of patients in a multidisciplinary setting. Unusual circumstances in the donor may preclude optimal benefit for the recipient such as a small kidney size with insufficient transplantable nephron mass. Moving forward with living donation may be a concern in some primary renal diseases with high recurrence rates, such as focal segmental glomerulosclerosis or atypical hemolytic uremic syndrome. These may be circumstances where the risk to the living donor is not justified by a durable beneficence to the recipient. Controversy in such cases may arise when donors assert their right to autonomy over the transplant center’s unwillingness to accept the risk to donor/benefit to recipient concerns. In such cases donors may wish to assume substantial risk, especially when the relationship to the recipient is emotionally close such as a parent to child. Living donation is accepted on ethical grounds, because donors voluntarily make their decision to donate (autonomy) with the understanding that the risks of the procedure (nonmaleficence) are justified

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by the benefit (beneficence) to the recipient. The transplant community has established guidelines for the donor evaluation process [13–16]. The donor’s decision should be one of free will based on altruism and not made on the basis of coercion or financial incentives. This is often difficult to assess. Coercion can occur within families (siblings, parents, children). There may be ambivalence regarding donation within the context of other emotionally close relationships such as between spouses. Transplant professionals must assess these and be certain that the living donor is appropriately motivated. For financial incentives, gifting beyond specified costs (mostly related to the logistics of the donor evaluation and recovery) is illegal in USA. Organs cannot be exchanged for “valuable consideration” as stated in the National Organ Transplant Act (NOTA). This relates specifically to the buying or selling of organs. No one is obligated to injure themselves ­significantly to save the life of another; however, the risks of donating in an appropriately motivated individual are considered acceptable. The mortality rates of donation are considered very low, 2–3 deaths/10,000 donors [17]. The perioperative morbidity is considered low and improved in the past 15 years with the wide application of laparoscopic donation. Many longer-term studies of donors suggest a favorable safety profile [18]. The incidence of hypertension and renal failure are no higher in the donor population out to 25  years than that observed for the general population. Nonetheless, donors should always be given the opportunity to back out if they do not feel comfortable. The transplant program’s response should be that the donor was not medically suitable without any more specifics being delivered. The transplant community is now faced with expanding the criteria that defines an acceptable risk for donation including donors with mild hypertension, small renal abnormalities (calcifications or cysts), advancing age, and other comorbidities (obesity, hyperlipidemia, active smoker, prior nephrolithiasis) [19]. There may be limits to the medical community’s ability to reliably predict

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the potential risks of donation out beyond 25  years. The critical issue is that the donor be informed and truly comprehend the potential risks of donation. Importantly, donors need to pursue healthy living habits lifelong. Regarding small renal abnormalities, it is generally accepted that the better of the two kidneys should remain with the donor. It is important that this principle is followed in the era of laparoscopic donation and the predilection for use of the left kidney to a greater extent than was used in the open donor nephrectomy era [20, 21]. Donors and transplant centers may differ on their willingness to assume these risks. As the emotional relationship of the donor to the recipient becomes closer, most donors and centers are willing to increase the level of risks associated with the donation process. A transplant center may opt to turn down a 63-year-old female altruistic donor with no relationship to a recipient because of hypertension while a 63-year-old spousal donor with hypertension may be an acceptable donor. It’s not just the medical condition itself but the context in which it is placed that can make all the difference. [22] As with many decisions, multiple complex factors are integrated into the decision-making process. Challenging decisions are often made through multidisciplinary committees that include participation of clinical ethicists.

Transplant Commercialism and Tourism First, some definitions should be clarified [23]. Transplant commercialism refers to the practice of using an organ as a commodity where it is bought or sold for material gain – organ sales. Transplant tourism is the movement of donors, recipients, or transplant professionals across national borders for the purpose of transplantation. Transplantation commercialism has become controversial as proponents on both sides of the issue have become vitriolic in crusading for their position [24]. Those in favor of organ sales identify that altruism has not provided enough organs to meet the demand and that paying for organs

D. A. Goldfarb and J.F. O’Hara Jr.

will increase the supply to shorten waitlists. The classical example that justifies this position is the system of rewarded gifting in Iran [25]. This is very different from a free-market type exchange that has historically existed in parts of Asia, South America, and the Middle East and driven organ trafficking [26]. A government-sponsored program of regulated paid donation was instituted in Iran in 1988, and by 1999 the renal transplant waitlist was eliminated. Equal access to transplantation was provided to both wealthy and poor. Additional arguments for commercialism include donor autonomy (“I own my body”). Other examples that justify the autonomy argument are the sale of other body components such as semen and human eggs. Additionally, using this argument, proponents of paid donation cite that people willingly take on hazardous occupations such as policeman, fireman, or military service. This is then posited as analogous to the risks assumed by living donors. The right of people to improve their economic standing is used to favor commercial transplantation. Some have argued that organ sales have the potential to eliminate black markets and transplant tourism provided there is a regulated system restricting exchanges only to citizens of a specific country. Proponents against organ sales identify problems with commodification (organs are not commodities). They also cite exploitation of the poor. This can occur even in regulated systems. Paid kidney donors in Iran were disproportionately poor compared to recipients. The greater concerns against organ sales derive from organ trafficking [23, 26]. This is defined as: “the recruitment, transport, transfer, harboring, or receipt of living or deceased persons or their organs by means of the threat or use of force or other forms of coercion, of abduction, of fraud, of deception, of the abuse of power, or of a position of vulnerability, or the receiving by, a third party of payments or benefits to achieve the transfer of control over the potential donor, for the purpose of exploitation by the removal of organs for transplantation.” The main concern is that vulnerable donors donate where the prime motivation is monetary gain. This is associated with nefarious business and medical practices.

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Often there are brokers who stand to gain the most from such transactions. For donors, they may lack the ability to understand the impact of donation on their health or may be inadequately screened and evaluated. Donors are often poor and uneducated. Conditions for surgery may be suboptimal. For recipients, particularly those participating in transplant tourism, there is the risk of transmission of infectious diseases (hepatitis and tuberculosis), surgical complications, and poor documentation of transplantation ­medical events [27]. It remains unanswered whether organ sales, even in a controlled-market system, would increase the number of donors beyond those achievable in a system of only altruistic donation. Some compelling proposals have recently been published [28]. Paid donation may paradoxically diminish the willingness of altruistic donors to donate. This may be analogous to the declining rates of living donation in pediatric kidney recipients noted since deceased donor allocation policy changed to prioritize donor kidneys of age 35 or younger preferentially to pediatric recipients [29]. In the Iranian model only 25% of living donors were related.

Summary and Conclusions Ethical issues are inextricable from all the domains of clinical transplantation. Cognizance of ethical aspects of care and pertinent legislation is a must to ensure that best practices are incorporated into the continuum of the process of care in transplantation.

References 1. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337–340. 2. Hamm D, Tizzard J. Presumed consent for organ donation. BMJ 2008;336:230. 3. Jousset N, Gaudin A, Mauillon D, Penneau M, RougeMaillart C. Organ donation in France: Legislation, ­epidemiology and ethical comments. Med Sci Law 2009;49:191–199.

397 4. Reich DJ, Mulligan DC, Abt PL, et al. ASTS recommended practice guidelines for controlled donation after cardiac death organ procurement and transplantation. Am J Transplant 2009;9:2004–2011. 5. Steinbrook R. Organ donation after cardiac death. NEJM 2007;357:209–213. 6. HRSA. 2008 OPTN/SRTR Annual Report: Transplant Data 1998–2007. The U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. Rockville, MD: HRSA, 2008. 7. ASA Committee on Transplant Anesthesia, Committee on Critical Care Medicine, and American Society for Critical Care Anesthesiologists. Sample Policy for Organ Donation After Cardiac Death. 2007. Accessed at http://www.asahq.org/clinical/ OrganDonationsamplepolicy.pdf 8. Bernat JL, D’Alessandro AM, Port FK, et al. Report of a National Conference on Donation after cardiac death. Am J Transplant 2006;6:281–291. 9. DeVita MA. The death watch: Certifying death using cardiac criteria. Prog Transplant 2001;11:58–66. 10. Boucek MM, Mashburn C, Dunn SM, et al. Pediatric heart transplantation after declaration of cardiocirculatory death. NEJM 2008;359:709–714. 11. O’Hara JF, Jr., Bramstedt K, Flechner S, Goldfarb D. Ethical issues surrounding high-risk kidney recipients: Implications for the living donor. Prog Transplant 2007;17:180–182. 12. Tiong HY, Goldfarb DA, Kattan MW, et  al. Nomograms for predicting graft function and survival in living donor kidney transplantation based on the UNOS Registry. J Urol 2009;181:1248–1255. 13. Ethics Committee of the Transplantation Society. The consensus statement of the Amsterdam Forum on the Care of the Live Kidney Donor. Transplantation 2004;78:491–492. 14. Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000;284:2919–2926. 15. 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. 16. Delmonico F. A Report of the Amsterdam Forum on the Care of the Live Kidney Donor: Data and Medical Guidelines. Transplantation 2005;79:S53–66. 17. 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. 18. Goldfarb DA, Matin SF, Braun WE, et al. Renal outcome 25  years after donor nephrectomy. J Urol 2001;166:2043–2047. 19. Reese PP, Caplan AL, Kesselheim AS, Bloom RD. Creating a medical, ethical, and legal framework for complex living kidney donors. Clin J Am Soc Nephrol 2006;1:1148–1153. 20. 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.

398 21. Wright AD, Will TA, Holt DR, Turk TM, Perry KT. Laparoscopic living donor nephrectomy: A look at current trends and practice patterns at major transplant centers across the United States. J Urol 2008;179:1488–1492. 22. Adams PL, Cohen DJ, Danovitch GM, et al. The nondirected live-kidney donor: Ethical considerations and practice guidelines: A National Conference Report. Transplantation 2002;74:582–589. 23. The Declaration of Istanbul on organ trafficking and transplant tourism. Transplantation 2008;86:1013–1018. 24. Matas AJ. The case for living kidney sales: Rationale, objections and concerns. Am J Transplant 2004;4:2007–2017. 25. Ghods AJ, Savaj S. Iranian model of paid and regulated living-unrelated kidney donation. Clin J Am Soc Nephrol 2006;1:1136–1145.

D. A. Goldfarb and J.F. O’Hara Jr. 26. Budiani-Saberi DA, Delmonico FL. Organ trafficking and transplant tourism: A commentary on the global realities. Am J Transplant 2008;8: 925–929. 27. Khamash HA, Gaston RS. Transplant tourism: A modern iteration of an ancient problem. Curr Opin Organ Transplant 2008;13:395–399. 28. Gaston RS, Danovitch GM, Epstein RA, Kahn JP, Matas AJ, Schnitzler MA. Limiting financial disincentives in live organ donation: A rational solution to the kidney shortage. Am J Transplant 2006;6: 2548–2555. 29. Agarwal S, Oak N, Siddique J, Harland RC, Abbo ED. Changes in pediatric renal transplantation after implementation of the revised deceased donor kidney allocation policy. Am J Transplant 2009;9: 1237–1242.

Chapter 23

World-Wide Long-Term (20–40 Years) Renal Transplant Outcomes and Classification of Long-Term Patient and Allograft Survivals William E. Braun, Sankar Navaneethan, and Deborah Protiva

Keywords  Long-term graft survival • Kidney transplant • Immunosuppression

Introduction Human renal transplantation became firmly established in 1954 with identical twin transplants and progressed to allografts from living related, living unrelated, and deceased donors, covering a span of 56 years now in the year 2010. This span of time may be viewed as the identical and then fraternal twin era (1954–1961) [1]; the pre-cyclosporine, deceased donor-transplant era (1962–1983) when prednisone and azathioprine were the primary immunosuppressants, accompanied by antilymphocyte globulin and donorspecific transfusions in the 1970s; the cyclosporine era (1984–2004) that includes the transition from the early cyclosporine formulation of Sandimmune to the microemulsion formulation of Neoral, the transition in purine antagonists from azathioprine to mycophenolate mofetil, and the use of OKT3. The early postcyclosporine era began about 2005 when tacrolimus eclipsed cyclosporine as the primary calcineurin inhibitor and sirolimus assumed a role in immunosuppression along with broader utilization of induction therapy in the form of W.E. Braun (*) and S. Navaneethan (*) Glickman Kidney & Urological Institute, Department of Neurology – Q7, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA e-mail: [email protected]; [email protected]

polyclonal thymoglobulin and monoclonal antiCD25 antibodies. Intuitively it was felt for many years that improvements in 1-year renal allograft survival would obviously lead to improvement in 5-year successes and beyond. However, about midway through the cyclosporine era transplant surgeons and nephrologists recognized that the agent that in high doses suppressed early allograft rejection and improved 1-year graft success, namely cyclosporine, was the same agent that could cause such severe nephrotoxicity that improvement even in 5-year graft survival and in graft half-life was not being realized [2], a phenomenon continuing even with newer immunosuppression protocols [3]. This rather shocking realization in the 1990s refocused the purpose of renal transplantation programs toward insuring true long-term allograft success and not just avoiding or decreasing early cellular rejection. However, “There is no apparent safe-haven point of time for immunosuppressed renal allograft recipients, who remain at increased risk for eventual renal allograft dysfunction, as well as cardiovascular, neoplastic, infectious, and metabolic diseases” [4]. The gold standard for measuring long-term success is actual patient and graft survivals. Actuarial estimations have also been used, as well as the popular concept of t½ for graft survival which, it should be emphasized, uses as the basis for estimated survivals only grafts functioning at 1  year [5]. The need for actual patient and graft survivals was clearly demonstrated by the finding that t½ significantly overestimates patient and graft survivals when compared to actual survival [6].

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_23, © Springer Science+Business Media, LLC 2011

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The definition of “long-term” renal transplants has been diffuse and variable. A definition of long-term renal transplant outcomes was originally proposed in 1995 and 2002 [4, 7]. It is modified here with a change in the “B” category to actuarial results, and the addition of a “C” category for studies reporting mean or other measures of survival data for a specified time period (Table 23.1). The studies reviewed in this chapter are those with actual, actuarial, or mean survival Table 23.1  Classification of long-term kidney allograft survival (Modified from [4]) Duration of function Classification of long-term patient (years) or allograft survival 1–4.9 Actual/minimum survival = Level 1A Actuarial survival = Level 1B Mean survival = Level 1C 5–9.9 Actual/minimum survival = Level 2A Actuarial survival = Level 2B Mean survival = Level 2C 10–14.9 Actual/minimum survival = Level 3A Actuarial survival = Level 3B Mean survival = Level 3C 15–19.9 Actual/minimum survival = Level 4A Actuarial survival = Level 4B Mean survival = Level 4C 20–24.9 Actual/minimum survival = Level 5A Actuarial survival = Level 5B Mean survival = Level 5C 25–29.9 Actual/minimum survival = Level 6A Actuarial survival = Level 6B Mean survival = Level 6C 30–34.9 Actual/minimum survival = Level 7A Actuarial survival = Level 7B Mean survival = Level 7C 35–39.9 Actual/minimum survival = Level 8A Actuarial survival = Level 8B Mean survival = Level 8C 40–44.9 Actual/minimum survival = Level 9A Actuarial survival = Level 9B Mean survival = Level 9C 45–49.9 Actual/minimum survival = Level 10A Actuarial survival = Level 10B Mean survival = Level 10C Allograft survival less than 1  year is considered shortterm. After the first 4-year segment of long-term survival from 1 to 5 years, long-term survival thereafter is classified in 5-year increments based on actual/minimum (level A), Actuarial (level B), or mean (level C) duration of allograft function. This same scheme can be also applied to patient survival

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data for 20 years (Levels 5A, 5B, and 5C, respectively), actual 25-year survival (Level 6A), or actual 30- year survival (Level 7A). Some of the studies are entirely in the pre-cyclosporine era, whereas others overlap the early cyclosporine era. The majority of studies describe the reporting center’s general population of transplant recipients, whereas others focus on subsets of patients with special conditions (e.g., hepatitis C) [8]. Our report is based on a search of MEDLINE (1996-January 2009) and SCOPUS (January 2009) with optimally sensitive search strategies and using relevant medical subject terms for studies that addressed the long-term outcomes of renal transplant patients. Identified studies were reviewed by two authors and selected upon consensus to be included in this review.

Overall Outcomes of Long-Term (20 Years or More) Renal Transplants Although long-term allograft results have been reported in highly variable ways, these studies provide at least basic patient and graft survival data for comparison of living donor and deceased donor transplants in the pre-cyclosporine (prednisone/azathioprine era) and initial cyclosporine era [9–31]. Of the 24 studies of renal transplant recipients having some form of 20-year survival data (levels A, B, or C), all except one [13] are single-center reports (Table 23.2). The most frequent causes of morbidity and mortality were cardiovascular disease, nonhepatitic infections, and malignancy in Western and non-Asian populations [9, 10, 12–23, 25, 26, 28–31], and infection (primarily hepatitis B and C) and malignancy in far eastern populations [11, 24, 27]. Of the 20 studies providing 20-year outcomes, 11 had actual survival data, [12–15, 17, 19, 22, 25–27, 30] 8 had actuarial 20-year results, [18, 20, 21, 23, 24, 28, 29, 31] and one reported mean results (16). In studies with actual 20-year data, patient survivals ranged from 8.1% [26] to 36.9%, [30] and allograft survival from 8.1% in a series

Denver, USA Richmond, USA Kyoto, Japan Helsinki, Finland Cleveland, USA

1962-1964 1962-1966

1967-1973

1968-1977

1967-1977

1963-1980

1979-2005

Rao, 1997 15

Peddi, 1998 16

Braun, 2001 17

Maffei, 2008 18

El Agroudy, 2008 19 1976-1985 1983-1988 Gheith, 2007 20 Kandaswamy, 200721 1984-1996

Sydney, Australia Minneapolis, USA Cincinnati, USA Cleveland, USA

1964-1972

Fehrman-Ekholm, 1993 13 Mahony, 1995 14

Mansoma, Egypt Mansoma, Egypt Minneapolis, USA

Brescia, Italy

Sweden

1964-1971

Candinas, 1992 12

Zurich, Switzer­land

City, Country

Period covered

Yoshimura, 2005 11 1970-1979 1964-1979 Kyllönen, 2001 22 1963-1983 Braun, 200932

Starzl, 1990 Lee, 1993 10

9

Study author, year

144 (144 grafts) 475 (475 grafts) 1263 (1263 grafts)

918 (918 1st DD)

547 (636 grafts)

– (283 grafts)

164 (164 grafts)

219 (232 grafts)

248 (248 grafts)

144/0 475/0 648/615

0/918

250/386

54/229

14/150

0/232

–

0/100

100 (100 1 DD) st

110 (110 grafts) 706 (824 grafts) 808 (936 grafts)

64/0 70/32 + 5 retransplants 110/0 135/689 331/605

Pred/AZA,ALG, Splenex Pred/AZA, ALG, Splenex Pred/AZA, ALG, Splenex Thymex Pred/AZA, CSA,TAC, SIR, MMF Pred/AZA, CSA Pred/AZA, CSA Pred/AZA, CSA, ALG, ATGAM, OKT3

Pred/AZA, ALG

Pred/AZA, ALG, total body irradiation, Act-C Pred/AZA

20-Year Survival

Pred/AZA Pred/AZA, total body irradiation Pred/AZA Pred/AZA Pred/AZA, ALG, Splenex, Thymex

25-Year Survival

Number and type of donor Type of (LD/DD) Immunosuppression

64 (64 grafts) 102 (107 grafts)

Number of patients (Number of grafts)

5A 5A 5A 5C 5A 5B

>20 20-26  > 20 19-29 20-35 < 20

21-28.5 5A <20               5B < 20 5B

5A

6A 6A 6A

>25 >25 25-40

20.3-27

6A 6A

25.5-27 >25

Follow-up duration (yrs).  Level

21.5*

19.2*

11.0* ‡†

16.5*

17.4

9.7*

22.0

62.5 3.7* 12.4*

23.4 19.6

Actual

37.5 38

72

Actuarial

Patient survival rate (%) (LD/DD)

Table 23.2  Characteristics of the population and outcomes in studies with actual or actuarial patient and graft survivals for ³ 20 yearsa

21.5 (21.5) (–)

19.2 (30.4/7.5)

11.0

16.5

9.1(–) (9.1)

9.7

16.0 (–) (16.0)

32.1 (32.1)(–) 3.7 12.4 (22.2/5.8)

15.6 (15.6)(–) 14.7(18.6/15.6)

Actual

(continued)

25 (25) (–) 30

50 (–) (50)

Actuarial

Graft survival rate (%) (LD/DD)

1964-1979

Kyllönen, 2001 22 Garcia-Maset, 2005 23 Xiao, 2005 24

1970-1980

1979-1999

1967-1983 New York, (pre-CSA) USA 1983-1998 (post-CSA) 1968-1986 Belfast, Ireland

1966-1976

Ohmori, 2001 27

Ciancio, 1999 28

Greenstein, 1998 29

Le Francois, 1987 31

Lyon, France

251 (251 grafts)

386 (440 grafts)

1545 (480 pre-CSA, 1065 post-CSA)

1642 (1679 grafts)

145 (145 grafts)

234 (270 grafts)

1804 (2037 grafts) 868 (1000 grafts)

–

706 (824 grafts)

Number of patients (Number of grafts)

96/154

40/400

525/ 1154

140/5

0/270

63/937

2/2035

–

135/689 5B

< 20

Pred/AZA, Irrad, ALG, CSA, MMF, TAC Pred/AZA

5A

5B

< 20,

5B

5B

5A

> 20,

Pred/AZA > 20 Mizoribine Pred/AZA, ALG, OKT3, < 20 CSA, TAC, MMF, IL2RB Pred/AZA, ALG, < 20, OKT3, CSA, TAC, MMF, IL2RB

5A

5A

36.9

26.2*

8.1*

(–) (23.3* for 1st DD)

15.2*

5A

> 20

5B

Actual

53

45 pre-CSA 70 post-CSA

69.2/ 65.6

67.8

82.2/62.1

Actuarial

Patient survival rate (%) (LD/DD) Follow-up duration (yrs).  Level

Pred/AZA, CSA, < 20 TAC, Sir, MMF, other 20- 33.3 Pred/AZA, Irrad, ALG, CSA, MMF, TAC Pred, AZA, CSA > 20

–

Pred/AZA

Number and type of donor Type of (LD/DD) Immunosuppression

–

26.2

8.1

(–) (23.3 for 1st DD)

15.2

Actual

19

26.0

8 pre-CSA 29 post-CSA

38.4/ 29.0

47.6

32.4/23.2

Actuarial

Graft survival rate (%) (LD/DD)

LD=Living donor, DD=deceased donor, yrs=years, Pred=prednisone, AZA=azathioprine, splenex=splenectomy, thymex=thymectomy, ALG=antilymphocyte globulin, Act-C=Actinomycin C, CSA=cyclosporine, TAC=tacrolimus, SIR=sirolimus, MMF=mycophenolate mofetil, ATGAM=antithymocyte gammaglobulin, OKT3=anti-CD3 monoclonal antibody, IL2RB=antiinterleukin-2 receptor monoclonal antibody *  With a functioning graft †  Ten additional 19–29 year survivors were performed at other centers ‡  Mean survival

McGeown, 1996 30

1968-1978

Delclaux, 2001 26

Bordeaux, France Kyoto, Japan Miami, USA

1968-1998

Helsinki, Finland Barcelona, Spain Bejing, China Belfast, Ireland

City, Country

Middleton, 2004 25

1977-2004

1980-2003

Period covered

Study author, year

Table 23.2  (continued)

23  World-Wide Long-Term (20–40 Years) Renal Transplant Outcomes

with only deceased donors [26] to 26.2% in a series almost exclusively living donors [27] and was usually, but not always [30], associated with lower survivals in deceased donor recipients. In studies with actuarial or mean survivals for 20 years, patient and graft survivals were higher (Table 23.2). Among five studies from the precyclosporine era of prednisone/azathioprine immunosuppression with actual 25-year data, the three that involved deceased donor grafts had overall patient survival with a functioning allograft ranging from 3.7% to 14.7% [10, 22, 32], whereas the two studies exclusively with living donors had actual survivals with a functioning graft of 15.6% and 32.1% [9, 11]. In two studies with actual 30-year data, patient survival with a functioning graft was 22.0% (9 of 41 with first deceased donor grafts) [25] and 10.8% (53 of 492) [32]. Some of these studies offer additional insights into the course of the transplant recipient after 20  years. In a large study in which 105 renal allografts functioned for more than 20  years, there was nearly 25% mortality over the next 10 years that was associated with a functioning allograft in 75% of the graft failures [17]. Half of the deaths were due to cardiovascular causes and one-quarter to malignancy [17]. Although hepatitis was rarely a cause of death, it was associated with 42% of all deaths [17]. Immunologic studies in 57 of these patients, stratified according to decreasing levels of renal function and including those who subsequently died, revealed that a low CD4+ lymphocyte count less than 600 cells/mm3 was disproportionately seen in those with a GFR less than 40 mL/min (71%) or who subsequently died (58%), whereas hypogammaglobulinemia with serum IgG levels less than 600 mg/dL and decreased B lymphocyte counts less than 60 cells/mm3 were similarly represented in all functional categories [17]. In a study of 918 recipients of a first deceased donor kidney transplant, patient outcomes after a return to dialysis before reaching the 20-year mark were reviewed in 224 of 240 patients [18]. Tenyear mortality for patients who returned to dialysis was 20% higher than for patients with a functioning graft (p < 0.0001), but this effect was not seen until after the second year following a return to

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dialysis. The causes of death in those who returned to dialysis were similar to what could be expected with long-term renal transplants, namely cardiovascular disease, infection, and cancer [18]. Several studies have noted that renal allografts could achieve successful function for more than 20 years despite early acute rejection episodes [4, 16, 19, 20, 22], with a frequency ranging from 33% to 62%. The fact that many of these acute rejections were within the first 3 months after transplantation and were intensively treated may have blunted their capacity to contribute to chronic rejection [4], and may have been an early validation of a point made many years later that failure to treat a rejection to the point that the creatinine returns to baseline is associated with worse allograft outcomes [3]. However, others have noted that one or more acute rejection episodes did result in higher serum creatinine levels when compared to recipients who were rejection-free [21, 33–38]. In a study of 824 kidney transplants performed in 706 patients in Helsinki, those recipients with greater than 20-year function had had a shorter time on dialysis prior to transplantation, were more likely to have had pre-transplant nephrectomies, were under the age of 30, had donors under the age of 40, and could overcome acute rejections that had been treated in 47% of the survivor group [22]. A large deceased donor kidney transplantation study from China pointed out that no donor in their series was over 55 years of age and fewer than 7% of the grafts were from female donors [24]. Among 38 renal allograft recipients from Japan whose grafts were functioning for over 20  years, morbidity after 20  years was caused primarily by hepatic failure related to both hepatitis B and C, and malignancy [27]. In a report of 1,642 kidney transplant recipients almost equally represented by three ethnic groups (black-Caribbean and African-American, Hispanic, and others primarily caucasian), none of whom received a kidney with less than a 1 HLA-DR match, several factors adversely affected actuarial 20-year graft survival [28]. Compared to 34% survival for non-AfricanAmericans, African-Americans had an overall 20-year graft survival rate of 13.6%, and nondiabetics 34.2% compared to 13.5% for those

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with diabetes. For the 412 non-African-Americans and nondiabetic patients under the age of 36, actuarial 20-year patient survival rates in the living-related and deceased donor groups were 85.0% and 79.3%, respectively, and graft survivals 55.7% and 46.5%, respectively, yielding results far superior to the overall series [28]. One of the most internally consistent renal transplantation programs directed by Dr. Mary G. McGeown from 1968 to 1988 in Belfast, Ireland, as a policy used low-dose steroids for induction, maintenance, and anti-rejection therapy even though 90% of the grafts came from deceased donors [30]. It was felt that this approach contributed to the low incidence of post-operative and later infections and minimized deaths from sepsis. Actual 20-year patient and allograft survivals in the Belfast patients, essentially none of whom received cyclosporine, and 90% of whom received deceased donor kidneys, were a remarkable 36.9% and 26.0%, respectively [30]. Actual graft survival at 30 years for first deceased donor kidneys was 22.0% (9/41) [25].

Subsets of Long-Term (20 Years or More) Renal Transplant Recipients Pediatric Recipients In addition to long-term outcomes in adults, there are long-term outcomes in pediatric renal transplant recipients who received their renal transplants at the University of California at San Francisco between the years 1964–1970 and were followed for at least 20  years [39]. Immunosuppression was primarily prednisone, azathioprine, and, in recipients of deceased donor kidneys, local irradiation of the graft and Actinomycin C. Of 37 children 3–16  years of age who received kidney transplants before June 1970 (23 from living related donors and 14 from deceased donors) cumulative patient survival rates at 20–26 years were 68%, and graft survival rates 23%. The actual patient survival rates at 20 years were 78% for children who received living donor transplants and 50% for those who received a

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deceased donor transplant. Actual graft survival rates at 20 years were 35% for living donor grafts and 21% for deceased donor grafts. In 25 patients at followup, the most frequent complications were cataracts in 14, hypertension in five, and aseptic necrosis in four. The majority of the patients were more than two standard deviations below average height. “Allografts lost after 10 years failed because of patients’ stopping of their immunosuppressant medications. Rehabilitation was generally good, with more than 70% employed or performing fulltime housework, more than 50% were married and 24% had children, and all had normal activity at least part of the time.” [39] In Hanover, Germany, 150 children who received a kidney transplant between 1970 and 1993 had a mean age at transplantation of 12.1 years (range 3.2–16.7), and a mean followup of 13.1  years (range 2.0–25.0  years) [40]. The actuarial 25-year patient survival was 81%, and first graft survival 31%. Immunosuppression consisted of azathioprine and high-dose prednisolone from 1970 to 1982, and subsequently cyclosporine and low-dose prednisolone from 1982 to 1995. Hypertension occurred in more than 80% of the patients, stunted growth in 44%, and malignancies in 2.6%. Rehabilitation in terms of education and socioeconomic achievement was documented in the majority of the adult patients, and only 14% were unemployed. In London, 300 children transplanted between 1973 and 2000 at a median age of 10.3 years (range 1.4–17.9) had an actuarial 20-year patient survival of 71.6% [41]. Actuarial 20-year graft survival was 36% and was exclusively those with deceased donor kidneys. From 1973 to 1983 immunosuppression consisted of prednisolone and azathioprine; cyclosporine was added beginning in 1984. Although the overall transplant survival rate was lower in children transplanted under 2  years of age, after 1990 age did not affect the outcome. In 183 pediatric recipients in Johannesburg, South Africa (44% black Africans, 40% Caucasian, 9% Asian, and 7% mixed race), actuarial patient survival for 20  years or more was 54% [42]. Although actuarial graft survival for 20  years was not provided, among the first deceased-donor recipients blacks experienced a continually widening inferior graft outcome, so

23  World-Wide Long-Term (20–40 Years) Renal Transplant Outcomes

that by 10 years graft survival was less than 10%. Black recipients were less likely to be transplanted preemptively, and were more likely to have serious mismatching and to be transplanted for disease that recurred in the graft. Greater noncompliance occurred among black males.

Protocol 20-Year Transplant Biopsy Protocol biopsies at 20 years in four renal transplant recipients of parental kidneys showed varying degrees of injury consistent with Banff chronic Grade 2 and 3 changes in the two grafts with decreased function, and Banff Grade 1 and 2 in the two well-functioning grafts [43]. These patients were receiving azathioprine, prednisolone, and mizoribine. By immunohistochemistry, FGF-1 was detected in the walls of arterioles and around the tubules.

23-Year Successes despite Long Cold Ischemia times As evidence of the fact that long ischemia times are not necessarily incompatible with long-term renal allograft survival, 3 of 33 kidneys shipped from the USA to Japan with cold ischemia times of 36–53 h continued to function for 23  years [44]. These recipients had four to six HLA mismatches. All had received deliberate blood transfusions prior to transplantation and received either monoclonal or polyclonal antibody induction and maintenance with azathioprine. Their serum creatinine levels were in the range of 0.7–0.99 mg/dL.

Effect of Viral Hepatitis on 20-Year Outcomes The effect of chronic viral hepatitis on 20-year allograft outcomes has been evaluated in three studies [8, 45, 46]. Of 54 patients whose allografts functioned for at least 20 years, 15 had ongoing

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viral infection: persistent hepatitis B surface antigenemia in three, hepatitis C in 11, and both viruses in one [8]. Diabetes mellitus was significantly more frequent in those with viral hepatitis (11 of 15) versus those without (10 of 39; p = 0.02). These patients also had a high rate of active viral replication (88%) and higher overall mortality [8, 45]. Hepatitis C infection was found to have a major impact on kidney transplant survival in the second decade after transplantation, resulting in 20-year survival that was significantly lower in patients with than without hepatitis C (63.9% vs 87.9%; P < 0.05), and the poor survival rate was due to liver disease in those with hepatitis C [45]. Ten patients with chronic active hepatitis C received IFN-a therapy that had to be discontinued in five patients either because of acute rejection, deterioration of diabetes, or depression. However, biochemical activity improved in eight cases, and HCVRNA titer was reduced in three patients. Following reports that cyclosporine inhibited the replication of hepatitis C virus in vitro [47], the effect of cyclosporine was tested in HCV positive patients, 44 of whom received cyclosporine and 41 of whom did not [46]. After 20  years patient survival was significantly worse among HCV antibody carriers in general (71.5% vs 85.7%), but there was no significant difference in patient survival after 20 years for HCV antibody carriers with or without cyclosporine therapy (74.7% and 70.7%, respectively) [46].

Malignancy at 20–25 Years The overall rates of malignancy in a Japanese renal transplant population was 17.3% at 20  years and 25.6% at 25  years [48]. In the second and third post-transplantation decades, patients without malignancy had significantly superior survival compared to those with cancer (80.3% vs 63.1% at 20  years). After skin cancer, the most frequent malignancies seen were renal cell carcinoma of a native kidney, hepatocellular carcinoma, nonHodgkin’s lymphoma, uterine cancer, and colorectal cancer [48, 49]. Varying descriptions of malignancies are included in other reports [9–32].

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Recurrent Glomerulonephritis at 20 Years During the period 1968–1996, death-censored renal allograft survival among recipients of HLA-identical living related transplants was significantly worse at 20 years for patients who had glomerulonephritis as their underlying disease (63%) compared to those who did not (100%) (P < 0.01) [50]. Recurrent glomerulonephritis was the cause of graft loss in five of the eight patients whose original disease was glomerulonephritis, and it was also diagnosed in four other patients whose grafts were still functioning. Although recipients of HLA-identical living related kidneys generally have a good prognosis with respect to graft survival, recurrent glomerulonephritis was a main cause of graft failure in these patients and is expected to become an even more prominent cause of graft failure with longer follow-up [50], a conclusion also supported by the 10-year study of Briganti [51].

20-Year Outcomes with ABO Incompatibility Among 39 ABO-incompatible kidney transplants performed in 38 recipients (31 living related and eight living unrelated) one of eight unrelated kidneys was functioning at 20 years with a serum creatinine of 1.0 mg/dL, whereas 18 of 31 living related were functioning a mean of 17 ± 13  years after transplantation with a median serum creatinine of 1.5 mg/dL [52]. “Splenectomy appeared to be a prerequisite for successful ABO-incompatible living transplantation” [52]. Although rituximab and IVIG were also used, no prospective randomized controlled studies were available at the time of their publication.

Effect of HLA Matching on 20-Year Outcomes Projected 20-year graft survivals were strongly influenced by Class I and Class II HLA matching

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in a cohort studied between 1987 and 1995 [53]. Projected 20-year graft successes were nearly 40% for those with 0-ABDR mismatches and decreased for each ABDR match until the success rates were only 13.4% with six ABDR mismatches.

Chimerism Beyond 20 Years In five kidney transplant recipients of 1- or 2-haplotype HLA- mismatched living related kidneys that were functioning for 27–29  years, chimerism was demonstrated by immunocytochemical and/or polymerase chain reaction techniques using native skin, lymph nodes, or blood [54]. Mixed lymphocyte reactions (MLR) in four patients whose kidney donors were still alive showed either no or only modest reactivity to the kidney donor but vigorous MLR response to third-party lymphocytes. These findings support the hypothesis that cell migration, repopulation, and chimerism were indicative of graft acceptance and acquired donor-specific unresponsiveness reflecting at least operational tolerance. All five of these patients at the time of testing were still receiving either prednisone, azathioprine, or both.

Urinary Cytolytic Molecules in Recipients with Allografts Functioning More than 20 Years Urinary mRNA profiling was performed in 26 patients with renal allografts functioning 28 ± 5  years with a mean serum creatinine of 1.27 ± 0.37  mg/dL [55]. Molecular quiescence defined these patients who had significantly lower levels of granzyme B (a cytotoxic attack molecule), PI-9 (proteinase inhibitor 9, an endogenous inhibitor of granzyme B), IP-10 (chemokine interferon inducible protein 10) and its ligand CXCR3, and CD103 (an integrin expressed on CD8+ cytotoxic lymphocytes) when compared not only to renal transplant recipients with acute rejection but also to those

23  World-Wide Long-Term (20–40 Years) Renal Transplant Outcomes

with stable short-term function (p < 0.0001). Moreover, mRNA for tolerogenic cytokines TGF-beta 1 and LKLF (lung Kruppel-like factor) was also increased in the 28-year group.

Acute Cellular Rejection and Antibody-Mediated Rejection after 20 Years Single case reports have documented that acute cellular rejection (ACR) can occur 27 years after a successful renal transplant [56], and antibodymediated rejection (AMR) with donor-specific antibody and C4d deposition in the peritubular capillaries 30  years after transplantation [57]. Biopsy-proved ACR occurred in the recipient of a deceased donor kidney who was on treatment with azathioprine and prednisone and whose recent previous biopsy showed focal segmental glomerulosclerosis and early transplant glomerulopathy [56]. The subsequent ACR with tubulitis, manifested with a rising serum creatinine and increasing proteinuria, occurred when the patient’s prednisone was tapered to 12.5 mg on alternate days [56]. The patient with AMR was receiving prednisone and azathioprine at the time a chronic AMR was identified with a rising serum creatinine and proteinuria [57]. The patient was treated with plasmapheresis, IVIG, and a change from azathioprine to mycophenolate mofetil along with institution of tacrolimus and continuation of prednisone. Eight years after the rejection was identified and treated, the graft failed, and the patient began hemodialygies.

Individual Long-Term Renal Transplant Successes (25 Years to More than 40 Years) Other individual long-term successful renal transplants performed at many different transplantation centers are annually updated in Clinical Transplants [58].

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Summary The 20-30 year actual long-term renal allograft survivals in pioneering transplant programs when patients were treated primarily with prednisone and azathioprine are encoura­ging. They represent both a milestone and a measure by which subsequent survivals with cyclosporine, tacrolimus, mycophenolic acid, sirolimus and numerous biologics will have to be judged. However, along with advances in immunosuppression have come equally significant improvements in drugs and interventions for the management of cardiovascular disease, hypertension, diabetes, hyperlipidemia, infections and malignancies, all of which should lead to improved patient and graft outcomes. Delineating the reason(s) for future renal transplant outcomes promises to be quite complex. However, the vanishingly small number of patients with grafts surviving 40 or more years confirms that thus far “There is no apparent safe-haven point of time for immunosuppressed renal allograft recipients who remain at increased risk for eventual renal allograft dysfunction, as well as cardiovascular, neoplastic, infectious, and metabolic diseases.” [4] Acknowledgements  We are indefted to Mrs. Sandra Bronoff for her exceptional skills and manuscript preparation, and to Marian T. Simonson, Systems Libarian.

References 1. Murray JE, Tilney NL, Wilson RE. Renal transplantation: A twenty-five year experience. Ann Surg 1976; 184(5):565–573. 2. Gjertson DW. Survival trends in long-term first cadaver-donor kidney transplants. Clin Transpl 1991:225–235. 3. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4(3):378–383. 4. Braun WE, Popowniak KL, Nakamoto S, Gifford RW, Jr., Straffon RA. The fate of renal allografts functioning for a minimum of 20  years (level 5A)—indefinite success or beginning of the end? A proposed classification of long-term allograft survivals. Transplantation 1995;60(8):784–790.

408 5. Opelz G, Mickey MR, Terasaki PI. Calculations on long-term graft and patient survival in human kidney transplantation. Transplant Proc 1977;9(1):27–30. 6. Meier-Kriesche HU, Schold JD, Kaplan B. Longterm renal allograft survival: Have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004;4(8): 1289–1295. 7. Braun WE, Yadlapalli NG. The spectrum of long-term renal transplantation: Outcomes, complications, and clinical studies. Transplant Rev 2002;16(1):22–50. 8. Younossi ZM, Braun WE, Protiva DA, Gifford RW, Jr., Straffon RA. Chronic viral hepatitis in renal transplant recipients with allografts functioning for more than 20 years. Transplantation 1999;67(2):272–275. 9. Starzl TE, Schroter GP, Hartmann NJ, Barfield N, Taylor P, Mangan TL. Long-term (25-year) survival after renal homotransplantation--the world experience. Transplant Proc 1990;22(5):2361–2365. 10. Lee HM, Posner MP, King AL, Brown KB, Reams DR. Status of long-term (25 years) survival of kidney transplant patients. Transplant Proc 1993;25(1): 1336–1337. 11. Yoshimura N, Akioka K, Ushigome H, et al. Twentyfive-year survival of living related kidney transplants: Thirty-five years’ experience. Transplant Proc 2005;37(2):687–689. 12. Candinas D, Keusch G, Conrad B, Schlumpf R, Decurtins M, Largiader F. A 20-year follow-up of cadaveric kidney allotransplantation. Transplant Proc 1992;24(6):2711–2713. 13. Fehrman-Ekholm I, Gabel H, Persson NH, Backman U. Characteristics of long-term survivors (> 20 years) after kidney transplantation. Transplant Proc 1993;25(1):1334–1335. 14. Mahony JF, Caterson RJ, Coulshed S, Stewart JH, Sheil AG. Twenty and 25 years survival after cadaveric renal transplantation. Transplant Proc 1995; 27(3):2154–2155. 15. Rao KV, Kasiske BL, Dahl DC, et  al. Long-term results and complications of renal transplantation: The hennepin experience. In: Terasaki P, Cecka JM (eds.). Clinical Transplants. Los Angeles: UCLA Tissue Typing Lab 1997:119–124. 16. Peddi VR, Whiting J, Weiskittel PD, Alexander JW, First MR. Characteristics of long-term renal transplant survivors. Am J Kidney Dis 1998;32(1):101–106. 17. Braun WE, Protiva DA. Emerging profiles in 105 recipients of renal allografts functioning for 20–35 years; the “watershed” effect. Transplant Proc 2001;33:1131–1133. 18. Maffei C, Sandrini S, Galanopoulou A, et al. Patient mortality after graft failure reduces kidney transplant patient survival only in the long term: An “intention to treat” analysis. Transplant Proc 2008;40(6): 1862–1864. 19. El Agroudy AE, El Dahshan KE, Abbass TM, Ismail AM, Shokeir AA, Ghoneim MA. Characteristics of recipients whose kidney allograft has functioned for

W.E. Braun et al. more than 20  years. Exp Clin Transplant 2008;6(2):155–160. 20. Gheith OA, Bakr MA, Fouda MA, Shokeir AA, Sobh M, Ghoneim M. Prospective randomized study of azathioprine vs cyclosporine based therapy in primary haplo-identical living-donor kidney transplantation: 20-year experience. Clin Exp Nephrol 2007; 11(2):151–155. 21. Kandaswamy R, Humar A, Casingal V, Gillingham KJ, Ibrahim H, Matas AJ. Stable kidney function in the second decade after kidney transplantation while on cyclosporine-based immunosuppression. Transplantation 2007;83(6):722–726. 22. Kyllonen L, Koskimies S, Salmela K. Renal transplant recipients with graft survival longer than 20  years: Report on 107 cases. Transplant Proc 2001;33(4):2444–2445. 23. Garcia-Maset R, Perich LG, Vallespin EV, Escayola MC, Gomez JM, Puigjaner RS. Living donor renal transplantation in Catalonia: Overall results and comparison of survival with cadaveric donor renal transplantation. Transplant Proc 2005;37(9):3682–3683. 24. Xiao X, Ao J, Lu J, et al. Kidney transplantation at the chinese people’s liberation army general hospital. In: Cecka JM, Terasaki PI (eds.). Clinical Transplants 2005. Vol 2005. Los Angeles: UCLA Tissue Typing Laboratory, 2005:187–197. 25. Middleton D, Douglas JF, Opelz G, Doehler B, McGeown MG. One thousand renal transplants in belfast. In: Cecka JM, Terasaki PI (eds.). Clinical Transplants 2004. Los Angeles: UCLA Immunogenetics Center; 2004:151–163. 26. Delclaux C, Morel D, Fernandez P, Merville P, Deminiere C, Potaux L. Long-term (> or = 20 yr) status of 14 cadaveric kidney-transplant recipients. Clin Transplant 2001;15(3):199–207. 27. Ohmori Y, Oka T, Nakane Y, et al. Twenty-year graft survival of living-related kidney transplantation in a single center. Transplant Proc 2001;33(7–8): 3414–3415. 28. Ciancio G, Contreras N, Esquenazi V, et al. Kidney transplantation at the University of Miami. In: Cecka JM, Terasaki PI (eds.). Clinical Transplants 1999. Los Angeles: UCLA Immunogenetics Center, 1999:159–172. 29. Greenstein SM, Kim D, Principe A, et al. Renal transplantation in a heterogeneous population: the thirtyyear Montefiore medical center experience. In: Cecka JM, Terasaki PI (eds.). Clinical Transplants 1998. Los Angeles: UCLA Tissue Typing Laboratory, 1998:187–193. 30. McGeown MG, Craig WJC. Results of renal transplantation five to twenty-six years after surgery, using azathioprine and low-dose prednisolone as sole immunosuppression. In: Cecka JM, Terasaki PI (eds.). Clinical Transplants 1996. Los Angeles: UCLA Tissue Typing Laboratory, 1996:265–270. 31. LeFrancois N, Elmghabbar N, Chossegros P, et  al. Long-term results in kidney transplantation: Patient

23  World-Wide Long-Term (20–40 Years) Renal Transplant Outcomes and graft survival, causes of graft failure and mortality, renal function and complications after 10  years. Transplant Proc 1987;19(5):3767–3768. 32. Braun WE. World-wide long-term (20–30  years) renal transplant outcomes and classification of longterm patient and allograft survivals. In:; 2009. 33. Foster MC, Rowe PA, Dennis MJ, Morgan AG, Burden RP, Blamey RW. Characteristics of cadaveric renal allograft recipients developing chronic rejection. Ann R Coll Surg Engl 1990;72(1):23–26. 34. Cecka JM. Early rejection: Determining the fate of renal transplants. Transplant Proc 1991;23(1): 1263–1264. 35. Gulanikar AC, MacDonald AS, Sungurtekin U, Belitsky P. The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants. Transplantation 1992;53(2):323–328. 36. Lindholm A, Ohlman S, Albrechtsen D, Tufveson G, Persson H, Persson NH. The impact of acute rejection episodes on long-term graft function and outcome in 1347 primary renal transplants treated by 3 cyclosporine regimens. Transplantation 1993;56(2):307–315. 37. Tesi RJ, Henry ML, Elkhammas EA, Ferguson RM. Predictors of long-term primary cadaveric renal transplant survival. Clin Transplant 1993;7:345. 38. Halloran PF, Aprile MA, Farewell V, et  al. Early function as the principal correlate of graft survival. A multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine. Transplantation 1988;46(2):223–228. 39. Potter DE, Najarian J, Belzer F, Holliday MA, Horns G, Salvatierra O, Jr. Long-term results of renal transplantation in children. Kidney Int 1991;40(4):752–756. 40. Offner G, Latta K, Hoyer PF, et  al. Kidney transplanted children come of age. Kidney Int 1999;55(4):1509–1517. 41. Rees L, Shroff R, Hutchinson C, Fernando ON, Trompeter RS. Long-term outcome of paediatric renal transplantation: Follow-up of 300 children from 1973 to 2000. Nephron Clin Pract 2007;105(2):c68–c76. 42. Pitcher GJ, Beale PG, Bowley DM, Hahn D, Thomson PD. Pediatric renal transplantation in a South African teaching hospital: A 20-year perspective. Pediatr Transplant 2006;10(4):441–448. 43. Okamoto M, Nobori S, Higuchi A, et  al. Clinico­ pathological evaluation of renal allografts of four patients by 20-year protocol biopsies. Clin Transplant 2003;17(Suppl 10):20–24. 44. Takahashi H, Okazaki H, Sekino H, Monden K, Amada N. Three kidneys shipped from the United States to Japan are functioning 23  years later. Clin Transpl 2006:559. 45. Hanafusa T, Ichikawa Y, Kishikawa H, et  al. Retrospective study on the impact of hepatitis C virus

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infection on kidney transplant patients over 20 years. Transplantation 1998;66(4):471–476. 46. Ichikawa Y, Kishikawa H, Nishimura K, et  al. Retrospective study of the effects of cyclosporine in comparison with azathioprine on renal transplant recipients infected with hepatitis C virus. Transplant Proc 2006;38(10):3451–3453. 47. Watashi K, Ishii N, Hijikata M, et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 2005;19(1):111–122. 48. Arichi N, Kishikawa H, Nishimura K, et  al. Malignancy following kidney transplantation. Transplant Proc 2008;40(7):2400–2402. 49. Ishikawa N, Tanabe K, Tokumoto T, et al. Renal cell carcinoma of native kidneys in renal transplant recipients. Transplant Proc 1998;30(7):3156–3158. 50. Andresdottir MB, Hoitsma AJ, Assmann KJ, Koene RA, Wetzels JF. The impact of recurrent glomerulonephritis on graft survival in recipients of human histocompatibility leucocyte antigen-identical living related donor grafts. Transplantation 1999;68(5): 623–627. 51. Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. NEJM 2002;347(2): 103–109. 52. Squifflet JP, De Meyer M, Malaise J, Latinne D, Pirson Y, Alexandre GP. Lessons learned from ABOincompatible living donor kidney transplantation: 20  years later. Exp Clin Transplant 2004;2(1): 208–213. 53. Terasaki PI, Cho Y, Takemoto S, Cecka M, Gjertson D. Twenty-year follow-up on the effect of HLA matching on kidney transplant survival and prediction of future twenty-year survival. Transplant Proc 1996;28(3):1144–1145. 54. Starzl TE, Demetris AJ, Trucco M, et al. Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation 1993; 55(6):1272–1277. 55. Muthukumar T, Dadhania D, Protiva D, et  al. Molecular quiescence, despite minimal immunosuppressive therapy, is the characteristic profile of renal allograft recipients with more than 2 decades of allograft function [abstract]. Transplant 2004; 78(Suppl D):81. 56. Shoker AS, Genesis R, George DH, Baltzan RB, Baltzan MA. Can acute cellular rejection occur 27  years after a successful renal transplant? Transplantation 1994;58(10):1131–1133. 57. Weinstein D, Braun WE, Cook D, McMahon JT, Myles J, Protiva D. Ultra-late antibody-mediated rejection 30 years after a living-related renal allograft. Am J Transplant 2005;5(10):2576–2581. 58. Multi-authored. Clinical Transplants 2007 & 2008. Los Angeles: Terasaki Foundation Lab, 2008.

Chapter 24

Quantitative Aspects of Clinical Reasoning: Measuring Endpoints and Performance Jesse D. Schold

Keywords  Quality • performance • cost • endpoints

Introduction As with any healthcare context, it is critically important that we have metrics to evaluate quality of care and performance in the field of transplantation. The proper interpretation and implications of research often depend upon the reliability of data sources and the use of appropriate statistical methodology. In addition, well-defined endpoints are important for numerous purposes, including: comparing the efficacy of treatments and interventions, assessing temporal changes, identifying risk factors, evaluating provider effectiveness, understanding the impact of healthcare policies, and identifying important early markers of disease processes. Endpoints are also critical for the design and conduct of clinical trials and for development and analysis of observational studies. Moreover, based on increased regulatory oversight of quality, transplant centers have significant incentive to monitor outcomes internally to meet criteria set by contracted agencies. Thus, in general, we require

J.D. Schold (*) Department of Quantitative Health Sciences, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA e-mail: [email protected]

quantitative metrics both to inform best practices to improve patient care. There are several considerations for which specific data sources, endpoints and analytic strategies are selected for research. These include which outcome measures are readily available (preferably in a standard and uniform manner), which outcomes are clinically relevant and which outcomes are important to patients, other caregivers or policymakers. This chapter provides a brief overview of: (a) the strengths and weaknesses of common data sources in kidney transplantation; (b) the specific endpoints which are utilized most frequently for research and quality assurance in this field; and (c) statistical considerations for evaluations of these endpoints.

Data Sources: Strengths and Weaknesses Research, quality assurance, and the application of investigation into clinical practice are only viable with reliable data sources. Without circumspection about the sources of data, findings may be erroneous or misleading or do little to guide prospective practices. It is important to consider that data derived from different sources can also be utilized for unique purposes and have a different variety of strengths and limitations. Researchers and consumers of research must be cognizant of these in order to best design studies and interpret and implement findings into practice in the best possible fashion. Data sources can be

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_24, © Springer Science+Business Media, LLC 2011

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broadly categorized as deriving from prospective trials or observational studies. A further distinction that will be discussed relevant to kidney transplantation is the use of single- or multicenter studies and the use of national registries. The general strengths and weaknesses of these data sources are considered. A complementary treatment of this subject is provided in the chapter on clinical trial design.

Clinical Trials Randomized controlled trials (RCT) are the gold standard for testing causal effects of treatment interventions. Well-designed RCT provide the best evidence for a research hypothesis that can mitigate the presence of any selection bias endemic to observational studies. The prospective nature of trials also help verify that findings are not due to secular trends and, if appropriately designed, provide a definitive answer to a given research hypothesis. Despite the significant advantages of RCTs, it is important to recognize that the design, conduct, and reporting of the trial remain critical to the appropriate interpretation of results. The primary limitations of clinical trials are related to significant resource constraints, inability to test for rare events or study question that may be considered unethical to test (e.g., the deleterious effects of smoking). In addition, there is substantial literature to suggest that clinical trials are both designed and conducted with highly varying levels of quality [1]. To address these concerns, the CONSORT group has published numerous articles in an attempt to standardize trials based on best practices [2, 3]. Thus, consumers should be cognizant of potential pitfalls or sources of potential bias that may accompany results of clinical trials. Clinical trials are typically designed and statistically powered to answer one (or occasionally a few) research questions based on a primary endpoint. One common misperception is that failure to detect significance for secondary endpoints

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suggests nonsignificant differences. Given that studies are rarely powered to detect significance of secondary endpoints, lack of statistically ­significant findings cannot be interpreted in the same manner as apply to primary endpoints. Another common source of contention about clinical trials is the use of subgroup and post hoc analyses [4]. While these analyses may provide additional information about the effects of an intervention, they cannot be assessed in the same manner as the primary research hypothesis for which a trial was designed. Most prominently, secondary analyses often do not maintain the effects of randomization (thus, they are still prone to selection bias) and each test may not be individually powered. In addition, it should be clear whether hypotheses were tested a priori and whether provisions for multiple testing were appropriately incorporated into the analysis. Another important consideration for the interpretation of clinical trials includes whether results are applicable in practice. One must consider the potential for a “study effect” in which, based on the conditions set for the trial (e.g., reduced priced medications, enhanced follow-up protocols, or selected populations), results may not always be applicable outside of the study ­setting. However, often findings from trials can be tested empirically with observational studies to establish whether results are consistent in a noncontrolled environment. More recently, trials in transplantation have been designed with noninferiority endpoints. The attraction of these designs is reduced resource requirements and potentially more rapid findings. However, there are also significant notes of caution about noninferiority trials, including the use of a somewhat arbitrary effect size and the choice of control groups [5]. Finally, due to resource constraints, trials often utilize composite endpoints. (For kidney transplantation these may include acute rejection, renal function decline, serious adverse events along with death and graft loss.) While each individual component of a composite endpoint may be clinically relevant, combining a wide array of outcomes into a singular event can lead to difficulty in the interpretation of results [6].

24  Quantitative Aspects of Clinical Reasoning: Measuring Endpoints and Performance

Single-Center Observational Studies In contrast to RCTs, observational (typically ­retrospective) studies have their own set of strengths and weaknesses. One of the key advantages of research deriving from single centers is the ability to acquire data with specific information related to a given research hypothesis. That is, rather than relying on available information from other existing sources, research deriving from single centers often have the luxury of collecting specific and most relevant information, in particular patient level and treatment decisionrelated data pertinent to a particular study question. This type of specificity often yields novel findings that often cannot be broadly captured across institutions. Another advantage of this data source is that it typically reflects findings from a consistent environment and care protocols. Based on this, the variability that may be attributed to different models of care at different institutions is less problematic for the interpretation of study findings. A significant limitation of single-center data is that it is often designed for administrative rather than research purposes. As such, many fields that would be desirable for research are either omitted or not available in a transparent fashion. As such, proactive approaches to research and in particular the design and implementation of data capture can be a critical step. Another primary limitation of this data source is a potential lack of external validity to other healthcare contexts. This includes how variables were attained and treated for analyses as well as the specific environment or population served. For example, a given institution may utilize protocol biopsies as a given standard and report events of acute rejections between treatment regimens. However, these results may not apply to institutions that only utilize biopsies for cause. As such, validation of any findings deriving from single centers is clearly important in order to understand whether results can be applied to novel populations or in a different healthcare ­setting. Moreover, depending on the specific question, there is always a concern for selection

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bias when comparing effects from nonrandomized settings. As will be discussed in the context of registry analyses, these biases can strongly impact the ability to provide an accurate comparison between study groups. Furthermore, single-center studies may lack sufficient statistical power to test hypotheses for “hard endpoints” such as patient death unless aggregated over a broad era. Acquiring data over a broad era may have a potential bias of other secular trends ­disproportionally affecting a given research hypothesis. These aspects should be considered for both the design and interpretation of studies deriving from single centers.

Multicenter Observational Studies The general principles of observational studies derived from a single institution apply to multicenter studies, which are often referred to as ­collaboratives. The additional advantages of aggregating data across centers are primarily: (1) to increase sample size and statistical power to investigate research hypotheses; and (2) to validate findings between settings, which may represent populations or environments with either measureable or unknown levels of heterogeneity. As compared to single-center observational studies, findings deriving from multiinstitution ­studies may be considered to have greater external validity (generalizability) and therefore applicable to novel settings. However, a nontrivial limitation of multicenter studies is often a lack of conformity of data which may compromise the ability to pool data in a standardized manner. As such prospective planning of these studies, prior to any data collection may often be beneficial.

National Registries Research in the field of kidney transplantation is fortunate to have a mandatory data collection process such that information of virtually the

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entire census of patients in the United States is available. Data collection for transplant candidates, recipients and donors is administrated by the United Network for Organ Sharing (UNOS). This agency oversees the collection of forms and compiles data for research files and study reports. In addition, the United States Renal Data System (USRDS) and the Scientific Registry of Transplant Recipients (SRTR) are contracted agencies that also utilize these data to produce research files. Data from each of these groups contains the census of kidney transplant recipients in the United States [7]. National registries have been utilized extensively for research and present a rare opportunity in medicine to evaluate a complete cohort of patients. However, as with smaller observational studies or randomized trials, national registries are also associated with various strengths and weaknesses [8]. An appealing facet of registry analyses are the relatively limited time and resource constraints for research that are commonly associated with RCTs. As compared to RCTs, studies can be carried out by analysts without the labor and resource intensive processes of patient recruitment and safety monitoring. In addition, registry data is typically validated and cleaned such that data fields are in a more useable form for research which is often not true when selecting primary data for single or multicenter studies. The advantages of registry analysis are particularly apparent when addressing less frequent events that can constitute an important safety endpoint (e.g., incidence of malignancies), which demand greater sample size than a typical study is routinely powered to reasonably detect. Registry data allows for examination of treatment effects of patients regardless of whether they consent or ultimately drop out of study ­protocols, as with RCTs. In addition, registry studies can often confirm significant effects tested in a prospective study in a nonstudy environment and verify whether results are applicable in populations different from the study population. Conversely, registry analysis can often justify the need for prospective trials, to determine whether results applicable in the general study population can be confirmed in a

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controlled ­setting and constitute a causal mechanism. Another distinct utility of registry studies is the ability to study the effects of risk factors that would be unethical to study via a prospective trial. Data derived from registries are also vital for descriptive statistics of the broad transplant population, understanding secular changes in the population and comparing characteristics and outcomes between regions and individual centers. The primary (and nontrivial) limitation of utilizing registry data for research is the presence of underlying selection bias for comparing study groups. As these analyses are nonrandomized, it is important to recognize that unobserved characteristics of subjects may systematically differ between any selected groups. Along with many statistical validation steps and procedures, it is equally important for these analyses to have studies based on a rationale or hypothesis a priori which is also based on clinical or research knowledge. The counter-example that is endemic to large registry analyses are commonly cited as data mining or fishing for “significant results.” There are also many aspects of these data that require experience and programming expertise. Certain fields change over time, have missing or outlier data and are considered more or less reliable indicators of clinical events. In addition, especially given the large population size, there are many circumstances in which statistically significant results may have little clinical impact. The clinical significance of results should always be a consideration for registry analyses. One of the current utilities of registry data is to assess center performance. This is accomplished by aggregating data from all centers and creating risk-adjusted metrics for quality of care. However, it should be noted that the original design of the forms for data capture for registries was not intended to be used for these purposes. As such, many fields that would be useful for risk adjustment or performance monitoring are not available. Although this deficiency may improve over time, it is a slow process to change forms in systematic manner and in the interim, imperfect risk adjustment may be one of the unintended consequences.

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Endpoints in Kidney Transplantation defined as transplant recipients’ need for dialysis Acute Rejection Acute rejection has historically been one of the primary endpoints in kidney transplantation for both observational studies and randomized controlled trials. Traditionally, studies that assess the efficacy of immunosuppressive trials expect to demonstrate effects via reduction in acute rejection rates that subsequently lead to differences in long-term graft survival. In the past decade, acute rejection rates have significantly declined. However, despite the reduction in acute rejection rates, long-term graft survival has remained stable [9]. These results raise some question whether acute rejection in itself is a sufficient surrogate endpoint for long-term events. One of the challenges for examining acute rejection as an endpoint in research is the lack of a uniform definition [10]. Acute rejection may be defined on treatment for the condition (indicating a clinically relevant need for care), biopsy proven rejection, and histological grade or based on other clinical indicators such as decline in renal function. This variability in definition leads to wide variation in the estimated effect of acute rejection on graft loss [11]. Other considerations for the use of acute rejection as an endpoint include observations that the timing of acute rejection may have different implications and rejection episodes that do not lead to decline in renal function have no significant impact on graft survival [12, 13]. Finally, some patients may experience multiple acute rejections episodes following transplantation. These repeated events require different analytic approaches as well as some consideration for whether each episode is clearly a distinct event or a product of ongoing processes.

Delayed Graft Function Delayed graft function (DGF) is a primary endpoint following the transplant surgery. DGF is a form of acute renal failure which is most commonly

within the first week following transplantation or occasionally anuria in the first 24 h following the procedure. Incidence of DGF is significantly higher for deceased donor transplants, donor kidneys with longer cold ischemia time, and transplants deriving from older donors [14]. Pulsatile perfusion is associated with a reduction in the incidence of DGF [15]. Graft loss and acute rejection following the incidence of DGF is also significantly increased [16]. One of the analytical challenges for assessing this impact of DGF on outcome is distinguishing the event from other surgical insults which may lead to early dialysis treatment among transplant recipients. In particular, patients who undergo a technical failure during surgery or complication postoperatively may require dialysis treatment that is not a classic form of acute tubular necrosis (ATN), yet these terms are often referred to synonymously. Center practice patterns may also substantially affect the incidence of DGF [17]. Thus, despite a relatively uniform definition of DGF that is conventionally used for research, there may be different causal factors that are important for the interpretation of study findings. Ongoing studies will be needed to assess whether reductions in DGF directly lead to improved graft survival.

Infections Infections are a common endpoint for clinical investigation in kidney transplantation. Kidney transplant recipients are susceptible to various types of infections due to immunosuppressive therapy, the surgical procedure, onset of other complications, and other comorbid factors [18–20]. Rates of infections have been relatively stable over the past decade [21]. Common types of posttransplant infections include cytomegalovirus (CMV), BK-virus, Epstein-Barr virus, and various other types of bacterial and fungal forms [22–24]. Some infections may be asymptomatic or poorly documented and each varies substantially in severity. From an analytical perspective,

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there are various specific considerations for assessing infection rates among kidney transplant recipients. One challenge is to quantify and classify the type and severity of infections in a systematic manner. Particularly given that some infections are not recorded or known, understanding the extent of infections between treatment groups can be a challenge. For certain types of infections, prophylaxis can strongly mitigate the likelihood of development and may need to be considered for analysis. Moreover, the particular inception and ending dates of infections is difficult to quantify in a systematic manner, yet important to guide analyses. Cumulatively, infections are common sequelae of kidney transplantation, but vary widely in incidence and severity, are not always clearly documented, and may be strongly correlated with treatment protocols.

Graft Loss Graft loss is a primary “hard” endpoint for clinical research investigation. Short-term (1-year) graft loss rates have declined over the past decade. However, short-term improvements have not translated into long-term improved graft ­survival [9]. Causes of long-term graft loss are likely multifactorial, but to some degree remain unknown [25]. Graft loss is generally defined as either a graft failure requiring a return to dialysis or retransplantation or patient death (this is also known as overall graft loss). Patient deaths are typically included in this outcome based on the assumption that many deaths are related to kidney function decline and as such it is difficult, if not impossible, to separate these endpoints from each other. However, it is also possible to also examine graft failures that explicitly occur without death. Often in the kidney transplantation literature these are referred to as death censored graft failures. The primary limitation of examining death censored graft failures as a study endpoint in isolation the notable bias of ignoring deaths. In survival analyses this is a clear case of nonrandom censoring, which can significantly alter research findings if deaths are nonrandomly

d­ istributed between study groups. One of the challenges for clinical investigation is that allograft failure rates are relatively low in the first year and as such demand either extensive follow-up periods or large sample size in order to test research hypotheses with sufficient statistical power. As such there have been extensive efforts to understand quality surrogate markers for long-term graft loss that can be utilized to assess treatment interventions with limited ­follow up accrual [26–28].

Patient Death Patient survival in the first year following renal transplantation is currently approximately 98% and 96% for living and deceased donor transplant recipients, respectively. The primary causes of death are cardiovascular, infectious, and malignancies, but documentation of the specific causes are often missing or unknown. However, one of the “successes” of the improvements in transplantation is that death with a functioning graft is now a common cause of graft loss [29]. That is, patients now are more and more likely to retain their graft until they die. Alternatively, death after graft loss is also an endpoint that may have different etiologies and implications for research [30]. The primary limitation of death as a study endpoint is a lack of statistical power for comparing study groups. Most trials cannot be designed for patient survival, particularly in the field of transplantation; the population size is too small for most studies using only death and graft loss as primary endpoints. In some respects, all other endpoints that are typically utilized for research and clinical investigation serve as proxies for patient death. For research and study design, we often assume that patients who are more likely to experience acute rejection, infections, and DGF are also more likely to subsequently lose their graft and ultimately more likely to die. Despite this, patient survival should always be considered a secondary endpoint; studies designed for other complications should incorporate a separate analysis or composite endpoint

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to validate that findings are not misleading based on differential mortality rates between study groups. Further understanding of events that ­ provide a direct causal pathway to mortality (as opposed to a general association) among transplant recipients are ongoing and will be important to research investigations.

Renal Function Renal function is an important and natural endpoint for studies in kidney transplantation. There is clear evidence that posttransplant renal function is associated with long-term graft and patient survival [31, 32]. There has been an evolution of equations utilized to estimate glomerular filtration rate (GFR), most recently the CKD-EPI equation to potentially replace for the formerly utilized MDRD equation [33]. GFR is associated with serum creatinine level, body size, race, gender, and age. Even early markers of renal function following transplantation have been shown to be associated with long-term outcomes [34]. However, renal function is not highly predictive of long-term outcomes [35]. The important distinction is that while renal function is associated with long-term graft and patient survival at an epidemiologic (population) level, it does not translate to predicting outcomes with a high degree of reliability for individual patients. Renal function levels can be modulated by different pharmaceutical interventions, patient nutritional status, and body fluid composition. Furthermore, it is not clear whether interventions that alter renal function without any other benefits necessarily translate to better long-term outcomes. This is an important matter for the design of clinical trials and observational studies that utilize renal function alone a primary endpoint.

Costs and Resource Utilization An important endpoint for research and the application of findings is costs. Kidney transplantation represents a unique healthcare intervention that

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is not only efficacious but is also cost effective [36]. However, this cost effectiveness is also relative to patient characteristics, therapeutic strategies, and type of complications [37–40]. The principles of health economics can effectively guide the most cost-effective utilization of scarce resources. These considerations should not be ignored, as care that is effective for some individuals but results in inefficient use of resources may lead to diminished care for other patients. These difficult challenges often resonate in kidney transplantation, including the most efficient utilization of scarce donor organs [41, 42]. Although it is often difficult to quantify the value of healthcare, economic constraints are a reality of transplantation and the society that it is carried out in, and an important consideration for the overall utility and viability of any intervention.

Provider Quality of Care There has been great momentum in the past decade to increase transparency and oversight of quality of care delivered by healthcare providers. This has been motivated by findings that quality of care in the United States is marginal compared to other industrialized nations and advancements in technology by which more data are readily accessible. In conjunction with the technological capabilities and proliferation of electronic medical records, hospital report cards have emerged in both the public and private sector. Transplant centers are currently evaluated for performance by the Scientific Registry of Transplant Recipients (SRTR). The SRTR reports risk adjusted graft and patient survival on a publicly available website [43]. These data include wait list outcomes, posttransplant outcomes, and ­certain demographic characteristics of the population. One of the primary metrics by which transplant centers are evaluated is the standardized mortality ratios (SMR). SMR is a commonly applied statistical metric that can be utilized to assess risk-adjusted outcomes at a provider or regional level based on indirect

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s­ tandardization of results to a normalized reference group. SMRs are utilized to assess performance of transplant centers comparing the observed number of events (graft losses or deaths) with the expected number of deaths based on adjustment for donor, recipient, and transplant covariates over a given follow-up period using the national experience over a contemporaneous time period as a reference group. An SMR equal to one indicate that centers have outcomes equivalent to what is expected based on the acuity level of their transplant population, while higher SMRs are indicative of poor performance relative to the number of expected events in the population. In addition, SMRs can be tested for statistically significant differences (relative to a null value of 1). Statistically significant differences indicate that centers perform better or worse than expected at a level that is unlikely due to random variation. One limitation of SMR as currently utilized is that larger centers are more likely to receive statistically significant ­differences relative to smaller centers due to increased statistical power afforded by the larger numbers of patients that they transplant. SMRs are currently a metric by which quality assurance by CMS and other insurance companies gauge the quality of transplant centers [44].

Patient Satisfaction and Quality of Life Perhaps one of the most overlooked yet important endpoints in healthcare is patient satisfaction. Patient satisfaction is: (1) often difficult to assess objectively; (2) can vary substantially by individual; and (3) unfortunately, is not always a primary focus of research. At the same time, many would argue that quality of life (as compared to quantity) should be a prominent (if not the primary endpoint) for research studies and policy development. Proxies for quality of life in transplantation include complication rates, ­re-hospitalizations, as well as graft survival. However, clinical endpoints alone clearly do not

fully ­characterize patient satisfaction and quality of life. Most research indicates that although kidney transplantation significantly improves life expectancy and improves quality of life relative to maintenance dialysis, it does not fully restore patients’ quality of life prior to end-stage renal disease onset due to complications, functional status, and perhaps relative to pretransplant expectations [45, 46]. Prospective studies designed to capture patient satisfaction in a uniform manner are important in transplantation and further application of these data for treatment interventions, allocation policy and decision making are needed.

Novel Endpoints One of the challenges for research in the field of kidney transplantation is that despite the innumerable data sources and endpoints, models examining outcomes for individual patients are not highly predictive [47]. Models for graft loss among kidney transplant recipients typically have a concordance index in the range of 0.62–0.68. By most academic standards, this reflects a relatively moderate ability to discriminate between patients who will or will not have an event incorporating all available information. While risk adjustment remains important to observational studies (and is almost always a significant improvement over crude unadjusted models), it is clear that there exist many unobserved factors that are associated with outcomes that are not currently codified or understood that are associated with outcomes for kidney transplant patients [48, 49]. As such, prospectively, it is important to the field to identify novel factors associated with outcomes. These may include undergoing research into genomics and proteomic markers, environmental factors, or healthcare system as well as many comorbid factors that are not currently collected or codified in a systematic manner. The moderate predictive power limits our ability to implement findings into practice for individual patients or for policy considerations, and improving our understanding

24  Quantitative Aspects of Clinical Reasoning: Measuring Endpoints and Performance

of these additional factors may be a focus of studies for years to come.

Statistical Models Utilized to Assess Endpoints Use of appropriate statistical models is critical for any research endeavor. Failure to incorporate appropriate methodology and attend to baseline assumptions can invalidate findings as well as waste valuable resources. It is important to understand that regardless of the type of scientific inquiry (i.e., a clinical trial or observational study), research should be based on the fundamental scientific method. These include a systematic and ordered approach to research, including identifying a specific topic or problem, formulating a hypothesis, testing the hypothesis, and reporting results. Well-founded hypotheses should lead to important findings independent of whether they support the null or research hypotheses and should be published in either case in order to avoid publication bias [50]. One of the most important considerations for observational studies is the presence of underlying selection bias. In general, without the luxury of a prospective randomized design, the question is not whether selection bias exists, but rather the degree of selection bias and the likelihood that it is directly related to a particular research hypothesis. There are various manners by which to address potential confounding, most commonly by utilizing multivariable models. Selection of covariates (adjustment factors) for multivariable models should be well founded based on the research hypothesis and the outcome of interest. Alternative approaches for analyses in the presence of potential selection bias are to utilize stratified models, incorporate propensity score adjustment, or identify instrumental variables. In general, the degree of potential selection bias and the availability of data that may serve as a proxy for this bias guide which type of adjustment to utilize. However, it is always important to recognize that hidden selection bias almost

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always exists for observational studies and even with appropriate statistical methodology, one must acknowledge that confounding can still influence observed effects. Considerations for the many basic statistical tenets are also critically important for research. These include identifying outliers and influential observations, testing for collinearity between explanatory variables, appropriate handling of missing data, detecting for the presence of nonlinear effects, incorporating model validation and tests for distributional assumptions. A common statistical problem endemic to medical research, including transplantation, is the use of covariates that are not baseline variables. That is, it is important to account for information in multivariable models that may confound findings, but if these events occur after a baseline period (as for a cohort for survival models), then appropriate statistical techniques must be employed.

Transplant Center Quality Assurance Given the increased regulatory environment that is now present in the field of transplantation, centers must now consider data and endpoints not only for research purposes, but particularly important for quality monitoring and quality assurance. Kidney transplant centers that fail to meet quality standards can lose certification and contracting with insurance companies. It is important in this regard for centers to be proactive about data quality and capture. As discussed previously, many administrative databases do not routinely capture fields that are important for both research purposes and for data that would be applicable to measuring quality and center performance. Another important consideration is that these data do not only include posttransplant outcomes, but the lengthy process by which transplant patients first receive care, including at the time of referral, evaluation, and after transplant candidacy on the waiting list. Monitoring quality of care at these early stages

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will likely be manifested with outcomes ­following ­transplantation and subject to regulatory oversight. In addition, regulatory oversight of quality in the field of transplantation may only be in its infancy in terms of scope and implications. Furthermore, programs that do fall below standards of quality must often demonstrate that they have existing quality assurance programs. Cumulatively, proactive quality monitoring, from the database design state, throughout the transplant process and to inform clinical decision making are critical steps in the modern transplant environment.

Summary The proper use and availability of metrics and quantitative reasoning for research and application to improve patient outcomes are critical to the field of kidney transplantation. Appropriate analysis of factors that explain patient outcomes leads to improved practice and further evolution of research. Understanding the strengths and limitations of data, endpoints, and appropriate analytical approaches leads to proper interpretation of existing research and prospective application of future studies. Both researchers and consumers of such research need to understand these principles to advance knowledge and improve patient care.

References 1. Juni P, Witschi A, Bloch R et  al. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999;282:1054–1060. 2. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357:1191–1194. 3. Moher D, Jones A, Lepage L. Use of the CONSORT statement and quality of reports of randomized trials: a comparative before-and-after evaluation. JAMA 2001;285:1992–1995. 4. Wang R, Lagakos SW, Ware JH, et  al. Statistics in medicine – reporting of subgroup analyses in clinical trials. NEJM 2007;357:2189–2194.

J.D. Schold 5. Wiens BL. Choosing an equivalence limit for noninferiority or equivalence studies. Control Clin Trials 2002;23:2–14. 6. Freemantle N, Calvert M, Wood J, et al. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA 2003;289:2554–2559. 7. Dickinson DM, Dykstra DM, Levine GN, et  al. Transplant data: sources, collection and research considerations, 2004. Am J Transplant 2005;5:850–861. 8. Kaplan B, Schold J, Meier-Kriesche HU. Overview of large database analysis in renal transplantation. Am J Transplant 2003;3:1052–1056. 9. Meier-Kriesche HU, Schold JD, Srinivas TR, et  al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378–383. 10. Fleiner F, Fritsche L, Glander P, et  al. Reporting of rejection after renal transplantation in large immunosuppressive trials: biopsy-proven, clinical, presumed, or treated rejection? Transplantation 2006;81:655–659. 11. Wu O, Levy AR, Briggs A, et al. Acute rejection and chronic nephropathy: a systematic review of the literature. Transplantation 2009;87:1330–1339. 12. Nett PC, Heisey DM, Shames BD, et al. Influence of kidney function to the impact of acute rejection on long-term kidney transplant survival. Transpl Int 2005;18:385–389. 13. Sijpkens YW, Doxiadis II, Mallat MJ, et  al. Early versus late acute rejection episodes in renal transplantation. Transplantation 2003;75:204–208. 14. Irish WD, McCollum DA, Tesi RJ, et al. Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients. J Am Soc Nephrol 2003;14:2967–2974. 15. Schold JD, Kaplan B, Howard RJ, et  al. Are we frozen in time? Analysis of the utilization and efficacy of pulsatile perfusion in renal transplantation. Am J Transplant 2005;5:1681–1688. 16. Shoskes DA, Halloran PF. Delayed graft function in renal transplantation: etiology, management and long-term significance. J Urol 1996;155:1831–1840. 17. Louvar DW, Li N, Snyder J, et al. “Nature versus nurture” study of deceased-donor pairs in kidney transplantation. J Am Soc Nephrol 2009;20:1351–1358. 18. Burroughs TE, Swindle J, Takemoto S, et al. Diabetic complications associated with new-onset diabetes mellitus in renal transplant recipients. Transplantation 2007;83:1027–1034. 19. Flechner SM, Avery RK, Fisher R, et al. A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Transplantation 1998;66:1682–1688. 20. Meier-Kriesche HU, Ojo AO, Hanson JA, et  al. Exponentially increased risk of infectious death in older renal transplant recipients. Kidney Int 2001;59:1539–1543. 21. Snyder JJ, Israni AK, Peng Y et  al. Rates of first infection following kidney transplant in the United States. Kidney Int 2009;75:317–326.

24  Quantitative Aspects of Clinical Reasoning: Measuring Endpoints and Performance 22. Abbott KC, Duran M, Hypolite I, et al. Hospitalizations for bacterial endocarditis after renal transplantation in the United States. J Nephrol 2001;14:353–360. 23. Abbott KC, Hypolite I, Poropatich RK, et  al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001;3:203–211. 24. Cosio FG, Nuovo M, Delgado L, et al. EBV kidney allograft infection: possible relationship with a perigraft localization of PTLD. Am J Transplant 2004;4:116–123. 25. Jevnikar AM, Mannon RB. Late kidney allograft loss: what we know about it, and what we can do about it. Clin J Am Soc Nephrol 2008;3(Suppl 2):S56–S67. 26. Hariharan S, Kasiske B, Matas A, et  al. Surrogate markers for long-term renal allograft survival. Am J Transplant 2004;4:1179–1183. 27. Kasiske BL, Massy ZA, Guijarro C, et  al. Chronic renal allograft rejection and clinical trial design. Kidney Int Suppl 1995;52:S116–S119. 28. Schold JD, Kaplan B. Design and analysis of clinical trials in transplantation: principles and pitfalls. Am J Transplant 2008;8:1779–1785. 29. Howard RJ, Reed AI, Hemming AW, et al. Graft loss and death: changing causes after kidney transplantation. Transplant Proc 2001;33:3416. 30. Kaplan B, Meier-Kriesche HU. Death after graft loss: an important late study endpoint in kidney transplantation. Am J Transplant 2002;2:970–974. 31. Hariharan S, McBride MA, Cherikh WS, et al. Posttransplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002;62:311–318. 32. Meier-Kriesche HU, Baliga R, Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation 2003;75:1291–1295. 33. Levey AS, Stevens LA, Schmid CH, et  al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–612. 34. Pascual J, Marcen R, Zamora J, et  al. Very early serum creatinine as a surrogate marker for graft survival beyond 10 years. J Nephrol 2009;22:90–98. 35. Kaplan B, Schold J, Meier-Kriesche HU. Poor predictive value of serum creatinine for renal allograft loss. Am J Transplant 2003;3:1560–1565. 36. Whiting JF, Woodward RS, Zavala EY, et  al. Economic cost of expanded criteria donors in cadaveric renal transplantation: analysis of Medicare payments. Transplantation 2000;70:755–760. 37. Abecassis MM, Seifeldin R, Riordan ME. Patient outcomes and economics of once-daily tacrolimus in

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renal transplant patients: results of a modeling analysis. Transplant Proc 2008;40:1443–1445. 38. Kutinova A, Woodward RS, Ricci JF, et al. The incidence and costs of sepsis and pneumonia before and after renal transplantation in the United States. Am J Transplant 2006;6:129–139. 39. Woodward RS, Schnitzler MA, Lowell JA, et  al. Effect of extended coverage of immunosuppressive medications by medicare on the survival of cadaveric renal transplants. Am J Transplant 2001;1:69–73. 40. Hornberger JC, Best JH, Garrison LP Jr. Costeffectiveness of repeat medical procedures: kidney transplantation as an example. Med Decis Making 1997;17:363–372. 41. Meier-Kriesche HU, Schold JD, Gaston RS, et  al. Kidneys from deceased donors: maximizing the value of a scarce resource. Am J Transplant 2005; 5:1725–1730. 42. Wolfe RA, McCullough KP, Schaubel DE, et  al. Calculating life years from transplant (LYFT): methods for kidney and kidney-pancreas candidates. Am J Transplant 2008;8:997–1011. 43. Dickinson DM, Shearon TH, O’Keefe J, et al. SRTR center-specific reporting tools: posttransplant outcomes. Am J Transplant 2006;6:1198–1211. 44. New Medicare Hospital Conditions of Participation for Transplant Centers. Centers for Medicare and Medicaid Services 12/23/09. https://www.cms.gov/ CertificationandComplianc/Downloads/ Transplantfinal.pdf 45. Dobbels F, De BL, De GS, et al. Quality of life after kidney transplantation: the bright side of life? Adv Chronic Kidney Dis 2007;14:370–378. 46. 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. 47. Schold JD, Howard RJ. Prediction models assessing transplant center performance: can a little knowledge be a dangerous thing? Am J Transplant 2006;6:245–246. 48. Schold JD, Srinivas TR, Howard RJ, et al. The association of candidate mortality rates with kidney transplant outcomes and center performance evaluations. Transplantation 2008;85:1–6. 49. Weinhandl ED, Snyder JJ, Israni AK, et al. Effect of comorbidity adjustment on CMS criteria for kidney transplant center performance. Am J Transplant 2009;9:506–516. 50. Stern JM, Simes RJ. Publication bias: evidence of delayed publication in a cohort study of clinical research projects. BMJ 1997;315:640–645.

Chapter 25

The Business of Transplantation Art Thomson

Keywords  Transplant • transplantation • organ • business and administration

Introduction The field of organ transplantation comprises a niche market in the United States. According to the American Hospital Association, there are 5,815 hospitals in the US [1]. Three hundred twenty-two, or about 5.5% of the hospitals, offer at least one type of organ transplant program [2]. The transplant service line is usually managed by a physician and administrator partnership and the transplant administrator has overall responsibility for managing business and administration. In 1997, the United Network for Organ Sharing (UNOS) established a Transplant Administrators Committee. The charge of the committee is as follows: The Transplant Administrators Committee considers issues related to the administration of transplant programs and provides input to other Committees and the Board with regard to the potential impact of developing policies and other OPTN requirements on transplant program operations. Through non-OPTN resources provided A. Thomson (*) Cleveland Clinic, General Surgery & Transplant Center, A100, 9500 Euclid Avenue, Cleveland, OH, 44195, USA e-mail: [email protected]

by UNOS as available, the Committee develops initiatives and tools that foster effective transplant program administration (e.g., the annual UNOS Transplant Management Forum, the transplant program staffing survey, and the standardized payer Request for Information (RFI) tool) [3]. Many transplant administrators actively engage and communicate with each other, sharing best practices via a listserv [4]. In 2006, the Association for Transplant Administration was formed as “a professional organization for the benefit of Transplant Administrators and those individuals involved in the diverse roles of Transplant Management” [5]. Transplant administrators have also developed a Community of Practice within the American Society of Transplantation. The responsibilities of the transplant administrator are varied and include finance, data ­management, quality assurance and process improvement, contracting, compliance, information technology, marketing, and public relations (Fig. 25.1) [6]. The transplant administrator also serves as liaison by representing the transplant program internally to hospital administration and externally to organizations such as the United Network for Organ Sharing (UNOS), the Centers for Medicare and Medicaid Services (CMS), Organ Procurement Organizations (OPO), The Joint Commission (disease-specific programs), and state health departments. While business responsibilities such as budgeting, billing, and personnel management mirror that of administrators for other healthcare specialties, transplantation is unique in several ways. Not the least of these is the scarce supply of organs for

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9_25, © Springer Science+Business Media, LLC 2011

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A. Thomson

Fig. 25.1  Transplantation is a true multidisciplinary medical enterprise. A transplant center’s function can be visualized in its clinical/medical and administrative domains. Each of these

domains reflects the dynamic interplay between numerous components. The representation is an oversimplification of the real-life complexity of an academic transplant center

transplantation. Solid organ transplantation has become one of the most regulated fields in medicine.

within the Health Resources Services Administration (HRSA) in the Department of Health and Human Services. HRSA oversees two contracts related to solid organ transplantation; one for operation of the OPTN and the second for management of the Scientific Registry of Transplant Recipients (SRTR) [8]. The United Network for Organ Sharing (UNOS) in Richmond, Virginia was awarded the first contract for operation of the OPTN in 1986 and has held the contract since that time [9]. UNOS also held the contract for the SRTR until 2000. In 2000, the SRTR contract was awarded to the University Renal Research and Education Association, now called the Arbor Research Collaborative for Health, located in Ann Arbor, Michigan [10]. Requirements for transplant

The Organ Transplant Network The National Organ Transplant Act of 1984 was the key legislative act in establishing the Organ Procurement and Transplant Network (OPTN) [7]. OPTN members include all organ transplant hospitals and organ procurement organizations in the United States. The federal government has responsibility for oversight of the OPTN and this responsibility rests within the Division of Transplantation (DOT), located

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hospitals are set forth in the OPTN Final Rule, 42 CFR Part 121 and in OPTN policies [11].

Setting Up a Transplant Program All hospitals must apply to UNOS to initiate an organ transplant program. The OPTN requirements for transplant hospitals can be found in the UNOS bylaws and policies at www.unos.org. To apply for a new organ transplant program, hospitals must participate in the Medicare or Medicaid Program. The hospital must also have available the facilities required to support the practice of organ transplantation, including an adequate number of operating rooms, intensive care unit beds, acute care beds, and proper staffing to assure the success of the program. Further, the hospital must have a contractual affiliation with an organ procurement organization and a histocompatibility laboratory and have access to collaborative support in related areas such as anesthesiology, nursing, physical therapy, radiology, and rehabilitation and ancillary services such as microbiology, clinical chemistry, and the monitoring of immunosuppressive drug levels. The hospital must also develop routine referral procedures to identify potential organ donors in the hospital as well as develop a protocol for donation after cardiac death. The UNOS Membership and Professional Standards Committee reviews applications for new programs. The most closely scrutinized portion of the application relates to key personnel for the transplant program. Each program must designate a primary physician and a primary surgeon and document that they meet the background and experience requirements of the OPTN. The primary physician and primary surgeon must each be an MD or DO, board certified and in good standing at the transplant hospital. They also must have met or exceeded minimum standards for experience in their transplant specialty by way of their training in a fellowship program or on-the-job experience. The primary physician and primary surgeon may or may not also be considered the medical and surgical

directors of the program. Other key personnel on the transplant team include clinical transplant coordinator, financial coordinator, mental health and social worker, data manager, dietitians and pharmacist. UNOS policies describe the role of these individuals in more detail. Programs must also assure round-the-clock medical and surgical coverage [12].

Administering a Program There is wide variability in the organizational structure of transplant centers. Some of this variance is accounted for by differing overall structures between hospitals. Regardless of the structure in place, transplant programs must draw on the expertise of a broad array of specialists. This can be a challenge in hospitals with traditional structures where specialists are grouped and separated by departmental lines (medicine, surgery, anesthesiology, etc.) A vertical integration of transplant programs, under the leadership of a strong medical and surgical director, will help assure that all resources are focused toward providing patient-centered, quality care [13]. Administrative duties for transplant programs fall into several categories: • • • • • •

Personnel Finance Compliance Organ procurement and preservation Marketing and communication Liaison to hospital administration and external organizations • Managed care • Data management and quality assurance

Personnel The typical organization of a transplant program includes an overall program director, a medical and surgical director (may be the same as program director), a clinical manager, transplant nurse

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coordinators, transplant administrative assistants, social worker and financial coordinator. A growing number of programs are also employing nurse practitioners and physician assistants. Since transplant programs must be available around-the-clock, many transplant personnel have on-call responsibilities and these call for special compensation. Another challenge related to transplant personnel is that once transplanted, the majority of patients are followed indefinitely posttransplant. This differs from other types of surgery where patients may return to the care of their personal physicians once stable after surgery. Transplant programs will need to continue to add posttransplant personnel even when levels of transplant activity are flat from year to year, ­simply because more patients are being followed by the team. The UNOS Transplant Administrators Committee sponsors a staffing survey of transplant programs. For programs that participate by completing a survey, the data can provide useful information for comparing and benchmarking staffing levels between programs of varying sizes by region of the country [14].

Finance The business of transplantation entails a complex flow of funds between donor hospitals, organ procurement organizations, and transplant centers. In addition, organ transplantation is one of the highest-cost surgical procedures. To effectively manage the business of transplantation, there must be close scrutiny and oversight of billing and reimbursement. Medicare is the national insurance program for individuals over the age of 65 or for those who are determined to be disabled. For kidney transplant patients who do not meet either of these requirements, there is a waiting period once dialysis is initiated before they are eligible for Medicare coverage. The percent of Medicare patients varies widely between transplant programs, with some being as high as 100%. The model for Medicare reimbursement for kidney

transplantation originated in 1972, with the passage of an amendment to the Social Security Act to include coverage for end-stage renal disease. This model was later extended to the nonrenal types of organ transplantation. Hospitals must apply to the Centers for Medicare and Medicaid Services for certification in order to be eligible for Medicare reimbursement. Once certified, there are three types of reimbursement from Medicare. The first is the diagnosis-related group (DRG) payment to hospitals (Part A) for inpatient stays. Each type of organ transplant is assigned to a DRG and the payment to the hospital is determined by several factors, including a national standard amount, local wage index, and a DRG weight (a measurement of resource consumption relative to other DRGs). The second is cost-based reimbursement of expenses accounted for in the organ acquisition cost centers. This is intended to reimburse hospitals for reasonable costs associated with deceased and live donor organ acquisition and pretransplant services ­provided to transplant candidates and live donors. The third is physician reimbursement (Part B), based upon a predetermined amount for each service described by Current Procedural Terminology (CPT) codes. Similar to DRG payments, the Part B payments to physicians are based upon several factors, including a relative value for the service, a geographic modifier and a conversion factor [15]. Medicare regulations require special handling of pre-transplant billing for potential transplant candidates and living donors. Services provided are charged to the organ Acquisition Cost Center for reporting and reimbursement via the hospital Medicare Cost Report. Kidney acquisition cost centers were established by regulation in 1974 as a means of reimbursing hospitals for reasonable expenses associated with organ procurement, recipient and living donor evaluation and selection and maintaining potential recipients on the waiting list [16]. The Medicare Cost Report includes the cost of evaluation services provided to all patients, regardless of payor type, and are multiplied by the ratio of Medicare patients to total patients transplanted plus organs procured during that plus organs procured in the hospital year. ­

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The same applies to patients on the waiting list for transplant for services provided to them to assure their continuing candidacy for transplant. Other transplant program expenses are also eligible for cost reimbursement via the hospital Medicare Cost Report including salary and benefits of pretransplant personnel and other direct and indirect expenses related to pretransplantation. Transplant administrators must develop a close working relationship with hospital finance personnel who prepare and submit the hospital Medicare cost report in order to assure accurate cost reimbursement for the transplant program. Figures  25.2–25.5 provide an overview of Medicare reimbursement by phase of transplant care, organ transplant DRG weights, and sample payment rates [17] (Fig. 25.6). Many commercial or managed care insurance companies have contracted with hospitals for transplant services. This can be an important source of referrals for programs with insurance case managers playing a role in where individuals go for transplant care. Contracts often provide a fixed rate for the transplant hospitalization up to a specific number of days. The pretransplant or posttransplant phase may also be included in the price. This calls for a robust cost

accounting system that can identify transplant patients and report the cost associated with their care during each phase of transplantation. Because there are a greater number of kidney transplant programs in the US than for other types of organ transplant programs, there is less “steerage” of patients to higher volume centers and commercial and managed care comprises a smaller percent of the overall case mix. The transplant administrator has responsibility for helping to assure a smooth and complete billing and collection process often in concert with the hospital or professional billing components. While managed care personnel typically handle the negotiation of contracts, transplant administrators play a key role by providing advice regarding rates and contractual language. Another tool available in the transplant administrators’ section of UNet is the OPTN/ UNOS Standardized Request for Information (RFI) document. This was initiated to provide transplant centers with a common survey form to provide key statistics on their transplant programs. Insurance companies and managed care companies are provided access to each transplant program’s RFI form. This has been widely accepted by transplant providers and insurance

Recipient Phases of Transplantation

Live Donor

Hospital

M.D.

Hospital

M.D.

Part A Organ Acquisition

Part A Organ Acquisition

Part A Organ Acquisition

Part A Organ Acquisition

Phase 1

Pre-transplant evaluation.

Phase 2

Patient accepted and listed with UNOS and is now in the maintenance or candidacy phase.

Phase 3

Patient admitted to hospital for organ transplant procedure and subsequent inpatient stay.

Part A DRG

Physician Part B Fee Schedule

Part A Organ Acquisition

Physician Part B Schedule

Phase 4

Patient discharged from hospital and posttransplant follow up care period starts.

APC Fee Schedule

Physician Part B Schedule

Part A Organ Acquisition

Physician Part B Schedule

Fig. 25.2  Medicare payments by phase of transplantation are shown for the various solid organ transplants (This material is reproduced with permission from the Transplant Education and Research Institute)

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Transplant DRG Weights Effective 10/1/09 & 10/1/08 FFY 2010

FFY 2009

% Change

Kidney : 652

2.9736

2.9556

+0.6%

Kidney-Panc: 008

5.0615

4.8811

+3.7

Pancreas: 010

4.2752

3.7246

+14.8%

Lung: 007

9.4543

9.5998

−1.5%

Transplant DRG New / Old

(This figure is reproduced with permission from the Transplant Education and Research Institute)

Fig. 25.3  Medicare PPS FFY 2010. Final rule impact on transplant rates. The impact of the CMS final rule on transplant rates in the USA are shown in this figure

Transplant DRG Weights Effective 10/1/09 & 10/1/08 FFY 2010

FFY 2009

% Change

Liver with mcc 005

10.1358

10.8150

−6.3%

Liver w/o mcc 006

4.7569

4.8839

−2.6%

Heart with mcc 001

24.8548

23.6701

+5.0%

Heart w/o mcc 002

11.7540

12.8157

−8.3%

Transplant DRG New / Old

Fig. 25.4  Medicare PPS FFY 2010. Final Rule Impact on Transplant Rates. The impact of the CMS final rule on transplant rates in the USA are shown in this figure

Organ

FY: 2010

(This figure is reproduced with permission from the Transplant Education and Research Institute)

FY: 2009

$ Difference

% Difference

Kidney

$29,084

$28,275

$809

+2.9%

KidneyPancreas

$49,405

$46,297

$3,108

+6.7%

Pancreas

$41,748

$38,250

$3,498

+9.1%

Lungs

$91,624

$89,833

$1,791

+2.0%

Fig. 25.5  Medicare IPPS FY: 2010. Final Rule Impact on Transplant DRG Rates. Sample Medicare transplant DRG rates. Sample Medicare reimbursement by solid

organ are shown along with changes in recent years (This material is reproduced with permission from the Transplant Education and Research Institute)

and managed care companies, eliminating the need for completion and submission of a wide variety of insurance survey forms [18]. The role of the financial coordinator cannot be overstated in terms of the importance to patients and to assuring a successful business operation. The financial coordinator first meets

with potential transplant recipients during their initial evaluation for a kidney transplant. The financial coordinator assesses insurance coverage, counsels patients and family members, provides cost estimates for all phases of care including medications, and secures insurance approvals. Some programs require patients to be cleared

429

25  The Business of Transplantation

Organ

FY: 2010

FY: 2009

Difference

% Difference

Liver w mcc

$98,047

$103,254

−$5,207

−5.0%

Liver wo mcc

$46,168

$48,445

−$2,277

−4.7%

Heart w mcc

$239,672

$221,934

$17,738

+8.0%

Heart wo mcc

$113,568

$120,157

−$6,589

−5.5%

Fig. 25.6  Medicare IPPS FY: 2009. Final rule impact on transplant DRG rates. Sample Medicare transplant rates. Sample Medicare reimbursement by solid organ

are shown along with changes in recent years (This material is reproduced with permission from the Transplant Education and Research Institute)

financially prior to initiation of a transplant evaluation. The financial coordinator remains an important contact for patients and family members as they progress through the phases of transplantation and have questions regarding financial or billing issues. The financial coordinator provides similar services to potential donors for living donor transplant programs [19]. Most transplant administrators spend a significant amount of time on management of the financial aspects of organ acquisition. This includes monitoring the influx of organ acquisition charges from OPOs for organs received for transplantation, and passing these charges on to patients and insurers as a component of the standard acquisition charge at the time of transplant. This charge represents the cost of acquiring the organ for transplantation. The pretransplant cost components of that charge may vary from transplant program to transplant program.

(evaluation, wait listing, transplant, and followup), transplant programs must submit a data form to UNOS at the time the patient is approved for transplant and placed on the waiting list, at the time they receive their transplant and annually while in the follow-up phase of their transplant. Transplant programs are required to have 95% of forms submitted within 90 days of their due date and 100% submitted within 180 days of their due date. Data quality is a key concern of most transplant programs, as many types of data will have a direct impact on key measures of the success of transplant programs such as graft and patient survival. Many of these requirements for transplant hospitals can be seen as an unfunded mandate, a necessary requirement to be in the business of transplant services [20]. The Centers for Medicare and Medicaid Services (CMS) has certified transplant programs since the early 1980s. In 2007, CMS revamped their regulations into new Conditions of Participation (CoP). Transplant programs that wish to participate in the Medicare program and have Medicare pay for transplant services must meet the CoP and must reapply and be surveyed again every 3  years. The primary requirements of the CoP are related to experience and there are volume and outcome requirements for each organ. Outcomes are publicly reported every 6 months by SRTR. Program specific reports can be compared to national outcomes. The report provides both expected and observed outcomes for each program. Initially the approval process begins with a letter to CMS requesting approval. CMS  will then obtain a report from UNOS

Compliance As mentioned earlier, the field of transplantation is probably the most regulated field in medicine. UNOS has established policies that place a wide range of operational requirements on transplant programs including organ acceptance, organ procurement, distribution and allocation of organs, packaging of organs, transplantation of foreign nationals, patient notification, data submission, and more. Data submission requirements on transplant programs are significant. For patients who proceed through all four phases of transplantation

A. Thomson

430

regarding experience (volume) levels, outcomes, and data submission. The review process is completed by a site visit to the transplant program by CMS to assess compliance with the CoP. CMS requires that transplant programs have a quality assurance and process improvement program in place. This often takes the form of a committee of transplant personnel. They must regularly review key data on transplant performance, identify areas of improvement, and implement quality projects based upon this [21].

Organ Procurement There are 58 organ procurement organizations (OPO) in the United States. OPOs are certified by CMS and have responsibility for coordinating the donation of organs for transplant. Transplant ­programs may be offered organs for transplant from their local OPO or from any OPO in the country, based upon OPTN/UNOS organ allocation ­policies. Transplant programs will either send a surgical team to procure the organ or rely on the services of a local expert for procurement. The transplant administrator helps to assure that  the program has the operational ability to respond to organ offers by sending a procurement team to the donor hospital. This may include contracting with air carriers or ground transportation to assure the availability of transportation.

Marketing Few would argue with the necessity of marketing in today’s healthcare environment. Developing a marketing approach for a transplant center requires the identification of marketing goals, development of a strategy to achieve the goals, and selection of marketing programs. The transplant administrator is often a key planner and participant in efforts to market a transplant program. Key customer groups include patients and their family members, referring physicians, and ­managed care and insurance companies. The need to ­market

a program will depend upon several factors, including access, number of patients on the waiting list, competition, and capacity. A principal method of marketing is via web sites. Transplant patients in particular are very savvy and do their homework in gathering key data and statistics on transplant programs as part of the process of their choosing a transplant program [22].

Internal and External Liaison The transplant physician director and administrator are the key liaisons and represent the ­program in issues that require interaction with hospital administration. The director and administrator also serve as a liaison to transplantrelated organizations outside the hospital such as UNOS, CMS, insurance and managed care ­companies, and state health departments. They also serve as a clearinghouse for information to and from the program.

Tracking Outcomes UNOS is the repository of data submitted by transplant programs. The SRTR receives transplant program data from UNOS, analyzes the data, and prepares program-specific reports for all transplant programs. These reports are made publicly available twice each hear and posted at www.ustransplant.org. The program-specific reports include wait list data, organ acceptance rates, mortality rates, transplant rates, waiting time for transplant, recipient and donor characteristics, and graft and patient survival rates, comparing expected to observed rates. The UNOS Membership and Professional Standards Committee monitors transplant activity and outcomes. Those programs that perform a low volume of transplants or with low survival rates may be flagged by the committee for ­further review and evaluation, including a site visit to the program. Outcomes are case mix adjusted and actual graft and patient survival is compared

25  The Business of Transplantation

with expected rates. A statistical analysis determines if the difference between actual survival and expected survival is considered statistically significant.

Conclusion The transplant community is small yet highly competitive and visible. Transplant hospitals that wish to grow programs and sustain growth in the long term must have an infrastructure that vertically integrates the multidisciplinary transplant team and assures sound business and administrative practices. The Transplant Administrator is responsible for overseeing operations and administrations including finance, data management, contracting, compliance, information technology, and marketing.

References 1. http://www.aha.org/aha/resource-center/Statistics-andStudies/fast-facts.html. Accessed January 22, 2010. 2. http://optn.transplant.hrsa.gov/latestData/advancedData.asp. Accessed January 11, 2010. 3. http://www.unos.org/members/committeesDetail. asp?ID = 28. Accessed January 13, 2010. 4. h t t p : / / h e a l t h . g r o u p s . y a h o o . c o m / g r o u p / TransplantAdministrators/. Accessed January 13, 2010.

431 5. http://www.ata1.org/index.php. Accessed January 13, 2010. 6. Zavala E, Crandall B. Guest editorial: the practice of transplant administration. Progr Transpl 2007;17(2): 81. 7. http://optn.transplant.hrsa.gov/policiesAndBylaws/ nota.asp. Accessed January 12, 2010. 8. http://www.hrsa.gov/privacyact/sorn/09150055.htm. Accessed January 12, 2010. 9. http://www.unos.org/whoWeAre/theOPTN.asp. Accessed January 12, 2010. 10. http://findarticles.com/p/articles/mi_m0YUG/ is_19_10/ai_n18610441/. Accessed January 12, 2010. 11. h t t p : / / e c f r. g p o a c c e s s . g o v / c g i / t / t e x t / t e x t idx?c = ecfr&sid = 1adadbc642b51651a039f47ebd46 0ab6&rgn = div5&view = text&node = 42:1.0.1.11.76 &idno = 42. Accessed February 1, 2010. 12. http://www.unos.org/policiesandBylaws2/bylaws/ UNOSByLaws/pdfs/bylaw_116.pdf. Accessed January 19, 2010. 13. Howard RJ, Kaplan B. The time is now: formation of true transplant centers. Am J Transpl 2008;8:1–5. 14. https://portal.unos.org. Accessed January 24, 2010. 15. Abecassis M. Organ acquisition cost centers part I: medicare regulations – truth or consequences. Am J Transpl 2006;6(12):2830–2835. 16. Rogers J. Managing the medicare organ acquisition cost reporting process. The Practice of Transplant Administration Workshop, September 2009, San Diego. 17. https://portal.unos.org/TxAdmins/rfi_select.aspx. Accessed February 1, 2010. 18. OPTN/UNOS Bylaws, Appendix B, II. Criteria for Institutional Membership, Transplant Hospitals. 19. h t t p : / / w w w. u n o s . o rg / P o l i c i e s a n d B y l aw s 2 / policies/pdfs/policy_23.pdf. Accessed January 24, 2010. 20. http://www.cms.hhs.gov/CertificationandComplianc/20_ Transplant.asp. Accessed January 24, 2010. 21. Zavala E. Transplant Center Marketing. Graft. 2001.

Index

A Abdominal CAT scan incisional hernia, 283 pelvis, 285 Acute tubular injury (ATI), 118 Allograft anatomically abnormal, 235 biopsy processing, 112–113 chronic, failure of, 79 early biopsies from donor biopsies, 113–114 early posttransplant graft dysfunction, 116–117 immediate posttransplantation biopsies, 114–116 rupture, kidney transplantation, 290 Alport’s disease, 365 American Diabetes Association, 317 Anastomosis, 215, 216, 252, 254–256. See also Kidney transplant recipient surgery Anemia, medical management diagnosis and management, 325–326 epidemiology and, 324–325 posttransplant erythrocytosis (PTE), 326 risk factors and pathogenesis, 325 Anencephalic infant donor kidney, 228, 230 Angiotensin converting enzyme inhibitors (ACEi), 314–315 Angiotensin receptor blockers (ARB), 314–315 Antibody-mediated rejection (AMR), 38 Antidepressants effects, in ESRD, 380 neuropsychiatric side effects, 381 Antihuman globulin (AHG) augmented assay, 33 Apparent volume of distribution (Vd), 91–92 Artery reconstruction superior mesenteric artery (SMA), 251–252 superior mesenteric vein (SMV), 252 revascularization, 254 thrombosis, in kidney transplantation, 287–288

B Bacterial infections Clostridium difficile, 348 legionellosis, 349 Listeria monocytogenes, 349 Mycobacterium tuberculosis, 348–349 Nocardia spp., 349 Rhodococcus equi, 349 Banff schema and rejection classification, 129–131 B-cell activating factor (BAFF), 16 B cells and antibody B-cell activating factor (BAFF), 16 B regulatory cells (B regs), 17 complement cascade, 14 major antibody initiated processes, 15 MHC antigens, 13–14 Belatacept/costimulation blockade, 68–69 BK virus and polyomavirus allograft nephropathy, 341–343 BK virus nephropathy (BKVN), 124 Bladder fistulae, 294 Bloodstream infections (BSI), 337 Boari flap repair, ureteral leaks, 302, 303 Body mass index (BMI), 364 Bone disease, 323–324 Bortezomib (velcade), 69 Breast cancer, 322 B regulatory cells (B regs), 17 Business and administration compliance, 429–430 finance diagnosis-related group (DRG), 426 medicare regulations, 426–427 medicare reimbursement, 427–428 internal and external liaison, 430 marketing, 430 multidisciplinary medical enterprise, 424 organ procurement, 430 organ transplant network, 424–425 personnel, 425–426 responsibilities, 423 tracking outcomes, 430–431 transplant program, 425

T.R. Srinivas and D.A. Shoskes (eds.), Kidney and Pancreas Transplantation: A Practical Guide, Current Clinical Urology, DOI 10.1007/978-1-60761-642-9 © Springer Science+Business Media, LLC 2011

433

Index

434 C Cadaveric donor kidney, bench table preparation, 299, 300 Calcineurin inhibitor, 88, 90–91, 381 choice of, 70–71 maintenance therapy cyclosporine vs. tacrolimus, 60, 62 dosing and monitoring, 61 side effects, 61–63 steroid avoidance regimens and cyclosporine withdrawal, 75–76 deteriorating graft function, 75 mycophenolate mofetil with sirolimus, 73 rationale and impetus, 72–73 stable graft function, 73–75 Calculated PRA (CPRA) system, 37 Calyceal fistulae, 293 Cancer, medical management breast cancer, 322 colorectal cancer, 322 malignant melanoma, 322 nonmelanomatous skin and lip cancers, 321–322 posttransplant bone disease, risk factors for, 321 prostate cancer, 323 viral infections, 322 Cardiovascular and pulmonary evaluation, living kidney donation, 361–362 Cardiovascular disease, medical management, 311 Catheter-related infections, 337 CAT scan incisional hernia, 283 pelvis, 285 Chronic kidney disease (CKD), 374 Clinical pharmacology apparent volume of distribution (Vd), 91–92 binding, 92 bioavailability calcineurin inhibitors, 90–91 corticosteroids, 91 mycophenolate mofetil (MMF), 91 calcineurin inhibitors, 88 clearance, 92–94 corticosteroids, 87–88 everolimus, 102 interactions, 96–97 m-TOR inhibitors, 88–89 mycophenolic acid (MPA), 88 pharmacogenetics, 95–96 restrictive clearance and protein binding, 94–95 therapeutic drug monitoring (TDM), 97–98, 100–102 Clonidine, 315 Clostridium difficile, 348 C2 monitoring, 97–98 CMV. See Cytomegalovirus Coagulopathy, 193 Cold ischemia time, 167 Colorectal cancer, 322 Complement-dependent cytotoxicity (CDC) assay, 25, 26 Coronary artery disease (CAD), 277 Corticosteroids, 87–88, 91

Cross-reactive groups (CREG) antigens, 33 Cryptococcal infections, 347 Cytomegalovirus (CMV) donor seropositive, recipient seronegative, 339 ganciclovir vs. valganciclovir, 339–340 infection and viremia, 340–341 prophylaxis/preemptive therapy, 339 D Delayed graft function (DGF), 415 Diabetes, medical management diagnosis and management American Diabetes Association, 316, 317 hypoglycemic agents, 318 epidemiology and clinical importance, 315–316 nonmodifiable and modifiable factors, 316 risk factors and pathogenesis, 316 DNA typing, 29, 30 Donor factors, renal allograft survival age, 166–167 center effect, 165 cold ischemia time, 167 deceased vs. living donor, 166 donor factors, 166 donor nephron mass, 167 donor-recipient factors, 163 expanded criteria donors, 167–168 gender, 167 HLA matching, 163–164 waiting time and preemptive transplantation, 164–165 year of transplant (era effects), 165–166 Donor nephrectomy, living kidney donation immediate complications, 366–367 late-term complications maternal and fetal, 367 outcomes and implications for, 367–368 Donor-specific T cell response, 3–5 Dual renal transplantation, 225–227 Dyslipidemia, 174, 320, 363 E Early transplant interval acute rejection, 119 acute tubular injury (ATI), 118 acute tubulointerstitial rejection, 119 infection, 123–125 recurrent disease, 124 vasculature endothelialitis, 119–121 glomerulitis, 122 Elderly deceased donor allograft, 225–227 Endpoints and performance measurement acute rejection, 415 assessment, 419 center quality assurance, 419–420 costs and resource utilization, 417

435

Index data sources clinical trials, 412 national registries, 413–414 observational studies, 413 strengths and weaknesses, 411–412 delayed graft function (DGF), 415 graft loss, 416 infections, 415–146 novel endpoints, 418–419 patient death, 416–417 patient satisfaction and life quality, 418 provider quality of care, 417–418 renal function, 417 End-stage renal disease (ESRD), 259 antidepressants, 380 pain, 379–380 psychiatric complications, 373 psychiatric referral, patients, 374–375 quality of life, 374 Epstein–Barr virus (EBV), 341 Erectile dysfunction (ED), 307–308 ESRD. See End-stage renal disease (ESRD) Ethical issues, of transplantation brain death dead donor rule, 391 definition, 392 death determinination, 393 donation after cardiac death (DCD), 392–393 donors, assessment of, 393–394 donors consent, 392 life-sustaining measurement, 394 living donor issues graft survivals, 395 primary renal diseases, 395 risks of donation, 395–396 medicolegal issues, 394 principles, 391 transplant commercialism and tourism, 396–397 Everolimus, 102 Expanded criteria donor (ECD) kidney ABO incompatible and positive cross-match renal transplant, 234–235 allograft kidney biopsy, 222 allograft with ureteral abnormalities, 238 anatomically abnormal allograft, 235 anencephalic infant donor kidney, 228, 230 bench table vascular reconstruction, 237, 238 clinical evaluation, 221 contaminated donor kidneys and systemic infection, 230–232 diabetes, 233 elderly deceased donor allograft and dual renal transplantation, 225–227 glomerulonephritis/lupus/membranous nephropathy/ preexisting lesions, 233–234 hepatitis, 232–233 horseshoe deceased kidney donor, 235 with hypertension deceased donor, 230 living donor, 230

metastatic malignant cells, 233 multiple arteries and vascular abnormalities, 236–237 non-heart beating donor, 224–225 organ preservation and pulsatile perfusion, 222–223 pediatric deceased donor kidney, 227 pediatric en bloc deceased renal transplantation, 227–228 polycystic deceased donor kidney, 235–236 prolonged preservation times, 224 reduced renal function, 224 selection criteria, 220–221 F Febrile transplant recipient, 349–350 Flow cytometric antibody screening, 34 Focal and segmental glomerulosclerosis, 194–195 FTY 720, 68 Fungal infections pneumocystis and, 346–347 practical approach to, 348 G Glomerular filtration rate (GFR), 365–366 Glomerulonephritis, 233–234 H Hematuria, 365 Hemorrhage, 287 Hepatitis viruses HBsAg-positive donor, 343–344 HCV, approach to, 344–345 Herpes simplex virus (HSV), 341 Histocompatibility laboratory, in clinical transplantation antibody-mediated rejection (AMR), 38 antihuman globulin (AHG) augmented assay, 33 B-cells cross-match, 41 and plasma cells, 32 complement-dependent cytotoxicity (CDC) assay, 25, 26 CPRA system, 37 CREG antigens, 33 DNA typing, 29, 30 flow cytometric antibody screening, 34 function of, 30, 31 human leukocyte antigen (HLA) antigen matching, 23, 24 ImmuKnow assay, 43 inheritance pattern, HLA genes, 23, 24 IVIg serum levels, 43 mixed lymphocyte culture (MLC), 28 peripheral blood mononuclear cells (PBMC), 28 PRA assessment, 36 regional organ procurement cross-match trays (ROP trays), 27 serial dilution analysis, 40 XM-ONE assay, 42

Index

436 Horseshoe deceased kidney donor, 235 Human herpesvirus 6, 7, and 8 (HHV-6, 7, 8), 341 Human leukocyte antigen (HLA) antigen matching, 23, 24 Hydrocele, 296 Hyperkalemia, 331 Hyperlipidemia, medical management diagnosis and monitoring NKF-KDOQI guidelines, 320 statins and niacin, 320 epidemiology and clinical importance, 319 risk factors and pathogenesis, 319 Hypertension, 174 diagnosis and management, 313 epidemiology and clinical importance, 312 living kidney donation, 362 risk factors and pathogenesis calcineurin inhibitors and corticosteroids, 312 TRAS, 313 treatment ACEi/ARB, 314–315 antihypertensives, 314 diuretics, 315 Hypoglycemic agents, 318 Hypomagnesemia, 331 Hypophosphatemia, 331 I IgA glomerulonephritis, 195 Immunosuppressive therapy acute rejection, treatment of antibody mediated rejection, treatment, 78–79 anti-T cell antibody therapy, 77–78 global considerations, 76–77 pulse corticosteroids, 77 treatment resistant rejections and late rejections, 78 anti-CD25 monoclonal antibodies/IL-2 receptor antibodies antiproliferative agent, choice of, 71–72 belatacept/costimulation blockade, 68–69 bortezomib (velcade), 69 calcineurin inhibitor and steroid avoidance regimens, 72–76 calcineurin inhibitors, choice of, 70–71 chronic allograft failure, 79 FTY 720, 68 induction regimen, choice of, 70 induction therapy depleting antibodies, 56–58 nondepleting antibodies, 58–59 ISA247, 67–68 Janus Kinase (JAK) inhibitors, 68 maintenance therapy antimetabolites, 63–65 calcineurin inhibitors, 59–63 corticosteroids, 66–67 intravenous immune globulin (IVIG), 67

mammalian target of rapamycin (m-TOR ) inhibitors, 65–66 pancreas transplantation, 79 PKC inhibition/AEB071 (Sotrastaurin), 68 vs. regimens, 50 rituximab, 69 sites and mechanisms of action antigen presenting cells (APC), 51 immunosuppressive drugs, 55 Impaired fasting glucose (IFG), 363 Induction therapy depleting antibodies, 56–58 nondepleting antibodies, 58–59 Infected kidney transplant wound, 284 Infectious complications, prevention and management bacterial infections Clostridium difficile, 348 legionellosis, 349 Listeria monocytogenes, 349 Mycobacterium tuberculosis, 348–349 Nocardia spp., 349 Rhodococcus equi, 349 BK virus and polyomavirus allograft nephropathy, 341–343 exposures and immunizations, 351 febrile transplant recipient, 349–350 fungal infections pneumocystis and, 346–347 practical approach to, 348 hepatitis viruses in, 343–345 postoperative infections bloodstream infections (BSI), 337 urinary tract infections, 337–338 posttransplant infections hospitalizations for, 335 immunosuppression, 335 periods of, 334 surgical site and intraabdominal infections, 335–337 pretransplant screening of, 333–334 viral infections adenoviruses, 345 CMV infection and viremia, 340–341 EBV, 341 parvovirus B19, 345 West Nile virus (WNV), 346 Infertility and sexual dysfunction, 326–327 Inheritance pattern, HLA genes, 23, 24 Intermediate and late transplant period, 125–127 Intravenous immune globulin (IVIG), 67 ISA247, 67–68 Ischemia-reperfusion injury, 1–3 Islets of Langerhans, 136 IVIg serum levels, 43 J Janus Kinase (JAK) inhibitors, 68

Index K Kaplan–Meier and proportional hazard models, 156, 157 Kidney transplant recipients, medical management anemia diagnosis and management, 325–326 epidemiology and, 324–325 posttransplant erythrocytosis (PTE), 326 risk factors and pathogenesis, 325 bone disease, 323–324 cancer breast cancer, 322 colorectal cancer, 322 malignant melanoma, 322 nonmelanomatous skin and lip cancers, 321–322 posttransplant bone disease, risk factors for, 321 prostate cancer, 323 viral infections, 322 cardiovascular disease, 311 diabetes diagnosis and management, 316–319 epidemiology and clinical importance, 315–316 risk factors and pathogenesis, 316 hyperkalemia, 331 hyperlipidemia diagnosis and monitoring, 319–320 epidemiology and clinical importance, 319 risk factors and pathogenesis, 319 hypertension diagnosis and management, 313 epidemiology and clinical importance, 312 risk factors and pathogenesis, 312–313 treatment, 313–315 hypomagnesemia, 331 hypophosphatemia, 331 pregnancy antenatal period, 327, 328 fetus, risks to, 329–331 infertility and sexual dysfunction, 326–327 mother, risks of, 327–329 optimal timing and contraception, 327 treatment in early posttransplant period, 324 in late posttransplant period, 324 Kidney transplant recipient surgery implant location, 211 pediatric en bloc transplant, 216–217 preparation of arterial, 212–213 donor kidney, 211–212 ureteral, 213–214 venous, 212 recipient surgery, 215–216 L Laparoscopic living kidney donation end stage renal disease (ESRD), 259 live donor nephrectomy, 259, 260 operative technique adrenal vein, 266

437 gonadal vein, 265, 266 left renal artery, 267, 269 left renal vein, 270 mesentery reflection, 264 patient positioning, 261–262 ureteral/gonadal vein dissection, 264 pre-operative evaluation, 260–261 Legionellosis, 349 Lip cancers, 321–322 Listeria monocytogenes, 349 Live donor nephrectomy, 259–260 Living kidney donation. See also Laparoscopic living kidney donation Amsterdam Forum guidelines, 358 donor evaluation age, 358, 360–361 cardiovascular and pulmonary, 361–362 contraindications to, 361 hematuria, 365 hypertension, 362 laboratory testing and predonation workup, 360 medical conditions in, 359–360 metabolic derangements, 363–364 nephrolithiasis, 364–365 renal mass and function, 365–366 donor nephrectomy, risks associated with immediate complications, 366–367 late-term complications, 367–368 end stage renal disease (ESRD), 357 success of, 357–358 Long-term kidney allograft survival, classification, 400 Lower urinary tract disease, 196 Lupus, 233–234 Lymphocele, in kidney transplantation abdominal CAT scan, pelvis, 285 drainage procedure, 286 postrenal transplant, management algorithm for, 286 M Maintenance therapy antimetabolites, 63–65 calcineurin inhibitors cyclosporine vs. tacrolimus, 60, 62 dosing and monitoring, 61 side effects, 61–63 corticosteroids, 66–67 intravenous immune globulin (IVIG), 67 m-TOR inhibitors, 65–66 Malignant melanoma, 322 Mammalian target of rapamycin (m-TOR) inhibitors, 65–66, 88–89 Maternal and fetal complications, donor nephrectomy, 367 Medical and surgical evaluation, kidney transplantation evaluation process coagulopathy, 193 education and consent, 185–187 elderly transplant recipient, 191–192 financial considerations, 192 highly sensitized patient, 193

438 Medical and surgical evaluation, kidney transplantation (cont.) medical evaluation, 187–191 patients with prior transplants, 192–193 waitlist management, 193–194 indications and contraindications, 184–185 kidney transplant candidate, 183 lower urinary tract disease management, 196 multiorgan transplants, 196 native kidney disease and recurrence focal and segmental glomerulosclerosis, 194–195 IgA glomerulonephritis, 195 nephrectomy indications, 195 obesity, 195 preemptive transplantation, 184 recommendations, 196–197 referral for, 184–185 Medical regimen, nonadherence, 375 Membranous nephropathy, 233–234 Memory cells, 12–13 Metastatic malignant cells, 232 Mixed lymphocyte culture (MLC), 28 Multiorgan transplants, 196 Mycobacterium tuberculosis, 348–349 Mycophenolate mofetil (MMF), 91 Mycophenolic acid (MPA), 88 N Native kidney disease and recurrence focal and segmental glomerulosclerosis, 194–195 IgA glomerulonephritis, 195 nephrectomy indications, 195 obesity, 195 Nephrectomy, 195 Nephrolithiasis, 364–365 Nocardia spp., 349 Non-heart beating donor, 224–225 Nonmelanomatous skin and lip cancers, 321–322 O Obesity, 195, 364 Organ allocation system donation service areas (DSAs), 386 DonorNet, 386 ethical issues, 385–386 factors dialysis time, 389–390 donor profile index, 389 life years from transplant (LYFT), 389 sensitization, 390 HLA matching, 387 national infrastructure, 385 organ procurement organization (OPO), 386 strengths and weaknesses, 388 wait time, 386–387 zero mismatch (0MM) sharing panel reactive antibody (PRA), 387 younger age, 387–388 Organ Procurement and Transplant Network (OPTN), 424

Index P Pancreas after kidney transplantation (PAK), 202–204 Pancreas transplant alone (PTA), 202–204 Pancreas transplant recipient categories of, 202–204 medical evaluation and preparation, 204–206 patient selection for, 201–202 Pancreatitis, 135–136 Panel reactive antibody (PRA) assessment, 36 Pathology allograft biopsy processing, 112–113 Banff schema and rejection classification, 129–131 biopsy, 111–112 early allograft biopsies donor biopsies, 113–114 early posttransplant graft dysfunction, 116–117 immediate posttransplantation biopsies, 114–116 early transplant interval acute rejection, 119 acute tubular injury (ATI), 118 acute tubulointerstitial rejection, 119 infection, 123–125 recurrent disease, 124 vasculature, 119–123 intermediate and late transplant period, 125–127 pancreas transplant acute rejection, 132–135 chronic rejection, 135 islets of Langerhans, lesions, 136 pancreatitis, 135–136 posttransplant proteinuria, 127–129 Patient and graft survival kidney transplantation, 158–159 pancreas transplantation, 159–161 selection, 375–376 Pediatric deceased donor kidney, 227 Pediatric en bloc deceased renal transplantation, 227–228 Pediatric en bloc transplant, 216–217 Pelvis, abdominal CAT scan, 285 Perioperative and anesthetic management kidney transplantation anesthetic management, 274 considerations to, 273, 274 deceased donor kidney management, 274 living donor management, 274–275 perioperative fluid management, 275–276 pharmacologic therapies, 276 recipient anesthetic management, 275 recovery room, 276 renal preservation, 275 pancreas transplantation anesthetic management, 278–279 coronary artery disease (CAD), 277 Peripheral blood mononuclear cells (PBMC), 28 PKC inhibition/AEB071 (Sotrastaurin), 68 Plain radiograph with artificial urinary sphincter, 307 of missed stent, 306 Pneumocystis, 346–347

Index Polycystic deceased donor kidney, 235–236 Polycystic kidney disease (PKD), 374 Portal vein mobilization, 251 Portal venous drainage, 253–254 Postoperative hemorrhage, 287 Postoperative infections bloodstream infections (BSI), 337 urinary tract infections, 337–338 Posttransplantation anemia (PTA), 324–325 Posttransplant bone disease, 321 Posttransplant erythrocytosis (PTE), 326 Posttransplant infections hospitalizations for, 335 immunosuppression, 335 periods of, 334 surgical site and intraabdominal infections, 335–337 Posttransplant lymphoproliferative disorder (PTLD), 341 Posttransplant proteinuria, 127–129 Posttransplant rehabilitation, 376 Preexisting lesions, 233–234 Pregnancy, medical management antenatal period, 327, 328 fetus, risks to, 329–331 immunosuppressive agents, 330 infertility and sexual dysfunction, 326–327 mother, risks of, 327–329 optimal timing and contraception, 327 Prophylactic ureteral stents, 305, 306 Prostate cancer, 323 Proteinuria, 174 Pseudoaneurysm, renal artery, 289 Psychiatric complications assessment, 375 contraindications, 375 dialysis, 373–374 ESRD, 373 impacting factors, 374 posttransplant rehabilitation, 376 symptoms and disorders alcohol and substance abuse, 379 antidepressant and antipsychotic drugs, 380–381 depression, 378 nonadherent patients, 378 pain, 379–380 posttransplant issues, 377–378 pretransplant issues, 376–377 psychosis, 378–379 sleep disorders, 379 PTA. See Pancreas transplant alone (PTA) R Randomized controlled trials (RCT), 412, 414 Recipient factors, renal allograft survival acute rejection, 170 age, 168–169 compliance, 173 dyslipidemia, 174 gender, 169–170 hypertension, 174 immunosuppression, 170–173

439 obesity, 173–174 race, 169 sensitization, 170 Recipient surgery, 215–216 Recurrent disease, 124 Regional organ procurement cross-match trays (ROP trays), 27 Rejection T cells mediated, 11–12 treatment of antibody mediated rejection, treatment, 78–79 anti-T cell antibody therapy, 77–78 global considerations, 76–77 pulse corticosteroids, 77 treatment resistant rejections and late rejections, 78 Renal allograft survival donor factors age, 166–167 center effect, 165 cold ischemia time, 167 deceased vs. living donor, 166 donor factors, 166 donor nephron mass, 167 donor–recipient factors, 163 expanded criteria donors, 167–168 gender, 167 HLA matching, 163–164 waiting time and preemptive transplantation, 164–165 year of transplant (era effects), 165–166 long-term outcomes, 161–163 outcomes data, 175–177 primary disease, recurrence of, 174–175 proteinuria, 174 recipient factors acute rejection, 170 age, 168–169 compliance, 173 dyslipidemia, 174 gender, 169–170 hypertension, 174 immunosuppression, 170–173 obesity, 173–174 race, 169 sensitization, 170 survival analysis donor source and quality, 158 durable survival benefit over dialysis, 158 graft survival, 157 Renal artery pseudoaneurysm, 289 stenosis causes of, 288 surgical revascularization, 289 thrombosis, 287–288 Renal mass and function, 365–366 Renal transplantation ABO-incompatiblity, 406 acute cellular rejection (ACR), 407 antibody-mediated rejection, 407

Index

440 Renal transplantation (cont.) chimerism, 406 cyclosporine, 399 definition of, long-term, 400 glomerulonephritis, 406 hepatitis effect, 405 history, 399 HLA matching effect, 406 long ischemia times, 23 years, 405 long-term successes, 407 malignancy, 405–406 outcomes of immunosuppression, 403 patient and graft survivals, 401–402 pediatric recipients, 404–405 protocol biopsies, 405 urinary cytolytic molecules, 406–407 Restless legs syndrome (RLS), 374 Revascularization arterial, 254 portal venous drainage, 253–254 systemic venous drainage, 254 Rhodococcus equi, 349 Rituximab, 69 S Scientific Registry of Transplant Recipients (SRTR), 417–418 Simultaneous pancreas kidney transplantation (SPK), 202–204 Single photon emission tomography (SPECT CT), ureteral fistulae, 290, 291 Skin cancers, 321–322 Solid organ transplantation clinical research collaboration postapproval clinical studies safety monitoring, 151–152 postapproval company-sponsored clinical studies, 151 clinical trial data management, 148–149 protocol, 147–148 regulatory considerations, 149–150 report, 150 statistical analytical plan (SAP), 149 control group, 144–145 endpoints, 145–146 experimental group, 144 study design definition, 139 observational, 142–143 randomized control (placebo or active), 140–142 registry analyses, 143–144 systematic reviews and metaanalysis, 143 study population, 146–147 SPK. See Simultaneous pancreas kidney transplantation (SPK) Splenectomy, 250 Standardized mortality ratios (SMR), 418

Statistical analytical plan (SAP), 149 Stenosis, renal artery, 288–289 Superior mesenteric artery (SMA), 251–252 Superior mesenteric vein (SMV), 252 Surgical complications, kidney transplantation urologic problems bladder fistulae, 294 calyceal fistulae, 293 hydrocele, 296 ureteral fistulae, 290–293 ureteral obstruction, 294–296 vascular problems allograft rupture, 290 arterial pseudoaneurysm, 289 arterial stenosis, 288–289 arterial thrombosis, 287–288 hemorrhage, 287 vein thrombosis, 288 wound hernias, 282–284 incision, 281–282 infections, 284 lymphocele, 284–287 Surgical techniques bench preparation arterial reconstruction, 251–253 duodenal segment, 251 inspection of, 250 mesenteric root, 251 portal vein mobilization, 251 splenectomy, 250 duct management, 254–256 incision and exposure, 250 revascularization arterial, 254 portal venous drainage, 253–254 systemic venous drainage, 254 Survival analysis, renal allograft donor source and quality, 158 durable survival benefit over dialysis, 158 graft survival, 157 Systemic venous drainage, 254 T T-cell receptors (TCRs), 8–11 T cells functional development, 5–7 mediated activation, 8–11 mediated cytolysis, 7–8 mediated rejection, 11–12 Technetium-99m mercaptoacetyl-tri glycine (Tc99m MAG-3) renal scan, 301 Therapeutic drug monitoring (TDM) C2 monitoring, 97–98 glomerular filltration rate (GFR), 100 mycophenolic acid (MPA), 101 Thrombosis, in kidney transplantation arterial, 287–288 vein, 288

441

Index Total body clearance (CLT), 92–94 Transplant-associated hyperglycemia (TAH), 315–316 Transplanted organs, immune response B cells and antibody, 13–17 chronic rejection, 17 cytolysis, T cell mediated, 7–8 donor-specific T cell response, 3–5 functional development, T cell, 5–7 ischemia-reperfusion injury, 1–3 memory cells, 12–13 rejection, T cell mediated, 11–12 TCR mediated activation, 8–11 Transplant renal artery stenosis (TRAS), 313, 315 Tubulointerstitial rejection, acute, 119 U United Network for Organ Sharing (UNOS), 423 Ureter fistulae MAG-3 isotopic renal scan of, 291 percutaneous management, 292–293 single photon emission tomography (SPECT CT), 290, 291 surgical reconstruction techniques, 292, 293 leaks from Boari flap repair of, 302, 303 necrosis, native ureter, 301, 302 Tc99m MAG-3 renal scan, 301 obstruction, kidney transplantation stricture, endourologic management, 295 ureteroneocystostomy, 294 prophylactic stents, 305, 306 stenosis antegrade nephrostogram, 304 stricture, recurrence of, 305 Urinary calculi, 305–306 Urinary retention diagnosis of, 306 treatment, 306–307 Urinary tract infections, 337–338 Urologic complications, renal transplantation erectile dysfunction (ED), 307–308 problems bladder fistulae, 294 calyceal fistulae, 293

hydrocele, 296 ureteral fistulae, 290–293 ureteral obstruction, 294–296 ureter cadaveric donor kidney, bench table preparation, 299, 300 leaks from, 300–303 prophylactic stents, 305, 306 stenosis, 303–305 urinary calculi in, 305–306 urinary retention, 306–307 V Varicella-zoster virus (VZV), 341 Vascular problems, in kidney transplantation allograft rupture, 290 arterial pseudoaneurysm, 289 arterial stenosis, 288–289 arterial thrombosis, 287–288 hemorrhage, 287 vein thrombosis, 288 Venous drainage portal, 253–254 systemic, 254 Venous thrombosis, in kidney transplantation, 288 Viral infections adenoviruses, 345 cancer, 322 CMV infection and viremia, 340–341 EBV, 341 parvovirus B19, 345 West Nile virus (WNV), 346 W Wound healing, 281 hernias, 282–284 incision corticosteroids, 281–282 demographic risk factors, 282 loculated wound seroma, 282 obese type 2 diabetic kidney transplant recipient, 283 infections, 284 lymphocele, 284–287