Peritoneal Dialysis: A Clinical Update (Contributions to Nephrology)

Peritoneal Dialysis: A Clinical Update We would like to dedicate this volume to the memory of Germano Pellizzoni: a pa...

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Peritoneal Dialysis: A Clinical Update

We would like to dedicate this volume to the memory of Germano Pellizzoni: a patient, a friend, a journalist and a person whose spirit and enthusiasm still lives with us. Centro Studi Ennio Valente & Associazione Amici del Rene di Vicenza

Contributions to Nephrology Vol. 150

Series Editor

Claudio Ronco

Vicenza

Peritoneal Dialysis A Clinical Update

Volume Editors

Claudio Ronco Vicenza Roberto Dell’Aquila Vicenza Maria Pia Rodighiero Vicenza

45 figures, 8 in color, and 20 tables, 2006

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Contributions to Nephrology (Founded 1975 by Geoffrey M. Berlyne)

Claudio Ronco

Roberto Dell’Aquila

Department of Nephrology St. Bortolo Hospital 1–36100 Vicenza (Italy)

Department of Nephrology St. Bortolo Hospital 1–36100 Vicenza (Italy)

Maria Pia Rodighiero Department of Nephrology St. Bortolo Hospital 1–36100 Vicenza (Italy) Library of Congress Cataloging-in-Publication Data Peritoneal dialysis : a clinical update / volume editors, Claudio Ronco, Roberto Dell’ Aquila, Maria Pia Rodighiero p. ; cm. — (Contributions to nephrology, ISSN 0302-5144 ; v. 150) Includes bibliographical references and index. ISBN 3-8055-8119-X (hard cover : alk. paper) 1. Peritoneal dialysis. I. Ronco, C. (Claudio), 1951– . II. Dell’Aquila, Roberto. III. Rodighiero, Maria Pia. IV. Series. [DNLM: 1. Peritoneal Dialysis. W1 CO778UN v.150 2006 / WJ 378 P4463 2006] RC901.7.P48P474 2006 617.4⬘61059—dc22 2006009470 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2006 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0302–5144 ISBN 3–8055–8119–X

Contents

XI Preface Ronco, C.; Dell’Aquila, R.; Rodighiero, M.P. (Vicenza) Basic Elements 1 Factors Affecting Hemodialysis and Peritoneal Dialysis Efficiency Ronco, C. (Vicenza) 13 Pathophysiology of Peritoneal Transport Twardowski, Z.J. (Columbia, Mo.) 20 A Simplified Approach to Understanding Urea Kinetics in Peritoneal Dialysis and Hemodialysis Misra, M.; Nolph, K. (Columbia, Mo.) 28 Peritoneal Ultrafiltration: Mechanisms and Measures Flessner, M.F. (Jackson, Miss.) 37 Evaluation of the Peritoneal Membrane Function by Three Letter Word Acronyms: PET, PDC®, SPA, PD-Adequest, POL: What to Do? Van Biesen, W.; Van Der Tol, A.; Veys, N.; Lameire, N.; Vanholder, R. (Ghent) 42 The Initiation of Peritoneal Dialysis: Planning the Initial Prescription Finkelstein, F.O. (New Haven, Conn.)

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Biology of Peritoneal Membrane 48 PD Membrane: Biological Responses to Different PD Fluids Jörres, A. (Berlin); Witowski, J. (Berlin/Poznan) 54 Repopulation of the Mesothelial Monolayer During Long-Term Experimental Peritoneal Dialysis Gotloib, L.; Wajsbrot, V.; Shostak, A.; Khrizman, V. (Afula) 62 Fibrosis and Sclerosis: Different Disorders or Different Stages? Garosi, G.; Cappelletti, F.; Di Paolo, N. (Siena) 70 What Did We Learn From Animal Models in Peritoneal Dialysis? Lameire, N.; Van Biesen, W.; Mortier, S. (Ghent); De Vriese, A. (Brugge) Update on Peritoneal Dialysis Solution 77 GDP and AGE Receptors: Mechanisms of Peritoneal Damage Schwenger, V. (Heidelberg) 84 Effects of Peritoneal Dialysis on the Vascular Bed of Peritoneal Membrane Van Biesen, W.; Mortier, S.; Lameire, N. (Brugge); De Vriese, A. (Ghent) 90 Effect of PD Solutions on Patient Outcome Lo, W.-K. (Hong Kong, SAR) 97 Peritoneal Transport with Icodextrin Solution Heimbürger, O. (Stockholm) Sodium and Water Homeostasis 104 Dry Body Weight:Water and Sodium Removal Targets in PD Krediet, R.T. (Amsterdam) 111 Is There a Competition Between Urine Volume and Peritoneal Ultrafiltration in Peritoneal Dialysis Patients? Kooman, J.P. (Maastricht); Cnossen, N.; Konings, C.J. (Eindhoven); van der Sande, F.M.; Leunissen, K.M. (Maastricht) 119 Application of Bioimpedance Techniques to Peritoneal Dialysis Zhu, F.; Wystrychowski, G.; Kitzler, T.; Thijssen, S.; Kotanko, P.; Levin, N.W. (New York, N.Y.) 129 Peritoneal Dialysis: A Clinical Update. Congestive Heart Failure and PD Tobe, S.W.; Raymond, N.; Ismail, N.A. (Toronto)

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Chronic Inflammation in Peritoneal Dialysis 135 MIA Syndrome in Peritoneal Dialysis: Prevention and Treatment Shahab, I.; Nolph, K.D. (Columbia, Mo.) 144 Being an Inflamed Peritoneal Dialysis Patient – A Dante’s Journey Carrero, J.J.; Axelsson, J.; Avesani, C.M.; Heimbürger, O.; Lindholm, B.; Stenvinkel, P. (Stockholm) 152 Serum Parameters, Inflammation, Renal Function and Patient Outcome Lo, W.-K. (Hong Kong, SAR) 156 Sterile Solutions and Peritoneal Inflammation Flessner, M.F. (Jackson, Miss.) Peritoneal Dialysis: Adequacy Issues and Beyond 166 Adipokine Signaling in the Peritoneal Dialysis Patient Axelsson, J.; Carrero, J.J.; Avesani, C.M.; Heimbürger, O.; Lindholm, B.; Stenvinkel, P. (Stockholm) 174 The Effect of Fibrosis on Peritoneal Transport Flessner, M.F. (Jackson, Miss.) Reviews in Peritoneal Dialysis 181 Peritoneal Dialysis Infections Recommendations Piraino, B. (Pittsburgh, Pa.) 187 Cloudy Peritoneal Dialysate: It’s not Always Infection Teitelbaum, I. (Denver, Colo.) 195 Peritoneal Access: The Past, Present, and the Future Twardowski, Z.J. (Columbia, Mo.) 202 How to Optimise Anaemia Therapy in Peritoneal Dialysis Patients Macdougall, I.C. (London) 214 Calcium and Phosphate Handling in Peritoneal Dialysis Cozzolino, M.; Gallieni, M.; Chiarelli, G.; Brancaccio, D. (Milan) Peritoneal Dialysis: A Therapy for Uremia and Beyond 226 Integration of Peritoneal Dialysis in the Treatment of Uremia Ronco, C.; Dell’Aquila, R.; Rodighiero, M.P.; Di Loreto, P.; Spanò, E. (Vicenza)

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235 The Role of Chronic Peritoneal Dialysis in the Management of the Patient with Chronic Kidney Disease Finkelstein, F.O.; Finkelstein, S.H.; Troidle, L.K. (New Haven, Conn.) 240 Peritoneal Dialysis Is Appropriate for Elderly Patients Teitelbaum, I. (Denver, Colo.) 247 The Impact of Peritoneal Dialysis Upon Quality of Life and Mortality of Patients with End-Stage Congestive Heart Failure Gotloib, L.; Fudin, R. (Afula) Transplantation and Peritoneal Dialysis 254 The Impact of the Pre-Transplant Renal Replacement Modality on Outcome After Cadaveric Kidney Transplantation: The Ghent Experience Van Biesen, W.; Veys, N.; Vanholder, R.; Lameire, N. (Ghent) 259 Transplantation Outcome in Patients on PD and HD Cancarini, G.C.; Sandrini, S.; Setti, G.; Bossini, N.; Cassamali, S.; Pertica, N.; Maiorca, P. (Brescia) Transplantation and Beyond 271 Peritoneal Dialysis after a Failed Transplant John, B.; Mushahar, L.; Davies, S.J. (Keele) Automated Peritoneal Dialysis 278 Automated Peritoneal Dialysis – Indications and Management Negoi, D.; Nolph, K.D. (Columbia, Mo.) 285 APD Schedules and Clinical Results Durand, P.-Y. (Nancy) 291 Evolution of Technology for Automated Peritoneal Dialysis Ronco, C. (Vicenza); Amerling, R. (New York, N.Y.); Dell’Aquila, R.; Rodighiero, M.P.; Di Loreto, P. (Vicenza) New Technologies 310 Continuous Flow Peritoneal Dialysis: Current State-of-the-Art and Obstacles to Further Development Ronco, C. (Vicenza); Amerling, R. (New York, N.Y.)

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321 Continuous Flow Peritoneal Dialysis: Ideal Peritoneal Dialysis or Second-Rate Hemodialysis? Bargman, J.M. (Toronto) 326 A New Home Based Bioimpedance System for PD Dell’Aquila, R.; Rodighiero, M.P.; Di Loreto, P.; Spanò, E.; Brendolan, S.; Crepaldi, C.; Nalesso, F.; Corradi, V.; De Cal, M. (Vicenza); Braganò, P. (Pero); Ronco, C. (Vicenza) 336 The Potential Application of Sorbents in Peritoneal Dialysis Winchester, J.F.; Amerling, R.; Harbord, N. (New York, N.Y.); Capponi, V. (Monmouth Junction, N.J.).; Ronco, C. (Vicenza)

344 Author Index 346 Subject Index

Contents

IX

Preface

The use of peritoneal dialysis is well established worldwide. In spite several advantages have been identified in terms of clinical efficacy, social impact and individual tolerance, peritoneal dialysis is still underutilized around the world. The significance of the present book is mostly related to the effort to identify possible barriers for a wider application of peritoneal dialysis and at the same time to carry forward the project undertaken by the Department of Nephrology Dialysis and Transplantation of Vicenza called USS PD: Understanding, Starting and Sustaining Peritoneal Dialysis. Since 1982, the International Vicenza Course on Peritoneal Dialysis has been considered one of the most important and complete educational events in the field of PD. This book is the compendium of the presentations given by leading experts in the field in the Course of 2006. The initial part of the course and thus of the book is dedicated to basic principles of PD, assuming that understanding how peritoneal dialysis works is one of the pre requisites to improve the quality of its application and ultimately the outcomes. The second part is dedicated to reviews of important issues which have been debated for many years and for which a state of the art discussion is needed. In depth reviews help the physician to identify the benefits and the problems involved in a PD program and thus become an important step for the process of starting a new program or new patients on PD. The third part is dedicated to potential complications and technical solutions designed to solve the problems of the different techniques. This part corresponds to the phase in which physicians must sustain the use of PD after having acquired the know how and the capacity of starting the program.

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In designing such initiative defined USS PD, we looked backward and we analyzed all the difficulties but also all the successes that led Vicenza to become an important reference center for peritoneal dialysis with more than 100 patients currently treated with this renal replacement technique. The acronym reminds the name of the USS Enterprise and the difficult pathway ‘to boldly go where no man has gone before’. The USS PD, includes many initiatives and the Vicenza Course and its book represent some of them. Others are postgraduate masters for physicians, specialization courses for nurses, programs of education such as the ‘PD start’ and the ‘PD GO’ with specific programs for beginners and finally stages for ‘research fellows’ that in several cases have been supported by the International Society of Nephrology. We are indebted with the faculty, with the sponsors, with Mario and Anna Saccardo and with all individuals who made possible these initiatives. We thank Karger for the timely publication of this book with the usual outstanding quality. We hope that our effort and the USS PD project will push everybody towards a wider utilization of peritoneal dialysis ‘to boldly go where no man has gone before’ i.e. to increase levels of PD utilization beyond any point of the past. Claudio Ronco, Vicenza Roberto Dell’Aquila, Vicenza Maria Pia Rodighiero, Vicenza

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Basic Elements Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 1–12

Factors Affecting Hemodialysis and Peritoneal Dialysis Efficiency Claudio Ronco Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy

Abstract The peritoneal dialysis system has three major components: the peritoneal microcirculation, the peritoneal membrane, and the dialysate compartment. All these three that includes the composition of the solution and the modalities of delivery. All these three components may have an important impact on the final performance of the technique. As in the hemodialysis system, factors affecting diffusion of solutes as well as factors affecting convective transport may contribute to the final clearance of a given solute. Ultrafiltration responds to the same pressures applied to the extracorporeal dialysis system, but osmotic gradients represent by far the most important active component. Copyright © 2006 S. Karger AG, Basel

The factors affecting the delivery of therapy in hemodialysis and peritoneal dialysis can substantially be divided into two groups: (a) factors affecting the technical performance of the dialytic technique (operational parameters), and (b) factors affecting the clinical results of a given technique (interaction between the technique and the patient’s organism). In this paper, we concentrate on the first group of factors. System operation is the foundation for an adequate therapy prescription and a crucial factor with which to comply in order to achieve the desired treatment delivery. Hemodialysis

Since the beginning of dialytic therapy, diffusion and convection have been combined in an attempt to replace renal function [1]. The knowledge of diffusion came from the industrial chemistry and dialyzers were designed to be ideal countercurrent exchangers [2]. Only later, convection was used in clinical practice

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showing potential advantages [3, 4]. Although ultrafiltration was employed first to treat overhydrated patients [5] convective solute removal was subsequently employed to enhance solute removal [6–9]. Figure 1 summarizes the factors influencing the solute transport across semipermeable membranes. Blood flow greatly affects the clearance of small solutes like urea while ultrafiltration rate primarily affects the removal of larger solutes like inulin. Increases in dialysate flow rate become important only with large surface areas dialyzers and mostly affect the clearance of small solutes. Finally, dialyzer surface area determines the maximal solute clearance at a given blood flow. All these aspects must also consider the type of membrane utilized and the hydraulic conditions within the hemodialyzer. Diffusion and Convection Diffusion is a process in which molecules randomly move in all directions. Statistically this movement results in a passage of solutes from a more concentrated area to a less concentrated one. Besides the concentration gradient (dc),

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the solute diffusive flux (Jd) through a semipermeable membrane depends on the temperature (T), the surface area and the diffusivity (D) of the solute, while it is inversely proportional to the membrane thickness (dx). Jd ⫽ D ⭈ A ⭈ T (dc/dx)

The convective process requires a fluid movement caused by a transmembrane pressure gradient. Therefore, the convective flux of a solute (Jc) will depend on the ultrafiltration rate (Qf), the solute concentration in plasma water (Cb) and the solute sieving coefficient (S). Jc ⫽ Qf ⭈ Cb ⭈ S

Being in ideal conditions: S ⫽ 1 ⫺ ␴, where ␴ is the reflection coefficient of the membrane. These definitions present convection and diffusion as two separate phenomena. However it is impossible to precisely define the contribution of each single process in the removal of solutes because of their continuous interactions. Membranes, Diffusivity and Sieving Different membranes are utilized in extracorporeal therapy [10]. Cellulosic membranes are considerably hydrophilic, with wall thickness values in the 5–15 ␮m range. Such membranes offer remarkable diffusive performances with limited solute sieving properties. Original synthetic high flux membranes had an internal skin layer surrounded by a microporous structure with a total thickness up to 100 ␮m. The polymer was hydrophobic and its efficiency in diffusion was poor. Only recently, partially hydrophilic synthetic membranes with a reduced wall thickness have been developed permitting the combination of diffusion and convection, as in the case of high flux dialysis or hemodiafiltration [10]. As solute molecular weight increases the diffusivity coefficient tends to decrease. Thus, the characteristics of the solute are extremely important and diffusion of solutes in the range of 5,000–20,000 Da may be poor even in the presence of a very permeable membrane. In this case, transport is mainly limited by the low diffusivity of the molecule rather than by the sieving characteristics of the membrane. In addition to the hydrophobic nature of the membrane, the membrane wall thickness and considerable amount of unstirred fluid inside the support structure remarkably slow down the solute transport. The structure of the recent synthetic high flux membranes partially avoids the above mentioned problems combining a relatively less hydrophobic nature with a reduced wall thickness and a more homogeneous structure. Solute diffusivity plays an important role also in blood and dialysate. The resistances generated by blood, dialysis fluid and membrane can be reported as a percent of the overall resistance to solute transport (total resistance ⫽ Rblood ⫹ Rmembrane ⫹ Rdialysate). At the cut off value, the resistance of the membrane

Factors Affecting Hemodialysis

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represents 100% of the total resistance. This resistance progressively decreases for smaller solutes while the resistances in the blood and dialysate compartments become increasingly important [11]. The resistance to the transport of larger solutes, due to their poor diffusion coefficients can be overcome by the use of convection. The convective flux is influenced by the permeability of the membrane, which is characterized by the observed sieving coefficient. The sieving coefficient is the ratio between the solute concentration in the filtrate and the solute concentration in plasma water, in the absence of a gradient for diffusion. However, solute distribution in the blood compartment is not homogeneous depending on polarization and other phenomena. As UF increases, part of the solute tends to accumulate at the blood/membrane interface, thus creating gradients for diffusion both towards the bulk region inside the hollow fiber and towards the dialysate compartment across the membrane. As a consequence diffusion is continuously interfering with convection and the sieving coefficient can be overestimated. In fact, the concentration in the bulk region (which is the value measured empirically) is generally lower than that at the blood/membrane interface. Therefore the difference between the observed sieving coefficient (So) and the true sieving coefficient (St) can be significantly affected by the amount of convection used. With low ultrafiltration values, So and St tend to be equal while large differences can be observed at high UF rates. The Membrane and the Blood Compartment For all membranes to some extent but particularly in the case of synthetic membranes, a protein layer is deposited on the internal surface of the fiber. This slightly reduces the membrane sieving coefficient with a rather constant trend. However, in case of high UF rates or high filtration fractions, a thick protein deposit on the membrane is induced by the additional phenomenon of polarization. This progressively reduces the membrane permeability and So becomes proportional to a new reflection coefficient (␴1) of the membrane. This layer is a function of several variables, and above all the value of ‘shear rate’ at wall. As the blood enters the hollow fiber, the shear stress generates different layers of blood from the bulk phase to the membrane interface flowing at different velocities. The ratio between the differential velocity of the fluid threads in the fiber and the differential distance from the center of the fiber (shear rate, expressed in s⫺1) is a function of blood viscosity and shear stress. The shear rate is also proportional to the blood flow per single fiber. The thickness of the protein layer at the blood membrane interface, depends on the wall shear rate value, and is extremely important for the membrane performance. The shear rate value linearly correlates with the shear stress in case of Newtonian fluids and the velocity profile is regularly parabolic. Blood approaches Newtonian behavior only at shear rates higher than 200 s⫺1.

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Ultrafiltration and solute sieving coefficients are considerably influenced by the wall shear rate because it contributes to keep the polarization layer very thin. This is particularly important for solutes in the middle-high range. Diffusion is also affected by the value of shear rate since high shear rates contribute to maintain the diffusion distance from blood to dialysate within minimal values. This is because concentration polarization and the secondary layer of proteins lead to the formation of a pseudo-membrane whose thickness is added to that of the original membrane. In clinical practice, high wall shear rates are obtained with high blood flows and appropriate device geometry, with relative preservation of UF rates and solute clearances. In a recent study carried out with dye injection in the blood compartment of different hollow fiber dialyzers, we could demonstrate that in peripheral fibers, blood flows and shear rates much lower than those observed in the central fibers of the bundle are observed [12]. This is even more evident when hematocrit rises above 35%. Based on the above mentioned issues we could speculate that blood flows higher than 350–400 ml/min must always be utilized in the presence of a 1.8–2.0 m2 dialyzer, if an optimal performance of all the fibers is to be achieved. The Dialysate Compartment While several attempts have been made to optimize the blood compartment, by creating adequate blood ports and flow distributors at the inlet of the dialyzer, very little attention has been paid to the dialysate compartment. The dialysate distribution may in fact be asymmetrical inside the dialyzer, presenting non-homogeneous distribution within the fiber’s bundle and consequent phenomena of channeling. This may prevent the optimal performance of the dialyzer and may affect the final performance of the treatment. Some attempts to avoid dialysate channeling have been made by new filter design. For example, an increased length of the fibers reduces contact because of a waived configuration of the fiber. An external irregular surface permits to avoid the perfect contact of adjacent fibers. Different systems of non-parallel orientation of the fibers or the use of tissue structures within the bundle may further help to maintain adequate distances between the external surface of adjacent fibers. The most recent approach is the use of spacing filaments (‘spacer yarns’) between the fibers or the creation of waved fibers (Moire’s structure). We have carried out a complex evaluation using an helical CT scan to achieve a detailed imaging of the dialysate distribution pattern after dye injection. The modified dialysate compartment with the spacing filaments between the fibers and the Moire’s structure displayed a more homogeneous distribution of the dye, as compared to the standard dialyzers in which a typical channeling effect was displayed in the peripheral regions [13].

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Interference between Diffusion and Convection Although convection and diffusion are described as two separate phenomena, in practice we cannot distinguish the single contributions given by the two mechanisms separately. Moreover, especially in treatments that present a combined utilization of diffusion and convection, there is a continuous interference between the two transport mechanisms [9]. In such circumstances, enhancement of one type of transport can produce effects on the other mechanism of transport that may be beneficial or detrimental. In hemodiafiltration, solutes are carried across the membrane at the same concentration as in plasma water because of high UF rate. This phenomenon mostly takes place in the proximal side of the filter and reduces the driving force for diffusion. In this case convection negatively affects diffusion that becomes more important in the distal side of the filter where UF approaches zero. This emphasizes the importance of the surface area for the diffusive performance in hemodiafiltration. However in hemodiafiltration the back-diffusion of substances like buffers from dialysate into the blood, may also be negatively affected at least in the proximal side of the filter where UF is higher. In high flux dialysis a typical filtration–backfiltration profile occurs. The minimal interference between convection and diffusion is achieved in the central part of the dialyzer at which the water flux in both directions is near zero. In the region near the blood ports, convection may interfere with diffusion both in the filtration and backfiltration modes. All these factors should be considered in prescribing and practically executing the dialysis procedure. Their knowledge allow to prevent system malfunction and permits to obtain the desired clinical results.

Peritoneal Dialysis

The peritoneal dialysis system has three major components: (1) the peritoneal microcirculation, (2) the peritoneal membrane, and (3) the dialysate compartment that includes the composition of the solution and the modalities of delivery. All these three components may have an important impact on the final performance of the technique [14]. Factors Affecting Solute Transport The Dialysate Compartment. In figure 2, urea clearance is plotted against dialysate flow rate. The curve identifies three specific regions. The first region includes the dialysate flow rates typical for continuous ambulatory peritoneal dialysis (CAPD) (3–5 exchanges/ day). In this region, the correlation is very steep, and clearance displays significant changes even in the presence of minimal

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changes even in the dialysate flow. However, minimal variations in dialysate flow rate may require changing from four to five exchanges/day. This region is therefore dialysate flow-dependent or flow-limited, since the volume of dialysate per day is the factor that chiefly limits the clearance value. In this region, it would be simple theoretically to increase the dialysate flow by a few ml/day to achieve much higher clearances and consequently, significant increases in Kt/V. However, while theoretically possible this would not be feasible in practice since it would mean carrying out 6–10 exchanges/day. The only possible way to increase the dialysate flow without increasing the number of exchanges is to increase the volume of solution per exchange. To achieve the same fractional clearance in patients weighing 60 and 90 kg, one must schedule 4 exchanges/day, with 2 and 3 l bags respectively. The impact of possible intraperitoneal pressure rise must be carefully checked to avoid middle- to longterm complications such as hernias, respiratory problems or decreased ultrafiltration. In conclusion, a typical CAPD technique is basically dialysate flow-limited. The second part of the curve is the typical region of automated or intermittent peritoneal dialysis. The dialysate flows may vary significantly due to a variation of the dwell time from 30 to 0 min, and on the number of exchanges per day. Based on a 30 min dwell time and 20 min for influx and outflow, twelve

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2–1 exchanges can be preformed overnight for an overall duration of 10 h. The clearance will be 19 ml/min or 11.4 l/day. When the dwell time is reduced to 0 and the dialysate flow is therefore increased, the clearance rises to 22–30 ml/min with a total clearance per day of 18 l/day. This would result in a rise in the weekly Kt/V in a 60 kg patient from 2.21 to 3.50. This treatment, which could be defined high-flux automated peritoneal dialysis (HFAPD), would however require 60 l of dialysis solution and the cost would become excessive. A good compromise could be the use of a tidal volume of solution that may contribute to increase the dialysate volume artificially and to a better utilization of the surface area available for the exchanges. The third part of the curve is the region where the plateau is reached, and further increases in dialysate flow rates do not result in parallel increases in clearance. This region has been explored experimentally especially utilizing continuous flow peritoneal dialysis (CFPD) performed with double lumen peritoneal catheters [15] and theoretical mathematical models based on masstransfer-area coefficient (MTAC) calculation [16]. The value of the mass transfer coefficient is a function of the product of the overall permeability of the peritoneum and the available surface area of the membrane. This parameter is based on the calculation made for each single subject of the maximal clearance theoretically achievable at infinite blood and dialysate flow rates, i.e. at a constantly maximal gradient for diffusion. The above mentioned regions of the curve describe the relationship between dialysate flow and solute transport. Other factors such as dialysate temperature, intraperitoneal volume and dialysate osmolality represent further factors affecting solute transport either by increasing the diffusion process or by adding some convective transport due to increased ultrafiltration rates. The Peritoneal Dialysis Membrane. The peritoneal dialysis membrane is a living structure that can be considered more a functional barrier than a precisely defined anatomical structure. Based on the flow/clearance curve described above, a question may arise: why is the value of the MTAC so low in peritoneal dialysis compared with other dialysis treatments, and is the membrane involved in such limitations? Recently, the three-pore model has been proposed by Rippe et al. [17], to explain the peculiar behavior of the peritoneal membrane in relation to macromolecules, micromolecules and water transport. According to this model, human peritoneum appears to behave as a membrane with a series of differently sized pores: Large pores of 25 nm (macromolecule transport), small pores of 5 nm (micromolecule transport) and ultra-small pores (water transport). The anatomical structure of these ultra-small pores corresponds to the ‘water channels’ created by a specific protein ‘aquaporin’ acting as a carrier for water molecules.

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This model locates the main resistance to transport at the level of the capillary wall, considering all other anatomical structures as a negligible site of resistance. Only recently, the interstitium has been added as an additional site of resistance. A controversial opinion is offered by the so-called ‘distributed model’ of Flessner and coworkers [18]. In this model, the main resistance to transport is apparently located in the interstitial tissue. This anatomical entity consists of a double density material, containing water and glycosaminoglycans in different proportions. The interstitial matrix seems to act as the main site of resistance to solute and water transport from the blood stream to the peritoneal cavity. The solute diffusivity in free water is greater than that in the tissue by more than one order of magnitude. Accordingly, not only the structure of the interstitium, but also the thickness of the glycoaminoglycan layer may play an important role in restricting the diffusive transport of solutes. There is a certain discrepancy between the two models and overall transport process is probably governed by a more complex and integrated series of events, each with a remarkable but not absolute importance. The Peritoneal Micro-Circulation. Despite several lines of evidence suggesting that peritoneal blood flow should be high enough to avoid any limitation in solute clearances and ultrafiltration, the real impact of effective blood flow on the efficiency of the peritoneal dialysis system is still controversial [19]. Recent experimental work has in fact suggested that peritoneal ultrafiltration and solute clearances might be blood flow-limited at least in some condition [20]. Mesenteric blood flow averages 10% of cardiac output, but the peritoneal capillary blood flow seems to vary between 50 and 100 ml/min. The ‘effective’ amount of flow involved in peritoneal exchanges is, however, unknown, and it could be much lower. Gas clearance studies have suggested that peritoneal blood flow may be as high as 68–82 ml/min [21], while other studies have suggested a much lower values of ‘effective’ blood flow [22]. Gas clearance studies were based on the assumption that peritoneal gas clearance is equivalent to effective blood flow, and this assumption may not necessarily represent the actual condition. In recent studies, we have obtained an indirect measure of ‘effective’ blood flow of between 25 and 45 ml/min [23]. In conclusion, controversy exists over whether the blood supply to the peritoneum and subperitoneal tissues limits the transport of solutes between the peritoneal cavity and the blood. Using a distributed model approach, Waniewski [24] predicted marked changes in the MTAC (ml/min) for small solutes when the tissue blood perfusion rate (Qb, ml/min/g tissue) was changed from 0.5 ml/min/g tissue to 0.1; MTACurea decreases from 23 to 14; MTACcreatinine decreases from 17 to 11; MTACglucose decreases from 13 to 8.

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Unfortunately, there are no direct measurements of Qb during peritoneal dialysis to test these calculations. In a study in rats, Kim et al. [25–26] found no blood flow limitations in the transfer of urea across the peritoneum of the abdominal wall, cecum, and stomach after acutely decreasing the blood perfusion 60–72% from its baseline in the underlying tissue. In these studies, the blood perfusion relative to control value was measured with laser Doppler Flowmetry, which does not provide an absolute measurement of Qb which could be used to test Waniewski’s assertion. As an alternative view, we have proposed that peritoneal blood flow might be a limiting factor in rapid peritoneal dialysis exchanges. The results obtained in a study where a fragment of human peritoneum was perfused in a closed vascular loop displayed a linear correlation between the inlet blood flow and the rate of ultrafiltration, with a stable value of the filtration fraction [22–23]. The linear correlation between small solute clearance and blood flow, even at the high blood flows, seems to suggest that small solute clearance in peritoneal dialysis can probably be limited more by the low effective blood flow than by the low permeability of the peritoneal membrane. For larger solutes such as inulin, the low diffusion coefficients of the molecule may represent the most important limitation to transport. All these observations led to the formulation of the ‘nearest capillary hypothesis’ [27]. Considering the peritoneal micro-vasculature as a network of capillaries with a three-dimensional distribution and different distances from the mesothelium, the diffusion distances of solutes as well as the glucose backdiffusion distances may be different in different populations of capillaries. In this condition, the capillary situated closest to the mesothelium would experience a greater osmotic effect compared with those located further away presenting a filtration fraction much higher compared with the others. The final effect would be represented by an average value of clearance and ultrafiltration to which proximal and distant capillaries are differently contributing. Clearance and ultrafiltration could be definitely limited by the low blood flow at least in the capillaries closest to the peritoneal mesothelium. While in distant capillaries blood flow could be enough to avoid significant limitations, the effective blood flow in the capillaries closest to mesothelium might definitely be too low. The vascular reserve, represented by the capillaries located far from the mesothelium, would only participate partially in the peritoneal exchanges because of the interference of the interstitial tissue. In such a condition, the central role of the interstitium becomes evident as well as its hydration state. Anatomical observations demonstrate that interstitial tissue surrounding peritoneal capillaries may vary in thickness from 15 to 300 ␮m. The different location of the capillary network in this tissue and the varying distance from the mesothelium may therefore contribute to explain the different transport rates observed in different portions of the human peritoneum [27].

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The nearest capillary theory may also contribute to explaining the pathological conditions of hyper- and hypopermeability of the peritoneal membrane. Hyperpermeability could occur due to reduction in the interstitial spaces and a consequent crowding of the capillaries in a position close to the mesothelium. On the contrary, hypopermeability could occur in the case of interstitial hyperhydration or in conditions of pathological processes affecting the capillaries proximal to the mesothelium.

Conclusion

We have discussed the major factors influencing the efficiency of hemodialysis and peritoneal dialysis. We have focused has been on those factors related to the dialysis procedure itself, recognizing that other factors, such as patient and staff compliance, also influence therapy delivery significantly. It is our hope that the preceding discussion prepares the reader for the discussions about specific quantification approaches discussed in other parts of this edition.

References 1 2 3 4 5 6 7 8 9

10 11

12 13

Alwall N: On the artificial kidney. I. Apparatus for dialysis of blood ‘in vivo’. Acta Med Scand 1947;128:317–321. Kolff WJ: First clinical experience with the artificial kidney. Ann Intern Med 1965;62:608–612. Henderson LW, Besarab A, Michaels A, Bluemle LW Jr: Blood purification by ultrafiltration and fluid replacement (diafiltration). Trans Am Soc Artif Intern Organs 1967;17:216–221. Henderson LW, Colton CK, Ford C: Kinetics of hemodiafiltration. II. Clinical characterization of a new blood cleansing modality. J Lab Clin Med 1975;85:372–375. Maher JF, Schreiner GE, Waters TJ: Successful intermittent hemo-dialysis – longest reported maintenance of life in true oliguria (181 days). Trans Am Soc Artif Intern Organs 1960;6:123–126. Bergström J: Ultrafiltration without dialysis for removal of fluid and solutes in uremia. Clin Nephrol 1978;9:156–161. Babb AL, Farrel PC, Uvelli DA, Scribner BH: Hemodialyzer evaluation by examination of solute molecular spectra. Trans Am Soc Artif Intern Organs 1972;18:98–105. Babb AL, Strand MJ, Uvelli DA, Milutinovich J, Scribner BH: Quantitative describtion of dialysis treatment: a dialysis index. Kidney Int 1975;7(suppl 2):23–28. Henderson LW: Biophysics of ultrafiltration and hemofiltration; in Maher JF (ed): Replacement of Renal Function by Dialysis. A Text-book of Dialysis, ed 3. Dordrecht, Kluwer Academic Publishers, 1989, pp 300–326. Vienken J, Ronco C: New Development in hemodialyzers. Contrib Nephrol 2001;133:105–118. Ronco C, Ghezzi PM, Brendolan A, Crepaldi C, La Greca G: The haemodialysis system: basic mechanism of water and solute transport in extracorporeal renal replacement therapies. Nephrol Dial Transplant 1998;13(suppl 6):3–9. Ronco C: Blood and dialysate flow distribution in hollow fiber hemodialyzers. JASN, in press. Ronco C, Brendolan A, Crepadi C, Rodighiero M, Everard P, Ballestri M, Cappelli G, Spittle M, La Greca G: Dialysate flow distribution in hollow fiber hemodialyzers with different dialysate pathway configurations. Int J Artif Organs 2000;23:601–609.

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14 15 16 17 18 19 20 21 22

23 24 25 26 27

Ronco C, Brendolan A, La Greca G: The peritoneal dialysis system. Nephrol Dial Transplant 1998;13(suppl 6):94–99. Amerling R, Ronco C, Levin NW: Continuous flow peritoneal dialysis. Perit Dial Int 2000;20 (suppl 2):S178–S182. Ronco C: Limitations of peritoneal dialysis. Kidney Int 1996;50(suppl 56):69–74. Rippe B, Simonsen O, Stelin G: Clinical implications of a three pore model of peritoneal transport. Perit Dial Int 1991;7:3–9. Dedrick RL, Flessner MF, Collins JM, Schultz JS: Is the peritoneum a membrane? ASAIO J 1982;5:1–8. Ronco C, Feriani M, Chiaramonte S, Brendolan A, Milan M, La Greca G: Peritoneal blood flow: does it matter? Perit Dial Int 1996;16(suppl 1):70–75. Ronco C, Brendolan A, Crepaldi C, Conz P, Bragantini L, Milan M, La Greca G: Ultrafiltration and clearance studies in human isolated peritoneal vascular loops. Blood Purif 1994;12:233–242. Aune S: Transperitoneal exchanges II: peritoneal blood flow estimated by hydrogen gas clearance. Scand J Gastroenterol 1970;5:99–102. Ronco C, Borin D, Brendolan A, La Greca G: Influence of blood flow and plasma proteins on ultrafiltration rate in peritoneal dialysis; in Maher JF, Winchester JF (eds): Frontiers in Peritoneal Dialysis. New York, Fieldrich and Associates Inc., 1986, pp 82–86. Ronco C, Feriani M, Chiaramonte S, La Greca G: Pathophysiology of ultrafiltration in peritoneal dialysis. Perit Dial Int 1990;10:119–126. Waniewksi J, Werynski A, Lindholm B: Effect of blood perfusion on diffusive transport in peritoneal dialysis. Kidney Int 1999;56:707–713. Kim M, Lofthouse J, Flessner MF: A method to test blood flow limitation of peritoneal-blood solute transport. J Am Soc Nephrol 1997;8:471–474. Kim M, Lofthouse J, Flessner M: Blood flow limitations of solute transport across the visceral peritoneum. J Am Soc Nephrol 1997;8:1946–1950. Ronco C: The nearest capillary hypothesis: a novel approach to peritoneal transport physiology. Perit Dial Int 1996;16:121–125.

Claudio Ronco, MD Department of Nephrology St. Bortolo Hospital IT–36100 Vicenza (Italy) Tel. ⫹39 0444 753 869, Fax ⫹39 0444 753 949 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 13–19

Pathophysiology of Peritoneal Transport Zbylut J. Twardowski University of Missouri, Columbia, Mo., USA

Abstract The peritoneal membrane has the surface area similar to the body surface area. It consists of mesothelial cells, interstitium, connective tissue fibers, blood vessels, and lymphatics. Solutes of various sizes traverse the peritoneal membrane through at least three various pores: ‘large’ pores located in the venular interendothelial gaps, small ‘paracellular’ pores, and ultrasmall, ‘transcellular’ pores or aquaporins localized in peritoneal capillaries and mesothelial cells. High molecular weight solutes are mass-transfer limited; thus, their clearances do not increase significantly with high dialysate flow. Clearances of small molecular weight solutes are dialysate flow limited. Ultrafiltration is proportional to the hydrostatic and osmotic transmembrane pressures. The peritoneum offers greater resistance to accompanying solutes than to water (solute sieving), so that the concentration of solutes in the ultrafiltrate is less than in plasma water. Sodium sieving leads to hypertension, which is frequently observed in patients treated with short-dwell or continuous flow peritoneal dialysis. Peritoneal equilibration test is the most commonly used test to characterize peritoneal function and select the most suitable dialysis technique for a patient. Long-term peritoneal dialysis is associated with progressive loss of ultrafiltration capability due to structural and functional alterations in the membrane mostly as the consequence of exposure to glucose degradation products or advanced glycation end products generated during the sterilization process. Copyright © 2006 S. Karger AG, Basel

A comprehensive description of the peritoneal anatomy and pathophysiology has been recently published [1]. The following is a short discussion of this topic.

Anatomy of the Peritoneum

The peritoneum is a membrane consisting of the parietal peritoneum lining the inner surface of the abdominal and pelvic walls including the diaphragm

and the visceral peritoneum that covers visceral organs and forms the omentum and the visceral mesentery, which connects loops of bowel [1]. The surface of the membrane is a shiny layer of flattened mesothelial cells, beneath which lies supporting interstitium containing extracellular fluid, connective tissue fibers, blood vessels, and lymphatics. All mesothelial cells have microvilli that markedly increase gross surface area and contain lamellar bodies, which are storage vesicles for surfactant that are secreted to the peritoneal cavity for better lubrication. The mesentery, as well as the omentum, consists of two sheets of mesothelium that enclose a layer of connective tissue. The total surface area of the peritoneal mesothelium is believed to approximate the surface area of the skin. Lymphatic drainage from the peritoneal cavity is arranged in two major routes: diaphragmatic and omental. The diaphragmatic route seems to be the most important one for transporting fluid from the peritoneal cavity.

Normal Function of the Peritoneum

The primary function of the peritoneum is to provide a smooth surface of contact between intra-abdominal organs and the abdominal wall. Microvilli with their glycocalyx charges trap water, lubricate the surface, and prevent friction [2]. The peritoneum contains only small amounts of fluid, which is constantly filtered into the peritoneal cavity from the capillaries and absorbed (mainly through the diaphragmatic lymphatics [3]) at the same rate of approximately 1 l/day [4]. The omentum has been called an ‘abdominal policeman’ because of its role in combating and localizing intraperitoneal infection. Living bacteria introduced into the peritoneal cavity induce antibody production in the cells comprising the milky spots, analogous to regional lymph nodes [5]. Omentectomy lowers the resistance to abdominal infections [5].

The Peritoneum as a Dialysis System

Resistance to Solute and Water Transport Solutes moving from peritoneal capillaries into the peritoneal cavity encounter at least six sites of resistance [6]: fluid films within peritoneal capillaries, the capillary endothelium, the capillary basement membrane, the interstitium, the mesothelium, and stagnant fluid films within the peritoneal cavity. Solutes of various sizes traverse the peritoneal membrane through at least three various pores [7]: ‘large’ pores located in interendothelial gaps, which

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occur particularly in the venular part of the capillary (radius 250X), small ‘paracellular’ pores (radius 47), and ultra-small, ‘transcellular’ pores (radius 4–5X). The ultra-small pores are aquaporins localized in peritoneal capillaries and mesothelial cells. Aquaporin-1 is permeable only to water, aquaporin-3 is permeable to water and other small molecules like glycerol and urea [8]. Solute Transfer by Diffusion The peritoneal dialysis system can be considered as nature’s version of a capillary kidney. In both of them, with infinite peritoneal capillary blood and dialysate flows, the clearance is directly proportional to the effective peritoneal surface area and inversely proportional to the overall resistance. The peritoneal mass transfer area coefficient (MTAC) is the inverse of diffusion resistance and represents the clearance rate that would be realized in the absence of both ultrafiltration and solute accumulation in the dialysate. To determine MTAC, a test exchange is performed with at least two measurements of dialysate and plasma solute concentrations at different dwell times [9]. The efficiency index most commonly used by clinicians is the clearance rate of a solute from the plasma. This is calculated by dividing the amount of solute removed per unit time, the mass transfer rate, by the concentration of solute in plasma. This calculation expresses the volume of plasma cleared of that solute per unit time. The instantaneous clearance is close to MTAC at the beginning of an exchange when the dialysis solution solute concentration is near zero. The instantaneous clearance approaches zero exponentially as the dialysate solute concentration approaches equilibrium with blood. Peritoneal dialysis clearance is a function of three parameters: the peritoneal capillary flow rate (100–200 ml/min [10]), the dialysate flow rate, and the MTAC [9]. The clearance can never exceed the lowest value of these three parameters. High molecular weight solutes are mass-transfer limited, thus, their clearances do not increase significantly with high dialysate flow. The clearance of a solute is considered as dialysate flow rate limited if the value of dialysate flow rate is markedly lower than the other two parameters. Such a situation is typical for CAPD, where urea clearance is close to the dialysate flow rate. Efficiency of removal of small molecular substances increases with increased number of exchanges in intermittent flow peritoneal dialysis and increased contact time between dialysate and the peritoneal dialysis membrane [11]. The latter is achieved by semicontinuous peritoneal dialysis [12], or tidal peritoneal dialysis [11], where only a part of fluid is drained and replaced during each exchange. Continuous flow peritoneal dialysis through two catheters or a double-lumen catheter [13] secures full contact of dialysate with the

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peritoneal membrane, but, at high dialysate flow, fresh fluid is not in direct contact with the membrane because of fluid channeling which restricts mixing. In CAPD, dialysis solution dose may be also increased by augmented volume per exchange. Some normal-sized adults tolerate up to 4 l of intraperitoneal volume without discomfort and such patients have been maintained on continuous ambulatory peritoneal dialysis with 2.5 or 3 l exchanges [14]. Ultrafiltration Ultrafiltration, i.e. solvent (water) movement across the peritoneal membrane is proportional to the transmembrane pressure (hydrostatic and osmotic), the membrane area, and its hydraulic permeability. Solute Transfer by Convection Solutes accompany the bulk flow of water from the peritoneal capillary blood into the peritoneal cavity by convection (solvent drag). For high molecular weight solutes the convective transport is more important than the diffusive one. Most solutes do not accompany the bulk flow of water in proportion to their concentration in extracellular water [15]. The peritoneum offers greater resistance to accompanying solutes than to water (solute sieving), so that the concentration of solutes in the ultrafiltrate is less than in plasma water. Although the sieving effect influences each solute, the most important clinical consequences of sieving are related to sodium. Convective net removal of sodium per liter of ultrafiltrate is usually well below extracellular fluid concentration. Thus, dialysate sodium concentration is initially reduced due to solute sieving with ultrafiltration and tends to increase later in the dwell time due to diffusion and diminished ultrafiltration rate. Dialysate sodium concentration decreases more in patients with low peritoneal transport characteristics [16]. The most important consequences of sodium sieving during dialysis are hypernatremia, thirst, and hypertension, which are frequently observed in patients treated with short-dwell or continuous flow peritoneal dialysis [11]. This problem may be overcome by lowering the sodium concentration in the dialysis solution to increase the diffusion gradient. A dialysis solution sodium concentration of 132 mEq/L seems appropriate for most patients treated with CAPD. Lymphatic Absorption Solutes of more than 19,400 Da are absorbed mostly by subdiaphragmatic lymphatics. Lymphatic fluid absorption in CAPD is approximately 1 l/day.

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Measurements of Peritoneal Functions

MTAC, accelerated peritoneal examination (APEX) [17], peritoneal (personal) dialysis capacity (PDC) [18] and peritoneal equilibration test (PET) are used to characterize peritoneal membrane functions. PET is the most widely used peritoneal function test, because of its standardization, simplicity, and usefulness in diagnostic and prognostic purposes. An abridged test [19] looking only for D/D0 glucose and dialysate to plasma (D/P) creatinine ratios, and drain volumes, is commonly used. For a full characterization of peritoneal membrane function, an unabridged test as described in 1987 [16], which include D/P urea, protein, creatinine, and D/D0 glucose, as well as D/P potassium, sodium, and corrected creatinine, drain volume and residual volumes should be used [16].

Peritoneal Function After Long-Term Exposure to Peritoneal Dialysis Solutions

Long-term peritoneal dialysis is associated with progressive loss of ultrafiltration capability. There are two possible mechanisms leading to this phenomenon. Firstly, effective peritoneal surface area progressively increases in long-term PD patients. This is related to increased number and surface area of peritoneal capillaries as a response to increased nitric oxide synthase activity and upregulation of vascular endothelial growth factor. Secondly, peritoneal membrane is gradually denuded of mesothelial cells leading to loss of mesothelial aquaporins, which are ultrasmall pores responsible for free water transport; consequently, there is no initial dip of sodium concentration during peritoneal equilibration test (fig. 1). Gradual decline of CA125 concentration in dialysate, a marker of mesothelial cell mass, has been found in long-term peritoneal dialysis patients [20] and loss of mesothelial cells in patients with ultrafiltration failure has been determined by peritoneal biopsy [21]. The structural and functional alterations in the membrane in longterm peritoneal dialysis are thought to be the consequence of the toxicity of glucose through the formation of glucose degradation products or the formation of advanced glycation end products generated during the sterilization process [22]. Replacing glucose by other osmotic agents, such as icodextrin, changing the sterilization process, replacing the lactate buffer by bicarbonate, blocking the formation of GDPs may be a significant step forward to improved membrane preservation during long-term peritoneal dialysis treatment [23].

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D/P 1.0 Drain volume⫽2,035 0.97

7–06–92

0.92 0.9 0.88

0.85

0.8

0.80

5–23–85 High

Drain volume⫽ 2,330

High average Low average Low 0.7 0

1.0

2.0

3.0

4.0

Fig. 1. Dialysate to plasma (D/P) sodium concentration ratios versus time (hours) in a patient with normal ultrafiltration (first study 05–23–85) and poor ultrafiltration (second study 07–06–92). The curves are superimposed on the population study results [16] showing D/P ratios in four transport categories. Drain volumes after 4-h dwell. Whereas sodium dialysate concentration markedly decreased in the first study due to high generation of ultrafiltrate with sodium sieving, the dialysate sodium concentration immediately started to rise in the second study because of poor generation of ultrafiltrate (Modified from Dobbie et al. [21]).

References 1

2 3 4 5 6

Twardowski ZJ: Physiology of peritoneal dialysis (chapter 14); in Nissenson AR, Fine RN (eds): Clinical Dialysis, ed 4. New York, NY, McGraw-Hill, Medical Publishing Division, 2005, pp 357–384. Andrews PM, Porter KR: The ultrastructural morphology and possible functional significance of mesothelial microvilli. Anat Rec 1973;177:409–426. Khanna R, Mactier R, Twardowski ZJ, Nolph KD: Peritoneal cavity lymphatics. Perit Dial Bull 1986;6:113–121. Courtice FC, Simmonds WJ: Physiological significance of lymph drainage of the serous cavities and lungs. Physiol Rev 1954;34:419–448. Liebermann-Meffert D, White H: The Greater Omentum. Berlin, Springer-Verlag, 1983. Nolph KD, Miller F, Rubin J, Popovich RP: New directions in peritoneal dialysis concepts and applications. Kidney Int 1980;18(suppl 10):111–116.

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7 8

9

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12 13 14 15 16 17

18 19 20

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Rippe B, Stelin G, Haraldsson B: Computer simulations of peritoneal fluid transport in CAPD. Kidney Int 1991;40:315–325. Lai KN, Leung JC, Chan LY, Tang S, Li FK, Lui SL, Chan TM: Expression of aquaporin-3 in human peritoneal mesothelial cells and its up-regulation by glucose in vitro. Kidney Int 2002;62:1431–1439. Popovich RP, Moncrief JW: Kinetic modeling of peritoneal transport; in Trevino-Bacerra A, Boen FST (eds): Today’s Art of Peritoneal Dialysis. Contrib Nephrol. Basel, Karger, 1979, vol 17, pp 59–72. Grzegorzewska AE, Antoniewicz K: An indirect estimation of effective peritoneal capillary blood flow in peritoneally dialyzed uremic patients. Perit Dial Int 1993;13(suppl 2):S39–S40. Twardowski ZJ: New approaches to intermittent peritoneal dialysis therapies (Chapter 8); in Nolph KD (ed): Peritoneal Dialysis, ed 3. Kluwer Academic Publishers, Dordrecht/Boston/ London, 1989, pp 133–151. Di Paolo N: Semicontinuous peritoneal dialysis. Dial Transplant 1978;7:839, 842. Ronco C, Gloukhoff A, Dell’Aquila R, Levin NW: Catheter design for continuous flow peritoneal dialysis. Blood Purif 2002;20:40–44. Twardowski ZJ, Prowant BF, Nolph KD, Martinez AJ, Lampton LM: High volume, low frequency continuous ambulatory peritoneal dialysis. Kidney Int 1983;23:64–70. Nolph KD, Hano JE, Teschan PE: Peritoneal sodium transport during hypertonic peritoneal dialysis: physiologic mechanisms and clinical implications. Ann Intern Med 1969;70:931–941. Twardowski ZJ, Nolph KD, Khanna R, Prowant BF, Ryan LP, Moore HL, Nielsen MP: Peritoneal equilibration test. Perit Dial Bull 1987;7:138–147. Verger C: How to use the peritoneum as a dialysis membrane. Methods of surveillance, criteria of efficacy and longevity as a dialysis membrane, consequences with respect to techniques of peritoneal dialysis (Article in French). Nephrologie 1995;16:19–31. Haraldsson B: Assessing the peritoneal dialysis capacities of individual patients. Kidney Int 1995;47:1187–1198. Twardowski ZJ: Clinical value of standardized equilibration tests in CAPD patients. Blood Purif 1989;7:95–108. Sanusi AA, Zweers MM, Weening JJ, de Waart DR, Struijk DG, Krediet RT: Expression of cancer antigen 125 by peritoneal mesothelial cells is not influenced by duration of peritoneal dialysis. Perit Dial Int 2001;21:495–500. Dobbie JW, Krediet RT, Twardowski ZJ, Nichols WK: A 39-year-old man with loss of ultrafiltration. Perit Dial Int 1994;14:384–394. Mortier S, De Vriese AS, Lameire N: Recent concepts in the molecular biology of the peritoneal membrane – implications for more biocompatible dialysis solutions. Blood Purif 2003;21:14–23. Passlick-Deetjen J, Schaub TP, Schilling H: Solutions for APD: Special considerations. Semin Dial 2002;15:407–413.

Zbylut J. Twardowski, MD, PhD Professor Emeritus of Medicine, University of Missouri, Dialysis Clinic, Inc. 3300 LeMone Industrial Blvd. Columbia, MO 65201 (USA) Tel. ⫹1 573 443 1531 x 256 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 20–27

A Simplified Approach to Understanding Urea Kinetics in Peritoneal Dialysis and Hemodialysis Madhukar Misra, Karl Nolph Department of Medicine, Division of Nephrology, University of Missouri Columbia, Columbia, Mo., USA

Abstract Urea, a small molecular solute, is the candidate molecule commonly used to understand solute kinetics both in peritoneal dialysis and hemodialysis. Serum urea or serum urea nitrogen levels are utilized to calculate measures of dialysis adequacy and nutritional status in dialysis patients. The kinetic behavior of this molecule is however different for a continuous therapy like peritoneal dialysis vis a vis an intermittent therapy like hemodialysis. This article presents a simplified approach to understanding urea kinetics on dialysis. Copyright © 2006 S. Karger AG, Basel

Urea, a surrogate molecule of uremic toxicity, is a product of protein catabolism. Urea nitrogen is readily measurable in serum, thus rendering itself to kinetic analysis. In a patient on dialysis, serum urea nitrogen is the most frequently assessed parameter to calculate dialysis dose and adequacy [1]. The Kt/V index, Gu (urea nitrogen generation rate) and normalized protein equivalent of nitrogen appearance (nPNA), all calculated from serum urea nitrogen concentration (BUN), are believed to be the standard indicators for assessing morbidity and mortality on dialysis [2, 3]. It is thus important not only to understand the relationship between nPNA at it relates to urea clearances on peritoneal dialysis (PD) but also to appreciate the differences in urea clearance requirements between PD and hemodialysis (HD). Formulae for estimating nPNA from urea nitrogen appearance in continuous ambulatory peritoneal dialysis (CAPD) patients (such as the modified Borah equation) [4, 5] have incorporated use of average measured protein losses in dialysate and urine in study populations. This is especially important in PD

since protein losses in dialysate can be substantial and are variable from patient to patient and in individual patients on different days. As in formulae used in HD, most formulae also use estimated non-urea nitrogen losses, nitrogen losses in stool, and nitrogen losses through skin. The relationship of nPNA to total urea clearance (by both PD and residual renal function) normalized to total body water (Kt/V) is different in PD and thrice weekly HD. At any given Kt/V, the nPNA in PD patients is higher than that in thrice weekly HD patients and is similar to that seen in patients with chronic kidney disease not yet on dialysis [6]. It has been postulated that the peaks and valleys of serum urea nitrogen in thrice weekly HD patients may lead to inhibition of protein intake. On the other hand, the nearly steady state serum chemistries in PD patients be associated with better appetite even though the mean values of serum urea nitrogen may be the same in PD and thrice weekly HD. Patient survival and other clinical outcomes in thrice weekly HD are similar to PD in many studies even though the total weekly Kt/V urea in PD patients is often 2/3 or less than that of the thrice weekly HD patients [7, 8]. It is possible that the control of peak serum urea nitrogen levels may be important for good clinical outcomes; higher Kt/V values are necessary in thrice weekly HD to maintain the peak values between dialysis treatments below the nearly steady state values of PD patients [9].

Small Solute Kinetics and Clearance in Native Kidneys, PD and HD

The process of uremic solute removal is different between native kidneys and dialysis. The native kidneys work continuously resulting in constant solute clearances and mass removal rates at steady state. In dialysis, toxins are removed through a single membrane based step. The solute kinetics in dialysis are governed by a relationship between clearance and mass removal that is particular to the type of dialysis. The clearance of a small solute like urea depends on the ratio of its mass removal rate and plasma concentration at steady state [10]. Although mass removals differ, clearances of urea nitrogen and urea are identical Curea(ml/min) Mass removal rate of urea nitrogen (mg/min) BUN (mg/ml)

Mass removal rate of urea nitrogen (mg/min)

(a)

Serum urea concentration (mg/min)

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At steady state, urea nitrogen removal rate equals urea nitrogen generation rate, to provide a constant blood concentration. Urea nitrogen generation and removal are near 65% of total nitrogen intake and losses respectively. It is obvious that two persons (in steady state) with different levels of native kidney function but the same rate of urea generation rate or Dietary Protein Intake (DPI) can have similar mass removal rates but different urea clearances and blood urea nitrogen (BUN) values at steady state. This relationship (a) is different between HD and PD. In intermittent HD, the mass removal rate of urea is maximum (owing to a higher BUN) in the early part of a dialysis session but falls off with time. This decline in BUN leads to proportional decline in the mass removal rate despite a constant instantaneous dialyzer urea clearance [11]. In HD, pre- and post-HD BUN are used to calculate the Kt/V. Using the same BUN values, one can also derive the mean BUN. However, this mean BUN occurs relatively early in the session (a non-linear decline) such that the instantaneous BUN is lower than the mean BUN for a large part of the HD session. The Kt/V value in a HD session (calculated by pre- and post-BUN) is therefore a composite value that is reflective of a short and efficient period of solute removal (during the early part of the HD session) and a long and inefficient period (during the latter part of the HD session), but at a constant clearance. Unlike in HD, during a typical CAPD exchange, a different relationship between mass removal rate and instantaneous clearance is observed. The mass removal rate declines despite a constant BUN because of an increase in the dialysate UN (a dialysate flow limited state). With declining trans-membrane diffusive gradient, there is a fall in instantaneous clearance. The clearance during a CAPD exchange (as well as mass removal rate) is actually a time averaged parameter derived by measuring solute mass in the effluent dialysate over an entire exchange. Therefore the small solute kinetics are inherently different in a continuous therapy like PD versus an intermittent therapy like HD. There is a time dependent decrease in mass removal rate in both therapies during HD sessions and during individual CAPD exchanges; however the clearance declines with time only on PD but not in HD. Further, the inter-compartmental mass transfer effects in HD also determine the clearance of solutes in HD. For patients in steady state on a constant protein intake, the weekly amount (mass) of urea nitrogen removed should be equal between HD and PD even though the urea clearance declines with time of exchange with PD but remains constant for HD. It is clear that even though one observes near steady state serum chemistries in PD and the stable patterns of peaks and valleys in HD, the patterns of removal are quite different (fluctuations in HD and more steady removal rates in PD).

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Understanding Urea Kinetics in Continuous (PD) and Intermittent (HD) Dialysis – A Simplified Approach

When studying urea kinetics on dialysis, it is useful to understand some basic concepts regarding urea and urea nitrogen. One must not confuse blood urea (MW 60) with BUN (MW 28). Urea nitrogen and urea clearances are however, identical. Most (95%) of nitrogen intake in humans is in the form of protein. In steady state, (neither catabolic nor anabolic), total nitrogen excretion is therefore a good indication of DPI. Sixteen percent of the ingested protein consists of nitrogen (1 g protein 16% nitrogen or 1 g nitrogen 6.25 g protein). Let us assume that for an anephric 70 kg patient, total body water (TBW) is approximately 40 l and DPI is 1 g/kg, i.e. 70 g. Therefore, for this patient in steady state, on an average daily diet of 70 g protein, the total nitrogen content that needs to be excreted in urine, stool, sputum and dialysate is equal to 11.2 g (16% of 70 g). Most of the nitrogen is excreted in urine and dialysate as urea nitrogen or small molecular weight non-urea nitrogen (such as creatinine, urate, and amino acids). Approximately 65% of total nitrogen is excreted as urea nitrogen. This may vary somewhat from patient to patient. Also, albumin losses in peritoneal dialysate and amino acid losses in hemodialysis dialysate could both reduce the percent of nitrogen removed as urea nitrogen to varying degrees depending on the magnitude of each. For the purposes of our illustrative calculations in this simplified model, we have taken the liberty of treating the percent of nitrogen removed as urea nitrogen as the same in PD and HD assuming the impact of albumin losses in PD and of amino acid losses in HD is the same relative to the relationship of total and urea nitrogen removals. Also, remember that our patient is considered anephric so that urinary protein losses do not confound the calculations. Daily urea nitrogen excretion is thus 0.65 11.2 7.3 and weekly urea nitrogen excretion is 7.3 7 51 g. Thus, in an anephric patient, dialysis must remove close to 51 g of urea nitrogen/week [b]. The clearance of urea on dialysis depends on the ratio of its removal rate and plasma concentration [see equation (a)] Curea(ml/min) Urea nitrogen Removal rate (R in mg/min) BUN (mg/ml)

or (in steady state) Curea(ml/min) Urea nitrogen Generation rate (G in mg/min) BUN (mg/ml)

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Table 1. Kt/V urea in CAPD and HD (3x/week) (TBW 40 l; DPI 70 g; UNG 7.3 g/day)

Kt/V Urea Cl (ml/min) Time UN removed (g) BUN (mg/dl)

PD

PD

HD

HD

1 7.9 3.5 days 25.5 64 Steady state

2 7.9 1 week 51 64 Steady state

1 190 3.5 h 17 Pre 90 Post 30

3 190 10.5 h/week 51 Time averaged 42.5/session

DPI Dietary protein intake; TBW total body water; UN urea nitrogen; UNG urea nitrogen generation.

Therefore at constant clearance and steady state, both BUN and R are determined by G. Table 1 represents an attempt to simplify the concept of urea kinetics in a continuous therapy like PD and an intermittent therapy like HD. These calculations are based on assumptions outlined in [b] above.

Peritoneal Dialysis

Calculating the Time Required to Achieve a Certain Kt/V in PD For Kt/V of 1 Kt/V 1 ‘t’ 1 V/K 1 40,000 ml/7.9 ml/min* 5,063.29 min or 5,063.29/ 1440 3.5 days. (*A typical averaged urea clearance on PD in ml/min with 80 l of equilibrated dialysate per week.) In other words, a Kt/V of 1 can be achieved in 3.5 days of PD. Therefore, one can calculate the time required for a Kt/V of 2/week: ‘t’ 2 V/K 2 40,000/7.9 7 days. More simply, if 3.5 days are required for a Kt/V of 1, then 2 3.5 or 7 days are required for a Kt/V of 2 at a urea clearance of 7.9 ml/min. Calculating the Urea Clearance (K) Needed to Achieve a Kt/V 2/week in PD Solving for ‘K’ K 2 V/t or 2 40/l 80 l. In other words, assuming complete equilibration of urea in long dwell CAPD exchanges, (D/P 1), a dialysate volume of 80 l of PD fluid/week (or 7.9 ml/min) will give a Kt/V of 2. This dialysate volume can be achieved by

Misra/Nolph

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using four 2.5 l bags and 10 l UF/week. Therefore, 80 l/week of dialysate is required to achieve a Kt/V of 2/week at a urea clearance of 7.9 ml/min. So in 3.5 days on PD, half of the weekly urea nitrogen load (25.5 g) must be removed to be in nitrogen balance. At a Kt/V of 2/week this anephric patient described above must remove near 51 g of urea nitrogen in dialysate per week to maintain nitrogen balance. Knowing this, the steady state BUN can be calculated. Calculating the Steady State BUN at a Kt/V of 2 in PD Eighty liters of equilibrated drainage per week must contain 51 g of urea nitrogen in this particular patient. The 51 g/80 l 0.6375 g/l 63.75 mg/dl. Since we have assumed equilibration with long dwell exchanges, the BUN is also 63.75 mg/dl.

Hemodialysis

Calculating‘t’ Required to Achieve a Kt/V of 1 Kt/V 1 ‘t’ 1 V/K or ‘t’ 1 40,000 ml/190 ml/min** 210 min or 210/ 60 3.5 h (Therefore a patient requires 3.5 h of HD as compared to 3.5 days of PD to achieve a Kt/V of 1.) **190 ml/min is an assumed urea clearance for HD in this patient Therefore one can calculate the ‘t’ required for a Kt/V of 3 in HD ‘t’ 3 40,000/190 632 min or 632/60 10.5 h. Calculating the Time Averaged BUN during a HD Session at a Kt/V of 3/week (3 3.5 h/week) Here we assume that the HD sessions are spaced at equal intervals so that starting BUN is always the same (for ease of illustrative calculations). Also, it is assumed that each session will remove the same amount of urea nitrogen equal to 1/3 of the weekly 51 g of urea nitrogen to be removed in steady state which 17 g/session. Kt/V 1 Urea nitrogen removed in mg BUN (mg/ml) TBW (ml) or, BUN urea nitrogen removed/TBW 17,000 mg/40,000 ml 0.425 mg/ml 42.5 mg/dl Remember that this is the time averaged BUN during a HD session and not the time average throughout the week. The calculated time averaged BUN of

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CAPD is the same both during treatment and weekly since the treatment is continuous. Although we can calculate the time averaged BUN during treatment with this simple approach, we cannot calculate the precise pre and post BUN values with simple math since the decline of the BUN during HD is not linear; a pre-BUN of 90 and post-BUN of 30 would be near the expected values.

Conclusion

These relatively simple calculations and the numbers in the table make several important comparisons between solute kinetics of CAPD and HD. These can be summarized as below: (1) A Kt/V of 1 takes near 3.5 days with PD and near 3.5 h with HD (variations depending on the clearances of the treatment). (2) A weekly Kt/V of 2 with PD can maintain a steady state BUN below the peak BUN values with HD at a Kt/V of 3/week-even when the time averaged BUN during HD treatments is less than the steady state BUN of CAPD. (3) The weekly removals of urea nitrogen by CAPD and HD become essentially identical as nitrogen balance is achieved (on a weekly basis); the similar removals of urea nitrogen require different BUN levels in these therapies that operate at different clearances. (4) It is possible that these differences of serum concentrations of urea and other small solutes (both in time average concentrations and degree of fluctuation) may, at least in part, account for the apparent differences in clearance requirements to achieve comparable clinical results with CAPD and HD.

References 1 2 3 4 5 6 7 8

Levine J, Bernard DB: The role of urea kinetic modeling, TAC urea and Kt/V in achieving optimal dialysis: a critical reappraisal. Am J Kidney Dis 1990;25:285–229. Lindsay RM, Henderson Lee W: Adequacy of dialysis. Kidney Int 1998;33(suppl 24):S92–S99. Held PJ, Port FK, Wolfe RA, Stannard DC, Carroll CE, DaugirDas CA, Bloembergen WE, Greer JW, Hakim R: The dose of dialysis and patient mortality. Kidney Int 1996;50:550–556. Borah MD, Schoenfeld PJ, Gotch FA, Sargent JA: Nitorogen balance during intermittent dialysis therapy of uremia. Kidney Int 1978;31:491–500. Depner TA: Prescribing Hemodialysis: a guide to urea modeling. Heidelberg, Kluwer Accademic Publishers, 1991. Mehrotra R, Saran R, Moore HL, Prowant BF, Khanna R, Twardowski ZJ, Nolph KD: Toward targets for initiation of chronic dialysis. Perit Dial Int 1997;17:497–508. Keshaviah P: Urea kinetic and middle molecule approaches to assessing the adequacy of hemodialysis and CAPD. Kidney Int Suppl 1993;40:S28–S38. Nolph KD: What’s new in peritoneal dialysis-an overview. Kidney Int Suppl 1992;38: S148–S152.

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9

10 11

Keshaviah PR, Nolph KD, Van Stone JC: The peak concentration hypothesis: a urea kinetic approach to comparing the adequacy of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis. Perit Dial Int 1989;9:257–260. Clark WR, Henderson LW: Renal vs continuous vs intermittent therapies for removal of uremic toxins. Kidney Int 2001;59(suppl 78):S298–S303. Henderson L, Leypoldt JK, Lysaght M, Cheung A: Death on dialysis and time/flux tradeoff. Blood Purif 1997;15:1–14.

Madhukar Misra, MD, MRCP (UK), FASN Associate Professor of Medicine, Division of Nephrology University of Missouri Columbia, MA 436, 1 Hospital Drive Columbia, MO 65212 (USA) Tel. 1 573 882 7992, Fax 1 573 884 4820 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 28–36

Peritoneal Ultrafiltration: Mechanisms and Measures Michael F. Flessner Department of Medicine, University of Mississippi Medical Center, Jackson, Miss., USA

Abstract The net ultrafiltration during peritoneal dialysis equals the osmotic ultrafiltration minus the fluid loss. Fluid loss is made up primarily of hydrostatic pressure-driven convection to the tissues surrounding the peritoneal cavity and a lesser amount of lymph flow. The cellular and blood capillary sources of water are distributed in an interstitial matrix, which decreases the effective osmotic pressure in the vicinity of the microvasculature. The interstitial matrix makes the process of fluid removal far less efficient than it would be if the blood capillaries were actually in direct contact with the peritoneal fluid. Osmotically driven water transport occurs chiefly across the blood capillary endothelium into the interstitium and ultimately out into the peritoneal cavity. Aquaporin-1, water-only channels, are important for solute-free water transport from blood capillaries. There may also be specialized water channels in cells, but this likely provides only a small component of solute-free water to the peritoneal cavity. Signs of ultrafiltration failure include loss of solute-free ultrafiltration and general decrease in ultrafiltration below 400 ml with a 4-h dwell of hypertonic dialysate. Copyright © 2006 S. Karger AG, Basel

While there are many theories of how water is extracted from the body during peritoneal dialysis, none of them fully explain the phenomena of net ultrafiltration (net UF). This chapter will relate the mechanisms of net ultrafiltration to basic anatomy and physiology of the peritoneal cavity and the peritoneal barrier. The focus will be normal physiology; subsequent chapters will deal with pathophysiologic conditions, such as peritoneal fibrosis [1]. Net UF is defined as [2] Net UF ⫽

Drain volume ⫺ Fill volume Dwell time

(1)

Plasma compartment Metabolism of osmotic solute

Pplasma

Cplasma Kf A MTAC Peritoneal barrier

Peritoneal dialysate ␲pd

Ppd Cpd

A⫽fluid contact area

Transfer via blood capillaries and tissue lymphatics

Direct lymph flow

␲plasma

P-driven convection to adjacent tissue

Fig. 1. Membrane model of transperitoneal transport (see text for discussion).

This equation does not tell us what mechanisms or forces govern the transfer of fluid. Figure 1 depicts the typical membrane model of transport between the plasma and the peritoneal cavity. The simplistic view of the peritoneal barrier considers it to be a membrane between the plasma and the peritoneal dialysate as illustrated by figure 1. Small solute (MW ⱕ 6,000 Da) transfer occurs in both directions across the membrane in accordance with the mass transfer-area coefficient (MTAC) Solute transfer ⫽ MTAC ⭈ (Cplasma ⫺ Cpd)

(2)

where Cplasma ⫽ solute concentration in the plasma; Cpd ⫽ solute concentration in the dialysate. Ultrafiltration across any membrane follows the classic Starling equation Fluid transport ⫽ Kf A ⭈ [Pplasma ⫺ Ppd ⫺ (␲plasma ⫺ ␲pd)]

(3)

where Kf ⫽ membrane filtration coefficient; P ⫽ hydrostatic pressure; ␲ ⫽ effective osmotic pressure. However, the simple membrane model cannot account for all processes that ultimately result in the measured net UF. Net Ultrafiltration: Osmosis and Fluid Loss

As illustrated by figure 1, the transfer of fluid to and from the peritoneal cavity is more complex than the simple membrane model. The net UF is made up of two components

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Right lymph duct Innominate vein

Parasternal Lymphatics 70–80% Thoracic duct 20–30% Sub-diaphragmatic lymphatics Diaphragm Cisterna chyli

Retroperitoneal LN Cisternal LN

Intestinal LN

Sacral LN Visceral drainage Lumbar LN

Fig. 2. Lymphatic drainage pathways from the peritoneal cavity.

Net UF ⫽ Osmotically-driven filtration – fluid loss

(4)

where Fluid Loss ⫽ fluid transfer from the cavity ⫽ direct lymph flow ⫹ hydrostatic pressure (P)-driven convection to the surrounding tissues. From the tissue, transfer into the blood capillaries or intra-tissue lymphatics carries the fluid back to the plasma compartment [2, 3]. The lymphatic flow is a minor part of the fluid loss term. Figure 2 depicts the lymphatic drainage from the peritoneal cavity. As illustrated, the majority of the lymphatic drainage, 70–80%, occurs via the sub-diaphragmatic lymphatics draining directly to the parasternal lymphatics and ultimately into the right and possibly the thoracic duct [4, 5]. There is also drainage via the visceral lymphatics flowing to the cisterna chyli at the base of the thoracic duct and draining ultimately into the left venous system. The lymphatic system is responsive to low levels of pressure and volume expansion within the peritoneal cavity [6]. In animal experiments, pressures above 1–2 mm of mercury did not result in significantly increased volume flow directly into the lymphatics but did increase the local absorption into tissues [6]; local convection into the tissue is signified by the deposition of protein into surrounding tissues.

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Clinical Measurements of Fluid Loss and Lymph Flow

Clinical studies have verified the findings in animal studies through the measurement of lymph flow and the total peritoneal fluid loss rate by utilizing PD solutions containing radioactive albumin. Albumin moves chiefly via convection into tissue and will not pass directly into the vascular system but is taken up by the lymphatics. Therefore its loss from the cavity is a marker of fluid movement from the cavity or total fluid loss; careful measurement of the appearance rate of labeled albumin in the plasma provides an estimate of the lymph flow. These investigators have demonstrated that the lymph flow is on the order of 9–21 ml/h while the total peritoneal fluid loss in ml/h varies between 60 and 91 ml/h [7–9].

Importance of the Intraperitoneal Hydrostatic Pressure

Durand et al. [10] demonstrated the importance of intraperitoneal hydrostatic pressure (IPP) in determining the fluid loss from the cavity. They carried out a careful study of the effect of IPP on the net UF in 34 patients. All patients were supine to minimize changes of IPP during dialysis with 3.86% dextrose solution. After 2 h, the net UF was measured and shown to vary indirectly with the IPP and to have a net fluid absorption rate from the peritoneal cavity between 31 and 36 ml/h/cm H2O of IPP [10]. Rusthoven et al. [11] have recently verified in children Durand’s measurements and demonstrated an inverse correlation between change in IP pressure and the body’s surface area. Both animal data and human data have demonstrated that fluid loss during peritoneal dialysis, i.e. flow back to the patient, can amount to 1.5–2 l/day. Increases in IP dwell volume increase the intraperitoneal pressure and may lead to a decrease in net UF. This can greatly affect children with a small body surface area and has been shown to have a negative correlation with body surface area and would likely have a similar effect in smaller adults.

Basic Physiology and Anatomy of the Peritoneal Barrier

Figure 3 illustrates a more complex picture of the peritoneal barrier that in figure 1 by demonstrating the potential barriers that might produce the osmotically-induced fluid transfer into the cavity, which is observed during peritoneal dialysis. The first barrier is the peritoneum itself; the second is the extracellular matrix; and the third barrier is the blood endothelium [3, 12].

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Peritoneum

Tissue space

Extracellular matrix

Osmotic pressure profile Osmotic solute

Lymph vessel

Osmotic filtration

Blood capillary Fibroblast

Muscle cells

Fig. 3. Distributed nature of peritoneal-blood barrier with three potential sources of transport resistance: (1) peritoneum, (2) extracellular matrix, (3) blood capillary endothelium (see text for discussion).

The peritoneum, made up of mesothelium and underlying connective tissue [13], is not a significant barrier to osmotic solutes. Flessner et al. [14] carried out experiments in rats in which the peritoneum was mechanically removed. They utilized transport chambers in which they placed hypertonic solutions to withdraw fluid from the tissue. In addition, they monitored the disappearance of radioactive mannitol (identical in size to glucose) from the chamber into the tissue. This experiment simulated two processes of transport occurring during a typical dialysate dwell. After 60 min, there was no difference in the flux of mannitol or in the osmotically driven fluid coming into the chamber. This demonstrated that the normal anatomic peritoneum is not a significant physical barrier to osmotic water flow or to small solute transport. The interstitium or extracellular matrix has several effects on water transport. The interstitium-cell matrix separates the solution in the peritoneal cavity from the capillary endothelium. The interstitium has relatively large gaps through which small molecules such as glucose easily pass and therefore cannot act as a membrane [15]. The interstitium is, however, a diffusion barrier for small sugars such as glucose. As is illustrated in figure 3, the glucose will diffuse into the tissue space and be gradually absorbed into the blood capillaries, which have plasma circulating at a lower concentration than the interstitium. Thus, although the interstitium itself is not a significant osmotic barrier to

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glucose, it has the effect of causing a decrease in the glucose concentration adjacent to the blood capillary as the distance from the peritoneum increases. The interstitial concentration approaches that in the plasma under normal conditions within a tissue thickness approximately 0.5 mm [16]. The interstitium also acts as a variably expansible sink for fluid loss, due to the effects of hydrostatic pressure discussed above [6]. This occurs particularly in the anterior abdominal wall and the diaphragm, across which the maximal pressures in the cavity are expressed. In animals, the interstitial fraction of abdominal wall tissue doubles between the pressures of 2–4 cm of water in the cavity [17]. The hydraulic connectivity goes up considerably, along with the fluid flow rate out of the cavity [18]. In this way, the interstitium absorbs much of this fluid that passes from the peritoneal cavity into the tissue. Alterations in the Starling forces around the blood capillaries result in absorption of much of this fluid that enters the peritoneal tissue space. In these expanded tissues, glucose will diffuse more rapidly into the tissue and be absorbed more rapidly, which dissipates the osmotic force and decreases net UF. Therefore, the microvasculature distributed within the tissue space results in a decreased efficiency of osmotic extraction of fluid from the blood due to: decreased effective osmotic pressure in the vicinity of the capillaries, convective fluid loss from the cavity into the tissue, and increased rate of loss of the osmotic solute. The size-discriminant barrier for both water and solutes is the capillary endothelium. Figure 4 illustrates the pore-matrix theory of transcapillary transport. The endothelium is depicted as a series of gaps, which are lined with glycocalyx [19]. Some of these gaps have a tight mesh work of glycocalyx within them and allow only small solutes up to perhaps the size of 5,000 Da to pass through. Larger proteins pass through less densely packed gaps. There is also an additional gap or channel called the Aquaporin, which has been established in animal studies as the Aquaporin-1 (AQP-1) [20, 21]. AQP-1 is the source of solute-free filtrate, which occurs during the first 15–30 min of a dialysis dwell of hypertonic solution [21, 22]. In the past 14 years, water-only channels or Aquaporin have become important in explaining the observed physiology of peritoneal dialysis. The water-only channel was hypothesized by Rippe [23] in his three pore model. AQP-1 was first discovered by Agre [24] in red cells. Carlsson [25] showed that inhibition of AQP-1 by mercuric chloride resulted in 66% less ultrafiltration in rats. Subsequently, Yang et al. [20] demonstrated that transperitoneal ultrafiltration in AQP-1 knockout mice was decreased 60% from that of normal mice. Some investigators demonstrated that solute-free filtrate is much less in PD patients with UF-failure and hypothesized that lack of AQP-1 channels was the mechanism [22]. Although it would seem logical that the decrease in solute-free filtrate in the patients with UF failure is correlated with decreased expression of

Peritoneal Ultrafiltration

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Transport paths

Transendothelial forces

Aquaporin

Osmotic pressure dominates Small solutes

Glycocalyx

Small pore equivalent

Hydrostatic & osmotic pressure

Large pore equivalent

Hydrostatic pressure dominates Protein

Interstitium

Capillary lumen

Fig. 4. Pore-matrix theory of transcapillary transport (see text for discussion).

AQP-1, Goffin et al. [26] showed that AQP-1 expression was normal in a long term peritoneal dialysis patient with impaired UF. Ni et al. [21], in careful studies in both normal and transgenic AQP-1 knockout mice, have demonstrated that the expression of the Aquaporin is chiefly in the peritoneal endothelium. They reaffirmed the finding by Yang and colleagues that the knockout mice have approximately 40% of the UF observed in normal mice. In addition, they demonstrated the loss of solute-free ultrafiltrate. This would seem to solidify the role of Aquaporin in the endothelial portion of the peritoneal barrier as the mechanism producing solute-free ultrafiltrate.

Remaining Questions Concerning the Mechanism of Net UF

There are several scientific questions, which remain unanswered concerning the mechanism of net UF. Because blood flow in the sub-mesothelium is limited, capillaries well beyond those in the superficial (⬍50 ␮m) must contribute to the observed filtration. There is no clear mechanism for movement of water from the deeper tissue to the peritoneum and out into the cavity. There may be contributions

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from intracellular water, but Ni et al. [21] failed to find evidence for AQP-1 water channels in mesothelial cells. Others, however, have demonstrated evidence for a decrease in the local intracellular space of peritoneal tissue during a hypertonic dwell [27] but have yet to determine the mechanism.

Acknowledgment This work was supported by US Public Health Service Grant RO1-DK-048479.

References 1

2 3 4 5 6 7 8 9

10 11

12 13 14 15 16 17 18 19

Williams JD, Craig KJ, Topley N, Ruhland CV, Fallon M, Newman GR, Mackenzie, RK, Williams GT: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002;13:470–479. Flessner MF: Net ultrafiltration in peritoneal dialysis: role of direct fluid absorption into peritoneal tissue. Blood Purif 1992;10:136–147. Flessner MF: The transport barrier in intraperitoneal therapy. Am J Physiol 2005;288:F433–F442. Flessner MF, Parker RJ, Sieber SM: Peritoneal lymphatic uptake of fibrinogen and erythrocytes in the rat. Am J Physiol 1983;244:H89–H96. Yoffey JM, Courtice FC: Lymphatics, Lymph, and the Lymphomyeloid Complex. London, UK, Academic, 1970. Flessner MF, Schwab A: Pressure threshold for fluid loss from the peritoneal cavity. Am J Physiol 1996;270:F377–F390. Daugirdas JT, Ing TS, Gandhi VC, Hano JE, Chen WT, Yuan L: Kinetics of peritoneal fluid absorption in patients with chronic renal failure. J Lab Clin Med 1980;85:351–361. Rippe B, Stelin G, Ahlmen J: Advances in Peritoneal Dialysis. Amsterdam–Oxford–Princeton, Excerpta Medica, 1981. Heimbürger O, Waniewski J, Werynski A, Park MS, Lindholm B: Lymphatic absorption in CAPD patients with loss of ultrafiltration capacity; in Heimbürger O (ed): PhD Thesis. Stockholm, Konogl Carolinska Medico Chirurgiska Institute, 1994, pp 1–21. Durand P-Y, Chanliau J, Gamberoni J, Hestin D, Kessler M: Hydrostatic intraperitoneal pressure and volume of ultrafiltration in CAPD. Adv Perit Dial 1993;9:46–48. Rusthoven E, van der Vlugt ME, van Lingen-van Bueren LJ, van Schaijk TCJG, Willems HL, Monnens LAH, Schroder CH: Evaluation of intraperitoneal pressure and the effect of different osmotic agents on intraperitoneal pressure in children. Perit Dial Int 2005;25:352–356. Flessner MF: Peritoneal transport physiology: insights from basic research. J Am Soc Nephrol 1991;2:122–135. Baron MA: Structure of the intestinal peritoneum in man. Am J Anat 1941;69:439–497. Flessner MF, Henegar J, Bigler S, Genous L: Is the peritoneum a significant transport barrier in peritoneal dialysis? Perit Dial Int 2003;23:542–549. Levick JR: Flow through interstitium and fibrous matrices. Q J Exp Physiol 1987;72:409–438. Flessner MF, Fenstermacher JD, Dedrick RL, Blasberg RG: A distributed model of peritonealplasma transport: tissue concentration gradients. Am J Physiol 1985;248:F425–F435. Zakaria ER, Lofthouse J, Flessner MF: In vivo effects of hydrostatic pressure on interstitium of abdominal wall muscle. Am J Physiol 1999;276:H517–H529. Zakaria ER, Lofthouse J, Flessner MF: In vivo hydraulic conductivity of muscle: effects of hydrostatic pressure. Am J Physiol 1997;273:H2774–H2782. Vink H, Duling BR: Identification of distinct luminal domains for macromolecules, erythrocytes, and leucocytes within mammalian capillaries. Circ Res 1996;79:581–589.

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20 21

22 23 24 25 26

27

Yang B, Folkesson HG, Yang J, Mattick LR, Ma T, Verkman AS: Reduced osmotic water permeability of the peritoneal barrier in aquaporin-1 knockout mice. Am J Physiol 1999;276:C76–C81. Ni J, Verbavatz J-M, Rippe A, Boisde I, Moulin P, Rippe B, Verkman AS, Devuyst O: Aquaporin-1 plays and essential role in water permeability and ultrafiltration during peritoneal dialysis. Kidney Int 2006. Smit W, Struijk DG, Ho-dac-Pannekeet MM, Krediet RT: Quantification of free water transport in peritoneal dialysis. Kidney Int 2004;66:849–854. Rippe B: A three-pore model of peritoneal transport. Perit Dial Int 1993;13(suppl 2):S1–S4. Agre P, Preston GM, Smith BL, Jung JS, Raina S, Moon C, Guggino WB, Nielsen S: Aquaporin CHIP: the archetypal molecular water channel. Am J Physiol 1993;265:F463–F476. Carlsson O, Nielsen S, Zakaria ER, Rippe B: In vivo inhibition of transcellular water channels (aquaporin-I) during acute peritoneal dialysis in rats. Am J Physiol 1996;271:H2254–H2262. Goffin E, Combet S, Jamar F, Cosysn JP, Devuyst O: Expression of aquaporin-1 in a long-term peritioneal dialysis patient with impaired transcellular water transport. Am J Med Sci 1999;33: 383–388. Zakaria ER, Lofthouse J, Flessner MF: Effect of intraperitoneal pressures on tissue water of the abdominal muscle. Am J Physiol Renal Physiol 2000;278:F875–F885.

Michael F. Flessner, MD, PhD Department of Medicine/Nephrology University of Mississippi Medical Center 2500 North State Street Jackson, MS 39216 (USA) Tel. ⫹1 601 984 5670, Fax ⫹1 601 984 5765 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 37–41

Evaluation of the Peritoneal Membrane Function by Three Letter Word Acronyms: PET, PDC®, SPA, PD-Adequest, POL: What to Do? W. Van Biesen, A. Van Der Tol, N. Veys, N. Lameire, R. Vanholder Department of Nephrology, University Hospital Ghent, Ghent, Belgium

Abstract This paper describes and reviews different methods to evaluate the peritoneal transport capacity. This evaluation is important because it will influence the preferred treatment regimen, and will also be a tool for longitudinal follow up both in the individual patient as in patient groups. Copyright © 2006 S. Karger AG, Basel

In contrast with hemodialysis, where the specifications of the chosen dialyzer are well known to the treating nephrologist, the transport properties of the peritoneal membrane are different between each individual patient, and can also vary over time in one particular patient. Knowledge of these properties is nevertheless very important to guide therapy, to evaluate changes of the peritoneal membrane over time, and also prognostic, as a negative relation between fast transport status and outcome has been notified. Different methods to describe the peritoneal membrane transport have been reported and applied. The most simple ones, the Peritoneal Equilibration Test (PET) [1] and it’s derivatives are purely descriptive, as they only give a graphical representation of the evolution of the dialysate concentration (D) in relation to the plasma concentration (P) for certain molecules over the dwell time. In the standard PET, the dwell time is 4 h, and the dialysate used is a 2.27% glucose solution. Based on these curves, patients are classified as high, high average, low average or low transporters, where the standard deviations of a reference population were set as cut-off points by Twardowski [1]. Although

this classification has the appearance of being easy, there are some pitfalls potentially leading to misinterpretation. First, the categorization into four groups has only limited value, as it has only been validated in a (limited) North American population. For other populations, epidemiological adaptations should be made, especially when patient physionomy is strongly different from the ‘average’ American patient, like e.g. in Asian patients. Second, the terminology of ‘high’ and ‘low’ is misleading, as they refer to amounts of transported molecules, whereas in fact, what they really represent is speed of transport over the membrane. As in ‘high’ transporters, there is also a rapid disappearance of glucose, these patients often suffer from negative ultrafiltration and thus a decreased drainage volume, and thus a lower amount of toxins removed compared to ‘low’ transporters, as was elegantly shown by Wang et al. [2]. It would thus be more appropriate to replace ‘high’ and ‘low’ by ‘fast’ and ‘slow’ transporters respectively. Even more appropriate is it to just drop the categorical classification, and use concepts of ‘D/P creatinine’ and ‘D/P urea’, as representatives of the small solute transport. This also allows to calculate immediately the amount of toxin removed during a certain dwell, and also the clearance. The slope of the D/P over time curve represents the speed of transport of that molecule. While being relatively easy to interpret, the classic PET has the disadvantage that it only give information on small solute transport and not on ultrafiltration, nor does it supply separate information on convection and diffusion or on ultrafiltration capacity. With the PET it is also impossible to dissect the cause of a fast transport status, as this can be caused by a large anatomical surface (but with ‘normal’ architecture) or by leakiness of the membrane (with increased vascularization or vasodilatation as in inflammation). To evaluate ultrafiltration capacity over time, it can be informative to relate ultrafiltration volume after 4 h to the D/P value [3]. Deviations from the diagonal line point to causes of ultrafiltration that are unrelated to small solute transport characteristics, e.g. presence of mechanical leaks. To evaluate ultrafiltration failure at a certain moment, it can be informative to use a 3.86% glucose solution, and also measure D/P sodium. In normal physiological conditions, there should be sodium sieving during the first part of the dwell, because of the activity of the ultrasmall pores, which only allow the transport of pure water. If there is no sodium sieving, than either the water transport over the ultrasmall pores is overwhelmed by diffusive transport of sodium over the small pores, e.g. during peritonitis, or there is a deficient water transport over the small pores. PET has however no way to evaluate net transcapillary ultrafiltration, as it does not allow to have an impression of the evolution of the intraperitoneal volume during the dwell. In order to do so, the standardized peritoneal membrane assessment (SPA) was developed [4]. During this test, which is preferentially performed using a 3.86% glucose, dextran is used as an intraperitoneal marker,

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which allows the calculation of the intraperitoneal volume. The appearance of dextran in the blood allows to calculate lymphatic flow, and thus the net transcapillary ultrafiltration. Krediet’s group [5] has elaborated elegant techniques to calculate sodium sieving and water transport over the small pores using this SPA. While the SPA is excellent for research purposes, the application in clinical practice is hampered by the laborious technique and the need to measure Dextran blue with HPLC techniques. An elegant alternative is the ‘mini-peritoneal equilibration test’ as proposed by La et al. [6]. In this 1 h equilibration test, the ultrafiltration over the small pores can be calculated based on the assumption that in the first hour of the dwell, sodium transport is only based on convection. In view of the importance of understanding peritoneal membrane properties of the individual patient and it’s evolution over time, some companies have developed computer software to help with the evalution and interpretation of peritoneal membrane transport data. There are three major software programs available on the market: Personal Dialysis Capacity test (PDC®) (Gambro, Lund, Sweden) [7], Patient On Line (POL®) (Fresenius Medical Care, Bad Homburg, Germany) [8] and PD-Adequest® (Baxter Healthcare Corporation, Deerfield, Ill., USA) [9]. All three programs are based on the law of mass conservation to model transport of solutes over the peritoneal membrane. PD-Adequest uses the Pyle-Popovich model [10], which is based on a twocompartmental model with one pore size. The program is fed with the D/P data from the classical PET, making it an easy to perform and widely accepted program. The predictions for transport of small solutes are quite acceptable, but as it is only a one-pore model, the predictions on ultrafiltration are rather poor. In a Second version, adaptations were made to the reflection coefficients of glucose to mimic the results obtained with the three pore model of Rippe. POL is in fact a black box model, that uses as the main parameter the ‘FT50’: the time needed to obtain a saturation of 50% (equivalent to a D/P of 0.5). Based on this value, all other parameters regarding small solute transport and ultrafiltration are calculated. The software accepts different input parameters: one single D/P values from a PET, but also D/P values of longer or shorter equilibration times. This allows the user to choose between convenience (only one determination of blood and dialysate sample) and precision (the more different D/P values, the more accurate the curve of D/P versus time and thus the FT50 value, will be), even dialysate samples from the habitual regimen of the patient can be fed into the program. The PDC-test is based on the three pore model of Rippe. It describes the peritoneal membrane characteristics by means of three parameters, that are derived from data obtained from 5 exchanges with different duration and different glucose strengths [11], this once again to enhance the information that is fed to the model on the behavior of the peritoneal membrane

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transport under different conditions. The three parameters are: (1) the surface area over diffusion distance, A0/dX, which represents the effective surface area available for diffusion, and is thought to be roughly comparable with the mass transfer area coefficient and the D/P value of the PET; (2) the reabsorption parameter, JvR, that measures the reabsorption of fluid from the peritoneal cavity after the osmotic gradient has disappeared, representing mainly the lymphatic flow, and (3) the large pore flow, JvL. The PDC test derived A0/dX is superior to the PET derived D/P creatinine to describe the transport of small solutes through the peritoneal membrane [12]. The PDC test has been validated to describe membrane characteristics in large patient groups, both in adults and in children [13, 14]. The PDC test has also been advocated to describe the evolution of the functional capacity of the peritoneal membrane over time [3, 15]. Large pore flow JvL is related with mortality [16]. As JvL represents the flow through the large pores, it is related to the ‘leakiness’ of the membrane, and thus potentially to inflammation. The relation between JvL and inflammation, and between JvL and fast transport might be of importance, as a good understanding of the underlying mechanism of the ‘fast transport’ status has therapeutic and prognostic consequences. It was demonstrated that the use of D/P creatinine based on the PET leads to an incorrect perception of the mortality risk of PD patients with fast transport status, as with PET-based information alone, the different causes of fast transport status can not be discriminated. In contrast, with the PDC-test, the combined interpretation of the large pore flow, JvL, and the unrestricted area for diffusion corrected for diffusion distance (A0/dX) allows to discriminate much better inflammation from anatomical constitution as a cause of a fast transport status.

Conclusion

Evaluation of the transport capacity of the peritoneal membrane is important, both to guide clinical decision making and prescription management, as in the follow up of peritonea membrane function over time. The PET is still the most simple and most widely used test with however the need to have the patient 4 h in the outpatient clinic, and with only limited information provided. Commercial software programs offer far more convenience, once the users (i.e. nephrologists and nurses) are used to applying them, as they allow to use more or less ‘normal’ dialysis days for sampling. Head to head studies comparing the results of these software packages are lacking. The miniperitoneal equilibration test can deliver interesting information on aquaporin function.

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References 1 2

3 4

5 6

7 8 9 10 11 12 13

14 15

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Twardowski ZJ: Clinical value of standardized equilibration tests in CAPD patients. Blood Purif 1989;7:95–108. Wang T, Heimbürger O, Waniewski J, Bergström J, Lindholm B: Increased peritoneal permeability is associated with decreased fluid and small-solute removal and higher mortality in CAPD patients. Nephrol Dial Transplant 1998;13:1242–1249. Davies SJ: Monitoring of long-term peritoneal membrane function. Perit Dial Int 2001;21:225–230. Pannekeet MM, Imholz AL, Struijk DG, Koomen GC, Langedijk MJ, Schouten N, de Waart R, Hiralall J, Krediet RT: The standard peritoneal permeability analysis: a tool for the assessment of peritoneal permeability characteristics in CAPD patients. Kidney Int 1995;48:866–875. Smit W, Struijk DG, Ho-Dac-Pannekeet MM, Krediet RT: Quantification of free water transport in peritoneal dialysis. Kidney Int 2004;66:849–854. La MV, Di Filippo S, Crepaldi M, Del Vecchio L, Dell’Oro C, Andrulli S, Locatelli F: Miniperitoneal equilibration test: a simple and fast method to assess free water and small solute transport across the peritoneal membrane. Kidney Int 2005;68:840–846. Rippe B: Personal dialysis capacity. Perit Dial Int 1997;17(suppl 2):S131–S134. Gotch FA, Lipps BJ: PACK PD: a urea kinetic modeling computer program for peritoneal dialysis. Perit Dial Int 1997;17(suppl 2):S126–S130. Vonesh EF, Keshaviah PR: Applications in kinetic modeling using PD ADEQUEST. Perit Dial Int 1997;17(suppl 2):S119–S125. Pyle W, Moncrief J, Popovich R: Peritoneal transport evaluation in CAPD; in Moncrief J, Popovich R (eds): CAPD update. New York, Masson Publishing USA Inc., 1981. Haraldsson B: Assessing the peritoneal dialysis capacities of individual patients. Kidney Int 1995;47:1187–1198. Johnsson E, Johansson AC, Andreasson BI, Haraldsson B: Unrestricted pore area (A0/Deltax) is a better indicator of peritoneal membrane function than PET. Kidney Int 2000;58:1773–1779. Van Biesen W, Carlsson O, Bergia R, Brauner M, Christensson A, Genestier S, Haag-Weber M, Heaf J, Joffe P, Johansson AC, Morel B, Prischl F, Verbeelen D, Vychytil A: Personal dialysis capacity (PDC(TM)) test: a multicentre clinical study. Nephrol Dial Transplant 2003;18:788–796. Schaefer F, Haraldsson B, Haas S, Simkova E, Feber J, Mehls O: Estimation of peritoneal mass transport by three-pore model in children. Kidney Int 1998;54:1372–1379. Imai H, Satoh K, Ohtani H, Hamai K, Haseyama T, Komatsuda A, Miura AB: Clinical application of the personal dialysis capacity (PDC) test: serial analysis of peritoneal function in CAPD patients. Kidney Int 1998;54:546–553. Heaf JG, Sarac S, Afzal S: A high peritoneal large pore fluid flux causes hypoalbuminaemia and is a risk factor for death in peritoneal dialysis patients. Nephrol Dial Transplant 2005;20:2194–2201.

W. Van Biesen Department of Nephrology, University Hospital Ghent De Pintelaan 185 BE–9000 Ghent (Belgium) Tel. ⫹32 9 240 4402, Fax ⫹32 9 240 4599, E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 42–47

The Initiation of Peritoneal Dialysis: Planning the Initial Prescription Fredric O. Finkelstein Clinical Professor of Medicine, Yale University, Hospital of St. Raphael, New Haven, Conn., USA

Abstract The initiation of peritoneal dialysis (PD) requires that the nephrologist address certain key issues. These include patient selection for PD, the timing of the placement of the PD catheter, the timing of the initiation of PD, the schedule of PD to be utilized, and the initial regimen of PD to be prescribed. In addressing these issues, the nephrologist needs to consider not only the medical condition of the patient but also the psychosocial status and quality of life concerns of the patient and his/her family. Furthermore, the dialysis treatment regimen needs to be organized to maintain the long term viability of PD therapy. Copyright © 2006 S. Karger AG, Basel

The initiation of peritoneal dialysis (PD) presents the nephrologist with certain issues and problems that need to be addressed, as outlined in table 1. These include patient selection for PD versus hemodialysis, planning the placement of the peritoneal catheter, the timing of the initiation of PD training, the schedule of PD to be utilized, and the initial dialysis prescription. The importance of the adequate education of the patient with chronic kidney disease has been emphasized in various publications, and has been discussed elsewhere in this issue. Once the patient has opted for PD as the initial therapeutic modality for end-stage renal disease, it is important to prepare the patient and his/her family for the realities of chronic PD. The issues that need to be discussed include the delivery and storage of supplies, the impact of the daily therapy on their lives, and the importance of careful attention to hygiene and treatment protocols. In making plans to start the chronic kidney disease patient on PD, consideration needs to be given to the timing of the placement of the peritoneal

Table 1. Factors to be addressed in initiating PD Education of the patient with chronic kidney disease Timing of the start of dialysis Timing of the placement of the PD catheter Dose of dialysis to be targeted Maintenance of volume control Psychosocial status and quality of life of the patient and his/her family Long term viability of the therapy: goals and objectives

catheter. The traditional approach has been to wait until the patient needs to start dialysis, place the chronic PD catheter, wait about 2 weeks until healing has occurred, and then initiate training. An alternative approach is to place the PD catheter weeks to months before PD training is to be started, bury the catheter beneath the skin, and then release the connecting port of the catheter when training is to be started, as originally proposed by Moncrief et al. [1]. It has been suggested that this approach is safe and may in fact reduce the subsequent risk of peritonitis because it permits time for adequate wound healing to occur and thus may reduce the risk of biofilm formation. Whether this in fact is true remains to be carefully evaluated. But, it certainly does facilitate the initiation of PD. The decision to commence dialysis needs to be based on a combination of clinical and laboratory assessments. When the creatinine clearance falls below 15 cc/min, careful attention needs to be paid to the clinical assessment of the patient. Factors that would lead the nephrologist to consider commencing dialysis at higher levels of creatinine clearance include poor nutritional status, hyperkalemia, metabolic acidosis, intractable fluid overload, and deterioration in cognitive functioning and/or quality of life assessment. The issue of cognitive function and quality of life decline are often overlooked in making the decision to start dialysis, since these parameters are more difficult to monitor objectively. Once the decision to start dialysis has been made, the nephrologist needs to decide whether to plan for CAPD or CCPD. This decision is usually made after discussion with the patient and the patient’s family and should be made primarily on quality of life concerns. What is the patient’s home and living situation? Does the patient need assistance from family members? What is the home environment like? The advantages of cycling PD are obvious – the patient usually does not have to do exchanges during the day and can generally achieve adequate doses of dialysis and volume control with the nightly regimen. Next the nephrologist needs to decide the amount of dialysis that should be prescribed. This requires measuring the endogenous renal function of the

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patient and then targeting the dose of dialysis that needs to be achieved with the dialysis regimen. The general standards of adequate dialysis dosing have been revised by national organizations. For example, the K/DOQI guidelines that have been recently published suggest a minimum Kt/V urea of 1.7, combining dialysis and endogenous renal clearances [2]. This target is reduced from previously published standards of 2.1. Creatinine clearance goals are no longer suggested. These recommendations are based on recently published clinical trials of randomized dialysis doses and monitored outcomes [3, 4]. How the targeted dose is to be achieved depends on several factors. First is the volume of dialysis fluid that can be comfortably instilled into the abdominal cavity. Although it has been reported that patients may not be very aware of the different volumes instilled into their abdominal cavity [5], there are certain groups of patients, such as small individuals and patients with polycystic kidney disease, who may be acutely aware of this volume. Next is the decision of how many exchanges are required to achieve the target for patients on CAPD or the duration of time for the patient to be on the cycler for patients on CCPD. These decisions need to be made after discussion with the patient and his or her family; the patient’s activity level, work schedule, and family’s life style needs to be considered. These issues need to be reevaluated and reconsidered as the dialysis training program progresses. The prescription that is eventually prescribed for the individual patient needs to be determined after the training period has been started and after there is a better understanding of the transport characteristics of the patient. The nurse usually gets a sense of this during the training period by monitoring the ultrafiltration volume achieved with exchanges of different tonicity. A formal assessment of the transport characteristics should be done, usually within 2–8 weeks after the start of the training period. Several options are available to assess the transport characteristics and it is advisable for the facility to familiarize itself with one of the testing procedures. Then, once the transport characteristics are determined, the final prescription can be written. The volume status of the patient requires continued assessment and then detailed discussions with the patient concerning the maintenance of optimal volume status. This is generally done by defining a weight which is optimal for the patient, based on clinical assessment. The patient then needs to be instructed to maintain this weight by modifying several parameters. First is the adjustment of salt and water intake. Second is a review of the dose of diuretics that is actually being taken; this is often overlooked but diuretics may be helpful in maintaining optimal weights in patients with some endogenous renal function. Third is the adjustment of the tonicity of the PD solutions to optimize ultrafiltration. The adjustment of the tonicity of dialysate is an area that is attracting more attention recently. There is increasing evidence that the dextrose exposure of the

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dialysate may negatively impact on the function of peritoneal membrane [6, 7]. For example, Davies et al. [6] have suggested that cumulative exposure to dextrose contributes to the enhancement of peritoneal transport characteristics. This in turn results in a requirement for more hypertonic dextrose in the dialysate to maintain optimal volume status. Thus, some investigators have suggested that dextrose exposure be limited from the inception of PD [7]. Mechanisms to achieve this goal include that consideration be given to the use of alternate osmotic agents in the PD solutions, such as icodextrin or amino acid containing solutions. Icodextrin is a high molecular weight dextrose polymer that removes fluid by oncotic forces. It is particularly useful in high and high average transporters, when used for the long dwell exchange in either CAPD or CCPD patients, since there is limited absorption of icodextrin [8]. In addition, since the icodextrin generally permits modest amounts of ultrafiltration during the long dwell exchange, the concentration of dextrose required for the other exchanges can usually be decreased. There is also interest in using other newer PD solutions. Amino acid solutions have been used to provide a substrate for protein synthesis and to replace dextrose for one of the exchanges [9]. Other more biocompatible PD solutions containing bicarbonate rather than lactate as alkali, having a more neutral pH, and having less glucose degradation products are now available [10]. The role these solutions play in the long term management of the PD patient remains to be determined. Preliminary results suggest that these solutions may be associated with lower peritonitis rates and better preservation of peritoneal membrane function [10]. Despite the quality of life benefits of PD therapy, its long term success for the ESRD patient remains problematic. Technique failure rates remain high [11]. The major factors that have been associated with technique failure include peritonitis, catheter related difficulties, problems with long term viability of the peritoneal membrane, and various psychosocial problems [11]. As PD therapy is initiated, it is important to keep these factors in mind and consider these issues in coordinating the long term care of the patient. For example, constant vigilance needs to be paid to those factors that might predispose the patient to peritonitis. These factors have recently been reviewed [12]. The psychosocial status of the patient needs to be addressed, not only in terms of the dialysis prescription, as mentioned above, but also in terms monitoring and assessing those factors which could negatively impact on the patient’s care. For example, depression has been associated not only with a higher mortality rate in dialysis patients but also with higher peritonitis rates in PD patients [13–15]. Thus, depression needs to be assessed in dialysis patients and appropriate measures undertaken to address this if necessary [16].

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In summary, the initiation of PD for the patient with chronic kidney disease offers many advantages in terms of life style benefits and satisfaction with therapy [17]. However, it requires that the nephrologist focus attention on a variety of issues that need to be addressed with the patient, the patient’s family, and the nursing and social work staff. Careful attention needs to be paid to the selection and proper preparation of the patient for PD, the timing of the initiation of dialysis, the dose of dialysis, the patient’s (and his/her family’s) overall quality of life, maintenance of adequate volume control, and the long term viability of the therapy.

References 1

2 3 4

5 6 7 8

9

10 11 12

13 14

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Moncrief JW, Popovich RP, Broadrick IJ, He ZZ, Simmons EE, Tate RA: The Moncrief-Popovich catheter. A new peritoneal access technique for patients on peritoneal dialysis. ASAIO J 1993;39:62–65. Piraino B, Burkhart J: Revision of K/DOQI guidelines for the peritoneal dialysis patient, in press. Lo WK, Ho YW, Li CS, Wong KS, Chan TM, Yu AW, Ng FS: Effect of Kt/V on survival and clinical outcome in CAPD patients in a randomized prospective study. Kidney Int 2003;64:649–656. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, Mujais S: Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13:1307–1320. Saskar S, Bernardini J, Fried L, Johnston JR, Piraino B: Tolerance of large exchange volumes by peritoneal dialysis patients. Am J Kidney Dis 1999;33:1136–1141. Davies S, Phillips L, Naish PF, Russell GI: Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol 2001;12:1046–1051. Sitter T, Sauter M: Impact of glucose in peritoneal dialysis: saint or sinner? Perit Dial Int 2005;25:415–425. Finkelstein FO, Healy H, Abu-Alfa A, Ahmad S, Brown F, Gehr T, Nash K, Sorkin M, Mujais S: Superiority of icodextrin compared with 4.25% dextrose for peritoneal ultrafiltration. J Am Soc Nephrol 2005;16:546–554. le Poole CY, Welten AG, Weijmer MC, Valentijn RM, van Ittersum FJ, Terr Wee PM: Initiating CAPD with a regimen low in glucose and glucose degradation products, with icodextrin and amino acids (NEPP) is safe and efficacious. Perit Dial Int 2005;25(suppl 3):S64–S68. Mortier S, Faict D, Schalkwijk CG, Lamiere NH, De Vreise AS: Long-term exposure to new peritoneal dialysis solutions: Effects on the peritoneal membrane. Kidney Int 2004;66:1257–1265. Finkelstein FO, Sorkin M, Cramton CW, Nolph K: Initiatives in peritoneal dialysis: where do we go from here? Perit Dial Int 1991;11:274–278. Piraino B, Bailie GR, Bernadini J, Boeschoten F, Gupta A, Holmes C, Kuijper EJ, Li PK, Lye WC, Mujais S, Paterson DL, Fontan MP, Ramos A, Schaefer F, Uttley L: Peritoneal dialysis-related infections recommendations: update. Perit Dial Int 2005;25:107–131. Lew SQ, Piraino B: Quality of life and psychological issue peritoneal dialysis patients. Semin Dial 2005;18:119–123. Lopes AA, Albert JM, Young EW, Satayathum S, Pisoni RL, Andreucci VE, Mapes DL, Mason NA, Fukuhara S, Wilsrom B, Saito A, Port FK: Screening for depression in hemodialysis patients: associations with diagnosis, treatment, and outcomes in the DOPPS. Kidney Int 2004;66: 2047–2053. Troidle L, Watnick S, Wuerth DB, Gorban-Brennan N, Kliger AS, Finkelstein FO: Depression and its association with peritonitis in long-term peritoneal dialysis patients. Am J Kidney Dis 2003;42: 350–354.

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16

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Wuerth D, Finkelstein SH, Finkelstein FO: The identification and treatment of depression in patients maintained on chronic peritoneal dialysis: results of an eight year experience. Semin Dial 2005;18:143–146. Rubin HR, Fink NE, Plantinga LC, Sadler JH, Kliger AS, Powe NR: Patient ratings of dialysis care with peritoneal dialysis vs. hemodialysis. JAMA 2004;291:697–704.

Fredric O. Finkelstein Yale University, Hospital of St. Raphael 136 Sherman Avenue New Haven, CT 06511 (USA) Tel. ⫹1 203 787 0117, Fax ⫹1 203 777 3559, E-Mail [email protected]

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Biology of Peritoneal Membrane Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 48–53

PD Membrane: Biological Responses to Different PD Fluids Achim Jörresa, Janusz Witowskia,b a

Department of Nephrology and Medical Intensive Care, Charité University Hospital, Campus Virchow-Klinikum, Berlin, Germany; bDepartment of Pathophysiology, University Medical School, Poznan, Poland

Abstract In chronic peritoneal dialysis (PD) alterations of both membrane structure and function occur with time on treatment, but also in relation to frequency and severity of infectious complications. In addition, therapy-associated factors such as the dialysis fluid bioincompatibility are important determinants for the longevity of the peritoneum as the dialysis membrane. Evidence available to date suggests that the elimination of glucose degradation products from multi-chambered PD solutions is particularly important to improve peritoneal cell function as well as to reduce protein glycation and peritoneal advanced glycation end products deposition. Results from recent prospective randomized studies suggest that chronic treatment with these novel PD fluids may indeed lead to a significant improvement of clinical outcomes in chronic PD patients. Copyright © 2006 S. Karger AG, Basel

The Peritoneal Membrane During Long-Term PD

During peritoneal dialysis (PD) the peritoneal membrane is repeatedly exposed to unphysiological challenges, including uraemic toxins, micro-organisms, dialysis fluids, and plasticizers. In addition, many patients experience acute peritoneal infections at some point during therapy. CAPD-associated peritonitis is characterized by a massive leukocyte infiltration that underlies the control by a complex network of cytokines and chemotactic factors. A severe peritonitis episode may lead to denudation of the peritoneal mesothelium and damage to the underlying interstitium. The ensuing repair processes involve the synthesis of extracellular matrix components and the repopulation of the denuded areas primarily by migration of mesothelial cells from the corners of lesions [1].

Recent in vitro studies suggest that this process may be impaired in the presence of PD fluids [2]. Whilst it has been suggested that alterations in peritoneal membrane morphology that are observed in chronic PD might be related to the number of peritonitis episodes [3, 4], peritoneal membrane changes may, however, also occur in patients that have never before experienced infectious complications. Certain morphological changes such as the thickening of the submesothelial compact collagenous zone are also present in pre-dialysis and haemodialysis patients, however, progressive membrane thickening and subendothelial hyalinization of vessels appear to be significantly correlated with duration of PD therapy [4]. Similarly, the peritoneal membrane of animals with experimental uraemia was found to be more vascularized and permeable, and to accumulate more advanced glycation end products (AGE) and angiogenic growth factors [5]. However, all these alterations were further amplified by PD. There is also evidence available suggesting that not only morphological, but also functional membrane alterations may be related to the type of dialysis solution used. In particular, increased peritoneal exposure to hypertonic glucose was shown to correlate with the increase in solute transport with time which is observed in a considerable proportion of patients [6]. Yet in addition to glucose, also glucose degradation products (GDPs) may contribute to this scenario. Animal experiments revealed that infusion of GDP-containing solutions into experimental animals results in peritoneal accumulation of methylglyoxal, the GDP, and of AGE and their receptor (RAGE) [7]. This is of particular interest as AGE accumulation in the peritoneal membrane correlates with changes in peritoneal transport and ultrafiltration [8, 9]. In vitro experiments showed that exposure of peritoneal mesothelial cells to GDP increased formation of AGE and expression of RAGE [10]. In turn, glycated proteins were found to activate production of proinflammatory cytokines by mesothelial cells [11]. Another striking finding that was recently reported is that during PD mesothelial cells may undergo a transition from an epithelial phenotype to a mesenchymal phenotype [12], another process that might be related to the mechanisms responsible for high solute transport rate [13]. Overall, the available evidence to date suggests that in addition to infectious complications and the mere duration of PD, therapy-associated factors such as the dialysis fluids and their biocompatibility are important determinants for the longevity of the peritoneum as the dialysis membrane. In the early years of PD biocompatibility the research focus was on the acute effects that buffers, acidity, and hyperosmolarity exert on peritoneal cell function [14, 15]. More recently, however, it has become apparent that GDPs are likely involved in the pathogenesis of chronic peritoneal membrane dysfunction, either directly or indirectly via the enhanced formation and deposition of AGE. As a consequence,

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the technical development of PD fluids has resulted in the recent introduction into clinical practice of a variety of novel solutions with neutral pH and reduced GDP content.

Glucose Degradation Products and the Peritoneal Membrane

The ideal solution to replace glucose as the osmotic agent in PD fluids is, at present, not available. The manufacturing process of glucose-based PD fluids may, however, be modified in order to substantially reduce glucose degradation. A key point in this process is the separation of highly concentrated glucose at a very low pH from catalyzing electrolytes and buffers in dual-chambered bags [16]. These also allow the use of different buffer systems (bicarbonate; lactate; lactate/bicarbonate) that finally result in a neutral or near-neutral pH after mixing of the two solution compartments prior to i.p. infusion. Meanwhile, a growing number of laboratory studies indicate that their in vitro-biocompatibility profile is significantly improved compared to conventional PDF [17–20]. In vitro studies also showed that GDP exert direct cytotoxic effects toward peritoneal mesothelial cells [21–23]. Animal experiments indicated that in contrast to conventional fluids, PD solutions with reduced GDPs content induce no major hemodynamic effects [24] and that the deposition of AGE, RAGE and collagen is reduced compared to conventional PD fluids [7]. Furthermore, chronic exposure of rats to PD solutions with low GDP and neutral pH resulted in less irritation to the peritoneal membrane and better preservation of mesothelial cell morphology, compared with animals receiving conventional solutions [25, 26]. More recently, clinical trials and ex vivo-studies have added evidence to the potential benefits of reducing GDP exposure. Patients receiving bicarbonate- and bicarbonate/lactate-buffered PD fluids retain improved peritoneal macrophage function and host defence status [27]. A randomized, prospective 12-month study compared a new 25 mmol/l bicarbonate plus 15 mmol/l lactate with a standard 40 mmol/l lactate-buffered PD solution in 106 patients, and reported relief of inflow pain and improved ultrafiltration with the novel solution [28]. Beneficial effects on inflow pain were also reported in a randomized, double-blind, cross-over study of novel bicarbonate (38 mM) or bicarbonate (25 mM)/lactate (15 mM) containing PD fluids [29]. A 2-year randomized clinical trial showed improved membrane transport characteristics, ultrafiltration capacity, and effluent CA-125, a proposed marker of peritoneal membrane integrity, with the novel fluid as compared to standard PDF [30]. A significant increase in effluent CA-125 was also observed with Balance, a novel lactatebuffered, dual chambered solution, when compared to standard PD fluid in a

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large randomized prospective cross-over trial [31]. Two prospective randomized trials in APD confirmed the increase in CA-125 with bicarbonate/lactate- or bicarbonate-buffered fluids [32, 33]. Furthermore, a reduction of systemic AGE load was reported in clinical studies using Balance [31], Gambrosol-Trio [34], and Bicavera [35]. Finally, a recent prospective observational study in a large cohort of Korean patients (⬎1,100) undergoing CAPD for 30 months detected improved survival of patients treated with new PD fluid (Balance) compared to those dialyzed with conventional PD fluid [36]. The results of this study may be of major clinical significance, if confirmed by other randomized and controlled trials. Indeed, the recent Euro Balance Trial [31] showed that the use of the new PD solution was associated with an improvement in residual renal function as another clear indication of improved clinical outcome.

Summary and Conclusions

Chronic exposure of the peritoneum to conventional PD fluids leads to alterations of both membrane structure and function, with the potential consequence of increased peritoneal permeability, rapid dissipation of the osmotic gradient and, ultimately, ultrafiltration failure and inadequate dialysis. Whilst the precise mechanisms leading to this complication remain to be fully elucidated, evidence available to date suggests that the elimination of GDPs (achieved in newer multi-chambered PD solutions) may significantly reduce this problem and potentially improve clinical outcomes in chronic PD patients.

References 1 2

3 4

5

6 7

Yung S, Davies M: Response of the human peritoneal mesothelial cell to injury: an in vitro model of peritoneal wound healing. Kidney Int 1998;54:2160–2169. Morgan LW, Wieslander A, Davies M, Horiuchi T, Ohta Y, Beavis MJ, et al: Glucose degradation products (GDP) retard remesothelialization independently of D-glucose concentration. Kidney Int 2003;64:1854–1866. Rubin J, Herrera GA, Collins D: An autopsy study of the peritoneal cavity from patients on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1991;18:97–102. Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, et al: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002;13: 470–479. Kakuta T, Tanaka R, Satoh Y, Izuhara Y, Inagi R, Nangaku M, et al: Pyridoxamine improves functional, structural, and biochemical alterations of peritoneal membranes in uremic peritoneal dialysis rats. Kidney Int 2005;68:1326–1336. Davies SJ, Phillips L, Naish PF, Russell GI: Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol 2001;12:1046–1051. Mortier S, Faict D, Schalkwijk CG, Lameire NH, De Vriese AS: Long-term exposure to new peritoneal dialysis solutions: effects on the peritoneal membrane. Kidney Int 2004;66:1257–1265.

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Honda K, Nitta K, Horita S, Yumura W, Nihei H, Nagai R, et al: Accumulation of advanced glycation end products in the peritoneal vasculature of continuous ambulatory peritoneal dialysis patients with low ultra-filtration. Nephrol Dial Transplant 1999;14:1541–1549. Nakayama M, Kawaguchi Y, Yamada K, Hasegawa T, Takazoe K, Katoh N, et al: Immunohistochemical detection of advanced glycosylation end-products in the peritoneum and its possible pathophysiological role in CAPD. Kidney Int 1997;51:182–186. Lai KN, Leung JC, Chan LY, Li FF, Tang SC, Lam MF, et al: Differential expression of receptors for advanced glycation end-products in peritoneal mesothelial cells exposed to glucose degradation products. Clin Exp Immunol 2004;138:466–475. Nevado J, Peiro C, Vallejo S, El Assar M, Lafuente N, Matesanz N, et al: Amadori adducts activate nuclear factor-kappaB-related proinflammatory genes in cultured human peritoneal mesothelial cells. Br J Pharmacol 2005;146:268–279. Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, Dominguez-Jimenez C, JimenezHeffernan JA, et al: Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003;348:403–413. Aroeira LS, Aguilera A, Selgas R, Ramirez-Huesca M, Perez-Lozano ML, Cirugeda A, et al: Mesenchymal conversion of mesothelial cells as a mechanism responsible for high solute transport rate in peritoneal dialysis: role of vascular endothelial growth factor. Am J Kidney Dis 2005;46:938–948. Jörres A, Gahl GM, Frei U: In vitro studies on the effect of dialysis solutions on peritoneal leukocytes. Perit Dial Int 1995;15:S41–S45. Jörres A, Gahl GM, Frei U: Peritoneal dialysis fluid biocompatibility: does it really matter? Kidney Int Suppl 1994;48:S79–S86. Lage C, Pischetsrieder M, Aufricht C, Jörres A, Schilling H, Passlick-Deetjen J: First in vitro and in vivo experiences with stay-safe balance, a pH-neutral solution in a dual-chambered bag. Perit Dial Int 2000;20(suppl 5):S28–S32. Jörres A, Williams JD, Topley N: Peritoneal dialysis solution biocompatibility: inhibitory mechanisms and recent studies with bicarbonate-buffered solutions. Perit Dial Int 1997;17(suppl 2): S42–S46. Sundaram S, Cendoroglo M, Cooker LA, Jaber BL, Faict D, Holmes CJ, et al: Effect of twochambered bicarbonate lactate-buffered peritoneal dialysis fluids on peripheral blood mononuclear cell and polymorphonuclear cell function in vitro. Am J Kidney Dis 1997;30:680–689. Topley N, Kaur D, Petersen MM, Jörres A, Williams JD, Faict D, et al: In vitro effects of bicarbonate and bicarbonate-lactate buffered peritoneal dialysis solutions on mesothelial and neutrophil function. J Am Soc Nephrol 1996;7:218–224. Topley N, Kaur D, Petersen MM, Jörres A, Passlick Deetjen J, Coles GA, et al: Biocompatibility of bicarbonate buffered peritoneal dialysis fluids: influence on mesothelial cell and neutrophil function. Kidney Int 1996;49:1447–1456. Witowski J, Korybalska K, Wisniewska J, Breborowicz A, Gahl GM, Frei U, et al: Effect of glucose degradation products on human peritoneal mesothelial cell function. J Am Soc Nephrol 2000;11:729–739. Witowski J, Wisniewska J, Korybalska K, Bender TO, Breborowicz A, Gahl GM, et al: Prolonged exposure to glucose degradation products impairs viability and function of human peritoneal mesothelial cells. J Am Soc Nephrol 2001;12:2434–2441. Witowski J, Bender TO, Wisniewska-Elnur J, Ksiazek K, Passlick-Deetjen J, Breborowicz A, et al: Mesothelial toxicity of peritoneal dialysis fluids is related primarily to glucose degradation products, not to glucose per se. Perit Dial Int 2003;23:381–390. Mortier S, De Vriese AS, Van DV, Schaub TP, Passlick-Deetjen J, Lameire NH: Hemodynamic effects of peritoneal dialysis solutions on the rat peritoneal membrane: role of acidity, buffer choice, glucose concentration, and glucose degradation products. J Am Soc Nephrol 2002;13: 480–489. Wieczorowska-Tobis K, Brelinska R, Witowski J, Passlick-Deetjen J, Schaub TP, Schilling H, et al: Evidence for less irritation to the peritoneal membrane in rats dialyzed with solutions low in glucose degradation products. Perit Dial Int 2004;24:48–57.

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Ikehara O, Nishimura H, Naito T, Higuchi C, Sanaka T: Effects of neutral pH and reduced glucose degradation products in a new peritoneal dialysis solution on morphology of peritoneal membrane in rats. Nephron Exp Nephrol 2005;100:e30–e39. Mackenzie RK, Jones S, Moseley A, Holmes CJ, Argyle R, Williams JD, et al: In vivo exposure to bicarbonate/lactate- and bicarbonate-buffered peritoneal dialysis fluids improves ex vivo peritoneal macrophage function. Am J Kidney Dis 2000;35:112–121. Tranaeus A, The Bicarbonate/Lactate Study Group: A long-term study of a bicarbonate/lactatebased peritoneal dialysis solution – clinical benefits. Perit Dial Int 2000;20:516–523. Mactier RA, Sprosen TS, Gokal R, Williams PF, Lindbergh M, Naik RB, et al: Bicarbonate and bicarbonate/lactate peritoneal dialysis solutions for the treatment of infusion pain. Kidney Int 1998;53:1061–1067. Rippe B, Simonsen O, Heimbürger O, Christensson A, Haraldsson B, Stelin G, et al: Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products. Kidney Int 2001;59:348–357. Williams JD, Topley N, Craig KJ, Mackenzie RK, Pischetsrieder M, Lage C, et al: The EuroBalance Trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane. Kidney Int 2004;66:408–418. Fusshoeller A, Plail M, Grabensee B, Plum J: Biocompatibility pattern of a bicarbonate/lactatebuffered peritoneal dialysis fluid in APD: a prospective, randomized study. Nephrol Dial Transplant 2004;19:2101–2106. Haas S, Schmitt CP, Arbeiter K, Bonzel KE, Fischbach M, John U, et al: Improved acidosis correction and recovery of mesothelial cell mass with neutral-pH bicarbonate dialysis solution among children undergoing automated peritoneal dialysis. J Am Soc Nephrol 2003;14: 2632–2638. Zeier M, Schwenger V, Deppisch R, Haug U, Weigel K, Bahner U, et al: Glucose degradation products in PD fluids: do they disappear from the peritoneal cavity and enter the systemic circulation? Kidney Int 2003;63:298–305. Schmitt CP, Von Heyl D, Haas S, Mehls O, Schaefer F, Mid European Pediatric PD Study Group (MEPPS): Peritoneal dialysis (PD) solution with reduced glucose degradation product (GDP) content lowers serum concentrations of advanced glycated endproducts (AGE) in children on automated PD (abstract). Nephrol Dial Transplant 2003;18(suppl 4):210–211. Lee HY, Park HC, Seo BJ, Do JY, Yun SR, Song HY, et al: Superior patient survival for continuous ambulatory peritoneal dialysis patients treated with a peritoneal dialysis fluid with neutral pH and low glucose degradation product concentration (Balance). Perit Dial Int 2005;25:248–255.

Professor Achim Jörres, MD Department of Nephrology and Medical Intensive Care Charité Universitätsmedizin Berlin Campus Virchow-Klinikum, Augustenburger Platz 1 DE–13353 Berlin (Germany) Tel. ⫹49 30 4505 53423, Fax ⫹49 30 4505 53916 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 54–61

Repopulation of the Mesothelial Monolayer During Long-Term Experimental Peritoneal Dialysis Lazaro Gotloib, Valery Wajsbrot, Avshalom Shostak, Vladimir Khrizman Department of Nephrology and the Research Center for Experimental Nephrology, Ha’Emek Medical Center, Afula, Israel

Abstract Background: Repopulation of the mesothelial monolayer after focal exfoliation, having the monolayer in vivo and in situ exposed to dialysis solutions, has not been thoroughly investigated. This study describes repopulation of a ‘doughnut’ like mesothelial ring exfoliated from the anterior liver surface of rats. Methods: Animals were divided into 5 groups of 20 rats each. Group 1 – control unexposed animals: mesothelial cell imprints were taken after 1 (5 rats), 5 (5 rats), and 15 (10 rats) days following the procedure of exfoliation. Group 2 – sham injected animals. Group 3 – rats IP injected once a day, during 30 consecutive days with Hank’s balanced salt solution. Groups 4 and 5 – same experimental protocol, but injecting 4.25% glucose single bag or 7.5% Icodextrin PDF. Imprints and/or biopsies were taken after a recovery period of 15 days, counted from the last IP injection. Results: Density distribution of mesothelial cells in group 2 was not significantly different from that seen in unexposed rats, whereas that seen in group 3 Hank’s balanced salt solution was marginally but significantly lower (p ⬍ 0.05) from that seen in controls. Eighty five percent of rats injected with 4.25% glucose developed fibrous adhesions, binding up together the exfoliated liver surface and the diaphragmatic muscle. For Icodextrin treated rats, the prevalence of fibrous adhesions was 95%. Conclusions: The ‘doughnut’ experimental model appears as a promising tool for in vivo and in situ investigation of mesothelial repopulation. Both osmotic agents substantially restrain mesothelial repopulation, leading to repair by connective tissue. Copyright © 2006 S. Karger AG, Basel

The mesothelial monolayer plays a prominent role in the complex biologic machinery involved in peritoneal permeability [1]. Acute exfoliation results in a dramatic alteration of peritoneal permeability [2] reminiscent of that seen in PD patients, showing failure of the peritoneum to function as a dialyzing membrane [3]. In the long run, continuous exposure of the monolayer to peritoneal dialysis

fluids (PDF) results in denuded areas that, if not immediately repopulated by new mesothelial cells, undergo repair by connective tissue [4, 5]. These unwanted developments represent the first step on the way leading to peritoneal sclerosis. In human patients, and as long as PD is performed, the mesothelium undergoes continuous injury induced by PDF, coupled to an also continuous process of regeneration [6]. Hence, the ability of the mesothelium to replace cells lost during the dialytic procedure becomes critical for long-term use and reuse of the peritoneum as a dialysis membrane. Early studies designed to unriddle the challenge posed by mesothelial regeneration were performed in the in vivo setup by several groups of investigators [7, 8]. On the other hand, Morgan el al. [9] had regard to remesothelization, after scratch-wounding the monolayer exposed to PDF, using an in-vitro model designed to evaluate repopulation of cultured mesothelium after mechanical injury. However, it should be retained that observations made in the in-vitro setup, using young and synchronized cells surrounded by an artificial environment, are a good way off from the homeostatic steady state inherent to the in vivo situation. Consequently, usefulness and relevance of information obtained from cultured mesothelial cells still remains questionable [10]. Topley [11] has also recently raised this concern. Having this problem in mind, we developed what we call the ‘doughnut model’, as a tool specifically designed to investigate mesothelial regeneration in the in vivo and in situ setup.

The Experimental Model

Experimental interventions were performed on Sprague Dawley albino rats under neuroleptanalgesia, done by one subcutaneous injection of 0.75 ml/kg body weight of a solution containing 0.5 mg/ml of droperidol and 0.001 mg/ml of fentanyl (both from Janssen Pharmaceutica. Beerse, Belgium). All procedures were conducted in accordance to the NIH guidelines for care and use of laboratory animals. The basic idea of the ‘doughnut’ implies a selective exfoliation of mesothelium, done after a small laparotomy, by means of a hollow glass rod with an internal diameter of 4 mm and a wall thickness of 0.8 mm. The rod, coated with 2% Agar (Sigma Israel, Holon, Israel), was applied to the anterior liver surface for 15–20 s, in order to peel off a ring of mesothelium (fig. 1A). Intraperitoneal instillation of the different dialysis solutions was carried out after closing the laparotomy (fig. 1B). Imprints of the anterior liver surface, centered on the exfoliated ‘doughnut’, and biopsies of the same area were sequentially taken according to the corresponding experimental protocol and using an already reported methodology [10].

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A

C

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F I

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Fig. 1. A Black star points at the peritoneal cavitary surface undressed from its mesothelial monolayer. The imprint was taken immediately after exfoliation (M: bordering mesothelial cells). (HE: ⫻100). B Open arrow points at the ‘doughnut’ like shaped ring of exfoliated mesothelium, located on the anterior liver surface. C Imprint taken 24 h after peeling off the annular piece of mesothelium from a rat not exposed to PDF. Open arrow points at one cell showing two nuclei, most likely in its way to cytokinesis. Black arrow indicates other mitotic cell in anaphase. (Star: exfoliated area of the ‘doughnut’.) (HE: ⫻1000). D Sample taken from the anterior liver surface of an unexposed animal, 5 days after the experimental exfoliation. Arrows point at new mesothelial cells migrating to the depopulated area (star). (M: bordering mesothelial cells). (HE: ⫻160). E This imprint was obtained from an untreated rat, 15 days after creation of the ‘doughnut’. Density of the mesothelial cells population looks normal. (HE: ⫻400). F This sample was taken from a rat that, after extensive exfoliation of the mesothelial monolayer by means of 0.125 mg% Trypsin, underwent transplantation of previously harvested and later cultured cells obtained from the same animal. The imprint was obtained 24 h after transplantation with cells being labeled with PKH26: White arrow points at fluorescent cells already implanted on the peritoneal surface. (PKH26: ⫻100). G Section of a sclerotic area dressing the anterior liver surface (L). The sample was taken from a rat treated by means of one daily injection of 4.25% glucose PDF,

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The Path to Homeostatic Repopulation

In order to investigate the course of this process, imprints were taken from control animals 1 (5 rats), 5 (5 rats) and 15 (10 rats) days after creating the ring of depopulated mesothelium. Twenty-four hours after the experimental intervention, bordering cells showed substantial mitotic activity (fig. 1C), coupled to centripetal migration that was more evident at the 5th day of follow-up (fig. 1D). Fifteen days after the exfoliation, the originally denuded area was dressed by an absolutely normal mesothelial monolayer (fig. 1E). The density distribution of cells was 91 ⫾ 6/33,000 ␮m2, not far from values seen in intact, unexposed animals (89 ⫾ 8/33,000 ␮m2, P: NS) [12]. This information supports the contention that repopulation takes place mostly by replication and centripetal migration of bordering mesothelial cells [13]. Other investigators postulated that repopulation originates from free floating mesothelial cells of the serosal cavity, settling on the injured areas [8], or even by migration and differentiation of mesothelial cell precursors located in the submesothelial interstitial tissue [14]. The coexistence of the former mechanism is sustained on the fact that mesothelial cells can be transplanted [15, 16] (fig. 1F). Certainly, evidence of the two latter proposed mechanisms cannot be explored in the in-vitro setup. Our observations lend ground to the concept that proliferation and migration from the edge of the injured areas are the main mechanisms involved in mesothelial healing. However, the proportional contribution of the other postulated mechanisms remains still unknown.

Effects of Dialysis Solutions Upon the Undressed Areas: Repopulation or Repair?

In order to answer this question, 4 additional groups of 20 rats each were subjected, immediately after the experimental exfoliation, to the following experimental interventions: Group 1 had one daily intraperitoneal sham injection during a period of 30 days. Group 2 was treated with one daily IP injection of

during 30 consecutive days. Notice the thick layer of fibrous tissue (F) that took the place of the missing mesothelial monolayer. (Asterisks: microvessels of neoformation.) (HE: ⫻400). H Biopsy of a fibrous adhesion between the exfoliated liver surface with an intestinal loop. The sample belongs to a rat exposed during 30 days to 7.5% Icodextrin PDF. (Asterisks: microvessels of neoformation. F: fibrous tissue.) (Van Giesson: ⫻400). I This rat was also exposed to 7.5% Icodextrin during 30 consecutive days. Note the fibrous adhesion (arrow) linking the exfoliated area of the liver (L) with the diaphragmatic muscle.

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10 ml/100 g body weight Hank’s balanced salt solution (HBSS) (Beit Ha Emek Biological Industries. Beit Ha Emek, Israel), during the same time interval. The same experimental protocol was applied to Groups 3 and 4, injecting 4.25% glucose, lactated single bag (Dialine. Teva, Ashdod, Israel) and 7.5% Icodextrin (Extraneal. Baxter, Castlebar, Ireland) solutions, respectively. After the 30 IP injections, animals were allowed a recovery period of 15 days, at the end of which laparotomy was performed in order to obtain imprints and/or biopsies of the peritoneal area where the original experimental exfoliation was performed. In the sham injected animals (group 1), imprints made in 18 out of 20 rats showed a normal mesothelium, having a density not far from that seen in intact, unexposed rats (91 ⫾ 6/33,000 ␮m2). However, two animals (10%) developed fibrous adhesions between the undressed liver area and the diaphragm. In rats exposed to HBSS, fibrous adhesions were observed in only one animal (5%), whereas the remnant 19 showed a normal mesothelial monolayer with a density of 82 ⫾ 8 cells/33,000 ␮m2. The difference with values seen in intact, unexposed rats (91 ⫾ 6 cells/33,000 ␮m2) was marginally significant (p ⬍ 0.05). The reason for this lower degree of repopulation in rats exposed to HBSS is not clear. It may be speculated that it reflects the effects of mechanical lavage done by the injected biocompatible solution upon the mechanisms involved in the repopulation of the injured monolayer. Given the nature of the experimental procedure of exfoliation, it may well be that the extremely low prevalence of adhesions seen in Groups 1 and 2 detected in few experiments (actually 3), derives its origin from a too traumatic handling of the rod applied to the liver surface. On the contrary, mesothelium of rats exposed to glucose or Icodextrin showed a substantially different reaction. From the 20 rats treated with high glucose, 17 (85%) showed extensive adhesions of the exfoliated area within the diaphragm. The three remaining animals showed a fibrous scar occupying the area of the exfoliated ring. At the microscopic level, biopsies taken from the affected areas showed a thick layer of fibrous tissue with evidence of neovascularization, dressing the anterior liver surface (fig. 1G). In turn, 19 out of the 20 rats (95%) injected with the Icodextrin solution showed extensive adhesions between the exfoliated liver area and intestinal loops, as well as with the diaphragmatic muscle (fig. 1I), reminding the classic images of sclerosing peritonitis [17]. Additionally, the only rat that failed to develop adherences displayed a dense fibrotic layer replacing the exfoliated ring of mesothelium. Microscopic examination of the fibrous area disclosed a rich net of microvessels of neoformation, embedded into a thick layer of connective tissue (fig. 1H). The higher prevalence of adhesions detected in rats exposed to both osmotic agents, compared with unexposed, intact rats and those belonging to the sham and HBSS injected groups, was significant at the p ⬍ 0.01 level.

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Discussion

The evidence offered in this paper points at the ‘doughnut’ in vivo and in situ model as a promising tool to investigate the repopulation of the injured mesothelium. Localized exfoliation of the monolayer in control animals unexposed to any other experimental intervention was repopulated after a period of around 2 weeks. Exposure of animals to a biocompatible solution as HBSS failed to radically interfere with the process of repopulation. However, a quite different picture was detected in rats exposed to single bag/high glucose concentration or to Icodextrin based PDF. In both cases, repair by connective tissue rich in microvessels of neoformation, as described in patients as well as in laboratory animals with peritoneal sclerosis [17], was observed in both experimental situations. At this point, it appears pertinent to wonder why, using PDF, the emerging picture is basically one of repair instead of repopulation. The answer to this question can be found having in mind that oxygen, so intimately linked to the origins of aerobic life, is also potentially poisonous and can induce catastrophic effects to all life forms. Both osmotic agents, glucose and Icodextrin, share the capability of liberating reactive oxygen species (ROS). In the case of glucose, this reaction is launched by the hexose itself [18] through activation of several mechanisms, or by liberation of glucose degradation products (GDP). These substances are generated at the time of heat sterilization of single bag dialysis solutions or during the shelf time [19]. The oxidative injury results in premature replicative senescence of the in vivo exposed mesothelium that leads, in turn, to a depopulated monolayer made up mostly by cells that have lost their regenerative capabilities [20]. In the case of Icodextrin, the oxidative injury, mediated by GDP generated during the dwell time [21], results in a low density mesothelial population devoid of mitotic activity and showing, in addition, high proportions of cells in apoptosis and secondary necrosis [22]. A more massive oxidative stress, done exposing the monolayer to deoxychyolate, induced both, mesothelial loss and extensive fibrosis of the peritoneal membrane [2]. As stated before, the presence of an intact mesothelial monolayer is quite critical for successful use and reuse of the peritoneum as a dialyzing membrane. In summary, the fibrous repair observed in this study, resulting from exposure to both osmotic agents, glucose and Icodextrin, reflects deep perturbation of the exposed mesothelial cell’s life cycle, resulting from sustained oxidative stress. The here presented experimental model, designed to evaluate the regenerative capabilities of the mesothelium, can be applied to identify, in vivo and in situ, possible negative effects of new dialysis solutions upon the life cycle of the monolayer, blocking the path to homeostatic repopulation.

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Finally, it may be expected that new, multicompartment bags for glucosed based PDF may well induce much lower degrees of oxidative stress, due to their more modest contents of GDP.

References 1

2 3 4 5 6 7 8 9

10 11 12 13 14 15 16

17 18 19 20

Gotloib L, Shostak A: Lessons of peritoneal ultrastructure: from an inert dialyzing sheet to a living membrtane; in Berlyne GM, Giovanetti S (eds): The Kidney Today – Selected Topics in Renal Science. Contrib Nephrol. Basel, Karger, 1992, vol 10, pp 207–235. Gotloib L, Wajsbrot V, Cuperman Y, Shostak A: Acute oxidative stress induces peritoneal hyperpermeability, mesothelial loss and fibrosis. J Lab Clin Med 2004;143:31–40. Lupo A, Rugin C, Lapolla A, Maiorca P, Arico CN, Bernich P, Marcantonio C, Brezzi B, Maschio G: The dialytic failure of the Peritoneal Membrane. Contrib Nephrol 2001;131:90–96. Di Paolo N, Garossi G: Peritoneal sclerosis. J Nephrol 1999;12:347–361. Gotloib L, Wajsbrot V, Shostak A: A short review of experimental peritoneal sclerosis: from mice to man. Int J Artif Organs 2005;28:97–104. Gotloib L, Shostak A, Bar Sella P, Kohen R: Continuous mesothelial injury and regeneration during long term peritoneal dialysis. Perit Dial Bull 1987;7:148–155. Whitaker D, Papadimitrou JL: Mesothelial healing: morphological and kinetic investigations. J Pathol 1985;145:159–175. Ryan GB, Grobety J, Majno G: Mesothelial injury and recovery. Am J Pathol 1973;71:93–112. Morgan LW, Wieslander A, Davies M, Oriuchi T, Ohta Y, Beavis MJ, Craig KJ, Williams JD, Topley N: Glucose degradation products (GPD) retard remesothelization independently of D-glucose degradation. Kidney Int 2003;64:1854–1866. Gotloib L, Wajsbrot V, Shostak A, Kushnier R: High glucose induces a hypertrophic senescent mesothelial cell phenotype after long, in-vivo exposure. Nephron 1999;82:164–173. Topley N: Peritoneal dialysis solution biocompatibility testing: a realistic alternative. Perit Dial Int 2005:25:348–351. Gotloib L, Wajsbrot V, Shostak A: Mesothelial dysplastic changes and lipid peroxidation induced by 7.5% Icodextrin. Nephron 2002;92:142–155. Watters W, Buck RC: Scanning electronmicroscopy of mesothelial regeneration in the rat. Lab Invest 1972;26:604–609. Ellis H, Harrison W, Hugh TB: The healing of the peritoneum under normal and pathological conditions. Br J Surg 1965;52:471–476. Di Paolo N, Vanni L, Sacchi G: Autologous implant of peritoneal mesothelium in rabbits and man. Clin Nephrol 1991;57:323–331. Foley-Comer AJ, Herrick SA, Al-Mishlab T, Prele CM, Laurent GJ, Mutsaers SE: Evidence for incorporation of free-floating mesothelial cells as a mechanism of serosal healing. J Cell Sci 2002;115:1383–1389. Di Paolo N, Sacchi G, Garosi G, Taganelli P, Gaggiotti E: Simple peritoneal sclerosis and sclerosing peritonitis: related or distinct entities? J Artif Organs 2005;28:117–128. Shostak A, Pivnik E, Gotloib L: Cultured rat mesothelial cells generate hydrogen peroxide: a new player in peritoneal defense? J Am Soc Nephrol 1996;7:2371–2378. Nilsson-Thorrel CB, Muscalu N, Andren AH, Kjellstrand PT, Wieslander AP: Heat sterilization of fluids for peritoneal dialysis gives rise to aldehydes. Perit Dial Int 1993;13:208–213. Shostak A, Wajsbrot V, Gotloib L: High glucose accelerates the life cycle of the in-vivo exposed mesothelium. Kidney Int 2000;58:2044–2052.

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21

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Ueda Y, Miyata T, Goffin E, Yoshino A, Inagi R, Ishibashi Y, Izuhara Y, Saito A, Kurokawa K, Van Ypersele de Strihou Ch: Effect of dwell time on carbonyl stress using icodextrin and amino acid peritoneal dialysis fluids. Kidney Int 2000;58:2518–2524. Gotloib L, Wajsbrot V, Shostak A: Icodextrin induced lipid peroxidation disrupts the mesothelial cell cycle engine. Free Radical Biol Med 2003;34:419–428.

Lazaro Gotloib, MD Department of Nephrology Ha’Emek Medical Center Afula 18101 (Israel) Tel./Fax ⫹972 4 659 1537 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 62–69

Fibrosis and Sclerosis: Different Disorders or Different Stages? Guido Garosi, Francesca Cappelletti, Nicola Di Paolo U.O.C. Nefrologia, Dialisi e Trapianto, Azienda Ospedaliera Universitaria Senese, Siena, Italy

Abstract Peritoneal sclerosis is very common in peritoneal dialysis (PD) patients. It can vary from the mild, clinically silent sclerosis always present after years of PD, to rare but dramatic and often fatal cases. In our opinion, peritoneal sclerosis is a single disorder, so its variable manifestations are different stages of one nosological entity: this opinion relies mainly on strong connections in pathophysiology. In our view, the frequency, pathology, animal models, etiology and pathogenesis often show a bimodal configuration with suggests that peritoneal sclerosis is actually two distinct nosological entities: simple sclerosis and sclerosing peritonitis. The former is very frequent, with minor anatomical alterations and low clinical impact; it is reproducible in animals by means of PD, and is clearly due to the poor biocompatibility of PD. The latter is rare, with radical anatomical alterations and high mortality; it can only be reproduced in animal models by means other than PD and seems to be due to factors both related and unrelated to PD. Copyright © 2006 S. Karger AG, Basel

Peritoneal sclerosis is a complex phenomenon. At one end we have simple sclerosis (SS): the mild, clinically silent sclerosis always present after years of peritoneal dialysis (PD). At the other end we have sclerosing peritonitis (SP) which is rare but dramatic and fatal. In our view [1], differences in frequency, pathology, animal models, and etiology point out that SP is not an evolution of SS: SP and SS are different disorders. This opinion arises mainly from the observation of peritoneal biopsies of PD patients and SP cases from Italy. On the contrary, according to Japanese authors [2], SP is an evolution of SS: SP and SS are different stages of the same disorder. This opinion relies

mainly on the strong connections in the pathophysiology of these two clinical situations.

Frequency

SS is the rule after years of PD: it can be demonstrated in all PD patients [3]. In our experience [1], about 80% of PD patients show SS. On the contrary, SP is rare, with a low prevalence and an incidence of less than five cases per thousand patient years [4]. This huge difference denies the hypothesis that SP is simply the evolution of SS. Moreover, there is an apparent absence of intermediate stages [1]: if SP were the common evolution of SS, intermediate stages with decreasing frequency should be found. On the other hand, it can be pointed out [2] that the frequency of SP increases with time of PD and membrane permeability. This characteristic indicates a role of PD in the development of SP.

Pathology

Table 1 shows the histologic characteristics of 180 patients with SS and 41 cases of SP. Our data confirm striking pathologic differences between SS and SP. SS [3, 5] seems just one of the morphological alterations always associated with PD; it is mainly a parietal alteration. It is important to stress that in SS there is no evidence of inflammation and severe calcification. There is slight vasculopathy, though never dramatic. The histological picture is quite monotonous. On the contrary, in SP [1, 5] sclerosis is very aggressive and develops in a violent and disorderly manner, involving the whole thickness of the peritoneum. In our experience, the sclerosis is at least several hundred microns thick in all patients. The thickness of sclerosis shows [1, 5] a bimodal distribution, with a huge difference between SS and SP, and a clear gap between the two; in our experience, there is a lack of intermediate stages. Moreover, in SP sclerosis is more evident in the visceral peritoneum (visceral peritoneum median ⫽ 1,200 ␮m, range 600–4,000 ␮m; parietal peritoneum median ⫽ 450 ␮m, range ⫽ 250–2,000 ␮m; Wilcoxon test p ⬍ 0.05), at variance with SS (visceral peritoneum median ⫽ 25 ␮m, range 10–40 ␮m; parietal peritoneum median ⫽ 50 ␮m, range 30–70 ␮m; Wilcoxon test p ⬍ 0.05). The Peritoneal Biopsy Study Group [3] demonstrated higher values for SS: in that study the maximum

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Table 1. Pathology of SS and SP (median and range; number of cases)

Thickness of sclerosis (␮m) Inflammation Parvicellular infiltration Mild Severe Microabscesses Giant cells Granulation tissue Vascular alterations Arterial thickening Mild Severe Arterial occlusion Arterial calcification Arterial ossification Tissue calcification Tissue ossification Presence of bone marrow

SS (n ⫽ 180)

SP (n ⫽ 41)

p

45 (10–70) 5/180 5/180 5/180 0/180 0/180 0/180 0/180 19/180 19/180 19/180 0/180 0/180 0/180 0/180 1/180 0/180 0/180

750 (250–4,000) 41/41 38/41 0/41 38/41 16/41 39/41 39/41 41/41 41/41 0/41 41/41 41/41 26/41 9/41 13/41 4/41 2/41

⬍0.01 ⬍0.01 ⬍0.01 ⬍0.05 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01

Statistical analysis: Mann–Whitney test (thickness of sclerosis), Chi-square test (other variables).

thickness of sclerosis (not a mean value) was recorded, and only parietal peritoneum was examined. It seems important to underline [1, 5] that inflammation is present in all patients with SP, as opposed to SS. In SP patients, aspects related to both acute (severe parvicellular infiltration, microabscesses) and chronic inflammation (giant cells, granulation tissue) can be observed. Acute inflammation is particularly evident in the deeper layer of the sclerotic tissue. Since these aspects are clear in all SP patients, we suggested [6] that the definition ‘SP’ rather than ‘encapsulating peritoneal sclerosis’ [4] be maintained. Regarding milky spots, these are submesothelial clusters of lymphoid tissue considered the site of origin of peritoneal resident white cells. In our experience [7], SS does not seem to influence milky spots. SP, instead, is associated with a heavy decrease in milky spots: out of 41 cases, we observed just 3 milky spots in 2 patients. In SP, milky spots are not near the mesothelium, but deep under the sclerosis: maybe here their functional characteristics are different.

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Our data show [1, 5, 6] that vasculopathy in SP is of another order of magnitude with respect to SS. In SP, vessel occlusion is the hallmark, often coupled with vessel calcification and even ossification, completely at variance with SS. The same concept seems to hold for tissue calcifications [1, 5]. They are less than occasional in SS, but are very frequent in SP, sometimes coupled with ossification. At high magnification real osteoclasts can be observed: these cells are witness to the metabolic activity of the ossification. In two cases we noticed even bone marrow inside islands of ossification. The calcifications are often mixed with inflammatory infiltrate and giant cells, and can therefore be considered dystrophic. To summarize, our data [1, 5, 6] shows quantitative and qualitative differences in pathology between simple sclerosis and SP, with poor documentation, if any, of transition stages. In our view, this is the main evidence suggesting that SS and SP are two different disorders. At the best of our knowledge, no quantitative study on SS and SP pathology supporting conflicting results is available. However, the descriptions of SP pathology by Japanese authors [2, 4, 8] usually do not mention significant inflammation, calcification and vasculopathy, or state that these changes can be found only in the advanced stage of clinical SP: in these descriptions, there is no clear difference between SS and SP. Therefore, according to this point of view, SP pathology could be considered as exaggerated SS alterations.

Animal Models

Rats and rabbits treated with PD show all the typical mesothelial and submesothelial morphological modifications induced by PD in humans, including SS [9, 10], with no need for the action of any other agent on the peritoneum. These phenomena are constant and reproducible, making these models suitable for comparing the biocompatibility of different PD solutions. No case of SS has ever been described in animals in the absence of PD. On the contrary, a pathologic process similar to SP, which presents with vomiting, abdominal pain, ascites and palpable intestinal masses, has been described [11] in dogs and cats unrelated to PD. SP has never been reproduced in animals by means of PD, whereas it has been induced without PD [12] by introducing various substances into the abdomen: household bleach, silica, talc, crocidolite, glass fibers, polypropylene, kevlar, asbestos. So, in our view animal models confirm substantial differences between SS and SP. The authors [2] who consider SS and SP as two stages of the same disorder do not consider the evidences of SP induced in animals without PD. They simply state that no animal model is able to mimic the clinical reality of long term PD, regarding animal models as unsuccessful in deciding the matter.

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Etiology and Pathogenesis

There is substantial agreement that the poor biocompatibility of PD (related to glucose, hyperosmolarity, low pH and lactate buffer) is the main reason why SS is constant in PD: many studies [1, 2] demonstrated the consequences of PD on mesothelial cells, macrophages, neutrophils, lymphocytes, and fibroblasts. This research provides biochemical documentation of functional changes in cells exposed to PD solutions. The authors considering SS and SP as two stages of the same disorder [2] support the hypothesis that the same factors are responsible also for SP. In this view, the time of PD and the degree of PD bioincompatibility are crucial in determining the onset of progressive sclerosis. So, SP is considered as the final evolution of SS, which will be reached sooner or later by any PD patient. In our opinion, this view is not correct. Unlike for SS, to date, no single causal factor has been identified which is alone sufficient to generate SP. Only a series of risk factors have been identified, which may or may not be related to PD. A link between duration of dialysis and incidence of SP [2] has often been reported, but it is not mandatory: SP may arise very early in PD [1, 5, 13], and often develops only after suspension of PD [2]. The poor biocompatibility of PD is an obvious risk factor for SP [1, 2]. However, SP arising due to poor biocompatibility can only be established in very few cases [1, 2]. In the past, the onset of SP has been associated with acetate buffer, chlorhexidine, povidone iodine, catheters, in-line bacterial filters, particles of plastics, and plasticizers. Acetate buffer showed the only significant association with SP: this led to its discontinuation throughout the world many years ago. The other associations were very uncertain and quite unable to explain the development of SP. Peritonitis is the most commonly invoked [2] pathogenetic factor for SP. This is supported by significant epidemiological data, but again peritonitis is not required for the development of SP, which may arise in patients who have never experienced peritonitis [14]. It is also recognized [5] that certain etiological agents are more dangerous than others, especially Staphylococcus aureus, fungi, Pseudomonas sp. and Haemophilus influenzae, maybe because they induce the formation of a great quantity of fibrin. Overall, PD is a serious risk factor for SP, but not an etiological factor. Even the better biocompatibility of recent PD solutions does not seem to be associated with a reduction in the frequency of SP. It is important to remember that in man there is no evidence of SS unrelated to PD. On the contrary, SP in non-dialytic patients is a well known nosological entity, first described by Owtschinnikow [15]. The number of cases of spontaneous SP greatly exceeds that of the PD-related form. These non-dialytic

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forms of SP may be associated with the use of ␤-blockers, the presence of tumors, or may be idiopathic. The ␤-blocker practolol was associated [16] with hundreds of cases of non-dialytic SP. Other ␤-blockers implicated include atenolol, metoprolol, propranolol, oxprenolol, and timolol. In experimental animals [17], ␤-blockers inhibit surfactant release from type II pneumocytes. A change in surfactant production could damage serous membranes throughout the body: in fact, pleural fibrosis, pericarditis, and joint effusions have been documented in 25% of patients with SP due to practolol [18]. Moreover, ␤-blockers in PD patients induce a decrease in ultrafiltration, irrespective of SP [19]. All these observations mean that ␤-blockers are contraindicated in PD patients. SP has often been reported [5, 20] in association with tumors: gastric cancer, ovarian thecoma, ovarian teratoma, carcinoma of the pancreas, multiple polyposis, histiocytic lymphoma, and renal carcinoma. The group of Ahlmén et al. [21] considered these cases of non-dialytic SP as a paramalignant phenomenon, induced by substances released by the tumor. In many cases of idiopathic, non-dialytic SP [22, 23], no correlation can be established with any potentially causal factor. Here, two considerations are important. The first is that in these forms, peritoneal impairment is often associated with a general connective tissue impairment, particularly of the serous membranes: this suggests an immune pathogenesis for SP. The second factor may be genetic predisposition, suggested by the high frequency of SP in women of subtropical areas [22] and familial forms such as familial multifocal fibrosclerosis [24]. Since nothing is known about immune disturbances and genetic predisposition in those few PD patients who develop EPS, it is a good topic for future research.

Conclusions

Only prospective studies in a significant number of PD patients can establish without any doubt if SS and SP are different disorders or different stages of the same disorder. This studies should include clinical characteristics, genetic profiles and close monitoring of the patients. Unfortunately, as inherent in determining etiological factors in any rare disease, this task is very difficult and requires an international collaborative approach. At the moment, in our opinion frequency, pathology, animal models and etiology strongly suggest that SS and SP are actually two distinct nosological entities. However, it is important to underline that an effort should be made to obtain PD modalities as biocompatible as possible and to identify patients at

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high risk for SP. This becomes mandatory if SP is the final evolution of SS, but remains very advisable even if PD is just a serious risk factor for SP, as suggested by our point of view.

References 1 2 3

4

5 6 7

8

9 10 11 12 13 14 15 16 17 18 19 20 21

Garosi G, Di Paolo N, Sacchi G, Gaggiotti E: Sclerosing peritonitis: a nosological entity. Perit Dial Int 2005;25:S110–S112. Nakayama M, Maruyama Y, Numata M: Encapsulating peritoneal sclerosis is a separate entity: con. Perit Dial Int 2005;25:S107–S109. Williams JD, Craig KJ, Topley N, Von Ruhland C, Fallon M, Newman GR, MacKenzie RK, Williams GT: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002;13:470–479. Kawaguchi Y, Kawanishi H, Mujais S, Topley N, Oreopoulos DG: Encapsulating peritoneal sclerosis: definition, etiology, diagnosis, and treatment. International Society for Peritoneal Dialysis ad Hoc Committee on Ultrafiltration Management in Peritoneal Dialysis. Perit Dial Int 2000;20:S43–S55. Garosi G, Di Paolo N: Peritoneal sclerosis: one or two nosological entities? Semin Dial 2000;13: 297–308. Garosi G, Di Paolo N: Inflammation and gross vascular alterations are characteristic histological features of sclerosing peritonitis. Perit Dial Int 2001;21:417–418. Di Paolo N, Sacchi G, Garosi G, Sansoni E, Bargagli L, Ponzo P, Tanganelli P, Gaggiotti E: Omental milky spots and peritoneal dialysis – review and personal experience. Perit Dial Int 2005;25:48–57. Honda K, Nitta K, Horita S, Tsukada M, Itabashi M, Nihei H, Takashi A, Oda H: Histologic criteria for diagnosing encapsulating peritoneal sclerosis in continuous ambulatory peritoneal dialysis patients. Adv Perit Dial 2003;19:169–175. Gotloib L, Wajsbrot V, Shostak A: A short review of experimental peritoneal sclerosis: from mice to men. Int J Artif Organs 2005;28:97–104. Garosi G, Gaggiotti E, Monaci G, Brardi S, Di Paolo N: Biocompatibility of a peritoneal dialysis solution with amino acids: histological study in the rabbit. Perit Dial Int 1998;18:610–619. Hardie EM, Rottman JB, Levy JK: Sclerosing encapsulating peritonitis in four dogs and a cat. Vet Surg 1994;23:107–114. Wirth T: The effect of asbestos cement, UICC asbestos samples and quartz on the peritoneum of the mouse. Pathol Microbiol (Basel) 1975;42:15–28. Oules R, Challan S, Brunner FP: Case-control study to determine the cause of sclerosing peritoneal disease. Nephrol Dial Transplant 1988;3:66–69. Mutoh S, Machida J, Ueda S, Kitamoto Y, Uemura S: Sclerosing encapsulating peritonitis occurring after very short-term intermittent peritoneal dialysis. Nephron 1992;62:119–120. Owtschinnikow PJ: Peritonitis chronica fibrosa incapsulata. Arch Klin Chir 1907;83:623–634. Thompson RPH, Jackson BT: Sclerosing peritonitis due to practolol. Br Med J 1977;1: 1393–1394. Mason RJ, Cott GR, Robinson PC: Pharmacology of alveolar type II cells. Prog Respir Res 1984;18: 279–287. Hall DR, Morrison JB, Edwards FR: Pleural fibrosis after practolol therapy. Thorax 1978;33: 822–824. Krediet RT: Beta-blockers and ultrafiltration failure. Perit Dial Int 1997;17:528–531. Sufrin G, Chason S, Golio A, Murphy G: Paraneoplastic and serologic syndrome of renal carcinoma. Semin Urol 1989;7:158–171. Ahlmén J, Burian P, Eriksson C, Schon S: Sclerosing encapsulating peritonitis once again. Perit Dial Int 1991;11:279–280.

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22 23 24

Dehn TC, Lucas MG, Wood RF: Idiopathic sclerosing peritonitis. Postgrad Med J 1985;61: 841–842. Narayanan R, Bhargava BN, Kabra SG, Sangal BC: Idiopathic sclerosing encapsulating peritonitis. Lancet 1989;ii:127–129. Comings DE, Skubi KD, Van Eyes J, Motulsky AG: Familial multifocal fibrosclerosis. Ann Intern Med 1967;66:884–892.

Guido Garosi, MD U.O.C. Nefrologia, Dialisi e Trapianto Azienda Ospedaliera Universitaria Senese Viale Bracci, 16, I–53100 Siena (Italy) Tel. ⫹39 0577 586307, Fax ⫹39 0577 586149 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 70–76

What Did We Learn From Animal Models in Peritoneal Dialysis? Norbert Lameirea, Wim Van Biesena, Siska Mortiera, An DeVrieseb a

Renal Division, University Hospital, Ghent, bRenal Unit, AZ Sint Jan AV, Brugge, Belgium

Abstract The development of animal models in peritoneal dialysis has led to some breakthroughs in the application of this dialysis modality in clinical practice. These breakthroughs are (1) a better understanding of the physiology and pathophysiology of solute transport and ultrafiltration mechanisms, (2) the observation and integration of the long-term structural and functional alterations of the membrane, (3) a better understanding of the biocompatibility issues involved in PD, leading to the clinical introduction of more biocompatible dialysis solutions and finally, (4) the development of colloid osmotic solutions containing polyglucose polymers for application in the long dwells. Intravital miscroscopy provides information in live animals about diverse functional parameters, such as blood flow rate, vessel diameter, permeability to macromolecules, leukocyte–endothelium interaction, capillary recruitment, and lymph vessel kinetics. Also evaluation of different parameters in a living experimental animal, allowing integration of function and structure is possible. A variety of chronic PD models have been developed, mainly to study effects of long-term peritoneal dialysate exposure on peritoneal membrane function and structure. The implementation of different blocking agents of biochemical substances in these models has elucidated many molecular biological mechanisms involved in these processes. The important roles of aquaporins, vascular endothelial growth factor, nitric oxide, advanced glycation end product formation and their receptor (RAGE) upregulation and the integrated roles of all these factors in the fibrotic alterations of the membrane as observed in patients on long-term PD have been investigated. More recently, genetically modified mice have been used as an important tool to investigate the molecular basis of peritoneal changes during dialysis and during acute peritonitis. Copyright © 2006 S. Karger AG, Basel

Animal Model Research: The ANIMOD Collaboration

Although animal models have been studied in the past to characterize the peritoneum as a dialyzing membrane [1], a renewed interest, in parallel with the

development of clinical continuous ambulatory peritoneal dialysis programs, has been observed in the 1980s. The different animal models that have been used with their advantages, limitations and technical aspects have recently been described [2–4] and it was pointed out that the large variety of available models make interpretation of the results and comparison of studies difficult. Species and strain of experimental animals, method of peritoneal access, study duration, measures of solute transport and ultrafiltration, and sampling for histology differ substantially among the various research groups and the need for a consensus on a standardized animal model of peritoneal dialysis (PD) was emphasized. The initiative to form an ‘ad hoc’ group of, mainly young researchers, interested in this field of basic research of peritoneal dialysis goes parallel with the regular meetings of Euro PD. Euro PD is an organization with as major aim the support of scientific research and the clinical application of PD in the treatment of end stage renal disease throughout Europe.

Relevance of the Animal Models for Clinical Practice

Jörres and Witowski [5] recently differentiated, three periods in the history of PD research. The first period, before 1980, was characterized by the establishment of clinical PD with emphasis on access to the peritoneal cavity, clinical procedures, treatment efficacy and infection control. In the second period, (from the mid-1980s to the early 1990s), further development of clinical routines in PD and of automated techniques was pursued and the first basic research on fluid biocompatibility and host defence mechanisms was performed, mostly studying peripheral blood and peritoneal leukocytes. The third episode starts from the mid-1990s until today, where sophisticated cell cultures and animal models have been used. Over the last decade, the long-term morphological and functional alterations of the membrane were explored and the first more biocompatible solutions were introduced in clinical practice. Both in vitro and in vivo research have played an important role in the major breakthroughs in the field of PD [6, 7]. These breakthroughs are (1) a better understanding of the physiology and pathophysiology of solute transport and ultrafiltration mechanisms; (2) the observation and integration of the longterm structural and functional alterations of the membrane, and (3) based on these insights, in depth research on the impact of dialysis solutions and inflammation on morphological and functional changes in the peritoneal membrane, more biocompatible dialysis solutions, and colloid osmotic solutions like polyglucose containing fluids for application in the long dwells were developed

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and clinically introduced. Before the introduction in the clinical situation, these alternative solutions had to prove their superiority in animal models. Animal models find thus their relevance both in the basic research, leading to development of improved solutions, as in the first clinical benchmarking of these solutions against the existing solutions.

Acute Models and Techniques

One of the most fascinating techniques used in acute models is the intravital microscopy, whereby the membrane is investigated under a video-microscope in live animals. This technique provides valuable information about diverse functional parameters, such as blood flow rate [8–10], vessel diameter [8, 11], permeability to macromolecules [12], leukocyte–endothelium interaction [9, 10], capillary recruitment [8], and lymph vessel kinetics. In addition, the architecture and density of the microvascular network can be studied [13]. The strength of intravital microscopy lies in its ability to permit evaluation of different parameters in a living experimental animal, allowing integration of function and structure [13]. Functional parameters can be evaluated before and after an intervention, such as exposure to dialysate or administration of a drug. The major drawback of the technique is that it does not permit repetitive observations in one animal, as the animals have to be sacrificed after the video-microscopy setting. Combination of ‘acute’ evaluation after chronic exposure of the peritoneal membrane has proven to result in highly relevant data.

Chronic Animal Models

A variety of chronic PD models have been developed, mainly to study effects of long-term peritoneal dialysate exposure on peritoneal membrane function and structure. The implementation of different blocking agents of biochemical substances in these models has elucidated many molecular biological mechanisms involved in these processes [14–17]. As examples, we quote the important roles of aquaporins [16, 18], vascular endothelial growth factor [12, 19], nitric oxide [20], advanced glycation end product (AGE) formation and their receptor (RAGE) upregulation [21, 22] and the integrated roles of all these factors in the fibrotic alterations of the membrane as observed in patients on long-term PD [23, 24]. It was also realized that the uremic state by itself is associated with structural and functional alterations in the membrane and that all alterations in a PD patient may not automatically be ascribed to the dialysis fluids [25].

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More recently, genetically modified mice, lacking either aquaporin or NO synthase have been used as an important tool to investigate the molecular basis of peritoneal changes during dialysis and during acute peritonitis [16, 26–28]. Peritoneal fibrosis is a well known and frequently occurring complication in PD [23, 24] and recent studies in our laboratory suggest that AGE ‘s play an important pathophysiologic role in the fibrotic process. AGEs exert some of their biologic actions through binding with a cell surface receptor, termed RAGE. Interaction of AGEs with RAGE induces sustained cellular activation, including the production of the fibrogenic growth factor, transforming growth factor-␤ (TGF-␤). TGF-␤ is pivotal in the process of epithelial-to-mesenchymal transition, through which cells of epithelial origin acquire myofibroblastic characteristics. Myofibroblasts are involved in virtually all conditions of pathological fibrosis. The role of the AGE–RAGE interaction in peritoneal fibrosis, was explored in three different animal models [22]; in uremia per se, in high glucose exposure of the peritoneum, and in the exposure of the peritoneal membrane to longterm classical, GDP-containing dialysate. All three models were characterized by accumulation of AGEs, upregulation of RAGE, and fibrosis. Antagonism of RAGE prevented the upregulation of TGF-␤ and fibrosis in the peritoneal membrane. Importantly, crossover from standard dialysate to low-GDP bicarbonate/lactate dialysate resulted in less pronounced VEGF expression and neoangiogenesis, and less severe AGE accumulation, TGF-␤ expression, and fibrosis compared to continuous standard dialysate exposure for 20 weeks. This was associated with an improvement in peritoneal ultrafiltration [29]. These results were recently confirmed in a model of PD using wild-type and RAGEdeficient mice [30]. Inflammation, neoangiogenesis and submesothelial fibrosis with increased expression of TGF-␤1 were augmented in wild type mice that were intraperitoneally infused twice daily over a period of 12 weeks with a high GDP fluid. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis and no fibrosis in the wild type mice. These findings contrasted with those in RAGE-deficient mice, which showed no increased inflammation, neoangiogenesis or fibrosis. These results demonstrate that peritoneal damage by GDP in PDF is dependent, at least in part, on AGE–RAGE interaction. These results were also recently corroborated by adenovirus-mediated gene transfer of active TGF-␤ into the peritoneum to induce peritoneal fibrosis similar to that in patients undergoing long-term PD [31–34]. A malignant form of this alteration is the encapsulating peritoneal sclerosis which is particularly frequent in Japan [35]. Many factors such as endotoxin contamination of the PD fluid, the use of antiseptics, carbonyl modifications, and AGEs in the peritoneal tissue may be involved in the pathogenesis of peritoneal fibrosis/sclerosis, but the underlying mechanisms remain unclear. To

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elucidate the mechanisms behind fibrosis, several animals models of peritoneal fibrosis have been developed [36]. Recent in vitro observations have demonstrated the presence of a local angiotensin II generating system in human peritoneal mesothelial cells and that Ang II produced by the cells mediates high glucose-induced upregulation of TGF-␤1 and fibronectin expression, and that Ang II-induced TGF-␤1 and fibronectin expression in these cells is mediated by NADPH oxidase-dependent ROS [37]. That, angiotensin II blockade may in the future be considered to prevent structural alterations in the membrane has been supported preliminary in animals by Duman et al. [38, 39] who found that administration of enalapril significantly reduces the thickness of the submesothelial connective tissue, produces fewer adhesions, and is associated with lower concentrations of TGF-␤.

Conclusions

So far, despite being very cumbersome, and highly labor-intensive, animal models have proven to be very effective tools to enhance our understanding of the peritoneal membrane and its function in PD. Until now, most groups have used rats or rabbits, mainly because of practical reasons and because of cost. The expansion of the available models to the use of mice will allow the implementation of many knock-out and genetically modified types, allowing further insights in the molecular basis of the processes going on in the membrane. Unfortunately, up to now, very little experience is available with larger animals. This would be the only way to also do research on impact of small solute adequacy, ultrafiltration and biocompatible solutions on the long-term. References 1 2 3

4 5 6 7

Putnam J: The living peritoneum as a dialysing membrane. Am J Physiol 1923;63:548–565. Mortier S, Lameire NH, De Vriese AS: Animal models in peritoneal dialysis research: a need for consensus. Perit Dial Int 2005;25:16–24. Lameire N, Van Biesen W, Van Landschoot M, Wang T, Heimbürger O, Bergström J, Lindholm B, Hekking LPH, Havenith CEG, Beelen RHJ: Experimental models in peritoneal dialysis: a European experience. Kidney Int 1998;54:2194–2206. Wieczorowska-Tobis K, Breborowicz A, Pawlaczyk K, Kuzlan-Pawlaczyk M, Polubinska A, Oreopoulos DG: Animal models for peritoneal dialysis. Perit Dial Int 1999;19:S189–S192. Jörres A, Witowski J: Lessons from basic research for PD treatment. Perit Dial Int 2005;25(suppl 3): S35–S38. Topley N: Peritoneal dialysis solution biocompatibility testing: a realistic alternative? Perit Dial Int 2005;25:348–351. Topley N: Animal models in peritoneal dialysis: more questions than answers? Perit Dial Int 2005;25:33–34.

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Mortier S, De Vriese AS, Van de Voorde J, Schaub TP, Passlick-Deetjen J, Lameire NH: Hemodynamic effects of peritoneal dialysis solutions on the rat peritoneal membrane: role of acidity, buffer choice, glucose concentration, and glucose degradation products. J Am Soc Nephrol 2002;13:480–489. Mortier S, De Vriese AS, McLoughlin RM, Topley N, Schaub TP, Passlick-Deetjen J, Lameire NH: Effects of conventional and new peritoneal dialysis fluids on leukocyte recruitment in the rat peritoneal membrane. J Am Soc Nephrol 2003;14:1296–1306. Zareie M, van Lambalgen AA, De Vriese AS, van Gelderop E, Lameire N, ter Wee PM, Beelen RH, van den Born J, Tangelder GJ: Increased leukocyte rolling in newly formed mesenteric vessels in the rat during peritoneal dialysis. Perit Dial Int 2002;22:655–662. Zakaria el R, Spain DA, Harris PD, Garrison RN: Generalized dilation of the visceral microvasculature by peritoneal dialysis solutions. Perit Dial Int 2002;22:593–601. De Vriese AS, Tilton RG, Stephan CC, Lameire NH: Vascular endothelial growth factor is essential for hyperglycemia-induced structural and functional alterations of the peritoneal membrane. J Am Soc Nephrol 2001;12:1734–1741. De Vriese AS, Lameire NH: Intravital microscopy: an integrated evaluation of peritoneal function and structure. Nephrol Dial Transplant 2001;16:657–660. Devuyst O: New insights in the molecular mechanisms regulating peritoneal permeability. Nephrol Dial Transplant 2002;17:548–551. Devuyst O: Molecular mechanisms involved in the peritoneal membrane exposed to peritoneal dialysis. Nefrologia 2003;23(suppl 3):32–37. Devuyst O, Ni J, Verbavatz JM: Aquaporin-1 in the peritoneal membrane: implications for peritoneal dialysis and endothelial cell function. Biol Cell 2005;97:667–673. Mortier S, De Vriese AS, Lameire N: Recent concepts in the molecular biology of the peritoneal membrane – implications for more biocompatible dialysis solutions. Blood Purif 2003;21:14–23. Carlsson O, Nielsen S, Zakaria E, Rippe B: In vivo inhibition of transcellular water channels (aquaporin-1) during acute peritoneal dialysis in rats. Am J Physiol 1996;271:H2254–H2262. Margetts PJ, Kolb M, Yu L, Hoff CM, Gauldie J: A chronic inflammatory infusion model of peritoneal dialysis in rats. Perit Dial Int 2001;21(suppl 3):S368–S372. Devuyst O, Combet S, Cnops Y, Stoenoiu MS: Regulation of NO synthase isoforms in the peritoneum: implications for ultrafiltration failure in peritoneal dialysis. Nephrol Dial Transplant 2001;16:675–678. De Vriese AS, Flyvbjerg A, Mortier S, Tilton RG, Lameire NH: Inhibition of the interaction of AGE-RAGE prevents hyperglycemia-induced fibrosis of the peritoneal membrane. J Am Soc Nephrol 2003;14:2109–2118. De Vriese AS: The John F. Maher Recipient Lecture 2004: rage in the peritoneum. Perit Dial Int 2005;25:8–11. Williams JD, Craig KJ, Topley N, von Ruhland C, Fallon M, Newman GR, Mackenzie RK, Williams GT: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002;13:470–479. Williams JD, Craig KJ, von Ruhland C, Topley N, Williams GT: The natural course of peritoneal membrane biology during peritoneal dialysis. Kidney Int Suppl 2003;S43–S49. Combet S, Ferrier ML, Van Landschoot M, Stoenoiu M, Moulin P, Miyata T, Lameire N, Devuyst O: Chronic uremia induces permeability changes, increased nitric oxide synthase expression, and structural modifications in the peritoneum. J Am Soc Nephrol 2001;12:2146–2157. Ni J, Moulin P, Gianello P, Feron O, Balligand JL, Devuyst O: Mice that lack endothelial nitric oxide synthase are protected against functional and structural modifications induced by acute peritonitis. J Am Soc Nephrol 2003;14:3205–3216. Ni J, Cnops Y, Debaix H, Boisde I, Verbavatz JM, Devuyst O: Functional and molecular characterization of a peritoneal dialysis model in the C57BL/6J mouse. Kidney Int 2005;67:2021–2031. Ni J, Cnops Y, McLoughlin RM, Topley N, Devuyst O: Inhibition of nitric oxide synthase reverses permeability changes in a mouse model of acute peritonitis. Perit Dial Int 2005;25(suppl 3):S11–S14. Mortier S, Faict D, Lameire NH, De Vriese AS: Benefits of switching from a conventional to a low-GDP bicarbonate/lactate-buffered dialysis solution in a rat model. Kidney Int 2005;67: 1559–1565.

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Schwenger V, Morath C, Salava A, Amann K, Seregin Y, Deppisch R, Ritz E, Bierhaus A, Nawroth PP, Zeier M: Damage to the peritoneal membrane by glucose degradation products is mediated by the receptor for advanced glycation end-products. J Am Soc Nephrol 2006;17:199–207. Margetts PJ, Gyorffy S, Kolb M, Yu L, Hoff CM, Holmes CJ, Gauldie J: Antiangiogenic and antifibrotic gene therapy in a chronic infusion model of peritoneal dialysis in rats. J Am Soc Nephrol 2002;13:721–728. Margetts PJ, Kolb M, Yu L, Hoff CM, Holmes CJ, Anthony DC, Gauldie J: Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 2002;160:2285–2294. Motomura Y, Kanbayashi H, Khan WI, Deng Y, Blennerhassett PA, Margetts PJ, Gauldie J, Egashira K, Collins SM: The gene transfer of soluble VEGF type I receptor (Flt-1) attenuates peritoneal fibrosis formation in mice but not soluble TGF-beta type II receptor gene transfer. Am J Physiol Gastrointest Liver Physiol 2005;288:G143–G150. Margetts PJ, Bonniaud P, Liu L, Hoff CM, Holmes CJ, West-Mays JA, Kelly MM: Transient overexpression of TGF-{beta}1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 2005;16:425–436. Oreopoulos D, Tranaeus A, Kawaguchi Y: A contemporary overview of encapsulating peritoneal sclerosis in Japan. Perit Dial Int 2005;25(suppl 4):S3–S6. Hoff CM: Experimental animal models of encapsulating peritoneal sclerosis. Perit Dial Int 2005;25(suppl 4):S57–S66. Noh H, Ha H, Yu MR, Kim YO, Kim JH, Lee HB: Angiotensin II mediates high glucose-induced TGF-beta1 and fibronectin upregulation in HPMC through reactive oxygen species. Perit Dial Int 2005;25:38–47. Duman S, Gunal AI, Sen S, Asci G, Ozkahya M, Terzioglu E, Akcicek F, Atabay G: Does enalapril prevent peritoneal fibrosis induced by hypertonic (3.86%) peritoneal dialysis solution? Perit Dial Int 2001;21:219–224. Duman S, Wieczorowska-Tobis K, Styszynski A, Kwiatkowska B, Breborowicz A, Oreopoulos DG: Intraperitoneal enalapril ameliorates morphologic changes induced by hypertonic peritoneal dialysis solutions in rat peritoneum. Adv Perit Dial 2004;20:31–36.

Norbert Lameire Renal Division, University Hospital 185, De Pintelaan BE–9000 Ghent (Belgium) E-Mail [email protected]

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Update on Peritoneal Dialysis Solution Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 77–83

GDP and AGE Receptors: Mechanisms of Peritoneal Damage Vedat Schwenger Division of Nephrology, Medical University Hospital, Heidelberg, Germany

Abstract Long-term peritoneal dialysis (PD) is limited by morphological changes of the peritoneal membrane. Structural changes were promoted by toxicity of glucose degradation products (GDPs) which are generated during heat sterilization in peritoneal dialysis fluids (PDFs). Besides their direct toxicity GDPs promote formation of advanced glycation endproducts (AGEs). RAGE (receptor for AGE) is the best characterized signal transduction receptor for AGEs and is expressed on mesothelial cells. The effects of PDFs with different amounts of GDPs were compared on morphological changes in the peritoneal membrane in a RAGE ⫺/⫺ mouse model. It could be demonstrated that RAGE plays a pivotal role in structural damage (e.g. inflammation, neoangiogenesis and fibrosis) of the peritoneal membrane. Further investigations of this pathway with regard to preventing peritoneal fibrosis should be performed to maintain the integrity of the peritoneal membrane in peritoneal dialysis patients. Copyright © 2006 S. Karger AG, Basel

Peritoneal dialysis (PD) is an accepted alternative to hemodialysis in the treatment of patients with endstage renal disease. Unfortunately, long-term PD is limited by structural and functional changes in the peritoneal membrane, resulting in treatment failure [1, 2]. Different conditions in PD patients promote these structural changes by accumulation of advanced glycation end-products (AGEs), e.g. exposure to a high concentration of glucose or of glucose degradation products (GDPs) and uremia, per se. Glucose is the most widely used osmotic agent in PD fluids to receive ultrafiltration, but the use of glucose is associated with negative effects. For example glucose-containing conventional PD fluids are a source of GDPs which are generated during heat sterilization [3].

Significance of GDPs for Peritoneal Integrity

GDPs are the topic for a large group of different carbohydrate degradation products classified as highly reactive carbonyl compounds as aldehydes and dicarbonyles (e.g. formaldehyde, acetaldehyde, glyoxal, methylglyoxal, 3deoxyglucosone, 3,4-di-deoxyglucosone-3-ene, 5-hydroxy-methylfufural) [4]. Originally a high glucose concentration was believed to be the main contributing factor in peritoneal damage that results in PD failure. In the meantime GDPs were identified as direct toxic compounds. On the one hand, such GDPs are highly reactive substances and exhibit considerable toxicity to the peritoneal membrane [5]. On the other hand, GDPs lead to the formation of AGEs. However, it is unclear to what extent peritoneal damage from GDPs is due to direct toxic effects or to indirect effects, such as the formation of AGEs from GDPs. But besides their capacity to form AGEs, GDPs develop not only local toxicity: we have demonstrated that GDPs enter the systemic circulation from the peritoneal cavity also [6]. Till now little was known about the systemic effects of GDPs.

GDP-Related Effects to Mesothelial Cells

Several studies have investigated the biocompatibility of different peritoneal dialysis fluids (PDFs) with various cells, such as fibroblasts and mesothelial cells (HPMCs) [7, 8]. Various factors which are responsible for biocompatibility, such as the buffer, glucose or GDPs formed during heat sterilization, have been shown to be critical. Exposure of HPMCs to GDPs resulted in a dosedependent inhibition of cell growth, viability, interleukin-6 and TNF-alpha release; on the other hand, synthesis of TGF-beta and VEGF was increased after exposure to different GDPs [9]. Additionally, experimental data have shown that mesothelial cell repair (remesothelialization) after exposure to GDPs was impaired, independent of D-glucose concentration [10]. Among other things, the transformation of epithelial to mesenchymal cells was responsible for this. Peritoneal mesothelial cells undergo a transformation from an epithelial cell type to a mesenchymal cell type with progressive loss of epithelial morphology, e.g. disruption of intracellular junctions and loss of apical-basolateral polarity [11]. The intracellular adhesion molecule, E-cadherin, appears to have a central role in the control of epithelial to mesenchymal transformation. After exposure of mesenchymal cells to peritoneal dialysis fluids, the expression of cytokeratine-18 and E-cadherin was reduced, the expression of alpha-SMA and vimentin as a sign of epithelial to mesenchymal transformation was increased [11]. Immunofluorescence studies demonstrated that tight junctions like ZO-1,

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Fig. 1. Staining for RAGE-antibodies in peritoneal tissue of healthy controls and PD patients (a), and in peritoneal tissue of PD patients at time of insertion of PD catheter and time of catheter removal (b). *p ⬍ 0.01.

occludine and claudin-1 became weak and were down-regulated after incubation with dialysis solution [12, 13].

Formation of AGEs and their Interaction with RAGE

Glucose and glucose derived carbonyl compounds react with the amino chain of proteins and form Schiff bases which will be rearranged to intermediate Amadori products and result in the formation of stable and irreversible cross-links between proteins and carbohydrates, the so-called advanced glycation end-products. These products may directly alter the structural integrity of the peritoneal membrane by excessive cross-linking of e.g. collagen. In the meantime AGEs have been detected immunohistochemically in the peritoneum of PD patients [1]. RAGE is the best characterized signal transduction receptor for AGEs [14]. It is a multiligand member of the immunoglobulin superfamily of cell surface molecules. The gene is localized on chromosome 6 near the HLA locus and it is composed of three immunoglobuline-like regions, (one V-domain, two C-domains), a short transmembrane domain and a 43-aminoacid cytoplasmatic tail. While the V-domain confers ligand binding, the cytoplasmatic tail is responsible for intracellular signalling. Primarily binding of AGEs to their receptor was regarded as a scavenger receptor involved in AGE removal and AGE clearance. This was supported by the fact that the expression of RAGE was increased in the state of uremia (fig. 1). However, ligand binding to RAGE results in an activation of key signal transduction pathways, such as NF-kappaB and multiple cellular signalling cascades like activation of MAP kinases [15]. Shortly after it was recognized that human peritoneal mesothelial cells also

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express RAGE [16], it became evident that a number of other ligands, like S100-calcranulines or amphoterine, also interact with RAGE. Thus RAGE is much more than a single receptor for AGEs or a scavenger receptor; it has a broad repertoire of ligands; RAGE should be considered as a pattern recognition receptor (PRR) [14]. Therefore, a direct interaction of GDPs with RAGE cannot be definitely excluded. However, the key pathophysiologic step seems to be GDP-dependent AGE formation in the uremic milieu, through which an enhanced expression of RAGE in the peritoneum could be observed. In the meantime it was demonstrated that in addition to RAGE other AGE receptors, including AGE-R-1 (p 60), AGE-R-2 (p 90) and AGE-R-3 (gallectin-3) are expressed on HPMCs [17]. Different GDPs exert differential regulation on the regulation and expression of these receptors on HPMC. However, the functional significance of these various forms have not yet been completely explained.

AGE/RAGE Interaction: Peritoneal Inflammation

RAGE was identified as a central signal transcription receptor for NF-kappa-B activation and of translocation of NF-kappa-B into the nucleus. NF-kappa-B activates the transcription of target genes such as cytokines or adhesion molecules [15]. Therefore, NF-kappa-B provides a rapid and sensitive cellular response and is responsible for the control of the initiation of inflammation, but also plays a central role in terminating inflammation. In otherwise healthy RAGE-bearing WT-mice treated with different GDP-containing PDFs, inflammatory cell number in visceral peritoneal tissue samples, CD-3 positive T-cells and EMSA for NF-kappa-B were increased compared to RAGE-dificient mice (RAGE ⫺/⫺) [18]. This data supports the hypothesis that interaction of AGE with its receptor RAGE might be involved in the regulation of inflammatory response to GDP-containing PDFs.

AGE/RAGE Interaction: Peritoneal Neoangiogenesis

In vitro and in vivo exposure of peritoneal cells to high glucose concentration stimulates the expression of VEGF. Additionally, a correlation between AGE accumulation and VEGF expression had been demonstrated. However, the inhibition of AGE–RAGE interaction with anti-RAGE antibodies did not prevent peritoneal neoangiogenesis [19]. In contrast to these observations, we could document a central role for GDP-induced upregulation of peritoneal neoangiogenesis by VEGF via AGE–RAGE interaction in the peritoneal membrane. RAGE-bearing WT-mice treated with high GDP solutions had an

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increased number of vessels per area and an enhanced expression of lectin and VEGF compared to RAGE ⫺/⫺ mice [18]. These results demonstrate a central role for GDP-induced upregulation of peritoneal neoangiogenesis by VEGF via AGE–RAGE interaction.

AGE/RAGE Interaction: Peritoneal Fibrosis

Due to its functional consequences, peritoneal fibrosis is in the focus of scientific investigations. The interaction of AGEs with RAGE upregulates TGF-beta, especially after transformation from epithelial to mesenchymal cell type. A role of RAGE for cellular transdifferentiation was also discussed [20]. Exposure of mesothelial cells to high glucose concentrations induces fibronectin, TGF-beta-1 and collagen production. Extracellular fibrosis in the peritoneum is less well understood. We could demonstrate that in RAGE ⫺/⫺ mice after 12 weeks of treatment, no peritoneal fibrosis or upregulation of TGF-beta-1 could be observed. In contrast, fibrosis and TGF-beta expression was increased in RAGE-bearing wild type mice after treatment with high concentrated GDP solution [18]. In the meantime it could be shown that AGE–RAGE interaction plays an important role in the induction of extracellular fibrosis in PD in a diabetic animal model [19]. Additionally we could demonstrate in our RAGE-deficient mouse model that AGE–RAGE interaction plays a pivotal role in the induction of peritoneal fibrosis in a non-diabetic mouse model also [18]. RAGE is causally involved in the generation of structural and functional damage to the peritoneal membrane, induced by GDP-containing PDFs.

Concluding Remarks

The finding that GDP-mediated toxicity exhibits not only local, but also systemic, toxicity argues strongly against the use of PDFs with a high GDP concentration. Further strategies to prevent local and systemic GDP-induced damage and consequently the development of peritoneal structural changes (i.e. fibrosis) may be of clinical need and benefit. We could demonstrate that the interaction of AGE with its receptor RAGE plays a pivotal role in structural damage of the peritoneal membrane after exposure of GDP-containing PDFs. Further investigations of this pathway with regard to preventing peritoneal fibrosis should be performed to maintain the integrity of the peritoneal membrane in peritoneal dialysis patients.

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Nakayama M, Kawaguchi Y, Yamada K, Hasegawa T, Takazoe K, Katoh N, Hayakawa H, Osaka N, Yamamoto H, Ogawa A, Kubo H, Shigematsu T, Sakai O, Horiuchi S: Immunohistochemical detection of advanced glycosylation end-products in the peritoneum and its possible pathophysiological role in CAPD. Kidney Int 1997;51:182–186. Williams JD, Craig KJ, von Ruhland C, Topley N, Williams GT: The natural course of peritoneal membrane biology during peritoneal dialysis. Kidney Int Suppl 2003;S43–S49. Wieslander AP, Deppisch R, Svensson E, Forsback G, Speidel R, Rippe B: In vitro biocompatibility of a heat-sterilized, low-toxic, and less acidic fluid for peritoneal dialysis. Perit Dial Int 1995;15: 158–164. Wieslander A, Linden T, Musi B, Jarkelid L, Speidel R, Beck W, Henle T, Deppisch R: Exogenous uptake of carbonyl stress compounds promoting AGE formation from peritoneal dialysis fluids. Contrib Nephrol 2001;82–89. Witowski J, Bender TO, Wisniewska-Elnur J, Ksiazek K, Passlick-Deetjen J, Breborowicz A, Jörres A: Mesothelial toxicity of peritoneal dialysis fluids is related primarily to glucose degradation products, not to glucose per se. Perit Dial Int 2003;23:381–390. Zeier M, Schwenger V, Deppisch R, Haug U, Weigel K, Bahner U, Wanner C, Schneider H, Henle T, Ritz E: Glucose degradation products in PD fluids: do they disappear from the peritoneal cavity and enter the systemic circulation? Kidney Int 2003;63:298–305. Witowski J, Wisniewska J, Korybalska K, Bender TO, Breborowicz A, Gahl GM, Frei U, PasslickDeetjen J, Jorres A: Prolonged exposure to glucose degradation products impairs viability and function of human peritoneal mesothelial cells. J Am Soc Nephrol 2001;12:2434–2441. Jörres A: Effect of peritoneal dialysis on peritoneal cell biology: peritoneal fibroblasts. Perit Dial Int 1999;19(suppl 2):S348–S352. Witowski J, Korybalska K, Wisniewska J, Breborowicz A, Gahl GM, Frei U, Passlick-Deetjen J, Jörres A: Effect of glucose degradation products on human peritoneal mesothelial cell function. J Am Soc Nephrol 2000;11:729–739. Morgan LW, Wieslander A, Davies M, Horiuchi T, Ohta Y, Beavis MJ, Craig KJ, Williams JD, Topley N: Glucose degradation products (GDP) retard remesothelialization independently of D-glucose concentration. Kidney Int 2003;64:1854–1866. Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, Dominguez-Jimenez C, JimenezHeffernan JA, Aguilera A, Sanchez-Tomero JA, Bajo MA, Alvarez V, Castro MA, del Peso G, Cirujeda A, Gamallo C, Sanchez-Madrid F, Lopez-Cabrera M: Peritoneal dialysis and epithelialto-mesenchymal transition of mesothelial cells. N Engl J Med 2003;348:403–413. Ito T, Yorioka N, Yamamoto M, Kataoka K, Yamakido M: Effect of glucose on intercellular junctions of cultured human peritoneal mesothelial cells. J Am Soc Nephrol 2000;11:1969–1979. Leung JC, Chan LY, Li FF, Tang SC, Chan KW, Chan TM, Lam MF, Wieslander A, Lai KN: Glucose degradation products downregulate ZO-1 expression in human peritoneal mesothelial cells: the role of VEGF. Nephrol Dial Transplant 2005;20:1336–1349. Bierhaus A, Humpert PM, Stern DM, Arnold B, Nawroth PP: Advanced glycation end product receptor-mediated cellular dysfunction. Ann N Y Acad Sci 2005;1043:676–680. Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Kloting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Haring HU, Schleicher E, Nawroth PP: Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes 2001;50:2792–2808. Ogata S, Yorioka N, Nishida Y, Shao JC, Yamakida M: Expression of Receptor for Advanced Glycation End Product mRNA by Human Peritoneal Mesothelial Cells. Nephron 2000;86:245–246. Lai KN, Leung JC, Chan LY, Li FF, Tang SC, Lam MF, Tse KC, Yip TP, Chan TM, Wieslander A, Vlassara H: Differential expression of receptors for advanced glycation end-products in peritoneal mesothelial cells exposed to glucose degradation products. Clin Exp Immunol 2004;138:466–475. Schwenger V, Morath C, Salava A, Amann K, Seregin Y, Deppisch R, Ritz E, Bierhaus A, Nawroth PP, Zeier M: Damage to the peritoneal membrane by glucose degradation products is mediated by the receptor for advanced glycation end-products. J Am Soc Nephrol 2006;17:199–207.

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De Vriese AS, Flyvbjerg A, Mortier S, Tilton RG, Lameire NH: Inhibition of the Interaction of AGE-RAGE Prevents Hyperglycemia-Induced Fibrosis of the Peritoneal Membrane. J Am Soc Nephrol 2003;14:2109–2118. Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert A, Thallas V, Atkins RC, Osicka T, Jerums G, Cooper ME: Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest 2001;108:1853–1863.

Vedat Schwenger Department of Nephrology Medical University Hospital DE–69120 Heidelberg (Germany) Tel. ⫹49 6221 91120, Fax ⫹49 6221 9112 229 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 84–89

Effects of Peritoneal Dialysis on the Vascular Bed of Peritoneal Membrane W. Van Biesenb, S. Mortierb, N. Lameireb, An De Vriesea a

Department of Nephrology, St Jans Hospital, Brugge, bDepartment of Nephrology, University Hospital Ghent, Ghent, Belgium

Abstract The vascularization of the peritoneal membrane is a key factor in the effectiveness of peritoneal dialysis as a dialysis modality. Over the last years, our understanding of how the peritoneal vasculature reacts to instillation of peritoneal dialysate has substantially improved. The changes in the structure of the peritoneal function over time on peritoneal dialysis as found in functional tests has been confirmed in biopsy studies performed on patients. These show both neoangiogenesis and fibrosis as the underlying morphological changes contributing to these phenomena. A thorough understanding of the biological processes involved in these alterations will be the clue for improvement of the treatment and a key to develop strategies to avoid these deformations. Copyright © 2006 S. Karger AG, Basel

It is an open door to state that the peritoneal vasculature is one of the most important players in peritoneal dialysis (PD) [1]. It determines the effective surface area of the membrane, an thus the correlate of ‘membrane surface’ in hemodialysis (HD) membrane, the perfusion (or bloodflow) of the membrane, the HD equivalent of the effective blood flow, and also the porosity and the transport capacity of the membrane, the equivalent of the flux properties of the HD membrane. Despite its importance, the peritoneal vasculature could until recently only be evaluated indirectly, either by performing functional (transport and ultrafiltration) tests [2], or morphological analysis on anatomopathological preparations. Functional tests were either perfomed as ‘peritoneal equilibration tests’ [3–6] evaluating the transport capacity of the membrane, or, more invasively, by measuring the flow through large mesenterial vessels with Doppler flow probes [7]. From the functional tests, it became clear that inflammation causes increased transport, because of intense vasodilation, e.g. during peritonitis.

The methodology of the flow probes on the larger arteries, e.g. the arteria mesenterica, was however somewhat prone to biased interpretations, as the actual exchange of solutes happens not in the large (arterial) vessels, but rather in the small capillaries, and in the venules. It appeared that the peritoneal membrane characteristics concerning small solute transport and ultrafiltration changed after some time of exposure to PD fluids, resulting in a reduced ultrafiltration and the emergence of a fast transport status [8]. Thanks to the Peritoneal Biopsy Registry [9], we learned that the peritoneal membrane of long term PD patients is featured morphologically by mesothelial, interstitial and vascular changes, such as neoangiogenesis, hyalinization of blood vessel media and reduplication of the vascular basement membrane. The extent of these findings was correlated with the duration of PD and the glucose exposure, but was also present in patients with uremia or on HD, implicating that some of the changes were at least partially related to uremia per se [10]. The most impressive alterations were found in patients with ultrafiltration failure, underlining the relevance of the observed findings. However, somewhat puzzling, some patients seemed to have far less damage than others, despite comparable duration of PD, raising the suggestion that the underlying biochemical factors inducing these peritoneal membrane alterations, were prone to genetical polymorphisms, as was demonstrated e.g. for IL-6 in fast transporters [11]. As potential candidates, vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta) were proposed, and indeed, these factors were found to be locally produced in the peritoneal membrane of patients exposed to glucose based dialysate solutions [12]. There was also a strict correlation between VEGF and small solute transport, pointing to a relation between neo-angiogenesis, fast transport status and ultrafiltration failure. Zweers et al. [13] were the first to analyze the impact of chronic peritoneal dialysate exposure in an animal model. They demonstrated that if rats were chronically exposed to intraperitoneal glucose, there was an increase in vascular density (expressed as vessels per high power field), accompanied by an increased fibrosis formation. Electron microscopy revealed profound lamination of the basal membranes of omental capillaries at 20 weeks. These morphological changes correlated with the functional increase of small solute transport and ultrafiltration failure observed in the test animals. These experiments again pointed to a pathophysiological role for glucose and/or its degradation products in the emergence of fibrosis and neo-angiogenesis during long term PD. The intravital microscopy technique in the rat model contributed a lot to our understanding of the reaction of the peritoneal vasculature as it allowed to visualize the peritoneal capillaries in vivo, both in acute and long term exposure of the peritoneal membrane to different types of dialysate solutions [14].

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The Intravital Microscopy Technique

This technique allows the visualization of the peritoneal microcirculation at the level of the arterioles, capillaries and the venules. In the rat model, after anesthesia, a short segment of the small bowel was exteriorized through a small midline abdominal incision in life animals. This segment was carefully spread over a plexiglass plate and than superfused with the desired medium. The capillaries were then visualized through a microscope with a magnification ranging from 5 to 40X, and images were videotaped by a high speed camera if necessary. Visualization and measurements were performed on mesenteric arteries with a diameter of 250–350 ␮m, but also on arterioles of 15–25 ␮m. Blood flow rate and perfused capillary length per area were calculated. Results were compared to ‘golden standard’ whereby superfusion with nitroglycerin 10⫺4M was performed. These experiments were performed under acute conditions with different PD fluids, but also in animals who previously had been instilled with PD fluids in a chronic way. The greatest disadvantage of the model is the fact that each individual animal can only be evaluated once.

Impact of Glucose on the Peritoneal Membrane Vascularization in a Diabetic Rat Model

In view of the hypothesized role of VEGF in the neoangiogenesis in longterm PD patients, De Vriese and coworkers [15] developed a chronic rat model of streptozotocin induced diabetes. Six weeks after injection, these animals had an increase in small solute transport, and ultrafiltration failure during a rat-PET test. On intravital microscopy, an impressive neovascularization and hyperpermeability of the peritoneal blood vessels was observed. These effects were completely blocked by injecting anti-VEGF in the peritoneum of the animals thrice weekly. It was clear that VEGF played a pivotal role between high glucose concentrations and hyperpermeability and neo-angiogenesis of the peritoneal membrane.

Acute Effects of Perfusion with Peritoneal Dialysis Fluid

When a ‘conventional’, glucose degradation products (GDP) containing dialysate solution was used, a maximal vasodilation was observed, even when the pH was corrected to neutral with NaOH [16]. In contrast, when low GDP solutions were superfused, e.g. Balance (Fresenius Medical Care, Bad Homburg, Germany), only a temporary vasodilation was observed, with near complete

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normalization after 20 min of continued superfusion. A solution containing bicarbonate (Bicavera®) as a buffer did not induce any vasodilation. At the level of the microcirculation, the GDP containing solutions resulted in an increase of arteriolar flow was observed, and an increase in capillary length per area, as a reflection of enhanced capillary recruitment. Use of lowGDP solution with lactate buffer caused a transient increase in capillary recruitment, whereas the bicarbonate solution did not result in any recruitment at all. From these experiments, it became apparent that presence of GDP’s and to a lesser extend lactate, caused capillary recruitment, while low pH, hyperosmolarity, and glucose concentration per se did not appear to contribute substantially to these phenomena.

Chronic Exposure Rat Models

In this model, animals were first exposed to repetitive instillation of dialysis fluid through a tunneled catheter [17]. Instillation was performed twice per day, during 12 weeks. Net ultrafiltration was lower, and small solute transport higher after instillation with standard PD fluid, but not with low GDP containing dialysate. As a correlate, the peritoneal membrane of animals exposed to standard dialysate were characterized by increased expression of VEGF, microvascular proliferation and submesothelial fibrosis on histologic evaluation, none of which was observed in the low-GDP dialysate instilled animals. Also, standard dialysate seemed to induce accumulation of advanced glycation end products (AGE’s) and upregulation of the receptor for AGE (RAGE). In cross-over experiments, it was demonstrated that these changes were timedependent, and, even more important, that switching from standard dialysate during 12 weeks, to low-GDP containing dialysate for 8 weeks, resulted in an improvement of the ultrafiltration failure, less VEGF expression and neoangiogenesis, less severe AGE accumulation, TGF-beta accumulation and fibrosis after 8 weeks. This demonstrated that the effects induced by standard dialysate solutions were reversible after switching to low-GDP solutions [18]. In the following experiments, whereby the role of the interaction AGE–RAGE was evaluated in streptozotocin induced diabetic rats, it was found that blocking this AGE–RAGE interaction prevented upregulation of TGF-beta, as was the development of submesothelial fibrosis and fibronectin accumulation, but that it did not impact on the neo-angiogenesis, eNOS expression or induction of elevated transport of small solutes [19]. The fibrosis observed in long term PD patients is thus at least partially induced by the AGE–RAGE interaction induced upregulation of TGF-beta activity. Despite the well known relation between VEGF expression and AGE accumulation [20], the AGE–RAGE interaction is

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thus not involved in neo-angiogenesis induced by hyperglycemia in the peritoneal membrane. So, AGE accumalation and VEGF levels are not causally related (at last not through the AGE–RAGE interaction), and their association is either coincidental, or induced by other mechanisms [21].

Conclusion

Long term exposure of the peritoneal membrane results in neo-angiogenesis and fibrosis. The most important culprits for these alterations are the GDP’s, although glucose itself still remains under suspicion as a potential culprit. VEGF plays a pivotal role in the neo-angiogenesis, which in its turn is responsible for the induction of fast transport status of small solutes and ultrafiltration failure. Although VEGF production and AGE-formation seem to be linked, this seems not to be related to the RAGE–AGE interaction. The fibrosis seems to be related to enhanced TGF-beta production, induced by the AGE–RAGE interaction.

References 1 2 3

4

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Ronco C: The ‘nearest capillary’ hypothesis: a novel approach to peritoneal transport physiology. Perit Dial Int 1996;16:121–125. Rippe B, Stelin G: How does peritoneal dialysis remove small and large molecular weight solutes? Transport pathways: fact and myth. Adv Perit Dial 1990;6:13–18. Van Biesen W, Carlsson O, Bergia R, Brauner M, Christensson A, Genestier S, Haag-Weber M, Heaf J, Joffe P, Johansson AC, Morel B, Prischl F, Verbeelen D, Vychytil A: Personal dialysis capacity (PDC(TM)) test: a multicentre clinical study. Nephrol Dial Transplant 2003;18:788–796. Van Biesen W, de Vriese AS, Carlsson O, Van Landschoot M, Dheuvaert T, Lameire NH: Comparison of the radioiodinated serum albumin (RISA) dilution technique with direct volumetric measurements in animal models of peritoneal dialysis. Perit Dial Int 2002;22:316–322. Lameire N, Van Biesen W, Van Landschoot M, Wang T, Heimbürger O, Bergström J, Lindholm B, Hekking LP, Havenith CE, Beelen RH: Experimental models in peritoneal dialysis: a European experience. Kidney Int 1998;54:2194–2206. Pannekeet MM, Imholz AL, Struijk DG, Koomen GC, Langedijk MJ, Schouten N, de Waart R, Hiralall J, Krediet RT: The standard peritoneal permeability analysis: a tool for the assessment of peritoneal permeability characteristics in CAPD patients. Kidney Int 1995;48:866–875. Kim M, Lofthouse J, Flessner MF: A method to test blood flow limitation of peritoneal-blood solute transport. J Am Soc Nephrol 1997;8:471–474. Davies SJ: Longitudinal relationship between solute transport and ultrafiltration capacity in peritoneal dialysis patients. Kidney Int 2004;66:2437–2445. Williams JD, Craig KJ, von Ruhland C, Topley N, Williams GT: The natural course of peritoneal membrane biology during peritoneal dialysis. Kidney Int Suppl 2003;S43–S49. Williams JD, Craig KJ, Topley N, von Ruhland C, Fallon M, Newman GR, Mackenzie RK, Williams GT: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002;13:470–479. Gillerot G, Goffin E, Michel C, Evenepoel P, Biesen WV, Tintillier M, Stenvinkel P, Heimbürger O, Lindholm B, Nordfors L, Robert A, Devuyst O: Genetic and clinical factors influence the baseline permeability of the peritoneal membrane. Kidney Int 2005;67:2477–2487.

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Zweers MM, de Waart DR, Smit W, Struijk DG, Krediet RT: Growth factors VEGF and TGF-beta1 in peritoneal dialysis. J Lab Clin Med 1999;134:124–132. Zweers MM, Splint LJ, Krediet RT, Struijk DG: Ultrastructure of basement membranes of peritoneal capillaries in a chronic peritoneal infusion model in the rat. Nephrol Dial Transplant 2001;16:651–654. de Vriese AS, Lameire NH: Intravital microscopy: an integrated evaluation of peritoneal function and structure. Nephrol Dial Transplant 2001;16:657–660. de Vriese AS, Tilton RG, Stephan CC, Lameire NH: Vascular endothelial growth factor is essential for hyperglycemia-induced structural and functional alterations of the peritoneal membrane. J Am Soc Nephrol 2001;12:1734–1741. Mortier S, de Vriese AS, Van de Voorde J, Schaub TP, Passlick-Deetjen J, Lameire NH: Hemodynamic effects of peritoneal dialysis solutions on the rat peritoneal membrane: role of acidity, buffer choice, glucose concentration, and glucose degradation products. J Am Soc Nephrol 2002;13: 480–489. Mortier S, Faict D, Schalkwijk CG, Lameire NH, de Vriese AS: Long-term exposure to new peritoneal dialysis solutions: effects on the peritoneal membrane. Kidney Int 2004;66:1257–1265. Mortier S, Faict D, Lameire NH, de Vriese AS: Benefits of switching from a conventional to a low-GDP bicarbonate/lactate-buffered dialysis solution in a rat model. Kidney Int 2005;67: 1559–1565. de Vriese AS, Flyvbjerg A, Mortier S, Tilton RG, Lameire NH: Inhibition of the interaction of AGE-RAGE prevents hyperglycemia-induced fibrosis of the peritoneal membrane. J Am Soc Nephrol 2003;14:2109–2118. Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, Bucala R, Adamis AP: Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest 1998;101:1219–1224. Treins C, Giorgetti-Peraldi S, Murdaca J, Van Obberghen E: Regulation of vascular endothelial growth factor expression by advanced glycation end products. J Biol Chem 2001;276:43836–43841.

W. Van Biesen Department of Nephrology, University Hospital Ghent De Pintelaan 185 BE–9000 Ghent (Belgium) Tel. ⫹32 9240 4402, Fax ⫹32 9 240 4599 E-Mail [email protected]

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Effect of PD Solutions on Patient Outcome Wai-Kei Lo Department of Medicine, Tung Wah Hospital, Hong Kong, SAR, China

Abstract With the recognition of the bio-incompatibility of conventional glucose based peritoneal dialysate (PDF), many new PDF has been developed and commercially available. All of them contain much less low glucose degradation product (GDP) solutions. Additional features are neutral or physiological pH, or glucose replaced by amino acid or glucose polymer icodextrin. These fluid has been shown to be more biocompatible in in-vitro and animal studies. There are short term randomized studies showing some benefit in certain clinical criteria, like increase in CA 125 in effluent PDF, better preservation of residual renal function, nutritional status, fluid and cardiovascular status, but beneficial effect on patient survival and long term peritoneal function has not been demonstrated apart from a non-randomized cohort study. To show such benefit on patient outcome, long term prospective randomized study is needed. Copyright © 2006 S. Karger AG, Basel

Lactate based low pH peritoneal dialysate with glucose as the main osmotic agent has been used since the conception of continuous ambulatory peritoneal dialysis, and still remains to be the mainstay of peritoneal dialysate (PDF) used by today. The clinical outcome in terms of patient survival, peritonitis rates has been progressively improving over the last 30 years. This improvement is obviously not related to any change in the nature of the PDF. Though patient survival varies among different countries, it is now generally accepted that PD patient survival is similar to hemodialysis patients in general, with an advantage in the first few years and young non-diabetic patients, but may be worse in old diabetic patients. Better preservation of residual renal function (RRF) by PD is thought to be one of the main reason for the initial survival advantage it carries. However, despite the long history of the glucose based low pH PDF, the high glucose concentration, low pH, high osmolality and the glucose degradation products (GDP) of the conventional PDF have been demonstrated in vitro and

in animal studies to be highly bio-incompatible and leads to the production of peritoneal inflammatory cytokines, VEGF and peritoneal fibrosis, and impair peritoneal defense. GDP is a group of compounds including acetaldehyde, formaldehyde, methylgycoxal, glycoxal, 5-hydroxymethyl furaldehyde, 2furaldehyde and 3-deoxyglucosone produced from glucose during heat sterilization process of PDF. The high glucose and GDP content have also been demonstrated to enhance the production of peritoneal and circulating advance glycation end-products (AGEs) which leads to peritoneal fibrosis and systemic inflammation which is very prevalent among PD patients. In human studies, the amount of glucose exposure has been showed to correlate with the progressive increase in peritoneal transport, which is a characteristic of progressive peritoneal failure. Apart from local effect, glucose absorbed through peritoneum also produces metabolic disturbances to the patient. Scientists have been active in developing more biocompatible PDF which are either non-glucose containing, low GDP containing, or have physiological (or close to physiological) pH. They are tested more biocompatible compared to the conventional PDF in vitro and in animal studies. These solutions provide hope for better preservation of peritoneum and improve patient and technique survival. To-date, several more biocompatible solutions are commercially available to our patients. The new generation more biocompatible PDF can be divided into glucose and non-glucose containing.

Glucose Containing PDF

The Low GDP, Slightly Acidic PDF (Gambrosol Trio®, Gambro) This product employs a multi-compartment to separate glucose from other electrolytes, such that during heat sterilization, less GDP is produced. It is still slightly acidic with pH around 6–6.5. A randomized study on a group of 80 prevalent and incident PD patients followed up for 3 years showed that dialysate cancer antigen 125 (CA 125), a marker for mesothelial cell mass and health, were higher, while the peritoneal inflammatory marker hyaluronic acid (HA) was lower in the low GDP PDF group compared to the conventional PDF group [1]. There was no difference in peritonitis rate. The drop out rate in this study was high and no survival difference could be demonstrated. The Neutral pH, Low GDP PDF (Balance®, Fresenius Medical Care) It employs a dual chamber bag system which allows mixture of two different PDF just before instillation into peritoneum, to produce a pH of 7 in the

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PDF. Glucose is contained in the acidic compartment which prevents the formation of GDP during heat sterilization. There are several clinical trials published. The EuroBalance study was a randomized cross-over study [2]. Patients used either the conventional or the Balance with the same connectology design for 3 months, and then was cross-over to the other PDF for another 3 months. Similar to other low GDP solutions, higher effluent levels of CA 125 and lower HA were found in patients employing Balance. There was no difference in VEGF and TNF-␣ levels. The only clinical benefits demonstrated was higher urine volume, but surprisingly, it was coupled with an increase in peritoneal transport and a lower ultrafiltration. It is possible that the higher urine volume was a consequence of lower ultrafiltration. This study was not designed to look into patient survival or any long term clinical outcomes. Another smaller scale prospective randomized study following up new patients for 12 months also showed significantly higher CA 125 and lower HA in the Balance group, and while effluent VEGF increased in the conventional group, it remained static in the Balance group [3]. These results suggest long term use of the low GDP solution may help to preserve peritoneum better, though the 1 year peritoneal transport did not differ between the 2 groups. The Koreans reported their retrospective comparison of 1,162 patients who used conventional (Stay-safe®) and the Balance solution from 83 centers over the same period of time [4]. Due to non-randomized nature, the conventional group was slightly older by a mean of 1.6 years (p ⫽ 0.049). It was found that the Balance group had a better patient survival at 28 months (p ⫽ 0.0032), which is more obvious in male patients and non-diabetic patients, but there was no difference in technique survival and peritonitis rate. Even after adjusted for age, Balance still carried an advantage on survival with relative risk of 0.748 (p ⫽ 0.046). This is the first report showing a survival advantage with the more biocompatible PDF. Unfortunately, RRF data was not available, and because of the retrospective nature, the reasons to employ the conventional or Balance solution and residual renal function were not known, selection bias and center effect could not be totally excluded. The Low GDP, Bicarbonate/Lactate Based, Physiological pH PDF (Physioneal®, Baxter Healthcare) This product also employs a dual chamber bag separating the bicarbonate and lactate compartment and mixed just before instillation into peritoneal cavity to provide a solution with pH 7.4 and physiological bicarbonate concentration. Low GDP is produced during heat sterilization by placing glucose in the acidic lactate compartment only. A randomized study over 6 months had

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showed that the effluent IL-6, VEGF and TNF-␣ were reduced compared to control [5]. Apart from reduction in infusion pain and higher serum bicarbonate level, the clinical benefit reported from a 12 months randomized study on prevalent patients was an improvement of ultrafiltration without changes in peritoneal transport [6]. A small randomized cross-over study in APD patients for a total of 12 months showed that effluent CA 125 concentration was higher, and IL-6 and plasma AGE were lower while using Physioneal compared to conventional PDF [7]. The phagocytic capacity of peritoneal macrophages in the effluent also improves after 5 months of Physioneal but remains the same with conventional PDF. Again, the cross-over nature was not designed to study patient survival or peritonitis rate.

Non-Glucose Containing PDF

At present, there are two different types of PDF with glucose being replaced by another agent to achieve ultrafiltration. As glucose is replaced, the GDP content is low or even absent. Amino Acid Containing PDF (Nutrineal®, Baxter Healthcare) It contains 1.1% amino acid and is originally designed to correct patients’ nutritional status by supplying extra nitrogen through the intraperitoneal route. It achieves ultrafiltration similar to 1.5% glucose. Short-term studies showed inconsistent results. Some showed improvement in muscle mass and serum albumin, while some did not. With the present understanding of contribution of inflammation being the main contributing factor to malnutrition, it is not surprising with the conflicting results. Most studies are short term 3–12 months. A long term study over 3 years showed that once daily Nutrineal prevented (not improved) the deterioration of nutritional status in terms of muscle mass and serum albumin which occurred in the control group who used only the conventional PDF [8]. A recent study employing cycler mixing of amino acid PDF with glucose containing Physioneal allowing simultaneous intraperitoneal amino acid and glucose instillation improved nitrogen balance compared to using pure Physioneal in a 7 days cross-over study [9]. Longer study is required to see if this strategy would improve nutritional status more efficiently and consistently. Amino acid PDF has proved to be more biocompatible than conventional PDF in vitro and in animal studies. Therefore, even if it is not as effective as a nutritional correction PDF, it may be considered as part of a more biocompatible

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PDF regime. The limitation is that only one bag can be used a day to avoid metabolic acidosis. Glucose Polymer Containing PDF (Extraneal®, Baxter Healthcare) The glucose polymer icodextrin has been studied to replace glucose in PDF for a long time. It is not osmotically active and removes fluid from the body by oncotic pressure. It is very effective in improving ultrafiltration in high peritoneal transport patients, and helps to correct the poor ultrafiltration with long night dwell or day dwell in APD patients. Its use may improve technique survival in ultrafiltration failure patients who might need conversion to hemodialysis [10], and improve the fluid status and cardiac function in a randomized study [11]. Prolongation of patient survival is expected in this group of patients, though such proof is still lacking at this moment. Because of the normal osmolality, absence of glucose and a low GDP content, it is also more biocompatible than conventional PDF. However, similar to amino acid solutions, consumption exceeding one bag is not recommended due to hypermaltosemia as a result of excessive icodextrin absorption. Therefore, patients cannot use icodextrin solution solely for peritoneal dialysis. As a result, it is often considered as part of a more biocompatible solution regime.

Combination Regime

As none of the present glucose-free solutions can be used to replace conventional PDF completely, regime with combination of different low GDP solutions was developed to minimize glucose exposure while maintaining low GDP exposure throughout. The combination of Nutrineal, Extraneal and Physioneal (NEPP) regime is under active clinical investigation. A recent randomized study reported that, over a 30 week period, NEPP leads to less glucose absorption and better preservation of effluent CA 125 content [12]. However, the peritoneal transport slightly increased. Longer study is needed to establish any clinical superiority. This reduction in glucose load is of particular important interest to diabetic PD patients. A small scale study showing that glycemic control in diabetic CAPD patients could be improved with a combination of Physioneal and Extraneal, followed by purely Physioneal over using conventional PDF [13]. Another combination regime under investigation is to employ PDF with lower amino acid concentration mixing with glycerol as osmotic agent. By such way, this amino acid PDF can be used for two exchanges to minimize glucose exposure. A small study employing this solution 2 exchanges of 0.6% amino acid with 1.4% glycerol PDF plus one exchange of Extraneal and one exchange

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of conventional PDF was well tolerated for a period of 12 weeks with an ultrafiltration capacity similar to 2.27% [14]. The advantage seen was glucose absorption is markedly reduced and the effluent CA 125 increased.

Conclusions

All these new generation PDF with low GDP have been demonstrated to be better than conventional PDF from the perspective of peritoneal mesothelial cell and inflammatory markers. It looks promising in better preservation of the peritoneum. They may improve patient survival by improving fluid control, improving nitrogen balance, reducing glucose load and systemic inflammation. However, the clinical benefit on patient outcome has yet to be proved by better designed and long term studies.

References 1 2 3

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Rippe B, Simonsen O, Heimbürger O, et al: Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products. Kidney Int 2001;59:348–357. Williams JD, Topley N, Craig KJ, et al: The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane. Kidney Int 2004;66:408–418. Kim YL, Do JY, Park SH, et al: Low glucose degradation products dialysis solution modulates the levels of surrogate markers of peritoneal inflammation, integrity, and angiogenesis: preliminary report. Nephrology 2003;8:S28–S32. Lee HY, Park HC, Seo BJ, et al: Superior patient survival for continuous ambulatory peritoneal dialysis patients treated with a peritoneal dialysis fluid with neutral pH and low glucose degradation product concentration (Balance). Perit Dial Int 2005;25:248–255. Cooker LA, Luneburg P, Holmes CJ, et al: Interleukin-6 levels decreases in effluent from patients dialyzed with bicarbonate/lactate-based peritoneal dialysis solutions. Perit Dial Int 2001;21(suppl 3): S102–S107. Tranaeus A: A long-term study of a bicarbonate/lactate-based peritoneal dialysis solution – clinical benefits. Perit Dial Int 2000;20:216–523. Fusshoeller A, Plail M, Grabensee, Plum J: Biocompatibility pattern of a bicarbonate/lactatebuffered peritoneal dialysis fluid in APD: a prospective randomized study. Nephrol Dial Transplant 2004;19:2101–2106. Li FK, Chan LY, Woo JC, et al: A 3-year, prospective, randomized, controlled study on amino acid dialysate in patients on CAD. Am J Kidney Dis 2003;42:176–186. Tjiong HL, van den Berg JW, Wattimena JL, et al: Dialysate as food: combined amino acid and glucose dialysate improves protein anabolism in renal failure patients on automated peritoneal dialysis. J Am Soc Nephrol 2005;16:1486–1493. Johnson DW, Arndt M, O’Shea A, et al: Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload. BMC Nephrol 2001;2:2. Davies S, Woodrow G, Donovan K, et al: Icodextrin improves the fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial. J Am Soc Nephrol 2003;14: 2338–2344. le Poole CT, Welten AG, Weijmer MC, et al: Initiating CAPD with a regimen low in glucose and glucose degradation products, with icodextrin and amino acids (NEPP) is safe and efficacious. Perit Dial Int 2005;25(suppl 3):S64–S68.

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Marshall J, Jennings P, Scott A, et al: Glycemic control in diabetic CAPD patients assessed by continuous glucose monitoring system (CGMS). Kidney Int 2003;64:1480–1486. Biesen WV, Boer W, Greve BD, et al: A randomized clinical trial with a 0.6% amino acid/1.4% glycerol peritoneal dialysis solution. Perit Dial Int 2004;24:222–230.

Dr. Wai-Kei Lo Department of Medicine Tung Wah Hospital Hong Kong, SAR (China) Tel. ⫹852 2589 8580, Fax ⫹852 2858 7340, E-Mail [email protected]

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Peritoneal Transport with Icodextrin Solution Olof Heimbürger Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Abstract Icodextrin is the only large molecular weight osmotic agent available in peritoneal dialysis solutions. Icodextrin (compared to glucose) has a prolonged positive ultrafiltration because of the slow absortion of icodextrin due to its large molecular weight. As icodextrin induces transcapillary ultrafiltration by a mechanism resembling ‘colloid’ osmosis (with the ultrafiltration occurring mainly through the small pores) almost no sieving of solutes is observed with icodextrin-based solution resulting in increased convective transport and clearance of small solutes. In general, the transport characteristics of the peritoneal membrane are similar with glucose- and icodextrin-based solution, but results from the EAPOS study suggests that use of icodextrin-based solution may be associated with less changes in peritoneal transport with time. Copyright © 2006 S. Karger AG, Basel

Conventional peritoneal dialysis (PD) solutions contain glucose as osmotic agent in order to apply enough osmotic force over peritoneal membrane to achieve sufficient ultrafiltration (UF). As glucose is a small solute, it will diffuse relatively rapid into blood resulting in a rather short-lasting positive net UF as well as a significant absorption of glucose contributing to metabolic disturbances. Therefore, several alternative osmotic agents have been tested, of which only amino acids and icodextrin (and to some extent glycerol) have been applied in the clinical setting. Icodextrin is the only large molecular weight osmotic agent that has been available in peritoneal dialysis solutions, and has been widely adopted in PD patients in order to improve fluid removal and to reduce glucose absorption.

PD with glucosebased solution

Na sieving

UF with glucose

UF with glucose

Convective Convective Na transport protein loss

Capillary wall

Pore: Anatomical correlate: Functional radius: Reflection coefficient for glucose ():

Water pore (aquaporin-1) 4–6 Å

Small pore (inter-endothelial cleft) 40–65 Å

Large pore (unknown) 200 Å

1

0.03

0.01

PD with icodextrinbased solution

UF with Convective icodextrin Na transport

Capillary wall

Almost no transport

Pore:

Water pore

Small pore

Convective protein loss

Large pore

Fig. 1. The three-pore model of peritoneal transport including the transcellular pore, the small pore and the large pores. With glucose-based solution, the crystalloid osmotic pressure induced by glucose is very efficient through the aquaporins and about 50% of the ultrafiltered fluid will pass through the aquaporins. Sodium is sieved at the aquaporins whereas no sodium sieving is observed at the small pores, and convective transport of sodium and other small solutes will take place. In addition, diffusive transport of sodium (and other small solutes) will occur through the small pores. With icodextrin-based solution, UF will almost entirely occur through the small pores and no sodium sieving will occur.

The Peritoneal Transport Process

The capillary wall is a tight structure considered to be the main transport barrier for diffusion and convection through the peritoneum (although it is likely that the interstitium may be a significant transport barrier for small solutes in pathological conditions with thickening and fibrosis of the peritoneal membrane). In contrast, the mesothelium will provide little resistance to fluid and solute transport. The peritoneal capillaries behave functionally as having a hetereporous structure, with a large number of ‘ultra-small’ water pores (radius 4–6 Å), a large number of ‘small pores’ (radius 40–65 Å), and a small number of large pores (radius 200–400 Å) through which macromolecules are filtered due to convective flow (fig. 1) [1, 2]. The anatomical correlates of the water pores are aquaporin-1, and of the small pores are the inter-endothelial clefts, whereas the anatomical correlate of the large pores is not established [1].

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Whereas only water may pass through the aquaporins, the small pores do not restrict the passage of small solutes but are impermeable for macromolecules larger than albumin (molecular weight 69,000 Da) [1, 2]. In addition to the transcapillary exchange between plasma and dialysate, there is a peritoneal absorptive flow of fluid and solutes, comprising of two different pathways [2]: (1) direct lymphatic absorption (mainly via the lymphatic stomata in the diaphragm, and to a lesser extent through visceral lymphatic pathways), and (2) fluid absorption into tissues [2]. UF in PD is achieved by the application of high concentration of an osmotic agent (usually glucose) in the dialysate, resulting in a high osmotic pressure gradient across the peritoneal barrier [2, 3]. The osmotic force for a solute across the different pores will be dependent on both the concentration difference and the reflection coefficient () for the particular solute across the pore. When glucose is used as osmotic agent, it will have a high osmotic pressure over the water pores (as they are impermeable for glucose and for glucose will be close to 1 across the aquaporins) and about half of the water flow from the capillaries will pass through these pores. In contrast, glucose can easily diffuse through the small pores and the osmotic force over the small pores will be relatively low, and (in spite of the large total area of the small pores) only about half of the UF will occur over the small pores [1]. However, the osmotic pressure gradient decreases rapidly due to the absorption of the osmotic agent, when small solutes like glucose, amino acids or glycerol, are used as osmotic agents. Small solutes are transported through the peritoneum mainly by diffusion (due to the concentration gradient between blood and dialysate) and to a lesser extent by convection into the peritoneal cavity (due to hydrostatic pressure differences and the osmotic disequilibrium caused by the osmotic agent) [1, 2]. The diffusive solute transfer rate is proportional to the concentration gradient between dialysate and plasma, the solute’s diffusion constant (which is inversely proportional to the solutes radius), the surface area available for diffusion, and inversely proportional to the diffusion distance [1, 2]. The ratio of the solute’s diffusion constant to the diffusion distance is called permeability (P) and the product of P and surface area (S) is usually denoted permeability surface area product (PS), which in PD also has been denoted diffusive mass transport coefficient (KBD), mass transfer coefficient or mass transfer area coefficient. Thus, the speed of diffusion for a solute will be dependent on the concentration gradient and the PS for the particular solute [2]. The convective transport of small solutes is dependent on the UF through the small pores, whereas the UF through the aquaporins will not result in convective transport as all solutes will be sieved at the aquaporins [2]. Therefore, the sieving of small solutes will be dependent of the fraction of UF that passes through small pores in relation to the total UF flow (through aquaporins and small pores), as no

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solutes will pass through the aquaporins and as the convective passage of small solutes through the small pores will not be subject to any sieving. (The large pores are so rare that the flow through this pathway may be neglected except for the transport of large macromolecules from blood to dialysate.)

Icodextrin

Icodextrin is a specific fraction of dextrin (a starch derived, water soluble, glucose polymer) isolated by fractionation of hydrolyzed cornstarch [4]. The structure of icodextrin is similar to (but less branched than) glycogen, consisting of polysaccharide polymers linked by -(1–4) and -(1–6) glucosidic bonds [5]. Icodextrin is a polydispersed mixture of polymers with varying chain lengths, and its molecular weight is characterized by both number average (Mn) and average molecular weight. The Mn for icodextrin (the arithmetic mean of the molecular weights of the individual glucose polymer molecules) range from 5,000 to 6,500 Da and the molecular weight [equal to the sum of (weight of molecules times molecular weight) for all the molecular species divided by the total weight of all molecules] range from 13,000 to 19,000 Da. The majority of icodextrin polymers (85%) have a molecular weight between 1,680 and 45,000 Da with only 6% having a molecular weight less than 1,680 Da [5].

Peritoneal Transport with Icodextrin Solution

Whereas glucose and other small molecules are absorbed from the peritoneal cavity primarily by diffusion across the peritoneal capillary endothelium [2], the diffusion component is limited for icodextrin as icodextrin cannot pass through the small pores due to its high molecular weight. Icodextrin absorption occurs primarily due to the relatively slow convective fluid movement out of the peritoneal cavity [2]. As a result the absorption of the osmotic agent is much slower, resulting in a longer duration of the osmotic gradient and a positive net UF. Thus, the osmotic pressure created by icodextrin will be relatively constant during the dwell and UF is sustained throughout the long dwell [6–9]. About 20–40% of the administered icodextrin is absorbed from the peritoneal cavity during a long dwell [5, 6]. Absorbed icodextrin is hydrolyzed in blood by circulating -amylase to smaller oligosaccharides including maltose, maltotriose, and maltotetraose, which can be found in blood of patients treated with icodextrin solution [6, 10, 11]. Maltose and other circulating icodextrin metabolites may be further metabolized to glucose by tissue maltases, and are excreted into the urine or into the PD [5].

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The 7.5% icodextrin solution has a calculated osmolality of 282–286 mOsmol/l, and is iso-osmolar with normal plasma and produces transcapillar UF by a mechanism resembling ‘colloid’ osmosis [7, 9, 12]. Hence, the water flow will occurs in the direction of the relative excess of relatively impermeable, large, molecules (i.e. icodextrin), rather than down the solute concentration (osmolality) gradient. This is explained by the heteroporous structure of the peritoneal membrane with a high osmotic pressure from icodextrin over the small pore system as icodextrin cannot pass through the small pores (and for icodextrin will be close to 1 over the small pores), whereas the water flow through the aquaporins will be very small due to the very low difference is osmolarity and the small total area of the aquaporins. As the UF with icodextrin solution will occur almost entirely through the small pores no sieving of small solutes will be observed with this solution (fig. 1).

Clinical Studies of Peritoneal Transport with Icodextrin Solution

Dwell studies using macromolecular volume markers have confirmed the slow continuous UF achieved by icodextrin solution [8, 12] and fits well with theoretical predictions using the three pore model [9, 13]. In controlled clinical trials in patients undergoing continuous ambulatory peritoneal dialysis [6, 11] or automated PD [14, 15], intraperitoneal administration of icodextrin for the long (8–16 h) exchange produced UF volumes which exceed those with 1.36 and 2.27% glucose solutions, and are equivalent to those obtained with 3.86% glucose. The icodextrin-based solution does not affect the peritoneal diffusive solute transport characteristics [8, 12] and PS values for small solutes are therefore in general similar to those obtained with glucose based solution. As the main osmotic effect of icodextrin will occur over the small pores, no sieving of solutes that can pass through the small pores will be observed (i.e. solutes smaller than albumin). For example, sieving of sodium will not be observed with icodextrin solution [2, 8, 12, 16] and the large osmotic fluid flow through the small pores will result in increased clearance of sodium, as well as of low molecular proteins like 2-microglobulin and leptin [7, 12].

Use of Icodextrin Solutions in High Transporters

Because of the slow absorption of icodextrin and the sustained UF with icodextrin solution it is theoretically well suited for patients with poor UF due

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to rapid glucose absorption. Several clinical studies also demonstrate that this is the case also in the clinical situation [11, 15, 17] where icodextrin solution can provides good UF and improve fluid status [16] also in these patients. In one study of patients that were on the verge of being transferred to hemodialysis (because of symptomatic fluid retention in spite of use of hypertonic glucose solution), use of icodextrin solution improved UF by 600 ml/day and made it possible to keep these on PD for an additional period of on average 11.6 months [18]. Similarly, icodextrin solution will preserve, maintain or even increase its UF capacity also during peritonitis, in contrast to the decline in UF with glucose-based solutions during peritonitis episodes [17].

Long-Term Effects of Icodextrin Solution on Peritoneal Transport

Peritoneal transport characteristics assessed from peritoneal equilibration test results (including estimated PS for urea, creatinine and glucose) were essentially stable both with icodextrin and glucose-based solution in two randomized multicenter trials (n 194 and 13, respectively) of stable PD patients followed for 1 and 2 years respectively [11, 19]. However, results from the EAPOS study (a 2 year, prospective, multicenter study of 177 anuric automated PD patients) [20] demonstrated that patients using icodextrin (n 82) had more stable peritoneal UF and diffusive solute transport compared to patients only using glucose based solutions. In summary, icodextrin provides a slow continuous UF in PD patients whereas the diffusive transport characteristics seem to be unaffected. Use of icodextrin solution is particularly indicated in patients with a high peritoneal transport rate and insufficient UF due to rapid glucose absorption.

References 1 2

3 4 5

Rippe B, Rosengren BI, Venturoli D: The peritoneal microcirculation in peritoneal dialysis. Microcirculation 2001;8:303–320. Heimbürger O: Peritoneal physiology; in Pereira BJG, Sayegh MH, Blake P (eds): Chronic Kidney Disease, Dialysis and Transplantation: A Companion to Brenner and Rector’s the Kidney, ed 2. Philadelphia, Elsevier Saunders, 2005, pp 491–513. Flessner MF: Peritoneal transport physiology: insights from basic research. J Am Soc Nephrol 1991;2:122–135. Alsop RM: History, chemical and pharmaceutical development of icodextrin. Perit Dial Int 1994;14(suppl 2):S5–S12. Moberly JB, Mujais S, Gehr T, Hamburger R, Sprague S, Kucharski A, Reynolds R, Ogrinc F, Martis L, Wolfson M: Pharmacokinetics of icodextrin in peritoneal dialysis patients. Kidney Int 2002;62(suppl 81):S23–S33.

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6

7 8

9 10

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13 14

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17 18 19

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Mistry CD, Gokal R, Peers EM, The MIDAS Study Group: A randomised multicentre clinical trial comparing isoosmolar icodextrin with hyperosmolar glucose solutions in CAPD. Kidney Int 1994;46:496–503. Mistry C, Mallick NP, Gokal R: Ultrafiltration with an isosmotic solution during long peritoneal dialysis exchanges. Lancet 1987;2:178–182. Asghar RB, Diskin AM, Spanel P, Smith D, Davies SJ: Influence of convection on the diffusive transport and sieving of water and small solutes across the peritoneal membrane. J Am Soc Nephrol 2005;16:437–443. Rippe B, Levin L: Computer simulations of ultrafiltration profiles for an icodextrin-based peritoneal fluid in CAPD. Kidney Int 2000;57:2546–2556. García-López E, Anderstam B, Heimbürger O, Amici G, Werynski A, Lindholm B: Determination of high and low molecular weight molecules of icodextrin in plasma and dialysate, using gel filtration chromatography, in peritoneal dialysis patients. Perit Dial Int 2005;25:181–191. Wolfson M, Piraino B, Hamburger R, Morton AR, The Icodextrin Study Group: A randomized controlled trial to evaluate the efficacy and safety of icodextrin in peritoneal dialysis. Am J Kidney Dis 2002;40:1055–1065. Ho-dac-Pannekeet MM, Schouten N, Langendijk MJ, Hiralall JK, de Waart DR, Struijk DG, Krediet RT: Peritoneal transport characteristics with glucose polymer based dialysate. Kidney Int 1996;50:979–986. Mujais S, Vonesh E: Profiling of peritoneal ultrafiltration. Kidney Int 2002;62(suppl 81): S17–S22. Posthuma N, ter Wee PM, Verbrugh HA, Oe PL, Peers E, Sayers J, Donker AJ: Icodextrin instead of glucose during the daytime dwell in CCPD increases ultrafiltration and 24-h dialysate creatinine clearance. Nephrol Dial Transplant 1997;12:550–553. Finkelstein F, Healy H, Abu-Alfa A, Ahmad S, Brown F, Gehr T, Nash K, Sorkin M, Mujais S, The Icodextrin High Trasnport Trial Group: Superiority of icodextrin compared with 4.25% dextrose for peritoneal ultrafiltration. J Am Soc Nephrol 2005;16:546–554. Davies SJ, Woodrow G, Donovan K, Plum J, Williams P, Johansson AC, Bosselmann HP, Heimbürger O, Simonsen O, Davenport A, Tranæus A, Divino Filho JC: Icodextrin improves the fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial. J Am Soc Nephrol 2003;14:2338–2344. Krediet R, Mujais S: Use of icodextrin in high transport ultrafilotration failure. Kidney Int 2002;62(suppl 81):S53–S61. Johnson DW, Arndt M, O’Shea A, Watt R, Hamilton J, Vincent K: Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload. BMC Nehrol 2001;2:2. Posthuma N, Verbrugh HA, Donker AJ, van Dorp W, Dekker HAT, Peers E, Oe PL, ter Wee PM: Peritoneal kinetics and mesothelial markers in CCPD using icodextrin for daytime dwell for two years. Perit Dial Int 2000;20:174–180. Davies Sj, Brown E, Frandsen NE, Rodrigues AS, Rodriguez-Carmona A, Vychytil A, Macnamara E, Ekstrand A, Tranaeus A, Divino Filho JC, The EAPOS Study Group: Longitudinal membrane function in functionally anuric patients treated with APD: data from EAPOS on the effects of glucose and icodextrin prescription. Kidney Int 2005;67:1609–1615.

Olof Heimbürger, MD, PhD Division of Renal Medicine, K56 Karolinska University Hospital, Huddinge SE–141 86 Stockholm (Sweden) Tel. 46 8 5858 3978, Fax 46 8 711 47 42, E-Mail [email protected]

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Sodium and Water Homeostasis Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 104–110

Dry Body Weight: Water and Sodium Removal Targets in PD Raymond T. Krediet Division of Nephrology, Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Abstract Background/Aims: Cardiovascular mortality is high in peritoneal dialysis patients. This may be due to the presence of hypertension and fluid overload. Dietary intake of water and sodium are likely to be important, especially in anuric patients. Methods: A review of the literature on assessment of fluid status, and on peritoneal removal of water and sodium. Results: MF-BIA added to clinical judgement is helpful for the assessment of fluid status. Natriuretic hormones in patients without heart failure are promising, but their value in clinical practice has not been established yet. Peritoneal ultrafiltration and sodium removal in anuric peritoneal dialysis patients are associated with survival. APD patients have lower sodium removal than CAPD, icodextrin increases it. The value of routine use of low sodium dialysis solutions has not been established. Definite targets on fluid and sodium removal have not been established, but the maintenance of euvalemia, while reducing the exposure to 3.86% glucose solutions at the same time, is largely facilitated by dietary salt and water restrictions. Conclusion: MF-BIA is a useful addition to clinical judgement of hydration status. The use of high dose loop diuretics facilitates water and salt removal in the presence of residual renal function. A dietary salt restriction of 4 g/day in anuric patients improves hypertension and is likely to reduce fluid intake. Copyright © 2006 S. Karger AG, Basel

Dialysis patients often have an expanded effective circulating volume due to an excess of water and salt, especially when they have become anuric. This is likely to be one of the causes of the excess mortality in dialysis patients [1]. Nevertheless most guidelines on adequacy of dialysis have not addressed the issue of achieving and maintaining an optimal fluid status. This review will focus on methods for the assessment of dry body weight and on targets for removal of excess water and sodium in peritoneal dialysis (PD) patients.

Dry Body Weight

Dry body weight in hemodialysis patients has been defined as the weight below which the patient is free of oedema, is normotensive, and without systemic complaints during dialysis [2]. It is often determined as the weight below which a patient becomes hypotensive during dialysis. Dry weight in PD is the weight associated with a normal extracellular volume. Due to the steady state condition in PD, euvalemia is more difficult to determine than in hemodialysis. The issue is not trivial, because an important part of PD patients has hypertension [3] and transfer from PD to hemodialysis has been associated with a decrease in bodyweight and in the number of antihypertensive agents [4]. Also a higher prevalence of overhydration and left ventricular hypertrophy has been found in CAPD patients compared with those on hemodialysis [5]. Furthermore, systolic blood pressure was a significant predictor of death in the Netherlands study on the adequacy of dialysis (NECOSAD) [6]. A careful clinical examination remains the cornerstone for assessment of dry body weight. In addition the assessment can be supported by imaging techniques, biochemical parameters, measurements of total body water and extracellular volume, and bio-impedance. Besides a simple chest X-ray, measurement of the diameter of the inferior cava vein by ultrasound has been advocated. This technique appeared very useful in hemodialysis patients [7], but the value in PD is less obvious [8]. Hypalbuminemia is related to survival in PD [9]. Although multifactorial in origin, part of it is due to overhydration [10]. An increase of extracellular volume leads to an increase of serum natriuretic peptides, produced by the myocardium [11]. These include atrial natriuretic peptide and B-type natriuretic peptide [12]. In CAPD patients levels in between pre and post hemodialysis have been reported [11]. In a random sample from the NECOSAD cohort we found that atrial natriuretic peptide and B-type natriuretic peptide levels above the median were associated with an 8-fold increase in the relative risk of death in PD patients (unpublished). Tracer dilution techniques can be considered to be a reasonable approximation of the gold standard of the quantity of body water and its distribution in the various compartments. Deuterium and tritiated water have been used for total body water measurements, bromide for the extracellular volume (ECV) and labelled red blood cells for the determination of plasma volume. However, these methods are too complex for use in clinical practice. In contrast, multifrequency bioimpedance analysis (MF-BIA) is a non-invasive technique that can be used at the bedside [13]. It allows the determination of dry body weight in hemodialysis patients [14]. Recently the value of MF-BIA was investigated in PD by comparison with total body water by deuterium and ECV by bromide [15]. MF-BIA underestimated total body water with on average 2 l and

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overestimated ECV 2.7 l. Despite excellent correlations between the methods, the limits of agreement showed a wide variation. However, it is likely that MFBIA can be used in longitudinal follow-up of patients. MF-BIA might also be used for establishment of the diagnosis of overhydration. It appeared that an ECV: height ratio of 10.94 l/m in males and 9.13 l/m in females had a sensitivity of 86% and a specificity of 80% to predict hypervolemia [8]. It can be concluded that besides clinical assessment MF-BIA can be a useful addition for the assessment of dry body weight in PD patients. However, it should never be used without taking the results of other investigations into account.

Water and Sodium Removal Targets

Maintenance of euvolemia is the obvious target. The use of high dose loop diuretics in patients with residual renal function facilitates this goal, because it increases renal water and sodium excretion [16]. The contribution of peritoneal ultrafiltration to patients survival was not significant in the CANUSA and NECOSAD cohorts [17, 18], perhaps because a possible effect was overruled by the magnitude of residual renal function. However a significant association was present in a study from Turkey in which it was analyzed as a continuous variable [19]. Also in anuric patients peritoneal ultrafiltration was associated with survival, but only when analyzed as a continuous variable [20]. A specific target could not be given. In the European APD Outcome Study (EAPOS) in anuric PD patients, baseline ultrafiltration ⬍750 ml/day was significantly associated with a lower patient survival, but the effect of ultrafiltration disappeared in the time-dependant analysis [21]. The European Best Practice Guidelines for Peritoneal Dialysis include a target of 1000 ml/day [22]. This was mainly based on the results of the study of Ates et al. [19] in which the quartile with the lowest fluid removal (⬍1265 ml/day) had the poorest survival. It should be stressed however, that the main objective to formulate an ultrafiltration target was to serve as a warning sign, that should be followed by investigations on hydration status and the possibility of ultrafiltration failure. Sodium removal by PD is mainly by convection, because of the (near) equilibrium that is often present between plasma and dialysate sodium concentrations. This explains the correlation between peritoneal ultrafiltration and sodium removal in CAPD patients [22]. Diffusion of sodium contributes to removal, especially in the presence of a high plasma concentration. Already in 1980 Nolph et al. [23] calculated that depending on the dialysate glucose concentration and plasma Na⫹, the amount of sodium removed could range from a kitchen salt equivalent of 4–18 g/day as shown in table 1. It is also dependent on

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Table 1. Dialytic removal of kitchen salt (g/day) on CAPD without UF failure in relation to plasma sodium and dialysis prescription Plasma Na⫹ 130 mmol/l 1.5% ⫻ 4 1.5% ⫻ 2 4.25% ⫻ 2 4.25% ⫻ 4

135 mmol/l

140 mmol/l

4

6

9

8

11

14

12

15

18

From [23].

Table 2. Removal of sodium during 6 h dwells and extrapolation to kitchen salt per day with 3.86% glucose according to peritoneal transport status

Fast Fast average Slow average Slow

Na⫹ (mmol/6 h)

Kitchen salt (g/24 h)

41 70 85 77

10 16 20 18

From [24].

peritoneal transport status, the so called fast transporters having the lowest Na⫹ removal (table 2) [24]. Sodium removal during CAPD averages 170 mmol/day, which is equivalent to 10 g of kitchen salt, but had a very wide range [19, 22]. On a diet containing 8 g of kitchen salt, it was 135 mmol/day, and increased to 179 mmol/day when an additional oral sodium intake of 60 mmol/day was added [25]. None of the above studies described the CAPD prescription with regard to the glucose concentration used, in achieving the 24 h dialysate sodium losses. Peritoneal sodium removal in APD patients is significantly lower than in CAPD because of sodium sieving, which is especially relevant during short dwells. Mean values of 130 mmol/day [19] and 53 mmol/day [21] have been reported. The latter is equivalent to 3 g of kitchen salt. The use of icodextrin,

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which does not cause sodium sieving, for the long dwell in APD patients increased total peritoneal sodium removal with 50 mmol/day [22]. Sodium removal is related to mortality. Kaplan-Meier analysis in CAPD patients showed that 3 year patient survival was 96% in patients with a total sodium removal exceeding 232 mmol/24 h and only 58% in those where it was less than 130 mmol/24 h [19]. Every 10 mmol/24 h sodium removal by dialysis decreased the relative risk of death with 12%. These results are in favour of the development of methods to increase peritoneal sodium removal. The most obvious one is to increase diffusive sodium transport by lowering the dialysate sodium concentration. Single 6 h dwell studies comparing a 2.27% glucose solution with an iso-osmotic solution containing 102 mmol/l of sodium, increased its removal from the body from 21 mmol/6 h to 71 mmol/6 h [26]. A clinical study for 6 weeks in six overhydrated patients using one exchange of a similar low sodium solution with an osmolality of 340 mosmol/kg H2O showed an increase in sodium removal of 131% [27]. It is regrettable that long-term studies in larger patient groups are still not available. Nevertheless, it is likely that APD patients could benefit from dialysis fluids with a sodium concentration between 125 and 130 mmol/l [28]. In the absence of dialysis solutions with a reduced sodium content, the need of recommendations on dietary sodium intake arises. Increasing oral kitchen salt intake in CAPD patients with 60 mmol/day, that means from a mean of 8 g to 11.5 g, for 6 weeks had no effect on body weight, but increased systolic blood pressure [25]. Conversely, reducing salt intake to about 4 g/day in hypertensive CAPD patients led to a normal bloodpressure in 74% of the patients, but decreased residual urine production from 558 to 211 ml/day in those with residual renal function [29]. In addition, it should be realized that salt intake increases thirst and that euvolemia in anuric patients with a large intake of water and salt can only be maintained by the use of 3.86% glucose solutions. These solutions are important in the pathogenesis of acquired ultrafiltration failure [30].

Conclusions

Maintenance of euvolemia is one of the major goals in PD patients. MFBIA can be used in addition to clinical assessment. The use of high dose loop diuretics facilitates water and salt removal in patients with residual renalfunction and can thereby reduce the peritoneal exposure to extremely high glucose concentrations. A dietary sodium restriction of 4 g kitchen salt (68 mmol Na⫹) per day in anuric PD patients improves hypertension and is likely to reduce fluid intake.

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References 1

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3 4 5

6

7 8

9

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11 12 13 14 15 16 17

18

19 20

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? Am J Kidney Dis 1998;32:853–905. Van der Sande FM, Levin NW, Koomen JP, Hoenick NA, Leunissen KML: Intradialystic complications: pathophysiology, prevention and treatments; in Hörl WH, Kock KM, Lindasy RM, Ronco C, Winschester JF (eds): Replacement of Renal Function by Dialysis, ed 5. Dordrecht, Kluwer Academic Publishers 2004, pp 1105–1127. Cocchi R, Esposti ED, Fabhri A, et al: Prevalence of hypertension in patients on peritoneal dialysis: results of an Italien multicenter study. Nephrol Dial Transplant 1999;14:1536–1540. Lameire N, Vanholder RC, Van Loo A, et al: Cardiovascular diseases in peritoneal dialysis patients: the size of the problem. Kidney Int 1996;50(suppl 56):S28–S36. Enia G, Mallamaci F, Benedetto FA, et al: Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than hemodialysis patients. Nephrol Dial Transplant 2001;16:1459–1464. Jager KJ, Merkus MP, Dekker FW, et al: Mortality and technique failure in patients starting chronic peritoneal dialysis: results of the Netherlands cooperative study on the adequacy of dialysis. Kidney Int 1999;55:1476–1485. Kouw PM, Kooman JP, Cheriex EC, Olthof CG, de Vries PM, Leunissen KM: Assessment of postdialysis dry weight: a comparison of techniques. J Am Soc Nephrol 1993;4:98–104. van de Kerkhof J, Hermans M, Beerenhout C, Konings C, van der Sande FM, Kooman JP: Reference values for multifrequency bioimpedance analysis in dialysis patients. Blood Purif 2004;22:301–306. Struijk DG, Krediet RT, Koomen GCM, Boeschoten EW, Arisz L: The effect of serum albumin at the start of continious ambulatory peritoneal dialysis treatment on patiënt survival. Perit Dial Int 1994;14:121–126. Jones CH, Smye SW, Newstead CG, Will EJ, Davison AM: Extracellular fluid volume determined by bioelectric impedance and serum albumin in CAPD patients. Nephrol Dial Transplant 1998;13:393–397. Wolfram G, Sitter T, Grottsman M, Gereer R, Schiff H: Assessment of dry weight in haemodialysis patients by the volume markers ANP and cGMP. Nephrol Dial Transplant 1996;11(suppl 2):528–530. Nakao K, Ogawa Y, Suga S, Imura H: Molecular biology and biochemistry of the natriuretic peptide system. I. natriuretic peptides. J Hypertension 1992;10:907–912. Matthie J, Zarowtiz B, De Lorenzo A, et al: Analytic assessment of the various bioimpedance nethods used to estimate body water. Appl Physiol 1998;84:1801–1816. Katzarski K, Charra B, Laurent G, et al: Multifrequency bioimpedance in assessment of dry water in haemodialysis. Nephrol Dial Transplant 1996;11(suppl 2):S20–S23. Konings CJAM, Kooman JP, Schonk M, et al: Assessment of fluid state in peritoneal dialysis patients. Perit Dial Int 2002;22:683–692. Van Olden RW, Guchelaar H-J, Struijk DG, Krediet RT, Arisz L: Acute effects of high-dose furosemide on residual renal function in CAPD patients. Perit Dial Int 2003;23:339–347. Bargman JM, Thorpe KE, Churchill DN, The CANUSA Peritoneal Dialysis Study Group: Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001;12:2158–2162. Termorshuizen F, Korevaar JC, Dekker FW, van Maanen JG, Boeschoten EW, Krediet RT, The NECOSAD Study Group: The relative importance of residual renal function compared with peritoneal clearance for patient survival and quality of life: an analysis of the Netherlands cooperative study on the adequacy of dialysis (NECOSAD)-2. Am J kidney Dis 2003;41:1293–1302. Ates K, Nergizoglu G, Keven K, et al: Effect of fluid and sodium removal on mortality in peritoneal dialysis patients. Kidney Int 2001;60:767–776. Jansen MAM, Termorshuizen F, Korevaar JC, Dekker FW, Boeschoten EW, Krediet RT, The NECOSAD Study Group. Predictors of survival in anuric peritoneal dialysis patients. Kidney Int 2005;68:1199–1205.

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22 23 24 25

26 27 28 29 30

Brown EA, Davies SJ, Ruttersford P, et al: Survival of functionally anuric patients on automated peritoneal dialysis. The EUROPEAN APD Outcome Study. J Am Soc Nephrol 2003;14: 2948–1205. Rodriguez EA, Carmona A, Fontan MF: Sodium removal in patients undergoing CAPD and automated peritoneal dialysis. Perit Dial Int 2002;22:705–713. Nolph KD, Sorkin MI, Moore H: Autoregulation of sodium and potassium removal during continuous ambulatory peritoneal dialysis. Trans Am Soc Artif Intern Organs 1980;26:334–338. Wang T, Waniewski J, Heimbürger O, Werynski A, Lindholm B: A quantitative analysis of sodium transport and removal during peritoneal dialysis. Kidney Int 1997;52:1609–1616. Fine A, Foataine B, Madge MA: Commonly prescribed salt intake in continuous ambulatory peritoneal dialysis patients is too restrictive: results of a double-blind crossover study. J Am Soc Nephrol 1997;8:1311–1314. Imholz ALT, Koomen GCM, Struijk DG, Arisz L, Krediet RT: Fluid and solute transport in CAPD patients using ultralow sodium dialysate. Kidney Int 1994;46:333–340. Nakayama M, Yokoyama K, Kubo H, et al: The effect of ultra-low sodium dialysate in CAPD. A kinetic and clinical analysis. Clin Nephrol 1996;45:188–193. Struijk DG, Krediet RT: Sodium balance in automated peritoneal dialysis. Perit Dial Int 2000;20 (suppl 2):S101–S105. Günal AI, Duman S, Özkakya M, et al: Strict volume control normalizes hypertension in peritoneal dialysis patients. Am J Kidney Dis 2001;37:588–593. Davies SJ, Phillips L, Naish PF, Russel GI: Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol 2001;12:1046–1051.

Prof. Dr. Raymond T. Krediet, MD, PhD Division of Nephrology, Department of Medicine Room F4 – 215, Academic Medical Center University of Amsterdam, PO Box 22660 NL–1100 DD Amsterdam (The Netherlands) Tel. ⫹31 20 566 5990, Fax ⫹31 20 691 4904 E-Mail [email protected]

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Is There a Competition Between Urine Volume and Peritoneal Ultrafiltration in Peritoneal Dialysis Patients? Jeroen P. Kooman a, Nynke Cnossenb, Constantijn J. Konings b, Frank M. van der Sande a, Karel M. Leunissen a a

Department of Internal Medicine, University Hospital Maastricht, Maastricht, Catharina Hospital Eindhoven, Eindhoven, The Netherlands

b

Abstract Many peritoneal dialysis patients are overhydrated. Overhydration may lead to hypertension and left ventricular hypertrophy, and may be related to inflammation and malnutrition. The presence of overhydration is not always detected by clinical examination. Especially patients with peritoneal ultrafiltration failure and/or negligible residual renal function are prone to overhydration. Treatment consists of a combination of sodium and fluid restriction, in combination with increased peritoneal ultrafiltration and loop diuretics in patients with residual diuresis. Peritoneal ultrafiltration can be enhanced by the use of hypertonic glucose solutions or icodextrin. In some, but not all, studies, residual renal function or diuresis declined with an increase in peritoneal ultrafiltration. At least in a subset of patients, underhydration might have played a role in this phenomenon. We propose to treat overhydration using both clinical criteria and objective techniques such as vena cava echography or bioimpedance measurements. Copyright © 2006 S. Karger AG, Basel

The Problem of Overhydration in Peritoneal Dialysis

Interest for problems in fluid homeostasis in peritoneal dialysis (PD) patients has re-emerged in the past years [1]. Among others, this is due to recent observational trials such as CANUSA [2] and EAPOS [3], in which respectively residual diuresis and peritoneal ultrafiltration were important predictors of mortality. Recently, Ates et al. [4] showed a significant inverse relation between total fluid and sodium removal, as well as urine output and 3-years mortality.

These data do not provide full proof that overhydration per se is responsible for the increased mortality, as malnutrition may lead to low fluid intake and subsequently low fluid removal [1, 5]. However, recent data in hemodialysis (HD) patients suggested a link between overhydration and mortality. Chertow and coworkers [6] observed a relation between shorter predialysis bioimpedance vectors, indicating an increased ratio between extracellular and intracellular water [7], and mortality in 3,009 hemodialysis (HD) patients. However, although the relation between abnormalities in fluid state and mortality is still based on circumstantial evidence, it is beyond doubt that overhydration plays a key role in the pathogenesis of hypertension and left ventricular hypertrophy (LVH) in PD patients [8–13]. The importance of overhydration in the pathogenesis of hypertension of end-stage renal disease was already acknowledged more than 40 years ago [14, 15]. Overhydration also appears to be related to inflammation and malnutrition, although the pathophysiologic mechanisms behind this relation remain to be studied [16–18]. Lastly, overhydration also is a risk factor for technique survival in PD patients [19].

Prevalence of Overhydration in PD Patients

Although data on the prevalence of overhydration in PD are limited, one study observed an elevation of pulmonary artery pressure above 25 mm Hg in 36% of PD patients [20]. In agreement, we observed an expansion of extracellular volume (ECV) in more than one than third of stable PD patients [11]. Moreover, a large survey showed that the great majority of PD patients needed antihypertensive medication for blood pressure control [21]. Plum et al. [22] found a comparable ECV in PD patients and HD patients before dialysis, whereas ECV was significantly higher compared to controls. Enia et al. [23] showed a higher prevalence of hypertension and LVH in long-term PD patients compared to HD patients. However, it should be noted that all these studies were performed before the widespread introduction of icodextrin. Moreover, regarding the comparison of PD and HD patients, differences in case mix play a role. Also, in long-term PD patients treated with strict attention for volume control, blood pressure control and left ventricular mass were comparable with HD patients [24].

Diagnosis of Overhydration

Whereas increased central venous pressure and (pulmonary) edema are clear indicators of overhydration, the absence of these clinical parameters does not mean that patients are not fluid expanded [25]. Hypertension is of course an

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important marker of, but not synonymous to overhydration. Also, office blood pressures are not always representative for 24-h blood pressure measurements [11]. Despite a significant difference in ECV between normotensive and hypertensive dialysis patients, also a wide overlap in ECV was observed between both groups [26]. Thus, normotensive patients may be overhydrated and a (small) percentage, of hypertensive patients may be normovolemic. Though, although no method as yet can be considered a gold standard, the use of objective techniques, such as vena cava echography or bioimpedance measurements may aid in assessing fluid state in dialysis patients [27, 28]. Recently, we showed that using strict clinical criteria including ambulatory blood pressure measurements, overhydration could be detected by multifrequency bioimpedance measurements with a sensitivity of 86% and a specificity of 80% [29]. Causes of Overhydration

Overhydration represents a misbalance between fluid intake and output. Regarding output, at the start of PD, the presence of residual diuresis will in general be able to prevent overhydration. Moreover, in the absence of peritoneal membrane failure, adequate ultrafiltration will generally be easy to achieve. However, in the course of dialysis treatment, residual renal function will often decline which may lead to overhydration if not compensated by a reduction in sodium and fluid intake or an increase in peritoneal ultrafiltration. Indeed, ECV was significantly and inversely related to residual renal function in PD patients [16]. The same holds true for LVH [30]. Regarding peritoneal ultrafiltration, especially in long-term PD patients ultrafiltration capacity of the peritoneal membrane may decline, possibly because of long-term glucose exposure [31]. We observed a significant relation between the D/P creatinine ratio and the change in ECV over a 4 months period [16]. In agreement, Asghar et al. [32] showed a higher peritoneal solute transport status in overhydrated patients. With regard to fluid intake, especially in peritoneal dialysis patients with decreasing urinary volume, attention for sodium and fluid restriction may be insufficient [33], despite the recommendations of the ad hoc committee of the International Society of peritoneal dialysis [34]. However, data on this subject are still limited [35]. Treatment of Overhydration

With volume and sodium restriction, Tang et al. [35] were able to improve fluid state in incident PD patients without the use of high glucose concentrations

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in the dialysate. Moreover, with the sole use of sodium and fluid restriction, Gunal et al. [10] were able to improve blood pressure control in a significant percentage of their study population. Urinary sodium and water removal can be increased with the use of loop diuretics [34, 36]. The use of higher peritoneal glucose concentrations by Gunal et al. [10] resulted in an impressive improvement of blood pressure control and a reduction in cardiothoracic ratio. However, long-term use of hypertonic glucose solutions may have detrimental effects on the peritoneal membrane, an effect which may be less pronounced with the use of the glucose polymer icodextrin [31]. Various studies showed an improvement in volume state with the use of the icodextrin 7.5% for the long dwell [37–39]. Also, a reduction in LVH was observed in one study [39]. However, data on blood pressure control of icodextrin 7.5% are somewhat controversial. Whereas Woodrow et al. [37] found an improvement in blood pressure control with the use of icodextrin, this was not confirmed in the randomised studies by Davies et al. [38] and Konings et al. [39]. It has been speculated that due to the oncotic effect of icodextrin metabolites which enter the systemic circulation [40], blood volume might have remained relatively stable in icodextrin treated patients despite a decrease in ECV [41]. This may be supported by the fact that atrial natriuretic peptide, a surrogate marker of intravascular fluid status, did not decline in icodextrin treated patients in the study of Davies et al., whereas it decreased in patients treated with standard glucose solutions. However, this hypothesis would appear to be in contradiction with the reduction in left ventricular mass observed by Konings et al. [37].

Effect of Treatment of Overhydration by Increasing Peritoneal Ultrafiltration on Residual Renal Function and Diuresis

In the study by Gunal et al. [10], residual renal function and diuresis declined to a highly significant degree when peritoneal ultrafiltration was increased with the use of hypertonic glucose solutions. Also a decline in residual renal function was observed with the use of icodextrin 7.5% in the study by Konings et al. [37]. In contrast, despite an increase in peritoneal ultrafiltration, three other studies did not find adverse effect on residual renal function with the use of icodextrin 7.5% [37, 42, 43]. Differences in patient characteristics and the magnitude of changes in fluid status may partly account for differences between the studies. For example, baseline residual glomerular filtration rate in the study by Konings et al. [37] was much higher compared to the patient groups studied by Davies et al. [38] and Plum et al. [42]. Excessive peritoneal ultrafiltration may have played a causative role in the decline in residual renal function studied by

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Konings et al. [44], as patients who showed the largest the decline in residual renal function were shown to be dehydrated. In contrast, patients included in the studies by Davies et al. [38] and Plum et al. [42] were probably more overhydrated at the start of the study, due to the lower residual renal function and/or peritoneal membrane failure. Thus, the use of icodextrin less likely resulted in dehydration in these studies. With regard to the study of Gunal et al. [10], the combination of sodium and fluid restriction, together with an increase in peritoneal ultrafiltration, resulted in a decline in body weight of ⫾4 kg [10]. Although the authors did not assess fluid status was not assessed in detail, it is not unlikely that several of their patients might have been dehydrated at the completion of the study.

Can a Decline in Renal Function with Strict Volume Control be Prevented?

It was postulated by Gunal et al. [45] that the preservation of residual renal function largely depends on the presence of overhydration, which could be explained through the concept of pressure natriuresis. Given the impressive improvements in both blood pressure and LVH in their studies which was achieved with strict fluid control, these authors suggest that even a large decline in residual renal function with the improvement of fluid state should be accepted [45]. However, given the strong relation between residual renal function and outcome, we believe that a more judicious approach might be warranted. As discussed above, it his likely that, if severe dehydration is prevented, residual renal function does not necessarily decline with an improvement in fluid state. At present, it would appear defendable to set and regularly check dry weight in PD by strict clinical criteria, preferably with the aid of objective techniques [28, 29, 46]. In a randomised study in HD patients, a reduction in left ventricular mass was observed when dry weight was assessed with the aid of vena echography compared to the sole use of clinical criteria [46]. Whether the use of icodextrin results in a better preservation of renal function compared to hypertonic glucose solutions remains to be studied. However, the potentially different effects of icodextrin on intravascular volume compared to hypertonic glucose solutions is not necessarily advantageous, given the strong relation between plasma volume, blood pressure and LVH [11, 36]. Future studies should be performed to compare the effects of icodextrin and hypertonic glucose on intravascular volume and decline in residual renal function. Moreover, it should be studied whether the use of objective techniques or the assessment of dry weight in PD patients is able to improve blood pressure control and LVH without negative effects on residual renal function.

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Cocchi R, Esposti ED, Fabbri A, Lucatello A, Sturani A, Quarello F, Boero R, Bruno M, Dadone C, Favazza A, Scanziani R, Tommasi A, Giangrande A: Prevalence of hypertension in patients on peritoneal dialysis: results of an Italian multicentre study. Nephrol Dial Transplant 1999;14: 1536–1540. Plum J, Schoenicke G, Kleophas W, Kulas W, Steffens F, Azem A, Grabensee B: Comparison of body fluid distribution between chronic haemodialysis and peritoneal dialysis patients as assessed by biophysical and biochemical methods. Nephrol Dial Transplant 2001;16:2378–2385. Enia G, Mallamaci F, Benedetto FA, Panuccio V, Parlongo S, Cutrupi S, Giacone G, Cottini E, Tripepi G, Malatino LS, Zoccali C: Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than haemodialysis patients. Nephrol Dial Transplant 2001;16:1459–1464. Gunal AI, Ilkay E, Kirciman E, Karaca I, Dogukan A, Celiker H: Blood pressure control and left ventricular hypertrophy in long-term CAPD and hemodialysis patients: a cross-sectional study. Perit Dial Int 2003;23:563–567. Wizemann V, Schilling M: Dilemma of assessing volume state–the use and the limitations of a clinical score. Nephrol Dial Transplant 1995;10:2114–2117. Katzarski KS, Charra B, Luik AJ, Nisell J, Divino Filho JC, Leypoldt JK, Leunissen KM, Laurent G, Bergström J: Fluid state and blood pressure control in patients treated with long and short haemodialysis. Nephrol Dial Transplant 1999;14:369–375. Katzarski KS, Nisell J, Randmaa I, Danielsson A, Freyschuss U, Bergström J: A critical evaluation of ultrasound measurement of inferior vena cava diameter in assessing dry weight in normotensive and hypertensive hemodialysis patients. Am J Kidney Dis 1997;30:459–465. Kouw PM, Kooman JP, Cheriex EC, Olthof CG, de Vries PM, Leunissen KM: Assessment of postdialysis dry weight: a comparison of techniques. J Am Soc Nephrol 1993;4:98–104. van de Kerkhof J, Hermans M, Beerenhout C, Konings C, van der Sande FM, Kooman JP: Reference values for multifrequency bioimpedance analysis in dialysis patients. Blood Purif 2004;22:301–306. Wang AY, Wang M, Woo J, Law MC, Chow KM, Li PK, Lui SF, Sanderson JE: A novel association between residual renal function and left ventricular hypertrophy in peritoneal dialysis patients. Kidney Int 2002;62:639–647. Davies SJ, Brown EA, Frandsen NE, Rodrigues AS, Rodriguez-Carmona A, Vychytil A, Macnamara E, Ekstrand A, Tranaeus A, Filho JC, EAPOS Group: Longitudinal membrane function in functionally anuric patients treated with APD: data from EAPOS on the effects of glucose and icodextrin prescription. Kidney Int 2005;67:1609–1615. Asghar RB, Green S, Engel B, Davies SJ: Relationship of demographic, dietary, and clinical factors to the hydration status of patients on peritoneal dialysis. Perit Dial Int 2004;24:231–239. Fine A, Fontaine B, Ma M: Commonly prescribed salt intake in continuous ambulatory peritoneal dialysis patients is too restrictive: results of a double-blind crossover study. J Am Soc Nephrol 1997;8:1311–1314. Mujais S, Nolph K, Gokal R, Blake P, Burkart J, Coles G, Kawaguchi Y, Kawanishi H, Korbet S, Krediet R, Lindholm B, Oreopoulos D, Rippe B, Selgas R: Evaluation and management of ultrafiltration problems in peritoneal dialysis. International Society for Peritoneal Dialysis Ad Hoc Committee on Ultrafiltration Management in Peritoneal Dialysis. Perit Dial Int 2000;20(suppl 4): S5–S21. Tang W, Cheng LT, Wang T: Diabetic patients can do as well on peritoneal dialysis as nondiabetic patients. Blood Purif 2005;23:330–337. Konings CJ, Kooman JP, van der Sande FM, Leunissen KM: Fluid status in peritoneal dialysis: what’s new? Perit Dial Int 2003;23:284–290. Konings CJ, Kooman JP, Schonck M, Gladziwa U, Wirtz J, van den Wall Bake AW, Gerlag PG, Hoorntje SJ, Wolters J, van der Sande FM, Leunissen KM: Effect of icodextrin on volume status, blood pressure and echocardiographic parameters: a randomized study. Kidney Int 2003;63: 1556–1563. Davies SJ, Woodrow G, Donovan K, Plum J, Williams P, Johansson AC, Bosselmann HP, Heimbürger O, Simonsen O, Davenport A, Tranaeus A, Divino Filho JC: Icodextrin improves the

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Jeroen P. Kooman Department of Internal Medicine, University Hospital Maastricht PO Box 5800 NL–6202 AZ Maastricht (The Netherlands) Tel. ⫹31 43 3875007, Fax ⫹31 43 3875006, E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 119–128

Application of Bioimpedance Techniques to Peritoneal Dialysis F. Zhu, G. Wystrychowski, T. Kitzler, S. Thijssen, P. Kotanko, N.W. Levin Renal Research Institute, New York, N.Y., USA

Abstract Peritoneal dialysis (PD) has been used as a home dialysis therapy for renal replacement for more than 30 years. In a recent assessment of treatment quality, the mortality of patients on PD was referenced as being higher than of those on hemodialysis. Several reports suggest that a high proportion of PD patients are overhydrated. Clinical assessment of dry weight in PD patients is difficult and further complicated by the paucity of signs and symptoms indicative of dehydration (such as intradialytic hypotension or muscle cramps). Monitoring tools used for fluid status estimation during hemodialysis, e.g. online blood volume and blood pressure measurement, are not readily available in PD patients. Bioimpedance analysis technique has been considered as a potential tool to measure body fluid non-invasively, inexpensively and simply. Although Bioimpedance analysis has been used in clinical studies for more than 20 years, the knowledge of the electrical properties of body tissues is still evolving. In this review we aim to clarify the principles of different bioimpedance techniques and to introduce their applications in PD patients. Copyright © 2006 S. Karger AG, Basel

Peritoneal dialysis (PD) has been used as a home dialysis therapy for renal replacement for more than 30 years. In a recent assessment of treatment quality, the mortality of patients on PD was referenced as being higher than of those on hemodialysis [1]. The relationships between the parameters of PD and individual physiological mechanisms are not entirely clear, and many reports suggest that a high proportion of PD patients are overhydrated [2, 3]. Clinical assessment of dry weight is a difficult task, further complicated in PD patients by the lack of treatment associated signs indicative of dehydration as may be observed in HD patients, such as intradialytic hypotension or cramps. Useful monitoring tools for fluid status estimation during hemodialysis, e.g. online blood volume and blood pressure measurement, are not available for application in PD patients.

Bioimpedance analysis (BIA) technique has been considered as a potential tool to measure body fluid noninvasively, inexpensively and simply [4, 5]. The number of publications reporting the use of bioimpedance to measure body fluid for assessment of hydration state is increasing [6–8]. Although BIA has been used in clinical studies for more than 20 years, the knowledge of the electrical properties of body tissues is still evolving [4, 9, 10]. At the current stage, the bioimpedance techniques can be classified according to: (1) the method of measurement, and (2) the method of analysis. This paper makes an effort to clarify the principles of different bioimpedance techniques and to introduce their applications in PD patients.

The Basic Concept of BIA

Bioimpedance is a noninvasive method used to obtain information concerning the body composition. A standard method of bioimpedance measurement employs four electrodes, which are placed on the skin surface. Two electrodes are used to inject a single or multifrequency electrical current, and the other two electrodes are used to measure the fall in potential between them. The resistance and reactance can then be calculated by the amperage and frequency of the current, and the measured drop in potential. The resistance value reflects the fluid volume, and the reactance value is related to the properties of the cell membranes. This information is used to estimate body composition parameters, such as extracellular fluid volume (ECV), intracellular fluid volume (ICV), and total body water (TBW). In addition, there is increasing interest in applying BIA to measure body muscle and fat mass.

Measurement Methods

Standard bioimpedance techniques can be classified into two different approaches: Wrist to ankle or so called whole body bioimpedance analysis (WBIA), and segmental bioimpedance analysis (SBIA) [11–13]. Figure 1a shows the WBIA electrode placement. The two measuring electrodes are placed on the wrist and ankle, respectively, and the injecting electrodes are placed about 2 in distally from the measuring electrodes. A basic assumption of WBIA is that the sum of the arm, trunk and leg volumes can be modeled as a cylinder with uniform conductivity. This methodology has been used for many years due to its advantages of simple operation and availability of suitable devices. However, the accuracy of this method can be questioned due to the fact that in WBIA the arm and leg contribute up to almost 90% of the total resistance, which leads to

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V

RA

Rwb

I

I V

V

RT Trunk

W

B

V I VECV kECV

kECV

( ) 2

L W

(

RL

2/3

)

1/3

VECV 2VA 2VL KVT

a

SBIA

b

S1

S3

V

VPC

V I1

S2

S4

I c

Leg

A

RE

K2B 2ECV 1 1,000 B

Arm

I2

Fig. 1. Measurement of whole body and segmental bioimpedance. I represents injecting current, V represents measuring voltage.

underestimation of fluid changes in the trunk by this method. The estimation of trunk fluid volume is further complicated by the inhomogeneity of the electrical current distribution in this segment. This may particularly be a problem in subjects with abnormal body fluid distribution, such as end-stage renal disease patients. To overcome this problem, SBIA measurements were proposed more than 10 years ago to measure the arm, trunk, and leg segments separately [12–14]. Figure 1b, c show examples of segmental measurements. SBIA satisfies the basic physical principle of a homogeneous distribution of resistance in each segment. Hence, their fluid volumes may be assessed more accurately. SBIA may be applied to any segment of the body. For example, to measure dynamic

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changes in fluid volume in the peritoneal cavity during dialysis, the lower trunk segment can be chosen (fig. 1c). With this method, ultrafiltration volume can be monitored, e.g. during continuous flow dialysis. However, the major disadvantage of SBIA is the complex placement of electrodes and, at present, the unavailability of a suitable commercial device.

Single or Multiple Frequencies

Two standard BIA methods can be distinguished by current frequency: (1) single frequency BIA, usually using 50 kHz, and (2) multifrequency BIA, providing a range of frequencies from 5 to 1,000 kHz. This paper will not discuss these two methods in detail. However, the knowledge of differences between them in terms of underlying principles of physics is vital for choosing the appropriate BIA method. Single frequency BIA was used in the early stages of the development of the technology. Using a 50 kHz alternating current a maximal value for reactance can be observed in most healthy subjects [15, 16]. This suggested that 50 kHz current is more sensitive for assessment of body tissue composition than any other frequency [17]. However, this sensitivity could influence the estimation of fluid volume when fat mass varies widely [18, 19]. With multifrequency BIA, also referred to as bioimpedance spectroscopy, data of resistance (R), reactance (Xc), impedance, and phase angle are measured at multiple frequencies. Subsequently, extracellular (RE) and intracellular (RI) resistance can be calculated applying the Cole–Cole model (fig. 2) [20].

Method of Analysis

Fluid Volume Estimation ECV and ICV estimations are the first step to analyze the body hydration state. Many equations have been published to calculate the ECV and ICV. In general, these calculations can be divided into two approaches: (1) Regression functions based on experimental data of bioimpedance, additionally using parameters such as age, gender, and weight as predictors. These functions are mostly used to calculate the fluid volume from the resistance at 50 kHz, and the parameters of individual physical characteristics might be useful to reduce the variation incurred by different body compositions [10, 15]. (2) A theoretical model utilizing a series of equations based on the knowledge of extra- and intracellular volume space distribution. This method, in general, is now being applied to multiple frequency BIA [11, 21].

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C RE XC RI

R

a

b

RH

R

RL

Fig. 2. a Shows the equivalent electrical circuit model, RE represents extracellular resistance, RI represents intracellular resistance, and C represents capacitance of cell membrane. b Shows the R–Xc graph with different frequency, RL and RH represent the resistance at lowest and highest frequency current, respectively.

Hydration Indicator It is clear that hydration status cannot adequately be inferred from absolute body fluid volume alone, as absolute body water to a large extent depends on body height, weight, and composition. A useful hydration indicator should exhibit little scatter in healthy subjects and be only marginally affected by variations in body fat and muscle mass. One approach to partially overcome this problem is by using ratios of fluid compartments as indicators of hydration status. The ratio of ECV to TBW has been proposed [22, 23]. It was suggested that by using the ECV/TBW ratio the insensitivity of BIA to fluid in the trunk may be compensated. In practice, however, standard deviation of this ratio is so large that its use is impracticable. Ratios used by other groups include ECV/body weight (BW) [24–26], ECV/body height [26–28], ECV/body surface area [29], ECV/ICV [23, 28] and ECV/lean body mass (LBM) [24]. ECV/body height was found to have higher sensitivity in detecting hypervolemia in PD patients than ECV/body weight or ECV/TBW [26]. 50 kHz bioimpedance Vector Analysis In this method (also R–Xc graph method), the impedance vector, defined by phase angle, 50 kHz resistance (an indicator of body fluid), and 50 kHz reactance (an indicator of body cell mass) reflects both hydration and nutritional

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Xc/H

Ellipses represent tolerance of hydration (%)

Xc1/H1

tg1 (Xc1/R1) R/H 0

R1/H1

Fig. 3. Bioimpedance vector method, R, Xc represent resistance and reactance in ohm; H represent the height of the patient. Phase angle () is tangent ratio of Xc to R.

status. This vector, normalized to body height, is plotted in a diagram containing the range obtained in a healthy population (fig. 3) [30–32].

Application of BIA to PD Patients

Methodology of the main studies regarding the use of BIA in PD patients is summarized in table 1. Mendley et al. [18] calculated Kt/Vurea in pediatric PD patients utilizing TBW estimated by single frequency WBIA (among other methods) as urea distribution volume. Beside WBIA, TBW was assessed by DEXA and derived from anthropometric equations, and compared to the gold standard method of 2 H2O dilution. Single frequency BIA with subsequent calculation of TBW using the equation by Kushner et al. [10] provided a useful estimate of TBW (mean difference compared to deuterium dilution: 0.33 1.44 l; 95% CI: 0.93–0.26; a RMSE of 1.45 l). Lindley et al. used bioimpedance-spectroscopy to assess body fluid status in 31 PD patients and 199 normal subjects. For each patient, a hydration score was calculated according to Lopot’s method, i.e. the number of standard deviations the ECW/TBW ratio was from the mean for the normal age- and gendermatched controls [33]. In the 31 PD patients the mean hydration score was significantly higher (1.3 vs. 0.0, p 0.0001) as compared to the healthy controls. Thirty-five percent had a hydration score higher than 2.0, compared with only 2.5% of the controls. The difference between the ECW and TBW

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Table 1. Bioimpedance studies in peritoneal dialysis patients Author

Study population

Frequency (kHz)

Method

BIA parameter

Dumler [16] Mendley et al. [18] Lindley et al. [33] Edefonti et al. [35] Plum et al. [29]

38 PD; 104 HD 14 PD 31 PD; 199 controls 7 PD 43 PD; 39 HD; 22 controls 59 PD

50 50 5–1,000 50 5–500

WBIA WBIA WBIA WBIA WBIA

5–500

WBIA

Domoto et al. [23]

7 female PD; 6 female controls

5–1,000

WBIA

Asghar et al. [22]

71 PD (full data only on 68) 40 PD (SBIA in 23 only) 37 PD

50

WBIA

5–500 50 and 5–500

WBIA; SBIA WBIA

5–500

WBIA

5–500

WBIA

ECV; ICV; TBW TBW ECV/TBW Phase angle; distance ECV/TBW; ECV/BSA; TBW/BSA ECV/TBW; ECV/BW; ECV/LBM ECV/ICV; ECV/TBW; ECV/BW; TBW/BW; ICV/BW; membrane capacitance Phase angle; ICV; TBW; ECV/TBW ECV; TBW; ECV/BW; TBW/BW Phase angle; ICV; ECV/height ECV/TBW; ECV/BW; ECV/height ECV/height; ICV/height; ECV/ICV

Jones et al. [24]

Konings et al. [25] van de Kerkhof et al. [27] van de Kerkhof et al. [26] Wang et al. [28]

48 PD; 42 HD; 20 controls 100 PD; 60 controls

BSA Body surface area; BW body weight; ECV extracellular volume; HD Hemodialysis; ICV intracellular volume; LBM lean body mass; PD peritoneal dialysis; SBIA segmental bioimpedance analysis; TBW total body water; WBIA whole body bioimpedance analysis.

ratio measured with the peritoneal cavity filled or drained was not significant (0.2 0.4%). Wang et al. [28] showed the relationship between blood pressure control and fluid status in peritoneal dialysis patients. Hundred PD patients (52 females) were divided into 3 groups: (1) normotensive – BP 130/80 mm Hg; (2) controlled hypertension with antihypertensive medication; (3) uncontrolled hypertension despite antihypertensive medication; 60 healthy subjects (25 females) served as a control group. ICV normalized for body height was significantly lower, and ECV/ICV was significantly higher in any group of PD patients compared to healthy controls. ECV normalized for height was significantly higher for patients in group 3 (uncontrolled hypertension) compared to those in group

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1 (normotension). ECV normalized for height correlated positively with SBP (r 0.42, p 0.01) and DBP (r 0.39, p 0.01). In 40 PD patients, Konings et al. [25] determined TBW and ECV by means of deuterium (2H2O) and sodium bromide (NaBr) dilution, respectively. This was then compared to TBW and ECV assessed by WBIA, to ECV measured by SBIA, and to TBW calculated by the anthropometric Watson formula. WBIA had no advantage over the Watson formula in the assessment of TBW. In addition, SBIA had no superiority over WBIA in assessing ECV. Zhu et al. [34] revealed the higher sensitivity of SBIA in detecting fluid changes in the peritoneal cavity as compared to WBIA. Edefonti et al. [35] studied the influence of the initiation of PD on the BIA parameters R, Xc, phase angle (PA), and distance (D) in an unselected cohort of children with advanced chronic kidney disease (CKD). Seven children (4 males; mean age: 8.15 4.22 years; 3 females; mean age: 7.46 3.95 years) with a residual creatinine clearance of about 5 ml/min/1.73 m2 were studied. PA and D are both indicators of nutritional status and are calculated as follows: PA arctan (Xc/R) 180/ , and D PA (10 Xc)/兹2. The mean values for Xc, PA, and D in children with CKD before initiation of PD were significantly lower when compared to the mean values of normal controls. The values significantly improved after 6 months of dialysis but remained, on average, lower than those of healthy children.

Summary of BIA Study in PD

Although there is rapid development of suitable devices for performing BIA measurements recently, the accuracy and reproducibility still have to be further improved in order for this method to be applied in routine clinical assessment of fluid status in PD patients. The ratio of whole body ECV to TBW might have the potential ability to provide hydration information for PD patients. However, TBW as assessed by BIA is the sum of ECV and ICV, and the accuracy of its estimation is largely limited by the low accuracy of ICV assessment compared to ECV measurement. This is because ICV estimation depends on differences in individual body composition. Single frequency 50 kHz BIA is based on an empirical method, the accuracy of which depends on the specific physical characteristics of the subjects studied, so that it cannot be applied to a large number of subjects. Multifrequency WBIA relies on a theoretical model; however, the possibility of further improvement in accuracy is limited by the inhomogeneous current density in the trunk. SBIA was proposed to overcome this disadvantage of WBIA in that the trunk could be

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separately measured. However, the absolute volume was found to be underestimated with this method. Recently, Zhu et al. [36] reported that this error of SBIA method was due to the use of an inappropriate resistivity coefficient. Finally, estimation of the hydration status of peritoneal dialysis patients could be performed using a similar principle as that used in hemodialysis, namely the continuous ultrafiltration accompanied by measurement of resistance in the calf. This might be possible in PD with continuous therapy. The end point would be stability of the resistance during fluid removal. Combination of BIA with a population adjusted measure of resistivity to confirm resistance stability might provide a more precise measure of hydration than is currently available.

References 1 2 3 4 5 6 7

8 9 10 11 12 13 14 15 16 17

Jaar BG, et al: Comparing the risk for death with peritoneal dialysis and hemodialysis in a national cohort of patients with chronic kidney disease. Ann Intern Med 2005;143:174–183. Konings CJ, et al: Fluid status, blood pressure, and cardiovascular abnormalities in patients on peritoneal dialysis. Perit Dial Int 2002;22:477–487. Oe B, et al: Hemodialysis (HD) versus peritoneal dialysis (PD): latent overhydration in PD patients? Int J Artif Organs 2002;25:838–843. Kushner RF: Bioelectrical impedance analysis: a review of principles and applications. J Am Coll Nutr 1992;11:199–209. Nyboer J: Electrical Impedance Plethysmography 1970. Morgenstern B, et al: Impact of total body water errors on Kt/V estimates in children on peritoneal dialysis. Adv Perit Dial 2001;17:260–263. Schmidt RJ, Dumler F: Bioelectrical impedance analysis: a promising predictive tool for nutritional assessment in continuous ambulatory peritoneal dialysis patients. Perit Dial Int 1993;13: 250–255. Wuhl E, et al: Assessment of total body water in paediatric patients on dialysis. Nephrol Dial Transplant 1996;11:75–80. Foster KR, Lukaski HC, Whole-body impedance – what does it measure? Am J Clin Nutr 1996; 64(suppl 3):388S–396S. Kushner RF, et al: Is the impedance index (ht2/R) significant in predicting total body water? Am J Clin Nutr 1992;56:835–839. De Lorenzo A, et al: Predicting body cell mass with bioimpedance by using theoretical methods: a technological review. J Appl Physiol 1997;82:1542–1558. Miyatani M, et al: Validity of estimating limb muscle volume by bioelectrical impedance. J Appl Physiol 2001;91:386–394. Organ LW, et al: Segmental bioelectrical impedance analysis: theory and application of a new technique. J Appl Physiol 1994;77:98–112. Bracco D, et al: Segmental body composition assessed by bioelectrical impedance analysis and DEXA in humans. J Appl Physiol 1996;81:2580–2587. Chertow GM, et al: Nutritional assessment with bioelectrical impedance analysis in maintenance hemodialysis patients. J Am Soc Nephrol 1995;6:75–81. Dumler F: Use of bioelectric impedance analysis and dual-energy X-ray absorptiometry for monitoring the nutritional status of dialysis patients. ASAIO J 1997;43:256–260. Piccoli A, et al: Equivalence of information from single versus multiple frequency bioimpedance vector analysis in hemodialysis. Kidney Int 2005;67:301–313.

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18 19 20 21 22 23 24 25 26 27 28 29

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Mendley SR, Majkowski NL, Schoeller DA: Validation of estimates of total body water in pediatric dialysis patients by deuterium dilution. Kidney Int 2005;67:2056–2062. Scharfetter H, et al: Assessing abdominal fatness with local bioimpedance analysis: basics and experimental findings. Int J Obes Relat Metab Disord 2001;25:502–511. Cole K, Cole R: Dispersio and absorption in dielectrics. I. Alternating current characteristics. J Chem Phys 1941:341–351. Matthie JR: Second generation mixture theory equation for estimating intracellular water using bioimpedance spectroscopy. J Appl Physiol 2005;99:780–781. Asghar RB, et al: Relationship of demographic, dietary, and clinical factors to the hydration status of patients on peritoneal dialysis. Perit Dial Int 2004;24:231–239. Domoto DT, Weindel ME: Bioimpedance analysis of fluid compartments in female CAPD patients. Adv Perit Dial 1998;14:220–222. Jones CH, et al: Extracellular fluid volume determined by bioelectric impedance and serum albumin in CAPD patients. Nephrol Dial Transplant 1998;13:393–397. Konings CJ, et al: Assessment of fluid status in peritoneal dialysis patients. Perit Dial Int 2002;22:683–692. van de Kerkhof J, et al: Reference values for multifrequency bioimpedance analysis in dialysis patients. Blood Purif 2004;22:301–306. van de Kerkhof J, et al: Bioimpedance analysis and assessment of intracellular water in peritoneal dialysis patients. Perit Dial Int 2003;23:591–593. Wang X, et al: Volume status and blood pressure in continuous ambulatory peritoneal dialysis patients. Blood Purif 2005;23:373–378. Plum J, et al: Comparison of body fluid distribution between chronic haemodialysis and peritoneal dialysis patients as assessed by biophysical and biochemical methods. Nephrol Dial Transplant 2001;16:2378–2385. Piccoli A: Identification of operational clues to dry weight prescription in hemodialysis using bioimpedance vector analysis. The Italian Hemodialysis-Bioelectrical Impedance Analysis (HDBIA) Study Group. Kidney Int 1998;53:1036–1043. Piccoli A, Pillon L, Dumler F: Impedance vector distribution by sex, race, body mass index, and age in the United States: standard reference intervals as bivariate Z scores. Nutrition 2002;18: 153–167. Piccoli A, et al: A new method for monitoring body fluid variation by bioimpedance analysis: the RXc graph. Kidney Int 1994;46:534–539. Lindley E, et al: A ward-based procedure for assessment of fluid status in peritoneal dialysis patients using bioimpedance spectroscopy. Perit Dial Int 2005;25(suppl 3):S46–S48. Zhu F, et al: Estimation of body fluid changes during peritoneal dialysis by segmental bioimpedance analysis. Kidney Int 2000;57:299–306. Edefonti A, et al: Changes in body composition assessed by bioimpedance analysis in the first 6 months of chronic peritoneal dialysis. Adv Perit Dial 1997;13:267–270. Zhu F, et al: Segment-specific resistivity improves body fluid volume estimates from bioimpedance spectroscopy in hemodialysis patients. J Appl Physiol 2006;100:717–724.

Nathan W. Levin, MD Renal Research Institute 207 East 94th Street New York, NY 10128 (USA) Tel. 1 212 360 4954, Fax 1 212 996 5905 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 129–134

Peritoneal Dialysis: A Clinical Update Congestive Heart Failure and PD S.W. Tobe, N. Raymond, N.A. Ismail Sunnybrook and Women’s College Health Sciences Centre, Toronto, Canada

Abstract Background: There is a belief that peritoneal dialysis may be an important treatment modality for refractory heart failure, allowing at least an improvement in quality if not quantity of life during the last stage of this debilitating chronic disease. This paper examines the rationale behind this modality, critically appraises the available literature, calls for more research in the area and puts forward a framework for considering peritoneal dialysis in refractory heart failure. Conclusion: When faced with a patient with refractory heart failure admitted to hospital on multiple occasions because of complications of volume overload, the following approach to initiating peritoneal dialysis should be considered: subjects for dialysis must have a minimal blood pressure, and those whose hemodynamic status improves with diuresis, even though they develop a pre-renal picture, may be the best candidates. Copyright © 2006 S. Karger AG, Basel

Heart failure (HF) is defined as a state in which the heart cannot provide sufficient blood flow to satisfy the metabolic needs of the body. In refractory HF, hemodynamic, neurohormonal and cellular changes lead to the need for frequent hospitalizations despite aggressive management with medication and lifestyle adaptations. At the stage of refractory HF, most patients have been thoroughly investigated for the possibility of improvement of cardiac function through revascularization or pacing strategies and further procedures have been ruled out as possessing too great a risk-to-benefit ratio. Medical care at this stage is focused on maintaining the best possible quality of life and minimizing hospitalizations. Fluid overload is responsible for much of the complications of refractory HF: the mismatch between salt and water intake and output leads to swings back and forth between HF and renal failure. Pursuing aggressive diuresis leads to pre-renal failure, but improving renal function by allowing volume overload

leads to complications and admissions. Nephrologists have experienced anecdotal cases where patients with refractory HF have been able to control their volume status with peritoneal dialysis (PD), dramatically reducing or eliminating hospital admissions. There is a belief by some that PD may be an important treatment modality for refractory HF allowing at least an improvement in quality if not quantity of life during the last stage of this debilitating chronic disease. We examine the rationale behind this modality, summarize a review of the available literature, call for more research in the area and put forward a framework for considering PD in refractory HF. A Medline literature search was conducted, using the headings, ‘heart failure’, ‘peritoneal dialysis’, and ‘hemodialysis’; and all references were also reviewed. HF increases in prevalence with age and is becoming increasingly prevalent over time [1]. The prevalence is estimated at 1% of the adult population and 5% of people over age 65 [1]. HF leading to repeated hospitalization is a growing problem worldwide. In the 1990s, 0.2% of the UK population was admitted for HF, accounting for 5% of all adult general medicine and geriatric hospital admissions [1]. In the United States, HF is the most common cause of hospitalization in people over the age of 65 [1]. Furthermore, one-third are readmitted within 12 months of discharge in the UK and within 6 months in the USA [1]. More than half of the readmissions for HF are for worsening symptoms [2]; of these readmissions, 5% are for refractory HF [3]. Even in the carefully managed environment of a controlled clinical trial, excessive salt intake was felt to be contributing to 22% of episodes of exacerbation of HF [2]. HF can be expressed in stages of severity, from structural heart disease without signs or symptoms to that with signs and symptoms and finally to refractory HF with marked symptoms at rest despite maximal medical therapy [4]. Each successive stage of HF is associated with greater degrees of activation of neurohormonal systems and is linked to reductions in renal blood flow [5]. HF associated with atherosclerosis and reduction in GFR is associated with risk factors for progressive renal ischemia and glomerular and tubular damage [6]. In patients hospitalized with refractory HF, 25% have reduced renal function and most have comorbid histories of hypertension, diabetes and coronary artery disease [3]. Elevated levels of neurohormones such as epinephrine and big endothelin in refractory HF may in part be responsible for reductions in renal blood flow and possibly renal ischemia [7]. These levels fall with successful medical therapy, thus therapies that reduce these levels may lead to a reduction of organ dysfunction [7]. Progress made in the last two decades in the pathophysiology of refractory HF suggests that the most rational therapeutic approach in managing it involves modulating the neurohormonal mechanisms activated by this condition [8]. Interrupting the renin angiotensin and aldosterone system with angiotensin

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converting enzyme inhibitors, angiotensin receptor blockers and spironolactone, as well as blocking the adrenergic system with beta-blockers has been shown to prolong life and reduce hospitalization and has become the mainstay of clinical recommendations [4]. Unchecked, these neurohormonal mechanisms lead to deleterious effects on coronary hemodynamics, cellular apoptosis, and systemic changes with loss of renal function [9]. Levels of endothelin, renal hypoperfusion and volume overload are all correlated [9]. Future drug therapies aimed at blocking the effect of high levels of endothelin, vasopressin, interleukins and tumor necrosis factor-alpha may also improve survival and delay progression toward refractory HF [10]. Other therapies for refractory HF include consideration for left ventricular assist devices, hemodynamic tailoring, including pulmonary artery catheterization, and infusion of positive inotropic agents [4]. Therapies that are not recommended include partial left ventriculectomy and regular intermittent infusion of positive inotropic agents [4]. Ultrafiltration through PD is less invasive than many of these therapies and may, in addition to maintaining volume control, impact on cytokines and inflammatory markers. The use of diuretics in refractory HF is critical in maintaining fluid balance. However the use of diuretics in these patients is also associated with worsening azotemia, metabolic alkalosis, hypokalemia and hyponatremia in a significant fraction of patients [11]. Meticulous identification and control of fluid retention is critical for the management of refractory HF [4]. Additionally, management of patients in a program with expertise in the management of HF is also recommended. It is interesting that HF clinics have developed much of the same expertise in salt and water management that has been the mainstay of management in home dialysis clinics. Erythropoeitin therapy, standard in the management of home dialysis patients has recently been introduced for the management of refractory HF. Anemia has been found in 40–50% of HF patients and its correction improves the quality of life, decreases the need for hospitalization and may stabilize renal function [12]. As HF is an inflammatory condition, cytokines and inflammatory markers such as tumor necrosis factoralpha are likely linked to a reduction of red cell production and modulation of heart function [13]. PD may lead to a reduction of inflammatory markers and this may be one of the reasons that erythropoietin requirements are lower in patients on PD compared to hemodialysis [14]. Erythropoeitin therapy should be considered for all patients with refractory HF started on dialysis. Removal of marked fluid overload is one of the most demanding and difficult challenges in the management of severe congestive HF, particularly once patients have become refractory to diuretic therapy [1]. Maintenance of appropriate arterial pressures reduces cardiac work, reduces sympathetic tone and may lead to reduction in neurohormonal levels such as angiotensin II. Restoration of cardiac volume from fluid removal may permit better cardiac myocyte apposition

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and an improvement in Starling’s forces [4]. In addition to volume control, dialysis may also prevent the unwanted effects of the loop diuretics including hypokalemia, metabolic alkalosis and hypomagnesemia. Since 1923, when the first treatment of this kind was performed, acute PD was used extensively over the years as a therapeutic modality in conditions associated with acute fluid overload [15]. In 1949, Schneierson introduced intermittent PD in severe cardiomyopathy [16]. Since then, several centres have published their experience with PD in acute and chronic management of severe HF [17]. The daily fluid removal rates required in HF management are achievable by PD as well as extracorporeal techniques, including intermittent or continuous haemofiltration or continuous veno-venous hemodialysis [18]. As dialysis removes potassium, it may be more permissive in the use of higher doses of ACEi or ARB or spironolactone. Whatever modality of dialysis is chosen, the goal is to maintain salt and water balance by removing volume by ultrafiltration. PD at home, possibly with only 1 or 2 exchanges daily, may provide sufficient volume control to restore a patient’s lifestyle. This may also give sufficient solute clearance as many patients have residual renal function. PD is believed by many nephrologists to be the modality of choice in the management of patients with stages III and IV HF, either as palliative therapy or as a bridge to transplantation [18]. PD has also been reported to be associated with a reduction in hospitalization rates. Gotloib et al. [19] reported on a single-centre experience with 20 patients with refractory HF, NYHA class IV, and found an improvement in the functional capacity and a reduction in hospitalization. The average GFR at initiation of dialysis was 14.8 ml/min, indicating that most had renal indications for dialysis in addition to CHF as the main indication and all had ejection fractions below 25% [19]. Initially all patients received CVVH to bring them down toward their goal weight and they were then given automated PD 8 h daily, 3 days per week [19]. The average ultrafiltration achieved was 2 liters per session and the average NHYA class in the 18 surviving subjects after one year was 1 [19]. Days of hospitalization fell from 157 in the whole group prior to the study to 13 during the dialysis therapy [19]. The dramatic improvement may have been due in part to correction of volume overload, including the CRRT prior to the start of PD, but for such a dramatic systemic effect one can speculate on the role of PD on the removal of middle molecular weight myocardial depressant factors. The survival of these patients, however, was determined by the underlying heart disease and did not seem to be affected by the PD therapy. A recent publication suggests that patients who are started on dialysis and who also have HF have better outcomes on hemodialysis [20]. This retrospective analysis of a large data set of dialysis patients from the United States renal data system showed that the mortality risk for new end-stage renal disease patients with coronary heart disease is significantly higher in those treated with

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PD than in those undergoing maintenance hemodialysis [20]. According to the United States renal data system, 30% of new hemodialysis and 22.9% of new PD patients have concurrent HF, yet HF is not one of the listed etiologies of end stage renal disease [21]. The report by Stack et al. [20] suggests that patients who require dialysis and have been reported to have HF and are put on hemodialysis have better outcomes than those in whom PD is chosen. The analysis is in prevalent dialysis patients who have already survived 3 months on dialysis and is therefore confounded by incidence/prevalence bias as well as the influence of physician choice of modality. This report does not address incident patients being considered for dialysis primarily for the management of refractory HF. Randomized controlled trials are required to test whether dialysis is appropriate in patients with this indication, and then to determine which mode of dialysis or sequence of therapies is recommended. Faced with a patient with HF refractory to medical therapy in whom no further procedures are possible, who is admitted to hospital on multiple occasions because of complications of volume overload, the following approach may be considered. Once issues of advanced directives and the patient’s wishes for end of life decisions are known, they may be considered for PD if they are a suitable candidate for a PD catheter and can maintain a reasonable blood pressure suggested as greater than 90 mm Hg systolic. Subjects who have an improvement of their hemodynamic status with diuresis, even while developing a pre-renal picture, may be the best candidates. Once the patient and family have been educated about PD as well as end of life discussions about goals for quality of life, a PD catheter should be placed. While the catheter is healing, correction of volume with hemofiltration, if resources are available, may improve outcomes. PD during the day or night or nighttime automated PD may be sufficient for volume removal. Volume reduction should be carried out slowly over days and weeks to achieve the dry weight while preventing concurrent symptomatic hypotension. Hopefully the patient can participate in a rehabilitation program during this time to improve their stamina and, with appropriate social supports, will enjoy an improved quality of this last stage of their life with a minimization or elimination of hospitalizations.

References 1 2 3 4

McMurray JJ, Stewart S: Heart failure: epidemiology, aetiology, and prognosis of heart failure. Heart 2000;83:596–602. Mosterd A, Hoes AW: Reducing hospitalizations for heart failure. Eur Heart J 2002;23:842–845. De Luca L, Gheorghiade M: Hospitalization for worsening chronic heart failure. Ital Heart J 2004;5(suppl 6):55S–62S. Hunt SA, Baker DW, Chin MH, et al: ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of

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5 6 7

8 9

10

11

12 13

14

15 16 17 18

19 20

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Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2101–2113. Miller J, Tobe S, Skorecki KL: Control of extracellular fluid volume and the pathophysiology of edema; in Brenner BM (ed): The Kidney, ed 5. W.B. Saunders Co, 1995, pp 817–872. Stack AG, Bloembergen WE: A cross-sectional study of the prevalence and clinical correlates of congestive heart failure among incident US dialysis patients. Am J Kidney Dis 2001;38:992–1000. Strametz-Juranek J, Pacher R, Kos T, et al: Sequential big endothelin plasma levels in heart transplant recipients during bridging therapy and after successful heart transplantation. J Heart Lung Transplant 2003;22:731–737. Chatterjee K: Congestive heart failure: what should be the initial therapy and why? Am J Cardiovasc Drugs 2002;2:1–6. Kos T, Pacher R, Wimmer A, et al: Relationship between kidney function, hemodynamic variables and circulating big endothelin levels in patients with severe refractory heart failure. Wien Klin Wochenschr 1998;110:89–95. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC Jr: ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the AHA/ACC task force on practice guidelines. www.acc.org/ clinical/guidelines/failure//index.pdf, 2005. Rosenberg J, Gustafsson F, Galatius S, Hildebrandt PR: Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature. Cardiovasc Drugs Ther 2005;19:301–306. Silverberg DS, Wexler D, Blum M, Schwartz D, Wollman Y, Iaina A: Erythropoietin should be part of congestive heart failure management. Kidney Int Suppl 2003;S40–S47. Ezekowitz JA, McAlister FA, Armstrong PW: Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12,065 patients with new-onset heart failure. Circulation 2003;107:223–225. Snyder JJ, Foley RN, Gilbertson DT, Vonesh EF, Collins AJ: Hemoglobin levels and erythropoietin doses in hemodialysis and peritoneal dialysis patients in the United States. J Am Soc Nephrol 2004;15:174–179. Kagan A, Rapoport J: The role of peritoneal dialysis in the treatment of refractory heart failure. Nephrol Dial Transplant 2005;20(suppl 7):vii28–vii31. Schneierson SJ: Continuous peritoneal irrigation in the treatment of intractable edema of cardiac origin. Am J Med Sci 1949;218:76–79. Mehrotra R, Khanna R: Peritoneal ultrafiltration for chronic congestive heart failure: rationale, evidence and future. Cardiology 2001;96:177–182. Colonna P, Sorino M, Agostino C, Bovenzi F, De Luca L, Arrigo F: Nonpharmacologic care of heart failure: counseling, dietary restriction, rehabilitation, treatment of sleep apnea, and ultrafiltration. Am J Cardiol 2003;91:41–50. Gotloib L, Fudin R, Yakubovich M, Vienken J: Peritoneal dialysis in refractory end-stage congestive heart failure: a challenge facing a no-win situation. Nephrol Dial Transplant 2005;20:vii32–vii36. Stack AG, Molony DA, Rahman NS, Dosekun A, Murthy B: Impact of dialysis modality on survival of new ESRD patients with congestive heart failure in the United States. Kidney Int 2003;64: 1071–1079. USRDS: the United States Renal Data System. Am J Kidney Dis 2003;42:1–230.

Sheldon Tobe, MD, FRCPC Division of Nephrology, Sunnybrook and Women’s College Health Science Centre Assistant Professor, University of Toronto 2075 Bayview Avenue, Room A240 Toronto, Ontario (Canada) M4N 3M5 Tel. ⫹1 416 480 6901, Fax ⫹1 416 480 6940, E-Mail [email protected]

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Chronic Inflammation in Peritoneal Dialysis Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 135–143

MIA Syndrome in Peritoneal Dialysis: Prevention and Treatment Irum Shahab, Karl D. Nolph Nephrology Division, University of Missouri, Columbia, Mo., USA

Abstract Malnutrition, inflammation and atherosclerosis are prevalent in end stage renal disease and constitute the Malnutrition–Inflammation–Atherosclerosis Syndrome. The syndrome is associated with high cardiovascular mortality and accounts for most of the premature deaths in peritoneal dialysis patients. Presence of elevated C-reactive protein levels correlates with malnutrition, decreased fluid removal and mortality in these patients. Early recognition of the syndrome is important to identify high risk patients. Nutritional support, changes in dialysis and drug therapy may decrease the cardiovascular morbidity and mortality. Copyright © 2006 S. Karger AG, Basel

Approximately 20% of dialysis patients die from cardiovascular events [1, 2]. Surprisingly, inflammation plays a key role in the development of atherosclerotic cardiovascular disease. A strong relationship exists between malnutrition, inflammation and the prevalence of cardiovascular disease, and has been recognized as the Malnutrition–Inflammation–Atherosclerosis Syndrome (MIA) [1], Malnutrition, Inflammation Complex Syndrome [2] or Malnutrition Inflammation Atherosclerosis Calcification Syndrome [3]. MIA is prevalent in patients on peritoneal dialysis (PD) and accounts for premature deaths [4]. This syndrome adds to the cardiovascular risk factors with inflammation playing a crucial part in MIA pathogenesis [5]. The presence of inflammation is associated with malnutrition, endothelial dysfunction and pro-coagulant and proatherosclerotic status in PD patients [5]. Inflammation is more common in malnourished patients starting PD and malnutrition and inflammation predicts outcome in PD patients [4].

Inflammation

C-reactive protein (CRP), a marker of inflammation, is elevated in PD patients [4]. Moreover, it is an independent predictor of the number of atherosclerotic plaques in carotid arteries and a single highly sensitive CRP predicts all cause mortality and cardiovascular mortality in PD [4]. The presence of low grade infections e.g. C. pneumoniae, dental abscess and peritonitis, co-morbid conditions like diabetes and congestive heart failure, and carbonyl stress secondary to accumulation of advanced glycation end products (AGE), bioincompatible PD solutions and exposure to endotoxin contaminated dialysate are possible contributing factors to inflammation [1, 2, 4, 6]. Moreover, oxidative stress with oxygen free radical generation, decreased levels of antioxidants (vitamins A, C, E, selenium, glutathione), concomitant diseases e.g. SLE, AIDS, and genetic pre-disposition to enhance production of IL-6 (linked to IL-10 genotype receptor polymorphism) and the CRP gene in Caucasians also pre-dispose to inflammation [2].

Malnutrition

Uremic malnutrition, characterized by insidious loss of somatic protein stores (lean body mass and serum creatinine) and visceral protein (serum albumin and pre-albumin) is associated with increased mortality [7]. A serum albumin of ⬍3.2 mg/dl is associated with a 5-fold relative risk of death and a serum creatinine of ⬍9 mg/dl, increases mortality by 2.2-fold [8]. However, malnutrition alone does not account for the high mortality which has been linked with underlying inflammation. Some have proposed that there are two types of malnutrition seen in chronic renal failure: one associated with low nutrient intake in the absence of inflammation and another associated with inflammation [9]. A strong relationship exists between hypoalbuminemia, malnutrition and inflammation. Factors possibly linked to the development of malnutrition in the presence of inflammation include decreased protein intake due to anorexia, nausea, vomiting and abdominal pain, increased catabolism due to insulin resistance and metabolic acidosis, increased resting energy expenditure, and factors specific to PD like dialysis solution bio-incompatibility, transperitoneal nutrient losses, and increased glucose absorption causing hormonal derangements [9]. Proinflammatory cytokines may directly affect the gastric and intestinal motility, modify gastrointestinal secretions, produce taste aversion, increase resting energy expenditure, promote protein hydrolysis and muscle breakdown through activation of the ubiquitin-proteosome proteolytic system, and increase production

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of anorectic hormones causing a negative protein balance [6, 9]. Moreover, increased free radical production or decreased antioxidant levels may cause endothelial dysfunction and subsequent atherogenesis [10]. Serum albumin is a principal anti-oxidant [9]. Hence hypoalbuminemia causes oxidative stress and atherogenesis [10]. However, in multivariate analysis, CRP, not albumin, is an accurate predictor of mortality [9]. Leptin a negative phase reactant regulates body weight [11]. Hyperleptinemia follows peritoneal glucose reabsorption [11]. With decreases in residual renal function and lean body mass, hyperleptinemia is associated with inflammation [12]. Hyperleptinemia increases triglycerides and total cholesterol levels and promotes accelerated atherosclerosis [11].

Atherosclerosis

Accelerated atherosclerosis and coronary artery calcifications are prevalent in PD patients [5]. Chronic inflammation is an important contributor. Proinflammatory cytokines (IL-6 and TNF-␣) and acute phase reactants (CRP and fibrinogen) are atherogenic and thrombogenic [1, 4, 5]. Oxidative stress, hyperphosphatemia, AGE and increased calcium phosphorus products impair endothelium dependent vasodilatation and promote accelerated atherosclerosis [9]. In certain infections, e.g. C. pneumonia, serum IgA titers predict progression of atherosclerosis through interaction with endothelial receptors [2]. Serum fetuin A, a circulatory inhibitor of calcifications is low in the MIA syndrome [3].

Peritoneal Transport

High early peritoneal permeability (D/P Cr) common in the MIA syndrome is associated with decreased ultrafiltration, increased glucose absorption, increased albumin losses and malnutrition [4]. Dialysate levels of IL-6 and VEGF are elevated in PD patients with high transport [4]. These may promote peritoneal neovascularization and produce the high transport status in MIA patients. Moreover, decreased total fluid removal is associated with increased morbidity.

Residual Renal Function

Presence of residual renal function (RRF) appears critical for long-term prognosis in the MIA syndrome. Loss of RRF impairs cytokine clearance and

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promotes accelerated atherosclerosis, hypercatabolism, decreased appetite, poor volume control, metabolic acidosis, elevated leptin levels and spontaneous dietary restrictions further aggravating the MIA syndrome [4, 13].

Metabolic Acidosis

The presence of metabolic acidosis exacerbates the MIA syndrome by stimulating protein catabolism and decreasing protein synthesis via ATP dependent ubiquiton–proteosome and branched chain keto-acid dehydrogenase [14].

Treatment and Prevention of Malnutrition

Nutritional Support Dietary counseling should be aggressive. Optimum treatment maintains a neutral nitrogen balance and prevent wasting and malnutrition. Recommended protein intake for patients on PD should be ⬎1.2 gm/kg standard body weight and a caloric intake of 3500 cal/kg/day [9, 15]. However studies are needed to define optimum protein intake and energy requirement in PD with MIA. Adequacy of Dialysis Sodium and volume removal are major independent predictors of patient survival [15]. Once a certain minimal small solute clearance is achieved, there is little gain by increasing the dose [15]. New pending K/DOQI guidelines suggest a Kt/V of 1.7 in asymptomatic patients as a minimum threshold. In general, glucose based dialysate absorbs 300–450 kcal of glucose/day; however, protein losses can be10 g/day [15]. Furthermore, significant improvement of albumin and pre-albumin were noted in malnourished PD patients using 1.1% amino acid dialysis solution [7]. Elevation in BUN with exacerbation of uremic symptoms, metabolic acidosis and loss of glucose are major limiting side effects of amino acid base dialysate [6, 7]. Treatment of Acidosis Correction of metabolic acidosis decreases TNF-␣ and ubiquitin proteosome and increases body weight. Recent use of Sevelemar, a phosphate binder fosters chronic acid loading and exacerbates metabolic acidosis [14]. On the other hand high alkali dialysate is associated with increased weight gain and decreased hospitalization [14]. Oral bicarbonate improves the SGA score [14]. Preliminary results of metabolic balance studies in PD patients demonstrate a

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30–59% improvement in nitrogen balance with a change of pH from 7.37 to 7.47–7.49 [14]. A total bicarbonate of ⬎22 mEq/l should be achieved [14]. Appetite Stimulants Commercially available appetite stimulants such as megestrol acetate, dronabinol, steroids and thalidomide due to their side effect profile are difficult to use in PD patients [10]. Non-lean weight gain with megestrol acetate, somnolence with dronabinol and thalidomide, thromboembolism and neuropathy with thalidomide, and osteoporosis with steroids are some of the common side effects [10]. Glucose degradation products in PD are involved in suppression of appetite and the degree of inhibition is proportional to pH and glucose concentration during heat sterilization [6]. Nutrineal (amino acid based dialysate) and Dianeal (gluscose based dialysate) both inhibit oral intake [6]. On the other hand, Physioneal (bicarbonate/lactate buffered solution) and Extraneal (Icodextrin based dialysate) reportedly have no impact on appetite [6]. Hence the concentration of glucose, amino acid and lactate may play a key role in regulation of appetite [6]. Moreover, ACE-inhibitors, anabolic steroids and r-IGF-1 are associated with better nutritional status and can be considered if the primary cause of malnutrition is low protein intake. However their effectiveness is blunted in the presence of inflammation [10].

Prevention and Treatment of Inflammation

Nutritional Treatment Strategies This involves utilizing the anti-inflammatory effects of various diets. Phytoestrogen of soy blocks inflammatory gene expression, ␻-3-fatty acids of fish, ␥-tocopherol of nuts and food rich in fiber lowers CRP levels and uncooked vegan diets are rich sources of vitamins A, C and E, the natural antioxidants [10]. Moderate alcohol consumption increases HDL, apo-lipoprotein A1 and has favorable hemostatic anti-inflammatory effects [10]. Diets low in AGE products are preferred [10]. Volume Control Vigorous volume control decreases systemic endotoxin levels and hence inflammation [1, 6]. Overnight use of Icodextrin yields good ultrafiltration even with high peritoneal transport and improves 2 year survival from 50 to 78% [6]. Measures should be taken to preserve RRF to ensure better volume control. Strict salt and fluid compliance is mandatory.

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Bio-Compatible PD Solutions Nutrineal Continuous losses of amino acid during typical PD are roughly 3–4 g/day, and protein losses 8–15 g/day. One exchange of 1.1% Nutrineal (amino acid solution) over a 4–6 h dwell replaces typical amino acid loss, corrects protein malnutrition and improves membrane viability [6]. Biocompatibility is better with high pH and there is the advantage of enhancing nitrogen intake without a concomitant phosphorus load. Ultrafiltration rates are comparable to 1.5% dextrose. Nutrineal may exacerbate metabolic acidosis and, hence, oral alkalization must be considered [6]. Physioneal Physioneal contains bicarbonate at physiological pH. Bircabonate/lactate buffered solutions are biocompatible and associated with mononuclear cytokine release, membrane viability and improvement of bactricidal activity of neutrophils and mesothelial cells and correction of metabolic acidosis [6]. Extraneal Icodextrin based solution improves hypertension and fluid overload by sustaining ultrafiltration for long dwells [6]. The UF is comparable or superior to 4.25% dextrose solution [16]. Peritoneal membrane viability and function are preserved. There are decreases in cholesterol and insulin resistance. In APD, increased daytime ultrafiltration noted with Icodextrin use is associated with significant decrease in the percent dextrose concentration needed in night time exchanges resulting in decreased glucose absorption and possibly better preservation of the peritoneal membrane [15]. Caloric load is equal to that of a dwell with 2.5% dextrose [15]. However sterile peritonitis and rash have been reported. Dialysis Fluid Adjunctive Hyaluronon protects and improves peritoneal membrane function by significantly reducing fluid absorption and, hence, improves fluid removal [6]. Moreover it may have a protective effect against peritoneal injury [6]. Improved systemic effects with new biocompatible solutions could have significant impacts on the MIA syndrome. Vitamin E coated PD plasticizers may also improve outcome through anti-oxidative properties [2]. Measures to Reduce AGE Studies are needed to elucidate if dietary restriction of intake of AGEs may reduce toxic AGEs and inflammation [10]. Drug therapy to induce breakdown of pre-existing AGE is being evaluated in clinical trials [10].

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Pharmacological Treatment Strategies Statins Statins exert anti-inflammatory actions by decreasing CRP and IL-6 secretion in adiopocytes [10]. Non-lipid lowering statins may be more beneficial in wasted PD patients because of the inverse relationship between total cholesterol and mortality in PD patients but this hypothesis is challenged [10]. ACE-Inhibitors Angiotensin II may contribute to the inflammatory processes within the vascular system by increasing IL-6 and TNF-␣ levels [10]. Decreases in inflammation (CRP) and decreases in wasting (increased SGA score) have been observed with use of ACE-inhibitors [10]. The Studies of Left Ventricular Dysfunction trial demonstrated a decrease risk of weight loss with use of ACEinhibitors [10]. Preservation of RRF improves prognosis in PD patients [10]. Angiotensin receptor blockers are equally effective as ACE-inhibitors in causing decreases of TNF-␣, IL-6 and adhesion molecules [4]. Antioxidants Vitamins E, C and N-acetylcystine have anti-inflammatory potential and improve endothelial dysfunction and decrease cardiovascular events [10]. However, vitamin E has detrimental effects on peritoneal permeability [4]. Vitamin C improves endothelial dysfunction via its anti-oxidant property and there is a reverse association between vitamin C and CRP levels [2, 9]. NSAIDs Non-steroidal anti-inflammatory agents mediate their anti-inflammatory effects via inhibition of prostaglandin synthesis [10]. However, there is an increased risk of bleeding and risk of decline in RRF; hence these are not commonly used [10]. ASA decreases CRP and IL-6 levels and has potent antiinflammatory properties [4]. Role of Glitazone Peroxisome proliferator activated receptor activators inhibit activation of the inflammatory response gene and promote deviation of the immune system away from Th-1 towards Th-1 cytokine production [10]. Role of Antibiotics Infections should be appropriately treated with antibiotics [4]. Clarithromycin decreases IL-6 levels and increases body weight [10]. Although live microorganisms (probiotics) protect the gut barrier, recent study show no benefit with regard to systemic inflammation [10].

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Targeted Anti-Cytokine Treatment Strategies

Thalidomide has immuno-modulatory, anti-inflammtory and anti-angiogenic properties through modulation of TNF-␣ by increasing degradation of TNF-␣ messenger RNA transcripts [10]. Other targeted therapies include: TNF receptor blockage (Entercept); anti-TNF-␣ antibody (Anfliximab); and the IL-1 receptor antagonist (IL-1-Ra or Anakinra) [10]. Lifestyle Modification Weight reduction and resistance training decrease CRP and IL-6 and increase serum albumin and transferrin [10].

Prevention and Treatment of Atherosclerosis

Coronary artery disease is associated with inflammation hence aggressive management of coronary artery disease is key [4].

Conclusion

Early recognition of MIA syndrome is important to identify high risk patients. With proper nutritional support, changes in dialysis and use of medications the overall morbidity and mortality may decrease. Future studies are necessary to verify the long-term benefits of any of the possible interventions mentioned.

References 1 2 3

4 5 6

Pecoits-Filho R, Lindholm B, Stenvinkel P: The malnutrition, inflammation, and atherosclerosis (MIA) syndrome – the heart of the matter. Nephrol Dial Transplant 2002;17(suppl 11):28. Kalantar-Zadeh K, Ikizler TA, Block G, et al: Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis 2003;42:864. Wang AY, Woo J, Lam CW, et al: Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. Nephrol Dial Transplant 2005;20:1676. Stenvinkel P, Chung SH, Heimbürger O, Lindholm B: Malnutrition, inflammation, and atherosclerosis in peritoneal dialysis patients. Perit Dial Int 2001;21(suppl 3):S157. Aguilera A, Sanchez-Tomero JA, Bajo MA, et al: Malnutrition-inflammation syndrome is associated with endothelial dysfunction in peritoneal dialysis patients. Adv Perit Dial 2003;19:240. Chung SH, Stenvinkel P, Bergström J, Lindholm B: Biocompatibility of new peritoneal dialysis solutions: what can we hope to achieve? Perit Dial Int 2000;20(suppl 5):S57.

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Ikizler TA: Protein and energy: recommended intake and nutrient supplementation in chronic dialysis patients. Semin Dial 2004;17:471. Avram MM, Fein PA, Bonomini L, et al: Predictors of survival in continuous ambulatory peritoneal dialysis patients: a five-year prospective study. Perit Dial Int 1996;16(suppl 1):S190. Stenvinkel P, Heimbürger O, Lindholm B, et al: Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MIA syndrome). Nephrol Dial Transplant 2000;15:953. Stenvinkel P, Lindholm B, Heimbürger O: Novel approaches in an integrated therapy of inflammatory-associated wasting in end-stage renal disease. Semin Dial 2004;17:505. Aguilera A, Bajo MA, Rebollo F, et al: Leptin as a marker of nutrition and cardiovascular risk in peritoneal dialysis patients. Adv Perit Dial 2002;18:212. Stenvinkel P, Lindholm B, Lonnqvist F, et al: Increases in serum leptin levels during peritoneal dialysis are associated with inflammation and a decrease in lean body mass. J Am Soc Nephrol 2000;11:1303. Jacobs P, Glorieux G, Vanholder R: Interleukin/cytokine profiles in haemodialysis and in continuous peritoneal dialysis. Nephrol Dial Transplant 2004;19(suppl 5):V41. Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD: Metabolic acidosis and malnutritioninflammation complex syndrome in chronic renal failure. Semin Dial 2004;17:455. Burkart J: Metabolic consequences of peritoneal dialysis. Semin Dial 2004;17:498. Finkelstein F, Healy H, Abu-Alfa A, et al: Superiority of icodextrin compared with 4.25% dextrose for peritoneal ultrafiltration. J Am Soc Nephrol 2005;16:546.

Irum Shahab, MD Nephrology Division, University of Missouri 1 Hospital Drive, MA 436 Columbia, MO 65212 (USA) Tel. ⫹1 573 882 7992, Fax ⫹1 573 884 4820 E-Mail [email protected]

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Being an Inflamed Peritoneal Dialysis Patient – A Dante’s Journey Juan Jesús Carrero, Jonas Axelsson, Carla Maria Avesani, Olof Heimbürger, Bengt Lindholm, Peter Stenvinkel Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden

Abstract Patients on peritoneal dialysis (PD) suffer from a high incidence of cardiovascular disease as compared to healthy individuals, and a markedly increased mortality that cannot fully be explained by traditional risk factors. Recent evidence suggests that end-stage renal disease is a state of systemic inflammation and oxidative stress, both of which appear to play an important role in the development of cardiovascular disease. Here, we review recent data looking at the impact of persistent inflammation (usually recognized by elevated serum levels of C-reactive protein) on morbidity and mortality in PD-patients. While many causes of inflammation are attenuated with PD, including volume overload and biocompatibility of membranes, PD is also associated with modality-specific causes of inflammation such as peritonitis, glucose degradation products and fluid bioincompatibility. Additionally, PD can lead to the uptake of large amounts of glucose from the fluid, resulting in a risk of increased oxidative stress, which also may contribute to inflammation. In addition, recent research shows that genetic factors are clinically important in determining inflammatory response. Finally, we briefly explore potential strategies specifically aiming at reducing intraperitoneal and systemic inflammation in PD patients. Copyright © 2006 S. Karger AG, Basel

Chronic Kidney Disease Prognosis; Lasciate Ogni Speranza Voi Ch’entrate

The Divine Comedy by Dante Alighieri (1265–1321) remains one of the pillars upon which the European literary tradition has been built. This epic poem is made up of three parts, corresponding with Dante’s three journeys to Hell, Purgatory and Paradise. In the first journey, an inscription at the entrance to hell

aims to prevent visitors from entering by stating the so famous quotation: ‘Abandon hope, all ye who enter here’ (Inferno, Canto 3, 1.1). Unfortunately, this might also be said of patients who are diagnosed with chronic kidney disease (CKD) and who are not eligible for transplantation. Indeed, despite recent improvements in the form of novel pharmacological treatments and constant refinements of dialysis technology, the vast majority of maintenance dialysis patients die within a 5-year period – a survival worse than that of patients with metastatic prostate or breast cancer. Cardiovascular disease (CVD) is the major cause of death, accounting for about 50% of the mortality. Recent evidence suggests that even subtle kidney dysfunction is a strong risk factor for cardiovascular events [1]. Two large randomized studies, the ADEMEX [2] and HEMO [3] trials, have shown that further increasing dialysis dose is not likely to bring down mortality. Instead, more focus is now being put on treatment of both traditional and non-traditional risk factors.

Inflammation in Peritoneal Dialysis – Still Some Things We Need to Understand

Amongst multiple risk factors for CVD in end-stage renal disease (ESRD), inflammation and oxidative stress stand out as the key players. Plasma CRP concentration, which is considered to be the best-characterized inflammation biomarker, is associated with poor outcome and increased risk of CVD both in the general population [4] and in ESRD [5]. Many studies have demonstrated a dose-response relationship between CRP and mortality in CKD [5]. Several of these dealt with PD patients specifically, showing that elevated CRP is an independent predictor of nonfatal myocardial infarction [6] and increased incidence of CVD [7], where PD individuals in the top CRP quartile had a CV risk five times higher than those in the lower quartile [7]. Although the debate whether inflammation reflects or causes vascular injury is still not settled, multiple pathophysiological pathways (both dialysisrelated and -unrelated) have been shown to link inflammation and oxidative stress with vascular injury. For instance, inflammatory response leads to proatherogenic changes in blood lipids, endothelial dysfunction, as well as vascular calcification through decreasing plasma levels of fetuin-A – a circulating inhibitor of calcification [8]. Also, inflammation was shown to be associated with significantly increased common carotid artery intima-media thickness in dialysis patients [9] and increased resting energy expenditure [10], both predictors of mortality in PD patients. Like the causes of CVD, the causes of inflammation in PD-patients are multifactorial. A reduction of kidney function per se is associated with an inflammatory

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p⬍0.05 6 hs-CRP (mg/l)

5 4 3 2 1 0 PD (n⫽ 39)

HD (n⫽28)

Baseline

4.9 (0.2–163)

5.6 (0.2–58)

After 12 months

5.4 (0.2–58)

2.5 (0.2–32)

Fig. 1. Evolution of inflammation (expressed as median and range of hs-CRP) of 67 CKD patients during 12 months of dialysis treatment. Baseline CRP was measured before initiation of renal replacement therapy. Thirty nine incident ESRD patients underwent PD and 28 patients HD for 12 months. Wilcoxon’s test showed statistical significance in the CRP change of the HD group.

response in both mild and advanced renal failure, suggesting that differences in residual renal function may contribute to this ‘uremic inflammation’, perhaps through the retention of circulating cytokines [8]. As the failing heart produces large quantities of pro-inflammatory cytokines, volume overload and/or congestive heart failure may also link inflammation to reduced residual renal function [8]. Not surprisingly, strong interrelations between inflammation, residual renal function and cardiac hypertrophy are found in PD-patients [11]. The dialysis procedure per se may also influence the prevalence of systemic inflammation. Own data showing changes in median CRP during 12 months of PD or HD is shown in figure 1. The reason(s) why CRP levels decrease significantly in HD but not PD patients are not evident, but may include recovery from intercurrent illnesses present at start of HD as well as frequent heparinization or less increase in visceral fat mass in this patient group. Heparin has been shown to have anti-inflammatory properties in renal patients, and a recent study showed decreasing systemic CRP when heparin was given intraperitoneally to PD patients [12]. Conventional bioincompatible glucose-based PD solutions may also contribute to systemic inflammation [13]. Conventional PD fluids usually have glucose as the osmotic agent and more importantly, they contain glucose degradation products (GDPs) generated during heat sterilization. GDPs have been shown to induce peritoneal inflammation and the formation of advanced glycation end products. Additionally, glucose-based solutions lead to a substantial uptake of glucose, that may be

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associated with the induction of oxidative stress, a potent cause of inflammation [14]. Treatment with PD may also give rise to local peritonitis, which may contribute to a low-grade systemic chronic inflammation [15]. Volume overload occurs frequently in PD patients and may itself be associated with immune activation. Thus, bacterial or endotoxin translocation potentially occurs in patients with severe gut edema, leading to immunoactivation and increased inflammatory cytokine production [16]. Finally, high-transporter patients were found to be more inflamed than low-transporters, suggesting that peritoneal transport status is also associated with inflammation in these patients [17]. However, not all PD patients show signs of inflammation and normal, or even low, CRP values are found in some patients. One explanation for this may be that genetic factors account for some of the inter- and intra-individual variability in the prevalence of inflammation. There are several candidate genes that have been associated with the prevalence of inflammation in ESRD-patients, and this may in turn affect the risk of CVD. For instance, it has been reported that a single nucleotide polymorphism in the IL-6 gene was associated with higher plasma IL-6 levels and more comorbidity [18], as well as higher diastolic blood pressure and left ventricular mass [19]. Moreover, genetic variations in the IL-6 gene seem to influence inflammatory and peritoneal transport parameters, thus contributing to the interpatient variability in small solute transport rate at the start of PD [20]. Also, genetically determined inter-individual differences in TNF-␣ [18], myeloperoxidase [21] and peroxisome proliferatoractivated receptor ␥ [22] release have been associated with the prevalence of inflammation, CVD and survival in CKD.

Potential Strategies to Modulate the Inflammatory Response in Peritoneal Dialysis

A representation of potential strategies aiming at reducing inflammation in the PD patient is shown in figure 2. At a rudimentary level, reducing complications is always about optimizing care. Thus, one obvious (but unfortunately often neglected) strategy is the optimization of PD prescription. Specifically, volume overload should be avoided, peritonitis should be prevented by stringent hygienic regiments and biocompatible PD solutions should be evaluated to see if they can contribute to reducing inflammation in this patient group. Strategies aiming to improve biocompatibility of PD solutions, including a reduction of GDP formation, and achieving better fluid balance are constantly being developed. Among these strategies, treatment with a biocompatible bicarbonate/lactate buffer system was associated with decreased intraperitoneal IL-6 synthesis and decreased VEGF secretion [23], and treatment with icodextrin-based solutions

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Tomorrow

Multigene DNA assays

Nutritional interventions Fish oil, antioxidants Pharmacological intervention Statins, ACEi, PPAR agonist, sevelamer

Optimization of PD prescription

Today

Improved fluid status, reduced peritonitis rate, biocompatible solutions

Basic patient care Control of infection processes, dental status, comorbidities, etc.

Fig. 2. Pyramid of current and future (speculative) control and treatment of inflammation in PD patients.

improved fluid removal and status [24], abnormal adipocytokine metabolism, dyslipidemia and insulin resistance [25]. Formation of GDPs can be reduced and even be avoided with the use of newer ‘biocompatible’ systems separating the glucose and the buffer. These newer solutions appear to have several local and systemic advantages over the conventional PD solutions [26], but it remains to be seen whether long-term use of these solutions will attenuate the development of peritoneal damage or reduce the incidence of CVD. As interventions directed towards traditional risk factors have so far not proven to be very effective, controlled studies are needed to evaluate if various novel pharmacological as well as non-pharmacological anti-inflammatory treatment strategies, alone or in combination, may be more effective than traditional strategies. To date, four classes of drugs; statins, angiotensin-converting enzyme inhibitors, peroxisome proliferators-activated receptor agonists and natural antioxidants, appear to be promising treatment options in dialysis patients. However, to the best of our knowledge, there are as yet no large,

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controlled trials of the safety and efficacy of any of these therapies in PD patients. Nutritional intervention may also be a potential strategy to reduce inflammation while ameliorating the protein-energy malnutrition of CKD. The anti-inflammatory properties of fish oil (␻-3-fatty acids) show promise in preventing CVD in the general population, but have not yet been evaluated in placebo-controlled intervention studies in ESRD. Also, vitamin E supplementation (using ␥-tocopherol), genistein (antioxidant and anti-inflammatory soy isoflavones) and anthocyanins (antioxidant flavonoids from wine or berries) are currently in the process of evaluation. Finally, it is only logical that genetic factors also influence the occurrence and severity of PD complications. Recent evidence suggests that several genes encoding for pro-inflammatory cytokines contain inherited polymorphisms that may affect both inflammatory complications and outcome in this patient group. In the future, prognostic or predictive multigene DNA assays will thus provide the nephrological community with a more precise approach for the identification of ‘high-risk’ PD patients and the ability to specifically target this patients group with anti-inflammatory and/or antioxidant treatment strategies.

Acknowledgements This manuscript was in part supported by grants from the Söderbergs Foundation (PS) and Swedish Medical Research Council (PS).

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Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N: Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant 2005;20:1048–1056. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, Mujais S: Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13:1307–1320. Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, Allon M, Bailey J, Delmez JA, Depner TA, Dwyer JT, Levey AS, Levin NW, Milford E, Ornt DB, Rocco MV, Schulman G, Schwab SJ, Teehan BP, Toto R: Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002;347:2010–2019. Willerson JT, Ridker PM: Inflammation as a cardiovascular risk factor. Circulation 2004;109: II2–II10. Stenvinkel P, Wanner C, Metzger T, Heimbürger O, Mallamaci F, Tripepi G, Malatino L, Zoccali C: Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage? Kidney Int 2002;62:1791–1798. Herzig KA, Purdie DM, Chang W, Brown AM, Hawley CM, Campbell SB, Sturtevant JM, Isbel NM, Nicol DL, Johnson DW: Is C-reactive protein a useful predictor of outcome in peritoneal dialysis patients? J Am Soc Nephrol 2001;12:814–821. Ducloux D, Bresson-Vautrin C, Kribs M, Abdelfatah A, Chalopin J-M: C-reactive protein and cardiovascular disease in peritoneal dialysis patients. Kidney Int 2002;62:1417–1422.

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Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, Heimbürger O, Cederholm T, Girndt M: IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia – the good, the bad, and the ugly. Kidney Int 2005;67:1216–1233. Stenvinkel P, Heimbürger O, Jogestrand T: Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity. Am J Kidney Dis 2002;39:274–282. Wang AY, Sea MM, Tang N, Sanderson JE, Lui SF, Li PK, Woo J: Resting energy expenditure and subsequent mortality risk in peritoneal dialysis patients. J Am Soc Nephrol 2004;15: 3134–3143. Wang AY, Wang M, Woo J, Lam CW, Lui SF, Li PK, Sanderson JE: Inflammation, residual kidney function, and cardiac hypertrophy are interrelated and combine adversely to enhance mortality and cardiovascular death risk of peritoneal dialysis patients. J Am Soc Nephrol 2004;15: 2186–2194. Sjoland JA, Pedersen RS, Jespersen J, Gram J: Intraperitoneal heparin ameliorates the systemic inflammatory response in PD patients. Nephron Clin Pract 2005;100:c105–c110. Schwenger V, Morath C, Salava A, Amann K, Seregin Y, Deppisch R, Ritz E, Bierhaus A, Nawroth PP, Zeier M: Damage to the peritoneal membrane by glucose degradation products is mediated by the receptor for advanced glycation end-products. J Am Soc Nephrol 2006;17:199–207. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM: The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002;62:1524–1538. Pecoits-Filho R, Stenvinkel P, Wang AY, Heimbürger O, Lindholm B: Chronic inflammation in peritoneal dialysis: the search for the holy grail? Perit Dial Int 2004;24:327–339. Enia G, Mallamaci F, Benedetto FA, Panuccio V, Parlongo S, Cutrupi S, Giacone G, Cottini E, Tripepi G, Malatino LS, Zoccali C: Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than haemodialysis patients. Nephrol Dial Transplant 2001;16:1459–1464. Chung SH, Heimbürger O, Stenvinkel P, Wang T, Lindholm B: Influence of peritoneal transport rate, inflammation, and fluid removal on nutritional status and clinical outcome in prevalent peritoneal dialysis patients. Perit Dial Int 2003;23:174–183. Balakrishnan VS, Guo D, Rao M, Jaberm BL, Tighiouart H, Freeman RL, Huang C, King AJ, Pereira BJ, Group HS: Cytokine gene polymorphisms in hemodialysis patients: association with comorbidity, functionality, and serum albumin. Kidney Int 2004;65:1449–1460. Losito A, Kalidas K, Santoni S, Jeffery S: Association of interleukin-6-174G/C promoter polymorphism with hypertension and left ventricular hypertrophy in dialysis patients. Kidney Int 2003;64:616–622. Gillerot G, Goffin E, Michel C, Evenepoel P, Biesen WV, Tintillier M, Stenvinkel P, Heimbürger O, Lindholm B, Nordfors L, Robert A, Devuyst O: Genetic and clinical factors influence the baseline permeability of the peritoneal membrane. Kidney Int 2005;67:2477–2487. Pecoits-Filho R, Stenvinkel P, Marchlewska A, Heimbürger O, Barany P, Hoff CM, Holmes CJ, Suliman M, Lindholm B, Schalling M, Nordfors L: A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. Kidney Int Suppl 2003:S172–S176. Yao Q, Nordfors L, Axelsson J, Heimbürger O, Qureshi AR, Barany P, Lindholm B, Lönnqvist F, Schalling M, Stenvinkel P: Peroxisome proliferator-activated receptor gamma polymorphisms affect systemic inflammation and survival in end-stage renal disease patients starting renal replacement therapy. Atherosclerosis 2005;182:105–111. Cooker LA, Luneburg P, Holmes CJ, Jones S, Topley N: Interleukin-6 levels decrease in effluent from patients dialyzed with bicarbonate/lactate-based peritoneal dialysis solutions. Perit Dial Int 2001;21(suppl 3):S102–S107. Davies SJ, Woodrow G, Donovan K, Plum J, Williams P, Johansson AC, Bosselmann HP, Heimbürger O, Simonsen O, Davenport A, Tranaeus A, Divino Filho JC: Icodextrin improves the fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial. J Am Soc Nephrol 2003;14:2338–2344.

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Dr. Peter Stenvinkel Department of Renal Medicine K56, Karolinska University Hospital, Huddinge SE–14186 Stockholm (Sweden) Tel. ⫹46 8 585 8253 2, Fax ⫹46 8 711 4742 E-Mail [email protected]

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Serum Parameters, Inflammation, Renal Function and Patient Outcome Wai-Kei Lo Department of Medicine, Tung Wah Hospital, Hong Kong, SAR, China

Abstract Early serum parameters predicting patient outcome mainly are albumin and prealbumin. They were initially thought to represent nutritional status. With the understanding of the contribution of inflammation to malnutrition, cardiovascular disease and mortality, these negative phase inflammatory markers probably represent inflammation more than nutrition. Similarly, C-reactive protein is also found to be a strong predictor of mortality. The other strong predictor of patient outcome is residual renal function. The interlink between preservation of residual renal function and inflammation is becoming a subject of growing interest. Copyright © 2006 S. Karger AG, Basel

Mortality in dialysis patients is high, both in hemodialysis and peritoneal dialysis alike. Two year mortality varies between 10 and 30%, much exceeds the general population of comparable age. Age and diabetes mellitus are consistent predictors of survival. These are factors that one cannot change. People are looking for other predictors of mortality. By identifying such factors, not only we can predict the prognosis, we can also identify the patient at risk for early intervention and help us to understand the disease process. Low serum albumin and pre-albumin have long been identified as a strong predictor of mortality [1, 2]. Albumin is almost always a strong independent risk factor for mortality in all mortality risk studies. They were initially thought to be nutritional markers and hence the idea of increasing protein supply or a positive nitrogen balance would improve survival arose. With the later understanding of the contribution of inflammation to malnutrition, the re-recognition of albumin and pre-albumin as a negative acute phase protein of inflammation, and dilutional hypoalbuminemia as a result of fluid overload, albumin is regarded as a composite marker representing inflammation, protein malnutrition

and fluid overload. As serum albumin assay is available in almost all laboratories while pre-albumin is not, and the assay of pre-albumin does not provide additional value over albumin, pre-albumin monitoring is rarely routinely performed for clinical use. The recognition of inflammation in contribution to malnutrition and atherosclerosis, the most important contributor to mortality related to cardiac diseases, leads to the search of other serum parameters that would predict mortality and cardiac disease. C-reactive protein (CRP), the most commonly assayed acute-phase protein in infection and inflammatory diseases, is the first inflammatory markers documented to be strongly associated with mortality in PD patients [3]. Its assay is available in most hospital laboratories. However, due to the fluctuating level of CRP, some suggested continuous monitoring of CRP is more useful than a baseline value [4]. Another inflammatory marker IL-6 level has also been reported to be predictive of survival [5]. As cardiac disease is one of the most, if not the most, important cause of death in dialysis patients, identifying parameters that would reflect cardiac disease or predicting cardiac event or cardiac mortality would be very useful. Apart from all-cause mortality, CRP has also been showed to be predictive of cardiac events [6]. Serum cardiac troponin T was found to be predictive of cardiac mortality [7, 8], probably more specific than CRP. Non-serum parameters that would correlate with cardiac events or mortality include peritoneal albumin excretion [9], left ventricular hypertrophy [10], cardiac valvular calcification [11] and hypertension [12]. Other blood or serum predictive factors for mortality included hemoglobin level [13], serum phosphate level [14], hypokalemia [15]. High peritoneal transport has long been recognized to be associated with high mortality in many studies, including the CANUSA study [16, 17]. Subsequent understanding of its pathogenesis and clinical consequence lead us to believe it was inflammation and fluid overload that leads to increase mortality in the high peritoneal transporters. However, not all reports showed that peritoneal transport is associated with mortality [18], reflecting that it is not the transport status per se is detrimental, and its ill effect can be managed clinically to reduce the risk of death, particularly when ultrafiltration is augmented [19]. Residual renal function (RRF) is now well recognized to be a much stronger predictor of patient survival than peritoneal clearance [20]. The effect of RRF is possibly related to better middle molecule clearance, better metabolic and endocrine effect, easier control of blood pressure and higher urine output to achieve fluid balance. In fact, RRF also correlates negatively with left ventricular hypertrophy, a predictor of cardiac mortality [21]. More recent data suggests that RRF interlinks with inflammation and left ventricular hypertrophy [22]. Thus preserving RRF becomes an important issue in peritoneal dialysis.

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Conclusion

The more mortality predictive factors we identified, the more we understand the complexity of how the body works and how different factors interlinked together. One cannot simply rely on a single factor to predict prognosis. The more factors we identify, the better we understand our patients.

References 1 2 3 4 5 6 7

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Avram MM, Fein PA, Bonomini L, et al: Predictors of survival in continuous ambulatory peritoneal dialysis patients: a five-year prospective study. Perit Dial Int 1996;16(suppl 1):S190–S194. Mittman N, Avram MM, Oo KK: Serum prealbumin predicts survival in hemodialysis and peritoneal dialysis: 10 years of prospective observation. Am J Kidney Dis 2001;38:1358–1364. Noh H, Lee SW, Kang SW, et al: Serum C-reactive protein: a predictor of mortality in continuous ambulatory peritoneal dialysis patients. Perit Dial Int 1998;18:387–394. Ates K, Ates A, Ekmekci, et al: The time course of serum C-reactive protein is more predictive of mortality than its baseline level in peritoneal dialysis patients. Perit Dial Int 2005;25:256–268. Pecoits-Filho R, Barany P, Lindholm B, et al: Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment. Nephrol Dial Tranplant 2002;17:1684–1688. Herzig KA, Purdie DM, Chang W, et al: Is C-reactive protein a useful predictor of outcome in peritoneal dialysis patients? J Am Soc Nephrol 2001;12:814–821. Lowbeer C, Gutierrez A, Gustafsson SA, et al: Elevated cardiac troponin T in peritoneal dialysis patients is associated with CRP and predicts all-cause mortality and cardiac death. Nephrol Dial Transplant 2002;17:2178–2183. Duman D, Tokay S, Toprak A, et al: Elevated cardiac troponin T is associated with increased left ventricular mass index and predicts mortality in continuous ambulatory peritoneal dialysis patients. Nephrol Dial Transplant 2005;20:962–967. Szeto CC, Chow KM, Lam CW, et al: Peritoneal albumin excretion is a strong predictor of cardiovascular events in peritoneal dialysis patients: a prospective cohort study. Perit Dial Int 2005;25: 432–434. Silaruks S, Sirivongs D, Chunlertrith D: Left ventricular hypertrophy and clinical outcome in CAPD patients. Perit Dial Int 2000;20:461–466. Wang AY, Wang M, Woo J, et al: Cardiac valve calcification as an important predictor for all-cuase mortality and cardiovascular mortality in long-term peritoneal dialysis patients: a prospective study. J Am Soc Nephrol 2003;14:159–168. Lynn KL, McGregor DO, Moesbergen T, et al: Hypertension as a determinant of survival for patients treated with home dialysis. Kidney Int 2002;62:2281–2287. Avram MM, Blaustein D, Fein PA, et al: Hemoglobin predicts long-term survival in dialysis patients: a 15-year single-center longitudinal study and a correlation trend between prealbumin and haemoglobin. Kidney Int 2003;87(suppl):S6–S11. Trivedi H, Tan SH, Prowant B, et al: Predictors of death in patients on peritoneal dialysis: the Missouri peritoneal dialysis study. Am J Nephrol 2005;25:466–473. Szeto CC, Chow KM, Kwan BC, et al: Hypokalemia in Chinese peritoneal dialysis patients: prevalence and prognostic implication. Am J Kidney Dis 2005;46:128–135. Canada-USA (CANUSA) peritoneal dialysis study group. Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. J Am Soc Nephrol 1996;7:198–207. Davies SJ, Phillips L, Russell GI: Peritoneal solute transport predicts survival on CAPD independent of residual renal function. Nephrol Dial Tranplant 1998;13:962–968. Park HC, Kang SW, Choi KH, et al: Clinical outcome in continuous ambulatory peritoneal dialysis patients is not influenced by high peritoneal transport status. Perit Dial Int 2001;21(suppl 3): S80–S85.

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Chung SH, Heimbürger O, Stenvinkel P, et al: Influence of peritoneal transport rate, inflammation, and fluid removal on nutritional status and clinical outcome in prevalent peritoneal dialysis patients. Perit Dial Int 2003;23:174–183. Bargman JM, Thorpe KE, Churchill DN: Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Asm Soc Nephrol 2001;12:2158–2162. Wang AY, Wang M, Woo J, et al: A novel association between residual renal function and left ventricular hypertrophy in peritoneal dialysis patients. Kidney Int 2002;32:639–647. Wang AY, Wang M, Woo J, et al: Inflammation, residual kidney function, and cardiac hypertrophy are interrelated and combine adversely to enhance mortality and cardiovascular death risk of peritoneal dialysis patients. J Am Soc Nephrol 2004;15:2186–2194.

Dr. Wai-Kei Lo Department of Medicine Tung Wah Hospital Hong Kong, SAR (China) Tel. ⫹852 2589 85 80, Fax ⫹852 2858 73 40, E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 156–165

Sterile Solutions and Peritoneal Inflammation Michael F. Flessner Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Miss., USA

Abstract There is now abundant evidence in both animal and human studies that sterile dialysis solutions result in the alteration of the peritoneal barrier. Mesothelial cells undergo an epithelialto-mesenchymal transition after less than 1 year of dialysis. After more than 6 years of peritoneal dialysis, there is extensive fibrosis and neoangiogenesis in the sub-mesothelial compact zone. Clinical studies demonstrate that the structural changes correlate with alterations in transport function and progressive ultrafiltration failure. The mechanisms of inflammation include cellular peroxide production, acidic solutions, glucose and its degradation products, and the integrated response of the cellular-cytokine cascade. Basic and translational research efforts are discussed to highlight our current knowledge in this area and the remaining questions. Copyright © 2006 S. Karger AG, Basel

Sterile dialysis solutions have been a suspected cause of chronic peritoneal inflammation for many years. Dobbie et al. [1] noted from his years of studying peritoneal biopsies that ‘there is the possibility that the peritoneum is in a state of chronic inflammation, owing to solutions which are non-compatible with biologic tissue’. Heimbürger et al. [2] had noted in longitudinal studies of peritoneal dialysis (PD) patients that nearly 40% of the patients experienced ultrafiltration failure after 6 years of continuous PD and subsequently had to transfer to hemodialysis. He concluded that this was likely due to the constant state of inflammation. In a landmark study, Williams and colleagues [3] compared the parietal peritoneal biopsies of 130 PD patients with those of normal, uremic, and hemodialysis control patients who had never been exposed to peritoneal dialysis fluid. They observed that the ‘submesothelial compact zone’ thickness increased significantly with PD duration, particularly after 72 months of exposure. The submesothelial vascular hyalinization with luminal narrowing or obliteration

correlated with months on PD and with the fibrosis in the compact zone. They also observed neoangiogenesis in patients below the compact zone with membrane failure. Their results also demonstrated significantly increased thickness in uremic and hemodialysis patients who had never been exposed to PD. Therefore, there is an additional component to the inflammatory changes in the peritoneum that is due to not only dialysis fluid exposure but also the uremic state itself.

Clinical Evidence

There is evidence for chronic functional changes in the peritoneal barrier, which are due to exposure to clinical dialysis solutions. In a prospective study of 233 PD patients over 54 months, Davies et al. [4] carried out consecutive peritoneal equilibration tests (PET) and demonstrated a significant increase in the dialysate to plasma creatinine concentration ratio (D/P) over 6 months. The D/P progressively increased over the following 42–48 months, indicating an increasing rate of solute transfer and potential for loss of the osmotic gradient. Ultrafiltration (UF) failure was associated with time on dialysis and the history of multiple bouts of peritonitis. In subsequent study a subset of the cohort [5], 13 out of 22 patients displayed stable solute transport over 5 years; the other 9 had progressive increase in solute transport. Although there were no differences in the rates of peritonitis between the groups, the latter group had earlier loss of residual function and required significantly more hypertonic solution. Davies and his co-workers [6] carried out prospective observations of longitudinal membrane function in 177 anuric APD patients. The treatment goals were a creatinine clearance of greater than 60 l/week/1.73 m2 and a daily UF of greater than 750 ml with the use of standard lactate glucose or Icodextrin solutions; measurement of solute transport and ultrafiltration were made annually. After statistical adjustment for age, comorbidity score, time on dialysis, and peritonitis, the study showed a significant decrease in ultrafiltration capacity over 24 months in the entire cohort. Those patients using higher glucose solutions appeared to lose a greater amount of ultrafiltration capacity over the 24 months. Patients treated with Icodextrin solutions demonstrated far less decrease in ultrafiltration capacity. Patients with no peritonitis demonstrated less decrease in ultrafiltration capacity than the patients with one or more episodes. The conclusion from this study is that exposure to higher levels of glucose over 24 months of APD is detrimental to the peritoneal barrier. Despite worse baseline characteristics, the Icodextrin group had better preservation of solute transport and UF. Inflammation and genetics appear to affect dialysis function and mortality. Chung et al. [7] carried out a prospective study of 82 PD patients. They measured the solute and fluid clearance in the typical PET, the C-reactive protein

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(CRP) as a surrogate for inflammation, and the 2-year survival. Their findings demonstrated that inflammation or elevated CRP predicted mortality. A reduced ultrafiltration correlated with poor nutrition, high CRP, and decreased small solute clearance. However, the PD transport status was not associated with survival. In recently published work, Gillerot et al. [8] investigated the association of polymorphisms of genes coding for vascular endothelial growth factor (VEGF), endothelial nitric oxide synthetase (ENOS), and interleukin 6 (IL-6) with baseline PET data in 152 Caucasian patients. They determined metabolites in the plasma and the dialysate and carried out RT-PCR of the IL-6-mRNA of 8 biopsies. Their statistical analyses demonstrated that certain polymorphisms of the IL-6 gene correlated with higher permeability parameters and inflammation. They also demonstrated that the investigated polymorphisms for VEGF and ENOS showed no effect on the baseline peritoneal permeability. The conclusions from this work are that functionally relevant polymorphisms of IL-6 contributed to the inter-patient variability and small solute transport at the start of PD. IL-6 appears to play a critical role in the immune function of the peritoneal barrier.

Cellular Immune Response System of the Peritoneal Barrier

The peritoneal barrier is an integrated system of cells that interact to produce the inflammatory response. Figure 1 illustrates the different cellular entities and molecular structures in the barrier, which has been exposed to dialysis solutions for several years: resident peritoneal macrophages, mesothelial cells, fibroblasts, parenchymal cells (muscle), and endothelial cells. These cellular structures are held together within the interstitial matrix, which likely provides a platform for cell-to-cell communication and influences the transport of cytokines that are produced and secreted by the various cells. Macrophages that reside on the mesothelial surface are activated not only by bacteria but also by current glucose solutions. Cytokines (IL-1, tumor necrosis factor-␣ (TNF-␣)) produced by the macrophage can turn on mesothelial cells, which can be upregulated to produce a host of prostaglandins, interleukins, hyaluronan, cancer antigen 125 (CA-125), and cytokines [9, 10]. It is likely that the Transforming Growth Factor ␤-1 (TGF-␤1) and basic Fibroblast Growth Factor (bFGF) produced by mesothelial cells influence fibroblasts within the underlying tissue interstitium [11]. These fibroblasts are stimulated to synthesize and secrete hyaluronan (HA) and collagen (Col), which expand the interstitial matrix and alter the structure of the barrier [12]. There may also be a possibility that these inflammatory substances affect muscle cells in the parenchymal tissues surrounding the peritoneal cavity [13]. The other important cellular entity within the system is the endothelial cell, which line the microvasculature and produce

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Submesothelial compact zone Mesothelial cells

Fibroblasts TGF-␤1 bFGF

MCPs, ILs, PGs, Rantes

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Fig. 1. Integrated cellular system of inflammatory response. Glucose and its degradation products initiate the cascade with stimulation of macrophages, which in turn up-regulate mesothelial cell production of a host of cytokines, HA, prostaglandins, interleukins. Fibroblasts and endothelial cells are in turn stimulated and play major roles in the integrated response (see text for more details).

nitrogen oxide synthetase (NOS) [14]. Inflammation alters the endothelial barrier, and fibrinogen, fibronectin, albumin, chemokines, and prostaglandins are released into the local tissue [15–17]. This cellular system provides an integrated response to stimulation by dialysis solutions, and the submesothelial compact zone [3] expands with time on dialysis, increasing the distance between the mesothelial cells and their basement membrane (see fig. 1). Dialysis Solutions and Alteration of Mesothelial Cells to a Fibroblast-like Phenotype

Chronic exposure of the human mesothelium to sterile PD solutions results in an epithelial-to-mesenchymal transition. Yanez-Mo et al. [18] recovered human mesothelial cells from the spent dialysate of 54 stable patients and cultured these, splitting them 2–3 times. Eighty-five percent of these patients had no previous peritonitis. They also cultured omental mesothelial cells, which were recovered

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from 39 patients. Omental fibroblasts were separated from three of these samples. Through molecular and cellular techniques, they demonstrated a transition from an epithelial type of mesothelial cell to a fibroblast-like cell with progressive and continuous exposure to clinical dialysis solutions. They showed the loss of normal markers of the mesothelium, such as ICAM 1 and cytokeratin, as the mesothelium was altered from an omental cobblestone-like cellular layer to a fibroblastic layer. For patients who were exposed to dialysate for more than 12 months, their mesothelial cells changed from 75% cobblestone phenotype to less than 30% with the remainder being fibroblast-like. In some patients they observed that in less than 9 months there was loss of cytokeratin in the mesothelial cell layer. This clearly supported the conclusion that chronic exposure to the peritoneum to the current glucose-based dialysis solutions leads to morphologic and phenotypic changes in the mesothelium with 24 months.

Mechanisms of Inflammation

There are several factors involved with chronic inflammation during PD, including: peroxide production by peritoneal macrophages, the low pH of current solutions, glucose, glucose degradation products, and the immune response including the cellular inflammatory-cytokine cascade. Peroxide production has been noted in cultured peritoneal macrophages from CAPD patients while those from healthy women undergoing laparoscopy are peroxide negative [19]. Cultured mesothelial cells spontaneously release hydrogen peroxide, but exposure of the cells to 4.25% dextrose PD solution results in increased hydrogen peroxide production at levels similar to that from stimulation with phorbol myristate acetate and super oxide dismutase [20]. While effects of pH on cultured mesothelial cells has been observed to be quite significant [21, 22], it has been noted in animal experiments [23] and clinical studies [24] that PD fluids are buffered from pH of 5.2–7.4 in 15–30 min. Although one might think that this is only a minor exposure of the cells to low pH, bicarbonate-buffered solutions were shown not to stimulate production of TGF-␤1 by cultured human peritoneal mesothelial cells [25]. A 6 month randomized control of bicarbonate lactate buffered solutions vs. conventional lactate solutions was carried out in 106 patients. The investigators observed an increase in CA-125 and a decrease in hyaluronan levels in overnight PD fluid. However, there were no changes in procollagen I, procollagen III N-terminal peptide or TGF-␤1 levels [26]. The high concentration of dextrose sets up an environment in the peritoneal cavity that is similar to uncontrolled diabetes. Studies in cultured cells have demonstrated that after 24 h incubation, high glucose up-regulates Protein

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Kinase C production 2-fold and mRNA expression of TGF-␤1 and fibronectin by 1.6 and 1.7-fold, respectively [27]. Surprisingly, Icodextrin solutions as well as lactate-buffered 4.25% dextrose PD solutions both increased TGF-␤1 secretion by cultured mesothelial cells 3-fold from controls. The TGF-␤1 was found to stimulate secretion of VEGF, procollagen I, procollagen III N-terminal peptide and fibronectin [25]. The conclusion from these studies is that glucose brings about major changes in the environment of the mesothelial cells as well as that of the cells underlying the mesothelium, and the production of various cytokines are increased as a result of this exposure. Extensive work has demonstrated that glucose degradation products (GDPs) may be a major factor in the transition of mesothelium from an epithelial to fibroblastic-like phenotype. Exposure of human peritoneal mesothelial cells (HPMCs) and L929 fibroblasts to acetaldehyde, formaldehyde, glyoxal, methylglyoxal, furaldehyde resulted in a dose dependent inhibition if cell growth, viability, and IL-1␤-stimulated IL-6 release [28]. Suppression of HPMC function was greater than that of fibroblast. Combination of the lowest concentrations of GDPs had significant effects on cell function, while filtered (low-GDP) solutions had significantly less effect on cell function. Intravital microscopy was used to analyze the vasoactive effects of PD solutions on the rat mesenteric vessels. Low GDP solutions caused transient vasodilation while conventional 4.25% dextrose solution resulted in maximal vasodilation, doubling of the arterial flow, and 20% increase in perfuse capillary lengths/area. Neutral-pH, lactate solutions had only transient effects [29]. Patient studies have revealed that peritoneal NOS activity rises 5-fold in long term dialysis patients and correlated with increased vascular endothelial area. VEGF was co-located in the peritoneal endothelium with advanced glycation end-products [30]. In a longitudinal study of 4 patients, levels of VEGF increased with duration of glucose PD; switching to Icodextrin or glucose-free solutions decreases the level of VEGF [31]. A recent study by Agalou et al. [32] have demonstrated the profound mishandling of protein glycation end products in uremia and on dialysis. PD patients had 18 times the level of GDPs in their plasma, urine and PD fluid as those of controls. GDPs increased in PD dialysate with dwell time and exceeded plasma levels markedly. The Euro-Balance trial [33] demonstrated in 96 patients that pH-neutral, low GDP solutions result in higher levels of CA-125 and procollagen peptide, low levels of hyaluronan, no change in TNF-␣ or VEGF and decreased AGE levels. An additional study by Lee et al. [34] retrospectively compared 551 patients on standard solution with 611 on low GDP solutions. The low GDP solution significantly improved patient survival but did not translate into any difference in technique survival, time to first episode of peritonitis, and overall peritonitis rates over a 30-month follow up period [35].

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Low GDP Solutions and Biocompatibility

Wieczorowska-Tobis et al. [35] carried out twice daily injections of dialysis solutions in rats over 6 weeks. They compared a low pH, high GDP solution with a normal pH, low GDP solution. The low GDP solution demonstrated lower levels of protein and hyaluronan in the dialysate as well as decreased levels of MCP-1, and RANTES, and decreased vascularity. Mortier et al. [36] have demonstrated the benefits of switching to low GDP solution. They carried out a 12–20 week exposure to two daily injections of solutions in rats. They compared standard glucose solution with low GDP and measured the ultrafiltration capacity, VEGF and TGF-␤1 expression, vascular density, advanced glycation end products, and degree of fibrosis. The standard solution caused loss of ultrafiltration and increase in all markers of inflammation. Crossover from the standard to the low GDP solution improved ultrafiltration, AGE and VEGF levels, and fibrosis. Contrary to the above findings, Musi [37] demonstrated that low GDP solutions showed less striking improvements. She used direct needle injections rather than a subcutaneous catheter, which had been used in Mortier’s studies and compared a 3.86% dextrose solution to low GDP vs. low GDP and glucosefree solutions. Inflammation was noted from all solutions with increased fibrosis over the diaphragm and liver with GDP containing solutions. Increased vascularity was observed in all solutions, but the vessel density of the low GDP was greater than that of the standard solution. The ultrafiltration improved with low GDP but small solute transport was unchanged. That these results differ from those in which an indwelling catheter is used may demonstrate a foreign body effect from the catheter. Solutions with an alternative osmotic solute to glucose appeared to show better preservation of the rat peritoneum. Zareie et al. [38] implanted subcutaneous ports and tunneled catheters in rats and carried out daily injections over 5 weeks. They compared the standard glucose solution with amino acid solutions. The low GDP-amino acid solution produced less angiogenesis, less fibrosis, no change in rolling leukocytes within mesentery vessels, and less mesothelial damage. Wu et al. [39] demonstrated that chronic use of solutions supplemented with N-Acetylglucosamine in the peritoneal cavities of rats over 8 weeks resulted in a denser interstitial matrix, improved net ultrafiltration, and decreased protein loss. Various additives have been shown to improve transport characteristics in appearance of the peritoneum. High molecular weight hyaluronan (MW ⬎ 500 kDa) have been shown to improve net fluid removal from the body and decrease protein transport across the peritoneum [40–42]. These additives have been shown to produce lower percentage of polymorphonuclear cells, lower levels of TNF-␣, MCP-1, IFN-␥ levels, and decreased dialysate elastase activity.

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Another approach to decreasing the inflammatory response is the blockade of immune mediators. Beavis et al. [43] exposed three-dimensional, human fibroblast cultures to cell-free, spent PD effluent from patients with peritonitis and observed marked proliferation. Co-incubation with IL-1ra, anti-bFGF, or anti-PDGF-AB reduced the proliferation 27–45%. Incubation of cultured mesothelial cells with Angiotensin Converting Enzyme (ACE) inhibitors significantly decreased levels of VEGF and TGF-␤1. In vitro, the blockade of various cytokines decreases inflammation by interfering with inflammatory pathways. However, the in vivo situation, as illustrated in figure 1, is quite complex and simple blockade typically does not result in decreased inflammation or alteration of the peritoneum.

Remaining Questions

Despite work over the last 10 years on biocompatibility, there still remain many unanswered questions. Low GDP solutions clearly have an advantage over high GDP solutions. But the continued presence of glucose remains a significant problem for the cells. Can we develop an alternative hypertonic agent? Are there mechanical stress effects from the large volume of any solution in the cavity, which might induce chronic changes in the peritoneum? Are there alternative additives that can be included in the solution to prevent chronic inflammation? These are significant questions and will continue to be a subject of research over the next several years.

Acknowledgment This work was supported by US Public Health Service Grant RO1-DK-048479.

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Witowski J, Korybalska K, Wisniewska J, Breborowicz A, Gahl GM, Frei U, Passlick-Deetjen J, Jorres A: Effect of glucose degradation products on human peritoneal mesothelial cell function. J Am Soc Nephrol 2000;11:729–739. Mortier S, deVriese AS, Van deVoorde J, Schaub TP, Passlick-Deetjen J, Lameire NH: Hemodynamic effects of peritoneal dialysis solutions on the rat peritoneal membrane: role of acidity, buffer choice, glucose concentration, and glucose degradation products. J Am Soc Nephrol 2002;13:1419–1422. Combet S, Miyata T, Moulin P, Pouthier D, Goffin E, Devuyst O: Vascular proliferation and enhanced expression of endothelial nitric oxide synthase in human peritoneum exposed to longterm peritoneal dialysis. J Am Soc Nephrol 2000;11:717–728. Zweers MM, Struijk DG, Smit W, Krediet RT: Vascular endothelial growth factor in peritoneal dialysis: a longitudinal follow-up. J Lab Clin Med 2001;137:125–132. Agalou S, Ahmed N, Babaei-Jadidi R, Dawnay A, Thornalley PJ: Profound mishandling of protein glycation degradation products in uremia and dialysis. J Am Soc Nephrol 2005;16:1471–1485. Williams JD, Topley N, Craig KJ, Mackenzie RK, Pischetsrieder M, Lage C, Passlick-Deetjen J: The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane. Kidney Int 2004;66:408–418. Lee HY, Park HC, Seo BJ, Do JY, Yun SR, Song HY, Kim YH, Kim YL, Kim DJ, Kim YS, Ahn C, Kim MJ, Shin SK: Superior patient survival for continuous ambulatory peritoneal dialysis patients treated with a peritoneal dialysis fluid with neutral pH and low glucose degradation product concentration (balance). Perit Dial Int 2005;25:248–255. Wieczorowska-Tobis K, Brelinska R, Witowski J, Passlick-Deetjen J, Schaub T, Schilling H, Breborowicz A: Evidence for less irritation to the peritoneal membrane in rats dialyzed with solutions low in glucose degradation products. Perit Dial Int 2004;24:48–57. Mortier S, Faict D, Lameire NH, deVriese AS: Benefits of switching from a conventional to a lowGDP bicarbonate/lactate-buffered dialysis solution in a rat model. Kidney Int 2005;67:1559–1565. Musi B, Braide M, Carlsson O, Wieslander A, Albrektsson A, Ketteler M, Westenfeld R, Floege J, Rippe B: Biocompatibility of peritoneal dialysis fluids: long-term exposure of nonuremic rats. Perit Dial Int 2004;24:37–47. Zareie M, van Lambalgen AA, ter Wee PM, Hekking LHP, Keuning ED, Schadee-Eestermans IL, Faict D, Degreve B, Tangelder G-J, Beelen RHJ, van den Born J: Better preservation of the peritoneum in rats exposed to amino acid-based peritoneal dialysis fluid. Perit Dial Int 2005;25:58–67. Wu G, Wieczorowska-Tobis K, Polubinska A, Korybalska K, Filas V, Tam P, French I, Breborowicz A: N-Acetylglucosamine changes permeability of peritoneum during chronic peritoneal dialysis in rats. Perit Dial Int 1988;18:217–224. Polubinska A, Pawlaczyk K, Kuzlan-Pawlaczyk M, Wieczorowska-Tobis K, Chen C, Moberly JB, Martis L, Breborowicz A, Oreopoulos D: Dialysis solution containing hyaluronan: effect on peritoneal permeability and inflammation in rats. Kidney Int 2000;57:1182–1189. Wieczorowska-Tobis K, Breborowicz A, Martis L, Oreopoulos D: Protective effect of hyaluronic acid against peritoneal injury. Perit Dial Int 1995;15:81–83. Wang T, Cheng HH, Heimbürger O, Chen C, Waniewski J, Bergström J, Lindholm B: Hyaluronan decreases peritoneal fluid absorption: effect of molecular weight and concentration of hyaluronan. Kidney Int 1999;55:667–673. Beavis MJ, Williams JD, Hoppe J, Topley N: Human peritoneal fibroblast proliferation in 3-dimensional culture: modulation by cytokines, growth factors and peritoneal dialysis effluent. Kidney Int 1997;51:205–215.

Michael F. Flessner, MD, PhD Department of Medicine/Nephrology, University of Mississippi Medical Center 2500 North State Street, Jackson, MS 39216 (USA) Tel. ⫹1 601 984 5670, Fax ⫹1 601 984 5765 E-Mail [email protected]

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Peritoneal Dialysis: Adequacy Issues and Beyond Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 166–173

Adipokine Signaling in the Peritoneal Dialysis Patient Jonas Axelsson, Juan Jesús Carrero, Carla Maria Avesani, Olof Heimbürger, Bengt Lindholm, Peter Stenvinkel Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden

Abstract Patients on peritoneal dialysis suffer from an increased incidence of cardiovascular disease, obesity, insulin resistance, as well as a markedly increased mortality rate. In both the general population and in renal patients current research implicates fat tissue as an important factor in modulating many of these complications through the secretion of various signaling peptides, mainly cytokines and adipokines. Whereas hemodialysis patients tend to lose fat mass after initiation of renal replacement therapy, peritoneal dialysis-patients instead gain fat, probably as a result of continuous glucose absorption. In the present overview we summarize some recent findings indicating that fat mass actively contributes to systemic inflammation and metabolic disturbances in chronic kidney disease. We conclude that adipokines are likely to influence several key survival factors in peritoneal dialysis patients, including systemic inflammation, endothelial health and appetite. Copyright © 2006 S. Karger AG, Basel

Adipose tissue is a complex organ with functions far beyond the mere storage of energy. Indeed, it has recently been shown that fat tissue secretes a number of adipokines (here defined as signaling proteins mainly secreted by adipocytes), including leptin, adiponectin and visfatin, as well as a cytokines (here defined as signaling proteins mainly secreted by other cells present in adipose tissue, but sometimes also to a lesser degree by adipocytes per se), such as resistin, tumour-necrosis factor (TNF)-␣ and interleukin (IL)-6. All of these adipokines have important endocrine functions in chronic kidney disease (CKD) and may also be important contributors to systemic inflammation in this patient group [1]. In peritoneal dialysis (PD) patients this is of special significance, as the initiation of therapy is often associated with an increase in fat

mass, likely, at least partly, related to glucose absorption from the dialysis fluid [2]. Although available evidence suggests that CKD is a state of chronic lowgrade inflammation, we do not yet fully understand the exact cause(s) of inflammation in this patient group. However, it appears likely that elevated plasma levels of inflammatory biomarkers, such as IL-6 and TNF-␣, in CKD are caused by a combination of factors including the uremic syndrome per se, age, chronic heart failure, persistent infections, as well as bioincompatibility of the dialyzer membrane and endotoxin absorption from contaminated dialysate or from the gut [3]. Inflammatory biomarkers, such as C-reactive protein, leucocyte count (WBC), fibrinogen and IL-6 are strong independent predictors of all-cause and cardiovascular mortality in CKD patients, suggesting that inflammation may play a pivotal role in the development of both malnutrition (i.e. wasting) and atherosclerosis (MIA) in this patient group [3].

Adipokines – Mysterious Acquaintances

The recently discovered role of adipose tissue as not only an inert storage depot but also a source of adipokines has opened up a brand new area for research. Adipokines may act as autogenic regulators of body fat depots, modulating gastrointestinal activities, metabolic changes and central nervous mechanisms. These are disturbances which have been speculated to play a central role in the development of the complications often observed in this patient group, such as insulin resistance, cardiovascular disease (CVD) and sarcopenia (loss of muscle mass) [4]. Furthermore, there are intimate links between adipokines and pro-inflammatory cytokines as well as between fat and muscle tissue [5]. Considering the dramatic effect the loss of renal function has on the clearance of these substances [6], the systemic effects of adipokines in CKD patients may be greater than in the general population. So far, relatively few studies have investigated the impact of adipokines on metabolic and inflammatory aspects of CKD. Leptin, the first adipokine described in 1994, was shown to correlate strongly with total body fat mass and to modulate feeding behavior in rats [7]. While leptin signaling is more complex in humans, loss of renal function leads to inappropriately elevated serum concentrations of leptin [8]. Leptin signaling in the central nervous system has recently been shown to be an important cause of anorexia in uremic rats [9]. In accordance, we have shown that increased serum leptin levels are inversely related to inflammation and predict longitudinal changes in lean body mass in patients starting PD [10]. Furthermore, serum leptin levels appear to be an independent predictor of epoetin requirements in uremia (even after adjustment

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for inflammation) and there is some evidence to suggest that this pleiotropic adipokine may have hematopoetic properties [11]. Indeed, in non-renal patients, leptin has been shown to be capable of initiating the recruitment and activation of immunocompetent cells, while leptin production may in turn be regulated by adipose tissue TNF-␣ levels [5]. Also of interest for nephrologists is the apparent ability of leptin to modulate bone modeling through central mechanisms [12], as well as the apparent ability of leptin to promote collagen formation in tissues [13], both of which may have as yet unexplored links to vascular calcification and bone disease in uremia. Indeed, a recent study showed that leptin is able to enhance vascular calcification in vitro and in mice, suggesting a much more direct connection between this hormone and CVD in uremia [14]. Adiponectin is another adipokine exclusively secreted from adipocytes and found in the circulation. In contrast to other adipokines, low circulating levels of adiponectin are generally found in insulin resistant populations at enhanced risk of atherosclerotic CVD, such as type-2 diabetes mellitus, obesity and essential hypertension. Although plasma adiponectin levels are generally markedly elevated in CKD patients [15, 16], it has been reported that dialysis patients with lower adiponectin levels have an increased mortality rate [15]. Also, a reciprocal relationship between C-reactive protein and adiponectin has been demonstrated in dialysis patients [16, 17]. However, in a recent small cross-sectional study of 44 PD patients, Diez et al. [18] found no association between serum adiponectin levels and prevalence of clinical CVD. One possible explanation for these discrepant findings is that adiponectin circulates in two distinct forms, which are simultaneously measured by commercial ELISAs; a high molecular weight form, and a more bioactive low molecular weight form. As the exact mechanisms whereby adiponectin mediates its’ effects are still unclear, further studies will surely lead to novel physiological and pathological roles for this intriguing molecule. Indeed, Qi et al. [19] recently demonstrated that adiponectin, like leptin, acts on the central nervous system, where it reduces food intake. Moreover, in cultured myocytes, adiponectin inhibits apoptosis and TNF-␣ production after ischemia [20]. Resistin may serve as an example of the close relationships between adipokines and cytokines. Resistin was initially described as ‘Found In Inflammatory Zone’ (FIZZ)-1, and described as a cytokine [21]. Later, animal studies implicated it in obesity-induced insulin resistance and type-2 diabetes mellitus, and it was reclassified as an adipokine [22]. However, despite the initial excitement surrounding this adipokine the true pathophysiological role of resistin in human disease remains unknown. It now seems clear that many different cell types secrete this peptide, with a predominance of immunocompetent cells [23]. Indeed, we and others have found that increased circulating resistin levels in CKD patients are not associated with insulin resistance or fat

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mass, but rather correlate closely with inflammatory biomarkers [24, 25], favoring classifying resistin as a cytokine.

Macrophages – the Link between Inflammation and Metabolism

As the biology of the adipose tissue is becoming more known, attention is being drawn to the close and interdependent signaling pathways of inflammation and metabolic control expressed there. Indeed, gene expression is highly similar between the two types of cells – adipocytes and macrophages – most common in adipose tissue. Thus, macrophages express many of the adipocytokines, such as PPAR-␥ and resistin, while adipocytes can express many ‘macrophage’ proteins, such as TNF-␣ and IL-6 [5]. These two cells also share functional capabilities, i.e. macrophages can take up and store lipids to become atherosclerotic foam cells, while preadipocytes under some conditions can exhibit phagocytic and antimicrobial properties and appear to even be able to differentiate into macrophages in the right environment (fig. 1). This suggests a potential immunological role for preadipocytes [5]. For nephrologists, the recent finding that obesity is characterized by macrophage accumulation in white adipose tissue [5] and that increased fat mass is associated with chronic systemic inflammation also in CKD [26] is of clinical interest as many PDpatients tend to gain visceral fat mass after initiation of therapy [27].

Adipose Tissue as a Contributor to Increased Systemic Inflammation

Although most of systemic circulating IL-6 is secreted from activated lymphocytes, other tissues, such as adipose tissue with resident macrophages, may contribute to about 20–30% of the production of IL-6 [28]. Furthermore, TNF-␣ is expressed by adipocytes, and this expression is markedly increased in obesity and has been linked to insulin sensitivity in various non-renal populations [5]. Clinical studies in obese individuals demonstrated a correlation between fat mass and proinflammatory cytokines, while weight loss was associated with a reduction in circulating levels of inflammatory biomarkers. It has also been demonstrated that the omental adipose tissue most affected by PD releases 2–3 times more IL-6 than the subcutaneous fat tissue [28]. Indeed, in a cross-sectional study of CKD patients starting RRT, we have demonstrated that whereas truncal (i.e. visceral) fat mass correlated significantly to circulating levels of IL-6, no significant correlation was demonstrated between non-truncal fat mass and this cytokine [26].

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Adipocyte

Macrophage

Stores lipids and regulates metabolic homeostasis

Inflammatory response Functional overlap?

Cytokines

Adipokines

• Resistin – Proposed to contribute to insulin resistance. • Migration inhibitory factor (MIF)-1 – Influences local inflammation. • IL-6 – Contribute to systemic inflammation. • TNF-␣ – Contribute to insulin resistance and recruitment of macrophages from the circulation.

• Adiponectin – Reduce vascular damage and increase insulin resistance. • Leptin – May influence appetite. • IL-6 – Contribute to systemic inflammation. • TNF-␣ – Contribute to insulin resistance and recruitment of macrophages from the circulation.

Fig. 1. The mutual interactions between adipocytes and adipose tissue macrophages interact to regulate metabolic homeostasis but may also under pathological conditions, such as CKD, contribute to insulin resistance, chronic inflammation and vascular damage. Modified from Wellen et al. [5]. Resident macrophages in the adipose tissue produce inflammatory biomarkers and are regulated by adipokines.

Is it Good to be Fat if You are on PD?

In contrast to findings in the general population, a number of studies have documented that a high body mass index (BMI) is associated with a better outcome in the renal population [29, 30]. Thus, a recent epidemiological study of PD patients showed that a high BMI was associated with decreased mortality during the first 3 years of therapy [31]. Compared to those with normal BMI, adjusted mortality hazard ratios in the first, second, and third year were significantly elevated for the underweight patients, whereas elevated BMI constituted

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a survival advantage. However, BMI is not a very precise parameter of nutritional status and does not reflect body composition (e.g. does not differentiate between muscle mass and fat mass). In a study of 70.028 patients that initiated dialysis in the United States from 1995–1999, it was demonstrated that a protective effect from a high BMI is only present in patients with a normal or high muscle mass [30]. In accordance with these findings, a recent study of 344 incident dialysis patients from Brazil showed that a BMI above 25 kg/m2 was only associated with a better survival if the midarm muscle circumference was at least 90% of normal, while patients with a BMI above 25 kg/m2 and a lower muscle mass had the worst survival [32]. Taken together, these results indicate that an increased fat mass in PD, like in other patients groups, may indeed have adverse metabolic consequences, including an increase in systemic inflammation, but that the effects of a decreased muscle mass (sarcopenia) are more important in determining short-term outcome.

Conclusion

Human adipose tissue has recently been shown to be a hormonally active system that secretes various adipokines and cytokines (a clear distinction is currently not always possible to make), both of which likely play an important role in the development of metabolic complications associated with obesity, such as insulin resistance, type-2 diabetes and premature atherosclerosis. Adipokines are of special interest in PD patients, as this group of patients tend to increase in abdominal fat due to glucose absorption from the dialysis fluid. Much research is still needed to elucidate the likely complex interactions between different fat tissue depots, muscle tissue and its’ effects on inflammation, vascular health and outcome in this high-risk population.

Acknowledgements This manuscript was in part supported by grants from the Swedish Kidney Foundation (JA), the Swedish Society for Nephrology (JA) and Söderbergs Foundation (PS).

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Stenvinkel P: Inflammation in end-stage renal disease – a fire that burns within. Contrib Nephrol 2005;149:185–199. Nawrocki A, Scherer PE: The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation. Curr Opin Pharm 2004;4:281–289. Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest 2005;115: 1111–1119. Pecoits-Filho R, Heimbürger O, Bárány P, Suliman M, Fehrman-Ekholm I, Lindholm B, et al: Associations between circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis 2003;41:1212–1218. Zhang Y, Proenca R, Maffei M, Barone M, Lori L, Friedman JM: Positional cloning of the mouse obese gene and its human homolouge. Nature 1994;372:425–432. Heimbürger O, Lönnqvist F, Danielsson A, Nordenström J, Stenvinkel P: Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol 1997;8:1423–1430. Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH: Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest 2005;115:1659–1665. Stenvinkel P, Lindholm B, Lönnqvist F, Katzarski K, Heimbürger O: Increases in serum leptin during peritoneal dialysis are associated with inflammation and a decrease in lean body mass. J Am Soc Nephrol 2000;11:1303–1309. Axelsson J, Qureshi AR, Heimbürger O, Lindholm B, Stenvinkel P, Barany P: Body fat mass and serum leptin levels influence epoetin sensitivity in patients with ESRD. Am J Kidney Dis 2005;46:628–634. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, et al: Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100:197–207. Cao Q, Mak KM, Lieber CS: Leptin enhances alpha1(I) collagen gene expression in LX-2 human hepatic stellate cells through JAK-mediated H(2)O(2)-dependent MAPK pathways. J Cell Biochem 2005. Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL: Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. Circ Res 2001;88:954–960. Zoccali F, Mallamaci F, Tripepi G, Cutrupi S, Parlongo S, Malatino L, et al: Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002;13:134–141. Stenvinkel P, Marchlewska A, Pecoits-Filho R, Heimbürger O, Zhang Z, Hoff C, et al: Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin. Kidney Int 2004;65:274–281. Huang C, Yen CJ, Chiang HW, Hung KY, Tsai TJ, Wu KD: Adiponectin in peritoneal dialysis patients: a comparison with hemodialysis patients and subjects with normal renal function. Am J Kidney Dis 2004;43:1047–1055. Diez JJ, Iglesias P, Fernandez-Reyes MJ, Aguilera A, Bajo MA, Alvarez-Fidalgo P, et al: Serum concentrations of leptin, adiponectin and resistin, and their relationship with cardiovascular disease in patients with end-stage renal disease. Clin Endocrinol (Oxf) 2005;62:242–249. Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, et al: Adiponectin acts in the brain to decrease body weight. Nat Med 2004;10:524–529. Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K, et al: Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 2005;11:1096–1103. Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, et al: FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 2000;19:4046–4055. Rea R, Donnelly R: Resistin: an adipocyte-derived hormone. Has it a role in diabetes and obesity? Diabetes Obes Metab 2004;6:163–170. Osawa H, Onuma H, Ochi M, Murakami A, Yamauchi J, Takasuka T, et al: Resistin SNP-420 determines its monocyte mRNA and serum levels inducing type 2 diabetes. Biochem Biophys Res Commun 2005;335:596–602.

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Axelsson J, Marchlewska A, Qureshi AR, Heimbürger O, Barany P, Lindholm B, et al: Circulating resistin levels correlate with residual renal function and inflammation, but not with insulin resistance in patients with end-stage renal disease. Kidney Int 2006; in press. Filippidis G, Liakopoulos V, Mertens PR, Kiropoulos T, Stakias N, Verikouki C, et al: Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients. Blood Purif 2005;23:421–428. Axelsson J, Qureshi AR, Suliman ME, Honda H, Pecoits-Filho R, Heimbürger O, et al: Truncal fat mass as a contributor to inflammation in end-stage renal disease. Am J Clin Nutr 2004;80: 1222–1229. Nordfors L, Heimbürger O, Lönnqvist F, Lindholm B, Helmrich J, Schalling M, et al: Fat tissue accumulation during peritoneal dialysis is associated with a polymorphism in uncoupling protein 2. Kidney Int 2000;57:1713–1719. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, et al: Subcutaneous adipose tissue releases interleukin-6, but not tumour necrosis factor-␣, in vivo. J Clin Endocrinol Metab 1997;82:4196–4200. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, Kilpatrick RD, Horwich TB: Survival advantages of obesity in dialysis patients. Am J Clin Nutr 2005;81:543–554. Beddhu S, Pappas LM, Ramkumar N, Samore MH: Effects of body size and body composition on survival in hemodialysis patients. J Am Soc Nephrol 2003;14:2366–2372. Snyder JJ, Foley RN, Gilbertson DT, Vonesh EF, Collins AJ: Body size and outcomes on peritoneal dialysis in the United States. Kidney Int 2003;64:1838–1844. de Araújo IKM, Draibe S, Canziani M, Manfredi S, Avesani C, Sesso R, Cuppari L: Nutritional parameters and mortality in incident hemodialysis patients: effect of body mass index, muscle mass, and dietary intake. J Ren Nutr 2006; in press.

Dr. Peter Stenvinkel Department of Renal Medicine K56 Karolinska University Hospital, Huddinge SE–14186 Stockholm (Sweden) Tel. ⫹46 8 585 8253 2, Fax ⫹46 871 1474 2 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 174–180

The Effect of Fibrosis on Peritoneal Transport Michael F. Flessner Department of Medicine, University of Mississippi Medical Center, Jackson, Miss., USA

Abstract Current sterile dialysis solutions cause inflammation in the sub-mesothelium that lead to fibrosis, angiogenesis, and eventual ultrafiltration failure. While the normal interstitium separates the peritoneal microvasculature from the dialysis fluid and makes trans-peritoneal transport less efficient, changes in the sub-mesothelial layer can result in progressive increases in solute transfer and ultrafiltration diminution. Years of exposure to dialysis solutions result in an epithelial-to-mesenchymal transition of mesothelial cells and the formation of an avascular layer of intersitial matrix and plasma proteins in the sub-mesothelial compact zone. The formation of this fibrotic layer separates the dialyzing solution from the exchange microvessels and markedly decreases the effective osmotic pressure near the exchange microvessels. Angiogenesis dissipates the osmotic driving force through increases the perfused vascular area and marked increases in solute permeability. These combined changes result in more rapid loss of the osmotic agent and diminished ultrafiltration. Copyright © 2006 S. Karger AG, Basel

Fibrosis has been demonstrated in peritoneal biopsies for many years. Dobbie et al. [1] were among the first to establish a peritoneal biopsy register and to make observations of the chronic changes in the peritoneum after years of peritoneal dialysis. The most marked changes were in cases of severe and recurrent peritonitis [2]. Others have made similar observations that long-term exposure to peritoneal dialysis solutions appears to increase fibrosis and the probability of ultrafiltration failure [3]. The most recent study by Williams et al. [4] has clearly demonstrated a marked increased in the fibrosis observed in the sub-mesothelial compact zone after 6 years of chronic exposure to peritoneal dialysis fluids; they also observed a marked increase in vasculopathy below the compact zone. Williams also showed that the peritoneum of uremic and current

hemodialysis patients who had never had exposure to peritoneal dialysis were abnormal as well; this finding implies that uremia induces inflammation in the peritoneum. To understand the abnormal fibrotic peritoneum, one must understand the normal components of the extracellular matrix, which makes up much of much of the submesothelial peritoneum.

Structure of the Normal Interstitium

The interstitium is a structured space between the cells. It is made up of water, small solutes (such as sodium, chloride, urea, glucose, amino acids), matrix macromolecules, and serum proteins, which have a concentration half that of plasma. The extracellular matrix itself is held together by collagen fibers anchored to cells. Rubin et al. [5] have best illustrated the cellular linkage and control by demonstrating with in vitro cell-gel matrices that fibroblasts are held together by collagen fibers via ␤1-integrin. Various maneuvers such as anaphylaxis or anti-␤1-integrin will cause a loosening of the contracted gel and a relaxation of the gel matrix. In contrast, molecules such as PDGF-1 will cause a compaction of the gel [6]. Wrapped around the collagen fibers and linked loosely to them are glycosaminoglycans including proteoglycans and hyaluronan (HA). HA varies in size from kilodaltons to 40 million daltons and has a tremendous capacity to imbibe water; the hydrated volume is 100–1,000 times the volume of dry molecules. The charge held by each HA dimer unit is ⫺1, and therefore HA also has the ability to exclude negatively charged molecules from its intersitial environment and to retain positively charged molecules such as sodium [7]. Muscle, which makes up most of the tissue space adjacent to the peritoneum, contains 50–100 mg collagen/g interstitium and 2.5–7.5 mg glycosaminoglycan/g interstitium, of which, 69% is HA and 31%, sulfated proteoglycan [8].

Interstitium and Peritoneal Transport

Functionally, the interstitium has a direct effect on both solute diffusion and fluid flow across the peritoneum. In solute transport either from or to the peritoneal cavity, the diffusion of small solutes is dependent upon the density of the interstitium and of the microvasculature [9]. Small sugars are significantly retarded in their penetration through tissue [10], with decreasing concentration profiles through all peritoneal tissues, due to the diffusion of the sugar through the interstitium and gradual uptake into distributed blood vessels. The interstitium has a significant effect on net ultrafiltration and water transport as well. Depending upon the hydraulic permeability of the interstitium,

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water flow will move more rapidly or more slowly through the peritoneum [11]. This can be either convection from the cavity due to hydrostatic pressure gradients from the cavity into the tissue, or it can be due to osmotic ultrafiltration that is occurring from the blood vessels into the cavity. It has been clearly shown that a large volume dwell (ⱖ2 l) exerts a positive intraperitoneal pressure across structures such as the abdominal wall and causes them to swell [12]. The swelling of sub-peritoneal tissue occurs independently of the dialysis solution osmolality [13]. Therefore, the peritoneal interstitium is not significantly affected by osmotic pressure but is chiefly affected by the hydrostatic pressure from the cavity. Loss of hyaluronan from the abdominal wall during dialysis has been shown to markedly increase flow into the tissue by increasing the hydraulic conductivity of the tissue [13]. While the normal subperitoneal extracellular matrix swells in the presence of dialysate in sufficient volume to exert a pressure of ⱖ2 mm Hg [13], the changes in a fibrotic peritoneum have not been determined. Interstitial swelling results in a more rapid diffusion of solutes to and from the peritoneal cavity and greater tissue permeability to water flow. Net ultrafiltration will increase or decrease depending on the osmolality of the solution and IP hydrostatic pressure.

Effects of Chronic Inflammation

As illustrated in figure 1 of Chapter on Sterile Solutions and Peritoneal Inflammation, glucose solutions appear to amplify production of cytokines and other products by mesothelial cells and by macrophages. Stimulated mesothelial cells secrete factors such as TGF-␤1 and bFGF as well as hyaluronan, MCP-1, RANTES, interleukins, and prostaglandins (See discussion of Sterile Solutions and Inflammation). These, in turn, stimulate fibroblasts to produce collagen and HA that deposit in the submesothelial compact zone [14]. The mesothelium simultaneously undergoes a transition from an epithelial cell type to a fibroblast-like cell [15], which migrates into the submesothelial compact zone [16]. These altered, fibroblast-like, mesothelial cells can produce significant amounts of collagen and hyaluronan. In addition, fibronectin is secreted into the expanded peritoneal interstitium [17].

Alteration in the Sub-Peritoneal Compact Zone

Williams and colleagues [18] clearly demonstrated that after 6 years of continuous peritoneal dialysis, a good percentage of patients would have marked increase in the thickness of the submesothelial compact zone. The layer

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Increased perfused capillary area rapidly dissipates an already depressed osmotic gradient

Rapid glucose diffusion through expanded matrix 4.25% dextrose 42.5 mg/ml

Glucose concentration profile

Lymph vessel

Avascular matrix

Peritoneal cavity

5 mg/ml Cplasma Blood capillary

(2 mg/ml)

Cells 0.6 mm

1 mm

Mesothelium

Fig. 1. Effects of an avascular layer of fibrotic matrix on the glucose concentration in the vicinity of the microvasculature. The glucose concentration in the vicinity of the subperitoneal microvessels determines the osmotic force for filtration from the blood to the interstitial space. The additional fibrotic material in the submesothelial compact zone results in a marked decrease in the glucose concentration and therefore the osmolality. Angiogenesis under this layer produces abnormal vessels that dissipate the glucose rapidly. Osmotic filtrate from the vessels into the interstitium cannot easily transport to the peritoneal cavity because there is no force to move it (see text for details).

resembles scar tissue with a relatively amorphous, avascular appearance [19]. In our own studies in chronic injections of dialysis fluids in rats, we note that in early time points, such as 2–8 weeks, there is not a uniform thickness of the fibrotic submesothelial compact zone. Indeed, some portions of specimens from the abdominal wall show almost no change while other show quite significant range with 10–200 ␮m of additional fibrosis. What appears to occur in the first few weeks of exposure is a spotty inflammation at different places of the peritoneum. We hypothesize that with time, these areas of inflammation and sclerosis gradually coalesce and become more uniform to cover much of the peritoneum that is in contact with the dialysis fluid. As the fibrosis becomes more uniform, the patient will gradually lose ultrafiltration. Because

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of alterations to the mesothelium itself, the solution may not spread to all parts of the normal peritoneum; this would have the effect of reducing the effective area of transfer for water flow. Ultimately, even the patient who does not experience severe adhesions or sclerosing encapsulating peritonitis will progress to ultrafiltration failure. This typically is characterized by a lack of significant fluid removal coupled with rapid glucose absorption during a 4 h dwell with a hypertonic solution [20].

Possible Mechanism for the Clinical Observations due to Fibrosis of the Peritoneum

An avascular layer in the sub-mesothelial compact zone results in a marked decrease in the concentration of osmotic agent in the vicinity of the filtering vasculature (see fig. 1). We assume that an avascular matrix of macromolecules is laid down over abnormal microvasculature, which includes vessels produced by angiogenesis (see Williams [18]). If we assume that the osmotic agent is glucose with a high concentration in the peritoneal cavity (42.5 g/l, 4.25% dextrose solution), the glucose will diffuse down its concentration gradient through the avascular gel matrix to the blood vessel underlying this matrix. Because of the potentially increased permeability of the abnormal, angiogenic vessels and the increased surface area of the microvasculature below the avascular layer, uptake of the glucose by these vessels will be quite rapid. Diffusion through such a matrix will occur rapidly as well, due to the low resistance of the abnormal interstitium and the lack of cells. As illustrated in the figure, the concentration could decrease from 42.5 g/l of Dextrose to 5 g/l if the thickness of this layer is 1 mm (mathematical model and parameters taken from [21]). Thus the glucose gradient or osmotic gradient between the interstitium and the blood vessels could be dissipated 7-fold by a 1 mm layer of scar tissue. The osmotic filtration from the abnormal blood vessels into the interstitium will likely occur at a low rate because of the reduced osmotic force adjacent to the microvasculature. The filtered fluid, once it leaves the blood and transports into the tissue, has no means to move from the deeper interstitium into the peritoneal cavity. Any hydrostatic pressure from the peritoneal fluid will overwhelm the small and poorly defined tissue-to-cavity water diffusion gradient and will not provide the force necessary for flow from the tissue. In addition, the fibrosis speeds the absorption of glucose into the gel-matrix and ultimately into the blood and effectively lowers the osmotic pressure adjacent to the blood vessels, resulting in eliminating or decreasing the osmotic filtration dramatically.

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Effects of Hydrostatic Pressure on Avascular Matrix

If a pressure gradient is placed across the scar as well as the normal tissues in the abdominal wall, an avascular matrix should swell with the inhibition of fluid just as the tissue swells [12]. The presence of the hydrostatic pressure driven flow into that scar tissue will overwhelm any type of osmotic induced flow outward from the tissue [22]. In addition, the swelling of the scar should increase the rate of diffusion and speed up the actual transmission of solutes such as glucose or creatinine and urea in the opposite direction.

Fibrosis and Solute Clearance

Because the diffusion of small solutes such as glucose is symmetrical across the peritoneal barrier, solute transport from the blood into the peritoneal cavity is accelerated in the same fashion as the absorption of glucose [23]. If we assume prior to the placement of dialysis fluid, that there is a relatively uniform concentration of solutes such as creatinine throughout the interstitium of the normal tissue underneath the scar and in the normal avascular matrix, then the imposition of the dialysis solution in the cavity will result in a rapid discharge of the solute from the scar into the dialysate. Because of the hyperpermeability of the vessels underneath the scar, the solute in the scar will be rapidly replenished in the scar tissue, which will continue to transfer rapidly into the peritoneal cavity. Thus the solute transport from the blood into the peritoneal cavity will occur quite rapidly in spite of this layer of avascular matrix (fig. 1).

Acknowledgment This work was supported by US Public Health Service Grant RO1-DK-048479.

References 1 2

3 4

Dobbie JW, Lloyd JK, Gall CA: Categorization of ultrastructural changes in peritoneal mesothelium, stroma and blood vessels in uremia and CAPD patients. Adv Perit Dial 1990;6:3–12. Dobbie JW: Ultrastructure and pathology of the peritoneum in peritoneal dialysis; in Gokal R, Nolph K (eds): The Textbook of Peritoneal Dialysis. Dordrecht, Netherlands, Kluwer Academic Publishers, 1994, pp 17–45. Heimbürger O, Waniewski J, Werynski A: Peritoneal transport in CAPD patients with permanent loss of ultrafiltration capacity. Kidney Int 1990;38:495–506. Williams JD, Craig KJ, Topley N, Williams GT: Peritoneal dialysis: changes to the structure of the peritoneal membrane and potential for biocompatible solutions. Kidney Int 2003;64(suppl): S158–S161.

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Rubin K, Sundberq C, Ahlen K, Reed RK: Integrins: transmembrane links between the extracellular matrix and the cell interior; in Reed RK, Mattale NG, Bert JL, Winlove CP, Laine GA (eds): Interstitium, Connective Tissue, and Lymphatics. London, Portland Press Ltd., 1995, pp 29–40. Rubin K, Gullberg D, Tomasini-Johansson B, Reed RK, Ryden C, Borg TK: Molecular recognition of the extracellular matrix by cell surface receptors; in Comper WD (ed): Extracellular Matrix. Amsterdam, Harwood Academic Publishers, 1996, pp 262–309. Fraser JRE, Laurent TC: Hyaluronan; in Comper WD (ed): Extracellular Matrix. Amsterdam, Harwood Academic Publishers, 1996, pp 141–199. Levick JR: Flow through interstitium and fibrous matrices. Q J Exp Physiol 1987;72:409–438. Flessner MF, Dedrick RL, Schultz JS: A distributed model of peritoneal-plasma transport: theoretical consideratons. Am J Physiol 1984;246:R597–R607. Flessner MF, Dedrick RL, Schultz JS: A distributed model of peritoneal-plasma transport: analysis of experimental data in the rat. Am J Physiol 1985;248:F413–F424. Flessner, MF, Lofthouse J: Hyaluronan content controls convective movement of protein and water through the subperitoneal interstitium. J Am Soc Nephrol 2000;11:207A. Zakaria ER, Lofthouse J, Flessner MF: Effect of intraperitoneal pressures on tissue water of the abdominal muscle. Am J Physiol Renal Physiol 2000;278:F875–F885. Zakaria ER, Lofthouse J, Flessner MF: In vivo effects of hydrostatic pressure on interstitium of abdominal wall muscle. Am J Physiol 1999;276:H517–H529. Jorres A, Ludeat K, Sander K, Dunkel K, Lorenz F, Keck H: The peritoneal fibroblast and the control of peritoneal inflammation. Kidney Int 1996;50(suppl 56):S22–S27. Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramierez-Huesca M, Dominguez-Jimenez C, JmienezHerrernan JA, et al: Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. New Engl J Med 2003;348:403–413. Margetts PJ, Bonniaud P: Basic mechanisms and clinical implications of peritoneal fibrosis. Perit Dial Int 2003;23:530–541. Flessner MF, Choi J, Credit K, Henderson K, Deverkadra R, He Z, Hughson M: Correlating structure with solute and water transport in a chronic model of peritoneal inflammation. Am J Physiol 2006;290:F232–F240. Williams JD, Craig KJ, Topley N, Ruhland CV, Fallon M, Newman GR, Mackenzie RK, Williams GT: Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002;13:470–479. Dobbie JW, Anderson JD, Hind C: Long-term effects of peritoneal dialysis on peritoneal morphology. Perit Dial Int 1994;14(suppl 3):S16–S20. Krediet RT, Lindholm B, Rippe B: Pathophysiology of peritoneal membrane failure. Perit Dial Int 2000;20(suppl 4):S22–S42. Dedrick RL, Flessner MF, Collins JM, Schultz JS: Is the peritoneum a membrane? ASAIO J 1982;5:1–5. Zakaria ER, Lofthouse J, Flessner MF: In vivo hydraulic conductivity of muscle: effects of hydrostatic pressure. Am J Physiol 1997;273:H2774–H2782. Flessner MF: Small-solute transport across specific peritoneal tissue surfaces in the rat. J Am Soc Nephrol 1996;7:225–233.

Michael F. Flessner, MD, PhD Department of Medicine/Nephrology, University of Mississippi Medical Center 2500 North State Street, Jackson, MS 39216 (USA) Tel. ⫹1 601 984 5670, Fax ⫹1 601 984 5765 E-Mail [email protected]

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Reviews in Peritoneal Dialysis Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 181–186

Peritoneal Dialysis Infections Recommendations Beth Piraino University of Pittsburgh, Pittsburgh, Pa., USA

Abstract Peritonitis remains a serious problem in peritoneal dialysis patients accounting for technique failure and contributing to mortality. Many peritonitis episodes are due to contamination at the time of the exchange and exit site infections. Protocols can be implemented by programs to diminish the risk of infection. Careful training, especially in handwashing technique and in doing the connection, are critical for preventing contamination related peritonitis. Peritonitis due to exit site infections can be reduced by use of exit site antibiotic cream. Gentamicin as opposed to mupirocin exit site prophylaxis reduces not only S. aureus but also P. aeruginosa infections. Refractory exit site infections can be managed with simultaneous catheter replacement. Once peritonitis occurs, prompt institution of empiric antibiotics, dictated by the history of the program’s infections, should be done. Initial therapy is then modified once the culture results are known. Catheters require removal if the peritonitis fails to resolve within 5 days of appropriate antibiotic therapy or if peritonitis is relapsing. Fungal peritonitis is best treated with prompt catheter removal. Implementation of protocols to prevent peritonitis and careful attention to both the organisms causing peritonitis and the rate of infection by a peritoneal dialysis center are essential for reducing infectious complications. Once infections occur, rapid steps to treat and manage are important to diminish the risk of mortality and subsequent peritoneal damage, areas requiring more research. Copyright © 2006 S. Karger AG, Basel

Peritonitis is a serious complication for peritoneal dialysis (PD) patients, contributing to hospitalization, technique failure, catheter loss, and death [1–4]. Death occurs in approximately 6% of episodes [3, 4], and older, malnourished patients with fungal, enteric or S. aureus peritonitis are particularly at risk. Over time peritonitis risk has decreased, particularly peritonitis due to coagulase negative Staphylococcus [5, 6]. Peritonitis rates of 0.5 episodes per year (an episode every 24 months) still commonly occur [7]. Some patients seldom if ever get peritonitis [7]. Hypoalbuminemia appears to be an important risk

factor for the subsequent development of peritonitis [7, 8]. The success of PD is very much tied to the ability of the dialysis program to reduce the risk of peritonitis, and when it occurs, manage the patient appropriately.

Presentation of Peritonitis

The usual presentation of peritonitis is abdominal pain, cloudy effluent or, most often, both. The pain can range from extremely severe to non-existent. All patients must be instructed to immediately call if the effluent is even slightly cloudy. Peritonitis is generally present if the white blood cell count in the effluent is 100/␮l or greater, with at least 50% polymorphonuclear cells. If the specimen is from an exchange with an abbreviated dwell time (e.g. if the patient was on the cycler), an aspirate from a drained abdomen, or obtained from a patient already on antibiotics, the percentage of polymorphonuclear cells (i.e. more than 50%) is a more reliable marker for peritonitis than the absolute number of white blood cells.

Causes of Peritonitis

The leading cause of peritonitis continues to be contamination at the time of the PD exchange. Peritonitis due to skin organisms such as coagulase negative Staphylococcus, corynebacterium, and Bacillus species are generally accepted as caused by contamination. However, PD patients may also have on their (unwashed) fingers Streptococcus viridans, S. aureus, micrococcus, Proteus species, Klebsiella pneumoniae, Enterobacter species, E. coli and Acinetobacter species [9]. Proper hand washing technique is critical for preventing contamination as a cause of peritonitis, as is the importance of adequate training of the patient in the proper connection method. Avoidance of manual spiking by use of double bag system for CAPD, or the use of the compact assist device for any cycler that requires spiking, is critical to decrease the risk of contamination. Spiking, such as is required with some cyclers, easily leads to contamination and therefore, connection methods that minimize contamination (e.g. assist devices for the connection) are critical. Another potential for a center to decrease peritonitis risk is to implement a program for decreasing and managing exit site infections. Prophylaxis with exit site antibiotic cream is very effective in preventing S. aureus exit site infections and thus peritonitis [10, 11]. Exit site mupirocin has no effect on Gram negative organisms [10]. In contrast, a recent double blinded randomized trial showed that gentamicin cream at the exit site (compared to mupirocin) reduced both

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Gram negative and Gram positive exit site infections, and also significantly lowered the risk of Gram negative peritonitis [12]. If a refractory exit site infection develops, particularly from P. aeruginosa, replacement of the catheter as a single procedure is very effective in decreasing the risk of P. aeruginosa peritonitis [13].

Management of Peritonitis

Upon presentation, a rapid assessment of the patient should include questions on breaks in technique, recent procedures that may have lead to peritonitis, change in bowel habits, prior peritonitis and catheter infection history. The exit site and tunnel should be closely examined for evidence of infection. The patient’s abdomen is drained and the effluent sent for cell count with differential, Gram stain, and culture. The cell count with differential will confirm the presence of peritonitis. Pain should be assessed promptly and adequate treatment given. The culture should be obtained by placing 5 ml in each of two tryptic soy broth blood culture bottles (aerobic and anaerobic) [14]. Hospitalization will depend on the severity of the peritonitis, a need for intravenous analgesia and fluids. The causative organism is generally not known when antibiotic therapy is ordered. Therefore, the initial therapy should be active against the most commonly occurring organisms, including Staphylococcus (both coagulase negative and positive), Streptococcus and Gram negative bacilli [15]. The ad hoc treatment guidelines of 2005 recommended a center specific approach to cover both Gram positive and Gram negative organisms, based on the history of infecting organisms in the program [15]. Some programs are seeing an increasing number of cases of peritonitis due to methicillin resistant coagulase negative Staphylococcus and therefore, empiric use of vancomycin is justified [5, 6]. Within 2–3 days, the organism is usually identified and sensitivities are available. Subsequent therapy is chosen to provide narrow coverage with the least toxicity. If the culture is negative, generally the aminoglycoside is stopped and a single drug such as a first generation cephalosporin or vancomycin continued alone.

Special Considerations

Fungal Peritonitis Fungal peritonitis accounts for about 5–6% of episodes [16, 17]. Usually the patient has severe abdominal pain, and the effluent white blood cell count is high.

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Gram stain is often helpful in establishing the diagnosis early. Candida is by far the most common organism. Risk factors include frequent peritonitis, immunosuppression, and antibiotic therapy. Mortality is high; therefore, rapid catheter removal is a prudent approach. Antibiotic therapy should be continued for a minimum of 10 days after catheter removal. The catheter can be re-inserted but a waiting period of 1–2 months is advisable but some patients will have peritoneal fibrosis making PD no longer an option. Prophylaxis with nystatin, given to the patient taking antibiotics, successfully reduces the risk of Candida peritonitis and should be considered in patients on long courses of antibiotic therapy [18].

Peritonitis Due to Mycobacterium

Tuberculous peritonitis occurs more frequently in Asia than in the western world, but may become more common in view of the current epidemic of mycobacteria infections [19]. As with other micro-organisms, the effluent white blood cells are predominately polymorphonuclear cells. Because the effluent AFB stain is generally negative and there is generally no tuberculous disease elsewhere, the diagnosis may be difficult. Therapy should consist of three drugs (isoniazid, rifampicin and pyrazinamide) for 9–12 months. Reportedly, the catheter does not always require removal.

Catheter Removal for Infection

Refractory peritonitis is defined as an episode in which there is no improvement 5 days after appropriate antibiotic therapy is initiated. Relapsing peritonitis is a second episode within 4 weeks of completion of therapy of a prior organism with the same organism or a sterile episode. Repetitive episodes with the same organism, even at a longer interval, may be due to sequestration of bacteria in the biofilm surrounding the intra-abdominal portion of the catheter which may not be clinically apparent [20]. In every case of relapsing and refractory peritonitis, removal of the catheter should be considered early to prevent death of the patient, loss of peritoneal membrane function, and repetitive episodes of peritonitis [1, 2]. In conclusion, peritonitis remains one of the most serious problems facing the PD patient and PD health care worker. Reducing rates of peritonitis can be achieved by careful patient training, use of the best connection technology (in particular avoiding manual spiking), and use of exit site antibiotic cream on a daily basis to prevent exit site infections. Refractory exit site infections should be managed by catheter replacement. Once peritonitis occurs, the treatment

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should be prompt. There should be no hesitation to remove the catheter if this appears to be appropriate.

References 1

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Choi P, Nemati E, Banerjee A, Preston E, Levy J, Brown E: Peritoneal dialysis catheter removal for acute peritonitis: a retrospective analysis of factors associated with catheter removal and prolonged postoperative hospitalization. Am J Kidney Dis 2004;43:103–111. Szeto CC, Chow KM, Wong TY, Leung C, Want A, Lui S, Li PK: Feasibility of resuming peritoneal dialysis after severe peritonitis and tenckhoff catheter removal. J Am Soc Nephrol 2002;13:1040–1045. Fried LF, Bernardini J, Johnston JR, et al: Peritonitis influences mortality in peritoneal dialysis patients. J Am Soc Nephrol 1996;7:2176–2182. Perez Fontan M, Rodriguez-Carmona A, Gardiz-Naveiro R, Rosales M, Villaverde P, Valdes F: Peritonitis-related mortality in patient undergoing chronic peritoneal dialysis. Perit Dial Int 2005;25:274–284. Zelenitsky S, Barns L, Findlay I, Alfa M, Ariano R, Fine A, Harding G: Analysis of microbiological trends in peritoneal dialysis-related peritonitis from 1991 to 1998. Am J Kidney Dis 2000;36:1009–1013. Kim DK, Yoo TH, Ryu DR, Zu AG, Kim HJ, Choi KH, Lee HY, Han DS, Dang SW: Changes in causative organisms and their microbial susceptibilities in CAPD peritonitis: a single center’s experience over one decade. Perit Dial Int 2004;24:424–432. Wang Q, Bernardini J, Piraino B, Fried L: Albumin at the start of peritoneal dilasyis predicts the development of peritonitis. Am J Kidney Dis 2003;41:664–669. Chow KM, Szeto CC, Leung CB, Kwan B, Law M, Li PKT: A risk analysis of continuous ambulatory peritoneal dialysis-related peritonitis. Perit Dial Int 2005;25:374–379. Miller TE, Findon G: Touch contamination of connection devices in peritoneal dialysis – a quantitative microbiologic analysis. Perit Dial Int 1997;17:560–567. Piraino B, Bernardini J, Fried LS: Aureus prophylaxis and trends in Gram Negative infections in peritoneal dialysis patients. Perit Dial Int 2003;23:456–459. Bernardini J, Piraino B, Holley J, et al: A randomized trial of Staphylococcus aureus prophylaxis in peritoneal dialysis patients: mupirocin calcium ointment 2% applied to the exit site versus cyclic oral rifampin. Am J Kidney Dis 1996;27:695–700. Bernardini J, Bender F, Florio T, Sloand J, PalmMontalbano L, Fried L, Piraino B: Randomized double blinded trial of peritoneal dialysis exit site mupirocin 2% versus gentamicin sulfate 0.1% cream. J Am Soc Nephrol 2005;16:539–545. Lui SL, Yip T, Tse KC, Lam MF, Lai KN, Lo WK: Treatment of refractory pseudomonas aeruginosa exit-site infections by simultaneous removal and reinsertion of peritoneal dialysis catheter. Perit Dial Int 1005;15:560–563. Lye W, Wong PL, Leong SO, et al: Isolation of organisms in CAPD peritonitis: a comparison of two techniques. Adv Perit Dial 1994;10:166–168. Piraino B, Bailie GR, Bernardini J, et al: ISPD guidelines/reommendations: peritoneal dialysis related infection recommendations 2005 update. Perit Dial Int 2005;25:107–131. Wang A, Yu A, Li PK, Lam P, Leung C, Lai K, Lui S: Factors predicting outcome of fungal peritonitis in peritoneal dialysis: analysis of a 9-year experience of fungal peritonitis in a single center. Am J Kidney Dis 2000;36:1183–1192. Bibashi E, Memmos D, Koklina E, Tsakiris D, Sofianou D, Papadimitrioiu M: Fungal peritonitis complicating peritoneal dialysis during an 11-year period: report of 46 cases. Clin Infect Dis 2003;26:1–6. Lo WK, Chan CY, Cheng SW, et al: A prospective randomized control study of oral nystatin prophylaxis for Candida peritonitis complicating continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1996;28:549–552.

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Lui S, Tang S, Li F, Choy B, Chan T, Lo WK, Lai K: Tuberculosis infection in Chinese patients undergoing continuous ambulatory peritoneal dialysis. Am J Kidney Dis 2001;38:1055–1060. Finkelstein ES, Jekel J, Troidle L, Gorban-Brennan N, Finkelstein FO, Bia FJ: Patterns of infection in patients maintained on long-term peritoneal dialysis therapy with multiple episodes of peritonitis. Am J Kidney Dis 2002;39:1278–1286.

Beth Piraino, MD University of Pittsburgh Suite 200, 3504 Fifth Avenue Pittsburgh, PA 15213 (USA) Tel. ⫹1 412 383 4899, Fax ⫹1 412 383 4898, E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 187–194

Cloudy Peritoneal Dialysate: It’s not Always Infection Isaac Teitelbaum Division of Renal Disease and Hypertension, Department of Internal Medicine, University of Colorado Health Sciences Center, Denver, Colo., USA

Abstract Background/Aims: Turbid peritoneal dialysate is most commonly due to bacterial peritonitis. However, not all instances of cloudy dialysate are due to infection. This paper will review the various non-infectious causes of cloudy dialysate fluid. Methods: Literature review and synthesis. Results: Cloudy dialysate may be due to pathologic increases of either cellular or non-cellular constituents of peritoneal fluid. Polymorphonuclear leukocytes may be increased due to either intra- or juxtaperitoneal inflammation or drug-induced chemical peritonitis. Increased eosinophils often represent a response to intraperitoneal air or an allergy to a component of the dialysis system. Red blood cells may be present due to one of many causes. Monocytes or malignant cells are relatively uncommon. The differential for the non-cellular causes of culture-negative cloudy dialysate is limited to elevated fibrin or triglycerides. The latter may be due to lymphatic obstruction, pancreatitis, catheter trauma, dihydropyridine calcium channel blockers, or the superior vena cava syndrome. Conclusion: After ruling out atypical infectious etiologies, a diverse set of aseptic causes remains in the differential diagnosis. Use of an organizational scheme based upon identification of the cellular or non-cellular constituent producing dialysate turbidity facilitates appropriate diagnostic and therapeutic interventions. Copyright © 2006 S. Karger AG, Basel

The diagnosis of infectious peritonitis is usually readily established by the findings of cloudy dialysate with polymorphonuclear cell predominance along with symptoms and/or positive cultures. When patients present with culturenegative cloudy dialysate atypical infectious etiologies such as mycobacteria, fungi, or parasites must be considered and ruled out. Yet, infection does not explain all cases of cloudy dialysate. We have previously presented a diagnostic approach based upon a determination of whether the dialysate turbidity is due to cellular or non-cellular elements in the peritoneal fluid (table 1) [1]. Herein I

Table 1. Non-infectious causes of cloudy peritoneal dialysate Cellular causes Polymorphonuclear leukocytes Intraperitoneal visceral inflammation (e.g. cholecystitis, appendicitis, bowel ischemia or obstruction, hernia incarceration, peptic ulcer disease) Juxtaperitoneal visceral inflammation (e.g. pancreatitis, splenic infarction, renal cell carcinoma, abscess) Endotoxin contaminated PD fluid Drug-associated (e.g. amphotericin, vancomycin) Eosinophils Allergic reaction to constituent of dialysis system (e.g. sterilant or plasticizer or other in bags, tubing, Tenckhoff catheter) Drug-associated (e.g. vancomycin, streptokinase) Intraperitoneal air-induced peritoneal irritation (e.g. following placement of Tenckoff catheter) Blood-induced peritoneal irritation (e.g. retrograde menstruation) Monocytes Icodextrin Gastroenteritis Renal allograft rejection Red blood cells Retrograde menstruation Ovulation Cyst rupture (ovarian or hepatic) Peritoneal adhesion formation Hypertonic dialysate Strenuous exercise Catheter-associated trauma Malignant Cells Lymphoma Metastatic involvement of the peritoneum (e.g. adenocarcinoma) Non-cellular causes Triglycerides Acute pancreatitis Neoplastic involvement of the lymphatics (e.g. lymphoma) Drug associated (e.g. dihydropyridine calcium channel blockers) Catheter-associated trauma Superior vena cava syndrome Fibrin Modified and reprinted with permission from [1].

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will review these etiologies and offer an algorithm to facilitate the evaluation of the peritoneal dialysis (PD) patient who presents with sterile cloudy dialysate. As space constraints limit the number of citations in this article, the interested reader is referred to the original review by Rocklin and Teitelbaum [1] for more references.

Cellular Causes of Cloudy Dialysate

Turbid dialysate may be due to the presence of polymorphonuclear leukocytes, eosinophils, monocytes, red blood cells, or malignant cells. Polymorphonuclear Leukocytes Reported causes of increased PMN leukocytes in patients with sterile effluent cultures include inflammation of intraperitoneal or juxtaperitoneal viscera, contamination of dialysate with endotoxin, and drug-induced chemical peritonitis. Cholecystitis, hernia with small bowel incarceration, mesenteric insufficiency, or appendicitis may present with clinical manifestations indistinguishable from infectious peritonitis [2]. Analysis of the turbid peritoneal effluent reveals a marked increase of PMN leukocytes which likely emanate from the inflamed viscera. Rupture of a sterile intraperitoneal abscess that may have formed as a consequence of previous intraabdominal infection (so called ‘acute sterile peritonitis’) may be another cause of culture-negative cloudy dialysate [3]. Inflammation of juxtaperitoneal viscera may also cause cloudy dialysate. The pancreas is separated from the peritoneal space by only a thin layer of peritoneum and loose connective tissue. Spread of inflammation from the pancreas to the abutting peritoneum is thought to explain the vigorous PMN influx and resultant cloudy dialysate that may be seen with acute pancreatitis [2]. Renal inflammation or splenic infarction may also cause sterile cloudy dialysate; patients with splenic infarction may present with red blood cells in the dialysate in addition to PMNs. Clinicians must also remain alert for retroperitoneal infectious and/or inflammatory processes. Investigation into the case of a 61-yearold female who presented with fever, severe abdominal tenderness and sterile cloudy dialysate revealed a flank abscess abutting the peritoneum [4]. Polymorphonuclear leukocyte influx and aseptic cloudy dialysate has also been reported in patients using PD fluid contaminated with endotoxin. Two separate epidemics of this nature have been reported [1]. Of interest, the endotoxin levels in some of the cases were below the maximum release cut-off of 0.5 EU/ml. It has been suggested that pre-sterilization colony counts may be a more appropriate measure for assessing dialysate sterility. The cases of aseptic

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peritonitis ceased after the recall of lots of PD solutions having more than 1 CFU/ml on pre-sterilization culture. Cloudy dialysate resulting from PMN influx with cell counts as high as 13,000/mm3 have also been reported as a consequence of intraperitoneal drug administration. Initially described with amphotericin B, two other case series focused attention on chemical peritonitis following intraperitoneal vancomycin administration. This was subsequently determined to be a consequence of impurities in specific formulations of the drug; this issue has been addressed and further cases have not been reported [1]. Eosinophils The first case of dialysate eosinophilia in a PD patient was reported in 1967 [5]. It is now recognized that cloudy effluent secondary to increased eosinophils is not uncommon, occurring in up to 40% of PD patients. The syndrome is usually seen early during the course of PD, is occasionally associated with peripheral eosinophilia, and usually resolves within 6 months [1]. This may represent an allergic reaction to a constituent of the PD system including the bags, lines, and/or Tenckhoff catheter [6]. Sterilants or plasticizers leeched from these components might produce peritoneal irritation and an eosinophilic immune response [7]. Daugirdas et al. hypothesized that early dialysate eosinophilia may result from intraperitoneal air introduced at the time of PD catheter placement. Chest X-rays performed shortly after surgical implantation of a peritoneal catheter often demonstrate free air under the diaphragm. It is plausible that the peritoneal space may respond to the presence of free air with an influx of eosinophils similar to the pleural space. As support for this hypothesis, sterile air was introduced into the peritoneal space of five PD patients. Turbid dialysate associated with eosinophil cell counts up to 335/mm3 occurred within 24 h and persisted for up to 7 weeks [8]. In two patients, monocytes were most prevalent (80 ⫾ 6.5%), while in three others a combination of eosinophils (63 ⫾ 12%) and monocytes (30 ⫾ 19%) was observed. Chemical peritonitis with eosinophil induced turbidity has been described following the intraperitoneal administration of vancomycin or thrombolytic agents; an association has been suggested for other agents as well (e.g. gentamycin, cephalothin, cefazolin, chloramphenicol, and amphotericin) [1]. Finally, blood in small quantities may induce an eosinophilic peritoneal response. Retrograde menstruation has been hypothesized to produce peritoneal fluid eosinophilia and increased dialysate turbidity [6]. Monocytes There have been several reports of sterile peritonitis with monocytes predominating in the dialysate associated with the use of icodextrin. This was determined

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to be due to contamination of the fluid with an Alicyclobacillus peptidoglycan introduced during the manufacturing process [9]. Since elimination of this contaminant there have been no further cases reported. We have also observed cloudy dialysate with monocytic predominance in several patients with recent diarrheal illnesses, likely viral gastroenteritides; it is interesting to speculate whether this represents transmural migration of the organism across the bowel wall. Finally, we have seen a single patient in whom the findings of abdominal pain and sterile turbid dialysate with monocytic predominance proved to be due to acute rejection of a previously failed renal allograft; symptoms and dialysate monocytosis resolved upon allograft nephrectomy (Teitelbaum, unpublished observations). Red Blood Cells Bleeding into the peritoneal space may also produce cloudy dialysate effluent. In most cases, mild episodic hemoperitoneum resolves without diagnosis in PD patients. Reported cases of opalescent dialysate associated with bleeding are most common in females; causes include ovarian cyst rupture, menstruation, and ovulation [10]. Suppression of ovulation should be considered in women with recurrent episodes of hemoperitoneum occurring midcycle. Other causes of mild bleeding include catheter-induced trauma, strenuous exercise, hypertonic exchange, and the formation of peritoneal adhesions [1]. Rupture of hepatic cysts in patients with polycystic kidney disease is another cause of bloody dialysate. Lastly, it should be recognized that any known cause of hemoperitoneum might result in bloody dialysate. Malignant Cells Cloudy dialysate may also result from the presence of a malignant population of cells. In one instance, relapse of non-Hodgkin’s lymphoma in a 67-yearold woman was established by cytologic examination of her aseptic, cloudy PD effluent. More than 80% of the nucleated cells were monomorphous, large, and had distinct round nuclei characterized by obvious nucleoli, and open punctate chromatin. These findings were consistent with large non-cleaved lymphoma cells [11]. In a similar case reported by Bargman et al. [12] cytological analysis of sterile cloudy dialysate established the diagnosis of a previously unrecognized lymphoma. Neoplasms metastatic to the peritoneum may also cause cloudy dialysate. Adenocarcinoma cells caused turbid effluent in a patient who subsequently had her recurrent endometrial carcinoma diagnosed by skin biopsy [13]. Non-Cellular Causes of Cloudy Dialysate

The differential for the non-cellular causes of culture-negative cloudy dialysate is limited to fibrin or triglycerides.

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Fibrin Fibrin strands are commonly seen in dialysis effluent, especially in patients just beginning PD or following an episode of infectious peritonitis. This nonspecific finding is easily recognizable by the observation of heterogeneously turbid fluid due to the presence of filaments that form a fibrin clot when the dialysate bag is left standing [1].

Triglycerides Dialysate rich in triglycerides characteristically appears white. The opalescence associated with the increased triglyceride levels waxes and wanes depending on the fat content of ingested meals [14]. The most common cause of chylous peritoneal dialysate is lymphatic obstruction secondary to malignancy, in particular lymphoma [12]. Acute pancreatitis may also cause chylous dialysate; the swollen pancreas might impede lymphatic drainage by directly compressing the lymphatic channels as they converge on the cisterna chili [15]. Superior vena cava syndrome has been reported to cause chylous peritoneal dialysate presumably by impairing lymphatic flow [16]. Tenckhoff catheter insertion and/or repeated mild trauma to the lymphatics due to catheter movement may lead to lymph leakage into the peritoneal cavity and increased dialysate turbidity [14]. Turbid dialysate due to elevated triglyceride content has also been reported in patients using certain dihydropyridine calcium channel blockers. The first drug of this class noted to increase effluent triglyceride content was manidipine. Subsequently benidipine, nisoldipine, and nifedipine were also reported to produce cloudy dialysate in some PD patients. The mechanism(s) by which these drugs raise the triglyceride content in the peritoneal space is unknown [17].

Conclusion

Culture-negative, cloudy peritoneal dialysate results from a diverse group of etiologies. Some are as benign as bleeding associated with ovulation or increased fibrin strands following the initiation of PD and will spontaneously resolve. Others, such as juxtaperitoneal visceral inflammation or malignancy, require prompt recognition and treatment when possible. A diagnostic algorithm based on the identification of the cellular or non-cellular constituent producing the increase in dialysate turbidity may facilitate appropriate diagnostic and therapeutic interventions (fig. 1).

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Cloudy dialysate and negative routine cultures

Cellular

Acellular Fibrin Triglycerides

Atypical cells

Typical cells

Diagnostic intervention

Consider/culture for atypical infections

⫺ History exam medications

⫹ Treat accordingly

Fig. 1. Algorithm for the evaluation of cloudy peritoneal dialysate with negative routine bacterial cultures. Reprinted with permission from [1].

References 1 2 3 4 5 6 7 8

9

10 11 12 13

Rocklin MA, Teitelbaum I: Noninfectious causes of cloudy peritoneal dialysate. Semin Dial 2001;14:37–40. Steiner RW, Halasz NA: Abdominal catastrophes and other unusual events in continuous ambulatory peritoneal dialysis patients. Am J Kidney Dis 1990;15:1–7. Alpert BA, Folkert VW, Longnecker RE, Sherman RA: Acute Sterile Peritonitis. Nephron 1982;30:187–189. Bistrup C, Biegel E, Pedersen RS: Sterile peritonitis in a CAPD patient caused by a juxtaperitoneal abscess. Nephrol Dial Transplant 1995;10:406–407. Lee S, Schoen I: Eosinophilia of peritoneal fluid and peripheral blood associated with chronic peritoneal dialysis. Am J Clin Pathol 1967;47:638–640. Gokal R, Ramos JM, Ward MK, Kerr DNS: ‘Eosinophilic’ peritonitis in continuous ambulatory peritoneal dialysis (CAPD). Clin Nephrol 1981;15:328–330. Spinowitz BS, Golden RA, Rascoff JH, Charytan C: Eosinophilic peritonitis. Clin Exp Dial Apheresis 1982;6:187–191. Daugirdas JT, Leehey DJ, Popli S, Hoffman W, Zayas I, Gandhi VC, Ing TS: Induction of peritoneal-fluid eosinophilia and/or monocytosis by intraperitoneal air in injection. Am J Nephrol 1987;7:116–120. Martis L, Patel M, Giertych J, Mongoven J, Taminne M, Perrier MA, Mendoza O, Goud N, Costigan A, Denjoy N, Verger C, Owen WF: Aseptic peritonitis due to peptidoglycan contamination of pharmacopoeia standard dialysis solution. Lancet 2005;365:588–594. Harnett JD, Gill D, Corbett L, Parfrey PS, Gault H: Recurrent hemoperitoneum in women receiving continuous ambulatory peritoneal dialysis. Ann Intern Med 1987;107:341–343. Vlahakos D, Rudders R, Simon G, Canzanello VJ: Lymphoma-mimicking peritonitis in a patient on continuous ambulatory peritoneal dialysis (CAPD). Perit Dial Int 1990;10:165–167. Bargman JM, Zent R, Ellis P, Auger M, Wilson S: Diagnosis of lymphoma in a continuous ambulatory peritoneal dialysis patient by peritoneal fluid cytology. Am J Kidney Dis 1994;23:747–750. Bagnis C, Gabella P, Bruno M, Cosseddu D, Marangella M, Vacha GM, Linari F: Cloudy dialysate due to adenocarcinoma cells in a CAPD patient. Perit Dial Int 1993;13:322–323.

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Porter J, Wang WM, Oliveira DBG: Chylous ascites and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 1991;6:659–661. Fontán MP, Pombo F, Soto A, Fontán FJP, Rodriguez-Carmona A: Chylous ascites associated with acute pancreatitis in a patient undergoing continuous ambulatory peritoneal dialysis. Nephron 1993;63:458–461. Rocklin MA, Teitelbaum I: Cloudy dialysate as a presenting feature of superior vena cava syndrome. Nephrol Dial Transplant 2000;15:1455–1457. Yoshimoto K, Saima S, Nakamura Y, Nakayama M, Kubo H, Kawaguchi Y, Nishitani H, Nakamura Y, Yasui A, Yokoyama K, Kuriyama S, Shirai D, Kugiyama A, Hayano K, Fukui H, Horigome I, Amagasaki Y, Tsubakihara Y, Kamekawa T, Ando R, Tomura S, Okamoto R, Miwa S, Koyama T, Izuka T, Honda Y, Echizen H: Dihydropyridine type calcium channel blocker-induced turbid dialysate in patients undergoing peritoneal dialysis. Clin Nephrol 1998;50:90–93.

Dr. Isaac Teitelbaum, Medical Director Home Dialysis Program, University of Colorado Health Sciences Center 4200 E. 9th Ave. Denver, CO 80262 (USA) Tel. ⫹1 303 372 6753, Fax ⫹1 303 315 4852 E-Mail [email protected]

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Peritoneal Access: The Past, Present, and the Future Zbylut J. Twardowski University of Missouri, Columbia, Mo., USA

Abstract In the early years of peritoneal dialysis, there was no specific device for peritoneal dialysis; rather the devices used in general surgery and urology were taken advantage of for peritoneal access. These early devices, used for short-term peritoneal dialysis, were plagued with multiple complications, such as pressure on intestines of rigid tubes, plugging of openings, leakage of fluid around the access, and difficulties in fixation of the tube on the abdominal wall. In the late 1940s, after World War II, multiple peritoneal dialysis solution compositions and multiple peritoneal accesses were tried, and first accesses specifically for peritoneal dialysis were designed. In the 1950s and particularly 1960s new access features solved most of the problems and eliminated most complications of peritoneal dialysis performed in the supine position. The invention of silicone rubber catheter with polyester cuff(s) was a greatest breakthrough in peritoneal dialysis access development. Unfortunately, none of the currently used catheters is trouble free; poor dialysate drainage, pericatheter leaks, exit site and tunnel infections, and recurrent peritonitis episodes are frequently encountered. Therefore, there is an incessant search for new technological solutions, including new shapes of intraperitoneal and intramural catheter segments, and new catheter materials are tried. Copyright © 2006 S. Karger AG, Basel

Early History of Catheter Development (1923–1968)

In the early years of peritoneal dialysis the access was not specifically designed for the peritoneal dialysis, rather the available equipment used for other purposes was adapted. Ganter et al. [1] used a metal trocar, Rosenak and Siwon [2] modified a glass cannula used for surgical drains making a bulbous tip with multiple side holes. Reid et al. [3] used a Foley catheter. Major problems in these years were leakage, infection and catheter occlusion by clot or omental fat sucked into the catheter lumen. Fine et al. [4] adapted a stainless

steel sump drain for dialysate outflow and a rubber mushroom catheter for dialysis solution inflow. Although these innovations showed some improvement in infection rate and drainage, the overall results were not satisfactory, rigid tubes damaged viscera, and pericatheter leaks were frequent. Rosenak and Oppenheimer [5] for the first time developed an access specifically for peritoneal dialysis. Rosenak and Oppenheimer access consisted of stainless steel flexible coil attached to a rubber drain. The outer portion of the steel tube was attached to an adjustable tie plate for fixation and prevention of leakage. This device did not gain popularity because major problems were not solved: the rigid tube irritated viscera; dialysate leakage and peritoneal contamination were not eliminated. Ferris and Odel [6] modified a Rosenak and Oppenheimer access by replacing a steel coiled wire tube with a polyvinyl tube. This was the first use of plastic material for the peritoneal access. Additionally, to keep the catheter in the true pelvis they provided metal weights at the catheter tips. Frank et al. [7] also modified the sump drain providing it with a flexible rubber portion implanted in a long subcutaneous tunnel to prevent fluid leakage. Unlike in the past [4], the authors used mostly intermittent not continuous peritoneal dialysis this time [7]. The next major progress was made in late 1950s when Maxwell et al. [8] from the University of California in Los Angeles introduced a polyamide (nylon) catheter with multiple tiny (0.02 in ⫽ 0.0508 mm) distal perforations. The small diameter of perforations prevented particles of omentum from entering the catheter. Smooth, plastic materials were much less irritating to the peritoneum than previously used glass, rubber or steel, thereby omental occlusion became less frequent. The drainage of fluid from the peritoneal cavity was markedly improved, but leakage continued to plague the access. To circumvent the dialysate leakage problem, Weston and Roberts [9] invented a stylet catheter, which was inserted without a trocar. A sharp stainless steel stylet inserted through the catheter was used to penetrate the abdominal wall. As a result, the abdominal opening fitted snugly around the catheter, thereby reducing leak rates. A major step forward in creating a permanent peritoneal access was made in 1964. Gutch [10] noticed lower protein losses with silicon rubber catheters as compared to those with polyvinyl ones that suggested less irritation of the peritoneum with a new material. About the same time, Russell Palmer with the help of Wayne Quinton, already successful in manufacturing silicon rubber shunts for hemodialysis, developed a catheter, which is a prototype of currently used coiled catheters [11]. The catheter was made of silicon rubber; the intraperitoneal end was coiled, a long subcutaneous tunnel was supposed to hinder periluminal infection. To impede further infection and leakage, a

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tri-flanged step was created for securing the catheter in the deep abdominal fascia. A major breakthrough came in 1968 when Tenckhoff and Schechter [12] published the results of their studies on a new catheter. Their catheter was an improved version of the Palmer catheter. An intra-abdominal flange was replaced by a Dacron cuff, a subcutaneous tunnel was shortened and the second, external cuff was used to decrease the length of the catheter sinus tract. A shorter subcutaneous tunnel and straight intraperitoneal segment facilitated catheter implantation at the bedside with the aid of a specially designed trocar. To avoid excessive bleeding the catheter was inserted through the midline. The Tenckhoff catheter has become the gold standard of peritoneal access. Some of the original recommendations for catheter insertion such as arcuate subcutaneous tunnel with downward directions of both intraperitoneal and external exits are still considered very important elements of catheter implantation. Few complications were reported in patients treated by periodic peritoneal dialysis in the supine position. However, in patients treated with continuous ambulatory peritoneal dialysis, complications became more frequent, due to high intra abdominal pressure in the upright position and numerous daily manipulations. Nevertheless, even today, almost four decades later, Tenckhoff catheter in its original form is one of the most widely used catheter types.

Modifications to Mitigate Complications of the Tenckhoff Catheter

The most common complications of the Tenckhoff catheter included obstruction, dialysate leaks, and external cuff extrusion. To decrease catheter migration out of the true pelvis with subsequent omental wrapping, Oreopoulos et al. [13] provided the intraperitoneal part of the catheter with silicone rubber discs, Chiaramonte et al. [14] decided to shorten the catheter and implant it very low, just a few centimeters above the symphysis pubis, Di Paolo et al. [15] returned to the idea of Ferris and Odel of providing weights into catheter tips. Valli et al. [16] replaced the intraperitoneal tubing with a balloon attached to the abdominal wall to avoid migration. Ash and Janle [17] replaced the intraperitoneal tubing with a longitudinal tube with 1-mm wide ‘flutes’ or grooves on the surface. Locating such catheter tip just below the parietal peritoneum was supposed to prevent omental wrap. To prevent pericatheter leakage, a group from Toronto Western Hospital provided the catheter with a polyester flange at the base of the deep cuff and silicone rubber ring (or bead) situated close to the flange that provided a groove in

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Year – Name

1968 – Straight

Intraperitoneal design

Extraperitoneal Name – Year design Single cuff – 1968 Toronto Western Hospital single cuff with flange and bead – 1982 Double cuff – 1968

1964 – Coiled

1976 – Straight with discs 1992 – Straight with weight (Di Paolo)

Toronto Western Hospital with flange and bead at deep cuff – 1982 Swan neck double cuff – 1985 Swan neck double cuff Missouri (slanted flange and bead) – 1985

1993 – T-fluted (Ash) Swan neck presternal – 1992 1983–1988 – Balloon (Valli) Pail handle (Cruz) – 1992 1985 – Short (Vicenza)

Swan neck with elongated superficial cuff (Moncrief-Popovich) – 1993

Skin Peritoneum

Fig. 1. Commonly used peritoneal catheters. Combinations of intra- and extraperitoneal segments. Modified from [21].

which a purse string could tie the peritoneum tightly [18]. Instead of implantation through the linea alba, the catheter was inserted through the rectus muscle. To follow original Tenckhoff recommendations that the catheter should be implanted with an arcuate subcutaneous tunnel with downward directions of both intraperitoneal and external exits the catheter should have a permanent bend between the cuffs, otherwise the shape memory tends to push the cuff out of the tunnel. The catheters with such a bend are called swan neck catheters [19]. Similar principle was applied by Cruz to polyurethane pail handle catheters [20].

Most Commonly Used Chronic Peritoneal Catheters

Figure 1 (modified from ref. 21) depicts the most commonly used catheters: Tenckhoff straight and coiled, Toronto Western Hospital, swan neck abdominal in various combinations, swan neck presternal, Cruz, Moncrief-Popovich, Di Paolo, T-fluted, Valli and Vicenza.

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Double-Lumen Catheters for Continuous Flow Peritoneal Dialysis

Continuous flow peritoneal dialysis, introduced in 1926 by Rosenak and Siwon [2], was used concomitantly with intermittent flow peritoneal dialysis until the late 1960s. High fluid flows were used with either two catheters [2] or double lumen catheters [22]. The double lumen catheter of Lange et al. [22] was composed of a short, thick, nylon external catheter and a long, narrow, internal nylon catheter. The short catheter was inserted to the abdominal cavity first and though its lumen was inserted the long catheter. Ultimately, the fluid inflow was through the inner catheter to the pelvic gutter and drainage through the large catheter with openings below the parietal peritoneum of the anterior abdominal wall. The continuous flow peritoneal dialysis was abandoned in the 1970s as associated with technical difficulties due to catheter obstruction, abdominal pain related to high flow, and less then expected dialysis efficiency because of fluid channeling [23]. There is a renewed interest in continuous flow peritoneal dialysis, as it is believed that new peritoneal accesses may make this modality successful. One of these catheters, a fluted double-lumen catheter, has been recently described by Diaz-Buxo [24]. The internal part of this double-lumen catheter is similar to the T-fluted catheter with the exception that the latter is a single-lumen catheter. Another catheter, a double-lumen catheter with diffuser, has been recently developed by Ronco et al. [25]. The intraperitoneal segment of the outflow tubing has a coiled design. The intraperitoneal segment of the inflow tubing is a short, thin-walled, silicone rubber, round tapered diffuser with multiple side holes. This design is a reversal of the catheter of Lange et al. [22] where inflow was to the pelvic gutter and drainage through the large catheter with openings below the parietal peritoneum of the anterior abdominal wall.

Concluding Remarks

The Tenckhoff catheter, developed in 1968, continues to be widely used for chronic peritoneal dialysis, although its use is decreasing in favor of swan-neck catheters. Soft, silicone rubber instead of rigid tubing virtually eliminated such early complications as bowel perforation or massive bleeding. Other complications, such as obstruction, pericatheter leaks, and superficial cuff extrusions have been markedly reduced in recent years, particularly with the use of swanneck catheters and insertion through the rectus muscle instead of the midline. However, the complications still occur so new designs are being tried. A renewed interest in continuous flow peritoneal dialysis stimulated the inventions of imaginative, double-lumen catheters.

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References 1 2

3 4 5 6 7

8 9 10 11 12 13

14

15 16

17 18

19 20

21

Ganter G: Ueber die Beseitigung giftiger Stoffe aus dem Blute durch Dialyse (On the elimination of toxic substances from the blood by dialysis). Münch Med Wochenschr 1923;70:1478–1480. Rosenak S, Siwon P: Experimentelle Untersuchungen über die peritoneale Ausscheidung harnpflichtiger Substanzen aus dem Blute (Experimental investigations on the peritoneal elimination from the blood of substances normally excreted in urine). Mitt Grenzgeb Med Chir 1926;39:391–408. Reid R, Penfold JB, Jones RN: Anuria treated by renal decapsulation and peritoneal dialysis. Lancet 1946;CCLI:749–753. Fine J, Frank HA, Seligman AM: The treatment of acute renal failure by peritoneal irrigation. Ann Surg 1946;124:857–878. Rosenak SS, Oppenheimer GD: An improved drain for peritoneal lavage. Surgery 1948;23: 832–833. Ferris DO, Odel HM: An improved plastic tube for use in peritoneal lavage: preliminary report. Proc Staff Meet Mayo Clinic 1948;23:612–614. Frank HA, Seligman AM, Fine J, Frank ED, Manheimer LA, Heimberg F, Rutenburg AM, Banks HH, Nachlas MM: Further experiences with peritoneal irrigation for acute renal failure. Ann Surg 1948;128:561–608. Maxwell MH, Rockney RE, Kleeman CR, Twiss MR: Peritoneal dialysis. JAMA 1959;170: 917–924. Weston RE, Roberts M: Clinical use of stylet catheter for peritoneal dialysis. Arch Intern Med 1965;115:659–662. Gutch CF: Peritoneal dialysis. Trans Am Soc Artif Intern Organs 1964;X:406–407. Palmer RA, Quinton WE, Gray JE: Prolonged peritoneal dialysis for chronic renal failure. Lancet 1964;1:700–702. Tenckhoff J, Schechter H: A bacteriologically safe peritoneal access device. Trans Am Soc Artif Intern Organs 1968;XIV:181–187. Oreopoulos DG, Izatt S, Zellerman G, Karanicolas S, Mathews RE: A prospective study of the effectiveness of three permanent peritoneal catheters. Proc Clin Dial Transplant Forum 1976;6:96–100. Chiaramonte S, Feriani M, Biasoli S, Bragantini L, Brendolan A, Dell’Aquilla R, Fabris A, Ronco C, La Greca G: Clinical experience with short peritoneal dialysis catheters. Proc Eur Dial Transplant Assoc Eur Ren Assoc 1985;22:426–430. Di Paolo N, Petrini G, Garosi G, Buoncristiani U, Brardi S, Monaci G: A new self-locating catheter. Perit Dial Int 1996;16:623–627. Valli A, Andreotti C, Degetto P, Midiri R, Mazzon M, Rovati C, Valentini A, Crescimanno U, Depaoli Vitali E, Manili L, Camerini C: 48-months’ experience with Valli-2 catheter; in Khanna R, Nolph KD, Prowant BF, Twardowski ZJ, Oreopoulos DG (eds): Advances in Continuous Ambulatory Peritoneal Dialysis. Selected Papers from the Eight Annual CAPD Conference, Kansas City, Missouri, February 1988. Toronto, Peritoneal Dialysis Bulletin, Inc., 1988, pp 292–297. Ash SR, Janle EM: T-fluted peritoneal catheter. Adv Perit Dial 1993;9:223–226. Ponce SP, Pierratos A, Izatt S, Mathews R, Khanna R, Zellerman G, Oreopoulos DG: Comparison of the survival and complications of three permanent peritoneal dialysis catheters. Perit Dial Bull 1982;2:82–86. Twardowski ZJ, Nolph KD, Khanna R, Prowant BF, Ryan LP: The need for a ‘Swan Neck’ permanently bent, arcuate peritoneal dialysis catheter. Perit Dial Bull 1985;5:219–223. Cruz C: Clinical experience with a new peritoneal access device (the Cruz catheter); in Ota K, Maher J, Winchester J, Hirszel P, Ito K, Suzuki T (eds): Current Concepts in Peritoneal Dialysis: Proceedings of the Fifth Congress of the International Society for Peritoneal Dialysis, Kyoto, July 21–24, 1990. Amsterdam, London, New York, Tokyo, Excerpta Medica, 1992, pp 164–169. Twardowski ZJ, Nichols WK: Peritoneal dialysis access and exit site care including surgical aspects (Chapter 9); in Gokal R, Khanna R, Krediet RT, Nolph KD (eds): Peritoneal Dialysis, ed 2. Dordrecht/Boston/London, Kluwer Academic Publishers, 2000, pp 307–361.

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Lange K, Treser G, Mangalat J: Automatic continuous high flow rate peritoneal dialysis. Arch Klin Med 1968;214:201–206. Twardowski ZJ: New approaches to intermittent peritoneal dialysis therapies (Chapter 8); in Nolph KD (ed): Peritoneal Dialysis, ed 3. Dordrecht/Boston/London, Kluwer Academic Publishers, 1989, pp 133–151. Diaz-Buxo JA: Streaming, mixing, and recirculation: role of the peritoneal access in continuous flow peritoneal dialysis (clinical considerations). Adv Perit Dial 2002;18:87–90. Ronco C, Gloukhoff A, Dell’Aquila R, Levin NW: Catheter design for continuous flow peritoneal dialysis. Blood Purif 2002;20:40–44.

Zbylut J. Twardowski, MD, PhD Professor Emeritus of Medicine, University of Missouri Dialysis Clinic, Inc., 3300 LeMone Industrial Blvd Columbia, MO 65201 (USA) Tel. ⫹1 573 443 1531 x 256 E-Mail [email protected]

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How to Optimise Anaemia Therapy in Peritoneal Dialysis Patients Iain C. Macdougall Department of Renal Medicine, King’s College Hospital, London, UK

Abstract As with other groups of chronic kidney disease patients, the treatment of anaemia is of paramount importance in the general management of patients receiving regular peritoneal dialysis. The availability of agents able to stimulate erythropoiesis has transformed the management of anaemia in CKD, but questions are still raised as to the optimum means of using these drugs. Iron management is also pivotal to the satisfactory correction of anaemia, and again there is much discussion as to whether oral or intravenous iron is the preferred mode of administration in peritoneal dialysis patients. On the basis of the published evidence to date, PD patients should maintain a haemoglobin above 11 g/dL in line with the US and the European Anaemia guidelines, and intravenous iron should be used to correct any iron deficiency. Oral iron may be effective in a minority of patients. This article aims to explore some of these issues in greater detail so that patients on peritoneal dialysis can derive the greatest benefits from correction of anaemia and maintenance of an adequate haemoglobin. Copyright © 2006 S. Karger AG, Basel

Anaemia is an almost universal complication of end-stage renal failure [1, 2], and the vast majority of dialysis patients receive anaemia therapy as part of their routine management. Peritoneal dialysis (PD) patients generally are less severely affected than their haemodialysis counterparts, with slightly fewer patients requiring regular erythropoiesis-stimulating agent (ESA) therapy. However, depending on the criteria for the introduction of ESAs, around 80–90% of PD patients will require this in order to maintain a haemoglobin concentration above 11 g/dl, in line with both the US and the European Guidelines on Renal Anaemia Management [3, 4]. The benefits of correcting anaemia and maintaining haemoglobin levels above 11 g/dl are two-fold: firstly, to limit the debilitating symptoms associated with chronic anaemia, such as low

energy levels, poor exercise capacity, exertional dyspnoea, etc. and secondly, to limit the adverse pathophysiological effects on the heart [5]. Quality-of-life in dialysis patients has also been shown to be significantly improved with a higher haemoglobin [6, 7]. The aim of this review is to discuss some of the critical issues in relation to optimisation of anaemia therapy in the PD population, including when to initiate therapy, target haemoglobin, how to treat the anaemia, how to manage anaemia during the infective complications of PD, etc. As far as is appropriate, these issues will be discussed with particular reference to PD, and some of the comments may not be generally applicable across the whole spectrum of chronic kidney disease (CKD) patients.

When to Initiate Anaemia Therapy

Since the decline in haemoglobin concentration in CKD patients is a gradual and continuous phenomenon [1], much discussion has evolved around the appropriate haemoglobin concentration at which anaemia should be investigated, and treatment initiated. According to various criteria, anaemia is present in males when their haemoglobin concentration is ⬍13 g/dl, and in females when the haemoglobin is ⬍12 g/dl [8]. There is, however, little or no evidence that initiating anaemia therapy at these levels is of any significant benefit to patients. The Working Groups of both the US and the European Guidelines on Renal Anaemia Management conducted extensive literature reviews regarding the most appropriate threshold haemoglobin at which anaemia therapy should be initiated [3, 4]. The general consensus is that, although there is no breakpoint value of haemoglobin below which the deleterious effects of chronic anaemia rapidly escalate, a recommended cut-off haemoglobin of 11 g/dl is a reasonable compromise. Pending further scientific evidence, this haemoglobin threshold is considered appropriate for all CKD patients, including those receiving PD.

Target Haemoglobin Concentration

This is the most debated topic in the field of Renal Anaemia Management. The early clinical trials of recombinant human erythropoietin (epoetin) therapy were designed to prove the concept that this new therapy was able to correct the anaemia of chronic kidney disease [9–11]. The target haemoglobin in these clinical trials was around 11–12 g/dl, and given that many of the patients recruited to these trials had starting haemoglobins around 6–7 g/dl, the clinical

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effects were dramatic. It was, however, recognised that the achieved haemoglobin in these clinical studies was lower than that for a non-uraemic age- and sexmatched population, and several studies were designed to examine whether a more complete correction of anaemia (e.g. a haemoglobin concentration around 14 g/dl) could result in lower mortality, reduced morbidity, and better qualityof-life [7, 12–15]. The largest randomised controlled trial involving over 1,200 patients was in the haemodialysis population [12], and the main conclusion was that there was no additional benefit to patients targeting a haemoglobin of 14 g/dl compared with a more conventional haemoglobin of around 10 g/dl. Although there are some limitations of this trial, it is the largest one of its kind ever performed, and it had a huge impact on the discussions about target haemoglobin. One of the critical issues is how applicable this large randomised controlled study [12] is to the PD population. It is generally recognised that haemodialysis patients may transiently increase their haemoglobin concentration further across a dialysis session by anything from 1 to 3 g/dl depending on how much fluid is ultrafiltered, and exactly how much this may have impacted on the outcome in the higher haemoglobin group is not clear. PD patients are not exposed to such dramatic fluid shifts, and thus maintain a more constant haemoglobin on a day-to-day basis. A Scandinavian randomised controlled trial [13] also compared target haemoglobins of 10 vs. 14 g/dl, and this study recruited all categories of CKD patients, including those on haemodialysis, PD, and pre-dialysis. Although there was no evidence of harm at the higher haemoglobin of 14 g/dl, the benefits were fairly minimal, being largely confined to quality-of-life assessments [13]. The costs associated with anaemia therapy at a higher target haemoglobin are significantly greater, and the general consensus from both the US and the European Guidelines [3, 4] is that targeting a haemoglobin of 14 g/dl for an entire CKD population is inappropriate, given the greater costs, minimal benefits, and greater potential for increased harm. There may be individual patients, however, who may benefit from a higher target haemoglobin concentration, and such individualisation of therapy is hard to prove in large clinical trials. Given that PD patients are not exposed to the rapid changes in haemoglobin caused by ultrafiltration across a dialysis session, there is perhaps less concern about such patients running a haemoglobin concentration of around 13–14 g/dl. The US and European Renal Anaemia Guidelines both recommend a haemoglobin concentration above 11 g/dl, with no fixed upper limit [3, 4]. Both guidelines, however, also advise caution to be exercised in specific patient groups, particularly those with cardiac disease or diabetes, but the evidence for this is largely derived from the trials in haemodialysis patients. Thus, if a PD patient easily achieves a haemoglobin of 13–14 g/dl on a low dose of ESA, then there is no evidence to suggest that this should be decreased to a lower haemoglobin

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Table 1. Basic screening tests for other causes of anaemia Ferritin, B12, and folate levels CRP level Haemoglobinopathy screen Serum immunoglobulin levels/protein electrophoresis to exclude myeloma ? PTH level

level. Almost without exception, all the randomised controlled trials regarding target haemoglobin have shown better quality-of-life indices at haemoglobin concentrations of 14 g/dl compared with 10 g/dl [13–15], but harder end-points such as cardiovascular mortality, cardiovascular morbidity, and left ventricular geometry show little difference across this range [14, 15].

How to Treat Anaemia in PD Patients

Exclude Other Causes of Anaemia Before more specific therapies such as ESAs and iron supplementation should be considered, it is important to consider and exclude other contributory causes of anaemia. As a very basic screen, the tests listed in table 1 should be requested, if not done previously. Thus, in addition to iron status, B12 and folate levels should be measured. A CRP level may be useful to indicate the degree of underlying inflammation, and assist in the interpretation of a ferritin level (which may be spuriously elevated in the presence of inflammation). If the ethnic background of a patient suggests that there may be an underlying haemoglobinopathy (e.g. sickle cell disease in Africans, thalassaemia in certain Mediterranean patients), then this should be screened for. Myeloma is a not-infrequent cause of anaemia and renal failure, and if there is any uncertainty regarding the cause of this patient’s chronic kidney disease, or if there are any other features to suggest myeloma, then measurement of serum immunoglobulins or protein electrophoresis may be appropriate. Finally, if not already performed, a PTH level may be useful in determining the degree of secondary or tertiary hyperparathyroidism, but there is considerable debate about whether parathyroid overactivity per se impacts on the degree of anaemia. In advanced cases of hyperparathyroidism, marrow fibrosis (osteitis fibrosa cystica) may be present, and this can reduce the number of active erythroid progenitor cells in the bone marrow.

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Nutrition and Dialysis Adequacy Again before considering more specific anaemia therapy, some attention should be paid to the nutritional status and adequacy of PD. Protein malnutrition may negatively impact on correction of anaemia, and other nutritional/ hormonal deficiencies should be excluded as appropriate. Thus, routinely screening for hypothyroidism may not be indicated in every patient, but if there are features suggestive of this condition, then measurement of thyroid function tests should be performed. There is a plethora of literature on dialysis adequacy and anaemia correction in haemodialysis patients, with fairly robust evidence to suggest that underdialysis may reduce the efficiency of this [16]. In PD patients, however, the evidence for this is much less strong; nevertheless, as a matter of general principle, some attention should be paid to ensuring that the patient is adequately dialysed.

Iron Management

Iron losses are much less in patients receiving PD compared with those receiving regular haemodialysis. Nevertheless, even PD patients may be in negative iron balance, due to poor dietary intake, anorexia, and impaired iron absorption, while increased iron losses may be due to occult gastrointestinal bleeding. On top of this, there is a need for increased iron supplementation to support the enhanced erythropoiesis during ESA therapy [17]. Screening for iron deficiency may be conducted by performing a variety of tests which include the serum ferritin level, serum iron/TIBC levels (transferrin saturation), percentage of hypochromic red cells, reticulocyte haemoglobin content (CHr), serum transferrin receptor, etc. [17]. The ferritin level is a useful guide to iron stores, but may be spuriously elevated in patients with liver disease and inflammation. The Guidelines on Renal Anaemia Management recommend a target ferritin range of between 200 and 500 ␮g/l in CKD patients [3], although most of the scientific evidence to support this recommendation comes from the haemodialysis literature. Nevertheless, the absolute minimum specified ferritin level of 100 ␮g/l in PD patients seems sensible, pending further studies. Likewise, minimum thresholds of 20–30% (for transferrin saturation), ⬍10% (for hypochromic red cells), ⬎29 pg/cell (for CHr) should be targeted, if measured [3]. With regard to iron replacement, there is ongoing controversy about this. In haemodialysis patients, intravenous iron is usually mandatory to support the iron requirements for enhanced erythropoiesis [3], while in PD patients this is less clear. Intramuscular iron is not generally recommended in CKD patients

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since the injections are painful, can result in brownish discoloration of the skin, and can cause intramuscular bleeding due to the platelet defects associated with uraemia. Oral iron is simple, cheap, and easy to administer. Unfortunately, there is increasing evidence that oral iron is not well absorbed in uraemic patients, due to increased hepcidin activity. Nevertheless, some nephrologists prefer to try supplementation with oral iron first, despite the fairly high incidence of gastrointestinal side-effects associated with this [18]. Ferrous sulphate (200 mg ⫻ 1–3/day) is as effective as any other oral iron, and is often the preferred starting option. A significant proportion of patients, however, will either not tolerate this, or alternatively have an inadequate response to oral iron. In such cases, intravenous iron may be used. Administration of IV iron in patients receiving PD is clearly less practical than in haemodialysis. Firstly, patients have no ready vascular access, and secondly they are attending hospital much less regularly. Nevertheless, there is reasonable evidence that intravenous iron supplementation can enhance the response to ESAs, and result in lower dose requirements of the latter agents [19, 20]. Intravenous iron may be given as a bolus injection or as an infusion. In the outpatient setting, bolus injections may be more convenient, and there is literature supporting the use of bolus injections of iron dextran [21] or iron sucrose [22]. In our unit, we administer 200 mg boluses of iron sucrose over 2 min, which we believe to be safe and effective [22]. Nevertheless, occasional reactions to all intravenous iron preparations may occur; with the exception of iron dextran which can cause anaphylaxis due to dextran antibodies, these reactions are usually due to too high a dose administered too rapidly. Other concerns about intravenous iron include enhanced susceptibility to infection or oxidative stress [23], but it is unknown at the present time whether there is any difference in the potential risks of these complications between bolus administration and infusion of IV iron. Also, much of the data to support these theoretical concerns is derived from in vitro studies, while the large clinical studies examining these issues do not generate any concerns regarding safety [24, 25]. Further data are, however, required to provide a more definitive answer to this ongoing controversy.

ESA Therapy

Choice of Agent At the present time, there are three licensed products which may be used to stimulate erythropoiesis in CKD patients. These include epoetin alfa (Eprex; Erypo in Germany), epoetin beta (NeoRecormon), and darbepoetin alfa (Aranesp). In Europe, epoetin alfa is currently not licensed for subcutaneous use, although this is currently under review by the EMEA. Thus, in the PD

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population, Eprex is not practical for chronic administration since it can only be given by the intravenous route. Both of the other agents are effective in PD patients, and a starting dose of 2,000 units of epoetin beta (NeoRecormon) 2–3 times a week, or 30 ␮g of darbepoetin alfa (Aranesp) once-weekly is reasonable [3]. Higher starting doses may be appropriate in certain specific circumstances e.g. patients with myeloma and end-stage renal failure. No agent is more effective than any other, and the choice of ESA is often driven by marketing pressures and personal preferen ces. Both agents have individual minor advantages; thus, darbepoetin alfa has stronger evidence for once-weekly administration in PD patients, while epoetin beta is often given more than once a week. However, subcutaneous darbepoetin alfa injections are more painful and irritant than epoetin beta injections; this is poorly documented in the scientific literature [26], but is a widely recognised perception. Route of Administration In PD patients, the only practical and sensible route of administration is the subcutaneous route [3]. Although IV administration is efficacious, the frequency of injections make it impractical for long-term use. In the very early days of epoetin use, the intraperitoneal route was examined in PD patients, but the bioavailability of erythropoietin administered IP was dismally low [27], again making this route impractical for long-term use. Thus, the wastage of this high-cost drug was too great to support the use of the intraperitoneal route of administration, even though the bioavailability may be slightly enhanced by instilling the erythropoietin into a dry peritoneum overnight. As with diabetics self-injecting insulin, PD patients are usually taught to selfadminister their own ESA subcutaneously at home. Although this practice is widely used, erratic use or even non-compliance should be considered in any patient either showing a poor response to ESA therapy or requiring high doses of the drug. Expected Response to ESA Therapy Provided iron stores are adequate to support the enhanced erythropoiesis (minimum ferritin 100 ␮g/l), the haemoglobin concentration should increase by approximately 0.25 g/dl of haemoglobin per week (1 g/dl per month) in patients commencing a weekly dose of 4,000–6,000 units of epoetin beta, or 30 ␮g of darbepoetin alfa. There is, however, considerable variability in responsiveness to ESA therapy from one patient to another, but somewhere in the region of 90% of patients should respond to these starting doses. If the haemoglobin rise is less than expected, then causes of a poor response to treatment should be considered and investigated.

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Table 2. Causes of a poor response to ESA therapy Major

Minor

Iron deficiency Infection/inflammation Underdialysis

Blood loss Hyperparathyroidism Aluminium toxicity B12/folate deficiency Haemolysis Marrow disorders, e.g. MDS Haemoglobinopathies ACE inhibitors Carnitine deficiency Obesity (SC EPO) Anti-EPO antibodies (PRCA)

Reticulocyte count

(Absolute ⫺ ⫻109/l)

High (⬎100 ⫻109/l)

Low (⬍40 ⫻ 109/l) ? Compliance

If SC and self-injecting

Look for blood loss/haemolysis Endoscopy/colonoscopy/ Coombs/bilirubin/LDH

? Iron deficiency

Ferritin/Fe/TIBC/%HRC

? Trial of IV iron Look for infection/ inflammation/ underdialysis

CRP/dialysis adequacy test ? ↑ dialysis

Vitamin B12 /folate/PTH ? on ACE-I (Hb electrophoresis)

? Bone marrow

Try ↑ dose of ESA

Fig. 1. Investigation of a poor response to ESA therapy.

Poor Response to ESA Therapy Any patient showing a sub-optimal response to ESA therapy should be investigated for an underlying cause [28]. The common causes of hyporesponsiveness are listed in table 2, and a suggested algorithm for investigating this

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problem is outlined in figure 1. Thus, the most common causes of a poor response to ESA therapy are iron deficiency, infection/inflammation, or underdialysis. Less common, but still important, causes of resistance to therapy include other haematinic deficiencies such as B12 or folate, bleeding, haemolysis, primary marrow disorders (such as myelodysplastic syndrome), and haemoglobinopathies. Antibody-mediated pure red cell aplasia, although sensationally highlighted in the literature over the last few years, is astonishingly rare, and should be considered only after other more common causes have been excluded. A useful screening test in any patient showing a less than optimal response to ESAs is the absolute reticulocyte count. Although this is not an exact science, patients receiving conventional doses of ESAs generally run reticulocyte counts between 50 and 100 ⫻ 109/l. Patients with low reticulocyte counts (e.g. ⬍40 ⫻ 109/l) should firstly be evaluated for compliance. Measurement of erythropoietin levels may expose any patient who denies this as a problem. Iron status should then be examined, and if there is any possibility of iron deficiency then a trial of intravenous iron may be useful. Investigation for underlying causes of infection/inflammation may be indicated if the CRP level is high, while attention should be paid to the possibility of underdialysis. Measurement of vitamin B12 or folate levels may be useful in excluding these less common haematinic deficiencies, and examination of the PTH level may exclude severe hyperparathyroidism. Some patients on ACE inhibitors appear to develop some resistance to ESA therapy [29]; this is an individual effect which is not usually seen on a population basis. Haemoglobin electrophoresis may be useful to exclude haemoglobinopathies if not previously performed. If there is still doubt about the poor response to therapy, then a bone marrow test may be useful, and will reveal such causes as myelodysplastic syndrome. If all else fails, then it may be appropriate to try escalating the dose of ESA therapy. If the reticulocyte count is high, particularly if this is above 200 ⫻ 109/l, then blood loss or haemolysis are the only possible causes of this. Endoscopy or colonoscopy may be appropriate for examination of bleeding, while a haemolysis screen may include a Coombs test, bilirubin level, LDH level, and haptoglobins.

How to Manage Anaemia During Peritonitis and Other Infective Complications of PD

As indicated above, patients may exhibit a poor response to anaemia therapy during the frequently encountered infective complications of PD, including peritonitis. Fortunately, such complications are usually transient in nature, and

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thus any exacerbation of anaemia is short-lived. Nevertheless, many nephrologists question what to do about the dose of ESA therapy during this interim period. Some physicians seem to continue with the present dose of ESA therapy, waiting for the infective episode to resolve, while others increase the dose of ESA therapy in the short-term. Others (for economic reasons) reduce the dose of ESA therapy, or even stop this altogether, believing that it is a waste of money since patients will not respond to therapy while the infection is rampant. This latter strategy, while economically understandable, often results in a more severe anaemia, and may also cause some difficulty in restoring the response to ESA therapy. The author’s personal preference would be to either leave the dose of ESA the same, or perhaps double the dose in the short-term. Also, intravenous iron should not be administered during any infectious complications, for two reasons. Firstly, any infection exacerbates a functional iron deficiency, by which the utilisation of iron is impaired. This is almost certainly mediated by hepcidin. Secondly, there is good evidence to suggest that iron enhances bacterial proliferation and reduces polymorphonuclear function, particularly phagocytosis [23]. For both these reasons, there is no indication to give IV iron at this time, and indeed to do so may be harmful. In summary, therefore, while the infectious complication is being treated with antibiotics, ESA therapy should be maintained with or without a dose increase, while IV iron therapy should be completely avoided. Monitoring of CRP and reticulocyte count may be useful as a guide to predicting when the response to ESA therapy might be restored.

Conclusions

Anaemia management in PD patients is not dissimilar from that in the haemodialysis or pre-dialysis populations, although some specific characteristics are present. Thus, PD patients are more responsive to ESA therapy than their haemodialysis counterparts, while the practical route of administration is the subcutaneous one. Administration of intravenous iron is less convenient in PD patients, but nevertheless should be considered in patients who might benefit from this. Pending further scientific evidence, bolus injections may be more practical than infusions of IV iron over several hours. Patients receiving regular PD should maintain a haemoglobin concentration above 11 g/dl, in line with the current US and European Guidelines. Finally, the advent of novel ESAs, such as CERA and Hematide, is imminent, and these therapies may be particularly useful in PD patients if their once-monthly administration schedules are confirmed to be effective and safe in this patient population.

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7

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10

11

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Hsu CY, McCulloch CE, Curhan GC: Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002;13:504–510. Pereira BJ: New perspectives in chronic renal insufficiency. Am J Kidney Dis 2000;36(suppl 3): S1–S3. Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckardt KU, Horl WH, Macdougall IC, Macleod A, Wiecek A, Cameron S, European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004;19(suppl 2):ii1–ii47. K/DOQI Anemia Guidelines in CKD patients. Am J Kidney Dis 2006; in press. Levin A, Singer J, Thompson CR, Ross H, Lewis M: Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis 1996;27: 347–354. Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ 1990;300: 573–578. Moreno F, Sanz-Guajardo D, Lopez-Gomez JM, Jofre R, Valderrabano F: Increasing the hematocrit has a beneficial effect on quality of life and is safe in selected hemodialysis patients. Spanish Cooperative Renal Patients Quality of Life Study Group of the Spanish Society of Nephrology. J Am Soc Nephrol 2000;11:335–342. World Health Orgainzation. Nutritional Anaemias; Report of a WHO Scientific Group. World Geneva, Switzerland, Health Organization’s, 1968. Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM: Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;2:1175–1178. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73–78. Macdougall IC, Lewis NP, Saunders MJ, Cochlin DL, Davies ME, Hutton RD, Fox KA, Coles GA, Williams JD: Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990;335:489–493. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584–590. Furuland H, Linde T, Ahlmen J, Christensson A, Strombom U, Danielson BG: A randomized controlled trial of haemoglobin normalization with epoetin ␣ in pre-dialysis and dialysis patients. Nephrol Dial Transplant 2003;18:353–361. Foley RN, Parfrey PS, Morgan J, Barre PE, Campbell P, Cartier P, Coyle D, Fine A, Handa P, Kingma I, Lau CY, Levin A, Mendelssohn D, Muirhead N, Murphy B, Plante RK, Posen G, Wells GA: Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 2000;58:1325–1335. Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D: Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 2005;16:2180–2189. Locatelli F, Del Vecchio L: Dialysis adequacy and response to erythropoietic agents: what is the evidence base? Nephrol Dial Transplant 2003;18(suppl 8):viii29–viii35. Macdougall IC: Monitoring of iron status and iron supplementation in patients treated with erythropoietin. Curr Opin Nephrol Hypertens 1994;3:620–625. Charytan C, Qunibi W, Bailie GR; Venofer Clinical Studies Group. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron Clin Pract 2005;100:c55–c62.

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Fishbane S, Frei GL, Maesaka J: Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995;26:41–46. Macdougall IC, Tucker B, Thompson J, Tomson CRV, Baker LRI, Raine AEG: A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 1996;50: 1694–1699. St Peter WL, Lambrecht LJ, Macres M: Randomized cross-over study of adverse reactions and cost implications of intravenous push compared with infusion of iron dextran in hemodialysis patients. Am J Kidney Dis 1996;28:523–528. Macdougall IC, Roche A: Administration of intravenous iron sucrose as a 2-minute push to CKD patients: a prospective evaluation of 2,297 injections. Am J Kidney Dis 2005;46:283–289. Fishbane S: Iron treatment: impact of safety issues. Am J Kidney Dis 1998;32(suppl 4): S152–S156. Hoen B, Paul-Dauphin A, Hestin D, Kessler M: EPIBACDIAL: a multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 1998;9:869–876. Feldman HI, Joffe M, Robinson B, Knauss J, Cizman B, Guo W, Franklin-Becker E, Faich G: Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 2004;15:1623–1632. Choukroun G, Gelu-Mantoulet S, Rouanet S, De Chasteigner A, Montestruc F, Berthoux F: Pain at the injection site: results of the first crossover study comparing epoetin beta and darbepoetin ␣ administered subcutaneously in healthy volunteers. Nephrol Dial Transplant 2005;20(suppl 5): v262. Macdougall IC, Roberts DE, Neubert P, Dharmasena AD, Coles GA, Williams JD: Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet 1989;1:425–427. Macdougall IC: Hyporesponsiveness to anemia therapy – what are we doing wrong? Perit Dial Int 2001;21(suppl 3):S225–S230. Macdougall IC: The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin. Nephrol Dial Transplant 1999;14:1836–1841.

Dr. Iain C. Macdougall Consultant Nephrologist, Renal Unit King’s College Hospital London SE5 9RS (UK) Tel. ⫹44 207 346 6234, Fax ⫹44 207 346 6472 E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 214–225

Calcium and Phosphate Handling in Peritoneal Dialysis Mario Cozzolino, Maurizio Gallieni, Giusy Chiarelli, Diego Brancaccio Renal Unit, S. Paolo Hospital, Milan, Italy

Abstract In the last 10 years, it has been well documented that mineral metabolism abnormalities in dialysis patients are associated with an enhanced risk of morbidity and mortality for cardiovascular disease. Extraskeletal calcifications represent one of the major risk factors involved in the pathogenesis of cardiovascular disease in this population. In fact, secondary hyperparathyroidism and hyperphosphatemia associate with increased cardiovascular mortality in uremic patients for two reasons: first for the passive deposition of calcium and phosphate in soft tissues; second for the active role of inorganic phosphate on direct induction of extraskeletal mineralization of the tunica media in the vasculature of these patients. In peritoneal dialysis patients, many unbalances of calcium and phosphate metabolism are present. In particular, recent cohort studies indicate that most patients do not reach targets indicated by clinical practice guidelines. Further efforts to control hyperphosphatemia are essential, in order to reduce the impact of secondary hyperparathyroidism both on bone and cardiovascular system. Copyright © 2006 S. Karger AG, Basel

In a recent large, prospective, multicenter, cohort study form the Netherlands [1], it was found that the presence of plasma phosphorus and Ca ⫻ P product concentrations greater than K/DOQI targets increased all-cause mortality risk in hemodialysis (HD) and peritoneal dialysis (PD) patients. In particular, all-cause mortality risk increased in HD patients by 40% and in PD patients by 60% for plasma phosphorus levels greater than the target. In addition, having elevated plasma Ca ⫻ P product levels increased mortality risk by 40% in HD patients and 50% in PD patients. In both patient groups, no significant effects were observed for plasma levels less than the targets. Therefore, Ca and P handling in dialysis patients, including and maybe even more importantly in PD, is of crucial importance for patient survival.

The reasons for the increased mortality of patients with poor phosphate control are not well defined, but its clear relationship with increased cardiovascular calcification is very likely a causative factor. During the last decade, many investigators have focalized their own research on the impact of hyperphosphatemia, elevated serum calcium–phosphate product levels, and secondary hyperparathyroidism on vascular calcification in dialysis patients, although the pathogenesis of this process is still incompletely understood [2, 3]. In fact, dialysis patients have increased arterial stiffness and high morbidity and mortality due to cardiovascular events, due to extensive arterial calcification [4]. Moreover, soft tissues and blood vessel walls mineralization occurs often in dialyzed patients compared to the non-uremic population [5–7]. Recently, many risk factors have been supposed to be associated with vascular calcification in dialysis patients (vintage on dialysis, inflammation, hyperhomocystenemia, etc.), but mineral metabolism disorders seem to play a major pathogenetic role in this disease [8]. Hyperphosphatemia has been recently investigated as inducing factor on extra-skeletal calcification in uremic population. In particular, elevated serum levels of phosphate are associated with ectopic calcifications and increased risk of calciphylaxis [9–11]. In vitro studies demonstrated that human vascular smooth muscle cells (VSMCs) are predispose to calcify, only if treated with a high phosphate medium (P 2.0 mmol/l), where calcium and vitamin D are not changed [12]. Furthermore, vascular calcification was shown to involve not only a passive calcium–phosphate deposition on atherosclerotic vessels but also an active ‘ossification’ of vascular structures. Since vascular calcifications are predictive of higher morbidity and mortality, the control of serum phosphorus in dialysis patients is crucial in preventing elevations in calcium–phosphate product, secondary hyperparathyroidism, and so far vascular mineralization [13]. Recent studies have shown that new pharmacological tools may be useful to prevent vascular calcifications in animals and humans [14–16].

Pathogenesis of Vascular Calcification

Vascular mineralization is characterized not only by a passive calcium– phosphate deposition in the vasculature, but also by an active transformation of arterial walls in bone structures regulated by genes associated with osteoblastic functions [2]. Recent studies identified a potential role of phosphate on ‘active’ regulation of vascular calcification. In vivo studies by Kuro-o et al. [17] illustrate a 2-fold

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increase in serum-phosphate levels in the KLOTHO-gene mutant mice, resulted in increased calcium–phosphate product with the development of vascular calcifications and osteoporosis, in the presence of normal renal function. In addition, Jono et al. [12] and Giachelli [18] showed that high phosphorus levels in the incubation media (2 mmol/l) increased human aortic smooth muscle cells calcification. Phosphate-containing mineral deposition was predominant in the extracellular matrix [12]. Furthermore, these in vitro studies indicated that high phosphate directly increases human aortic smooth muscle cells calcification by inducing the expression of the sodium–phosphate cotransporter Pit-1 and the osteoblast-specific genes Osf2/Cbfa-1 [12]. Cbfa-1 is a transcription factor that regulates the expression of osteocalcin [19], one of the key osteoblast-specific genes in vitro and in vivo. Further evidence has been reported on the function and action of a boneassociated protein: osteopontin. In two recent studies, Wada et al. [20] proposed that osteopontin acts as an inhibitor of calcification of VSMC cultures, while Jono et al. [21] demonstrated that the phosphorylation of osteopontin was a mandatory step to inhibit VSMCs calcification. Thus, osteopontin is both an important bone mineralization modulator and a potent inhibitor of vascular calcification. In very recent review article, Giachelli et al. [22] analyzed the opposite roles of phosphate and osteopontin on regulating vascular calcification. In fact, while phosphate induces directly vascular smooth muscle cells mineralization, osteopontin may stimulate cellular mineral resorption and inhibit calcium–phosphate deposition. Furthermore, smooth muscle cells isolated form osteopontin knock-out mice (OPN ⫺/⫺) have a significant higher calcification grade when are incubated in a medium containing elevated concentrations of inorganic phosphate [23]. Clearly, there are growing data that suggest that vascular calcification is an active process. Moreover, considering serum calcium and phosphate levels, physio-chemically crystallization should immediately occur, in the absence of active inhibitors. However, serum biological macromolecules have an inhibitory effect on calcium–phosphate precipitation. Loss of these inhibitory proteins, such as BMP-7, fetuin-A, and matrix GLA protein (MGP) determines arterial mineralization. Bone Morphogenic Protein-7 (BMP-7) is a crucial element for the development of kidneys, eyes and bones [24]. Interestingly, BMP-7 expression decreases early in the course of renal failure [25]. This state of BMP-7 deficiency has important consequences in the pathogenesis and treatment of chronic renal insufficiency [26], but is also very interesting for the pathogenesis and treatment of vascular calcifications. Indeed, BMP-7 maintains VSMC differentiation and prevents their transformation into an osteoblastic phenotype [27]. Thus, the state of BMP-7 deficiency, characteristic of chronic renal failure,

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could favour vascular calcification, especially in the context of atherosclerotic lesions. ␣2-Heremans-Schmid glycoprotein, also known as human fetuin, is another important inhibitor of extraskeletal calcification. Serum concentration of AHSG falls during the cellular immunity-phase of inflammation [28]. In vitro, fetuin inhibits the de novo formation and precipitation of calcium–phosphate, with no effects on hydroxyapatite once it is formed [29]. AHSG antagonizes the antiproliferative action of TGF-␤1, blocks osteogenesis and deposition of calcium-containing matrix in dexamethosone-treated rat bone marrow cells [30]. Fetuin-deficient mice develop extensive ectopic calcifications in myocardium, kidney, lung, tongue, and skin [31]. In addition, HD patients with lower serum fetuin levels have increased mortality due to cardiovascular events [32]. This observation by Ketteler et al. [32] suggests that AHSG is involved in preventing the accelerated extraskeletal calcification observed in CKD. The potential role of fetuin in the pathogenesis of extraskeletal calcification in CKD patients is still poorly understood. Clearly, AHSG binds calcium and hydroxyapatite, fetuin knock-out mice have soft tissue calcifications, and serum AHSG levels are reduced in both uremic and inflammatory conditions. Therefore, loss of serum and local fetuin could directly promote vascular calcification in uremic patients. MGP is a member of the vitamin K-dependent protein family with unique structural and physical properties. During the first 2 months of life, MGPdeficient mice develop diffuse arterial calcification, osteoporosis, and pathological fractures [33]. For its properties as extracellular matrix protein with high affinity for calcium and phosphate, MGP plays an important role in the prevention of vascular calcification and in the pathogenesis of osteoporosis [34], although its effects in CKD patient are still unclear. Binding bone morphogenetic protein-2 (BMP-2), MGP elicits an inhibitory mechanism on mineralization [35]. In conclusion, several studies support an active role of phosphate on regulating arterial mineralization, ‘similar’ to bone formation. However, new evidences are necessary to better understand pathogenic mechanisms of vascular calcification in chronic kidney disease, and the potential role of phosphate on controlling directly this disease.

The Impact of Vascular Calcification in Dialysis Patients

Cardiovascular events are the most frequent cause of death in patients with chronic renal failure [4]. Calcification of soft tissues and blood vessel walls occurs frequently in dialyzed patients compared to the non-uremic population [36]. Hyperphosphatemia and increased calcium–phosphate product are important

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contributors to vascular calcifications in uremic patients and also appear to be associated with increased mortality [2]. In particular, elevated blood levels of phosphate associate with ectopic calcifications and increased risk of calciphylaxis [11]. Unfortunately, the pathogenic effects of hyperphosphatemia, high calcium–phosphate product, and secondary hyperparathyroidism on enhancing vascular calcification in chronic renal failure are still poorly understood. Since vascular calcifications are predictive of higher morbidity and mortality, the control of serum phosphorus in patients with chronic renal failure is crucial in preventing increases in calcium–phosphate product, secondary hyperparathyroidism, and so far ectopic calcifications [11]. In the past, the standard treatment for the hyperphosphatemia of chronic renal failure consisted of dietary phosphate restriction, dialysis treatment efficiency, and administration of phosphate-binders (aluminum salts, calcium carbonate or acetate). Recent studies described the limitations of calcium salts as phosphate-binders and the elevated calcium load in patients with advanced renal failure [13]. Moreover, with such therapeutic approach more than 50% of patients did not achieve a good control of serum phosphate levels. Recently, new phosphate binders, that do not contain aluminum or calcium, and therefore lack the side effects associated with classical phosphate-binders, opened new perspectives in preventing ectopic calcification in end-stage renal disease. Recent studies have shown that new therapeutical tools may be useful to prevent vascular calcifications in animals and humans [16].

Renal Osteodystrophy in PD Patients

Compared to HD, patients undergoing PD appear to have an increased prevalence of low-turnover bone disease. A recent bone biopsy study from Spain [37] found that adynamic bone disease (ABD) was present in 63% of PD patients, associated with low PTH (mean levels 88 ⫾ 78 pg/ml). In this patient population, PTH levels less than 150 pg/ml showed a sensitivity of 91.6%, specificity of 95.2%, and positive predictive value of 97% for the histological diagnosis of ABD. However, a PTH level between 150 and 450 pg/ml was poorly predictive of bone turnover, and PD patients might have ABD despite a PTH level higher than 150 pg/ml. Surprisingly, despite the availability of PD solution with lower calcium concentrations than in the past, changes in the dialysis population, the dialysis regimen, and the supportive care that have occurred in the last 15 years, bone biopsy data from the Spanish study are not different form those reported by Sherrard et al. [38] in 1993. The North-American patients had a prevalence of ABD of 61%, compared to a prevalence of 36% in HD patients.

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Table 1. Risk factors for adynamic bone disease in peritoneal dialysis patients

Age Diabetes Oversuppression of PTH with vitamin D Circulating antagonist PTH fragments Calcium overload Calcium-based phosphate binders High calcium dialysate

Sharon Moe recently summarized the available data on renal osteodystrophy in PD patients [39]. She pointed out that risk factors for ABD identified in cross-sectional studies include age, oversuppression of PTH with vitamin D, diabetes, circulating antagonist PTH fragments, and possibly calcium overload from calcium salts or high calcium dialysate (table 1). A reduced bone turnover in PD patients compared to HD was confirmed by Kurz et al. [40] with radiolabeled calcium kinetic studies. They found a reduced calcium uptake in bone at a given level of PTH, implying a lesser degree of bone turnover. One key factor involved in the development of ABD in PD patients is the frequent presence of a positive calcium balance, which may result in oversuppression of PTH and result in a loss of the normal oscillatory secretion pattern of PTH [41]. In vitro, bone formation is stimulated by oscillatory PTH compared to inhibition by constant PTH release [42], forming the basis of PTH as an anabolic therapy for the treatment of menopausal and corticosteroid osteoporosis [43]. The importance of positive calcium balance in the oversuppression of PTH is further supported by the increase of low PTH levels to more desirable levels in PD patients treated with lower calcium dialysate [44] or switched from calcium-containing phosphate binders to the non-calcium-containing phosphate binder sevelamer [45].

Calcium Balance in PD Patients

When dealing with total serum calcium levels of PD patients, one should always keep in mind that they might have low albumin levels as well. Therefore, total serum calcium should always be corrected for serum albumin levels in order to determine the presence or absence of hypercalcemia. High normal levels of serum calcium suppress PTH, but this approach is now disputed. Indeed, vitamin D therapy is a much more potent suppressor of PTH than is supraphysiological serum calcium level. In addition, there is increasing evidence that elevated phosphorus and calcium ⫻ phosphorus product may lead to extraskeletal calcification and increased morbidity and mortality in HD, and in

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PD as well [46]. Therefore, lower calcium levels are now recommended, especially in patients whose PTH is suppressed, as is observed with ABD. The calcium concentration of PD fluids is generally 1.25–1.75 mmol/l (2.5–3.5 mEq/l), with 1.25 mmol/l the recommended concentration in the new K/DOQI guidelines. Calcium transfer across the peritoneum in PD patients is a passive process dependent on diffusion and convection. Thus, the net calcium flux will be dependent on the patient’s serum calcium level, the calcium concentration in the dialysate, and the dialysis dextrose concentration, determining the entity of ultrafiltration. Sanchez et al. [47] recently compared the effects on bone metabolism of low calcium PD fluid (1.25 mmol/l) with that of a standard calcium dialysate (1.75 mmol/l) in 24 patients. They found a significant increase in serum PTH levels and a higher intake of calcium salts in the low calcium group, with no differences in serum calcium, serum phosphate and bone histological outcomes. In the nineties, Bender et al. [48] studied calcium balance in PD patients: a 1.75-mmol/l dialysate calcium concentration determines a positive balance regardless of the dextrose concentration, whereas a 1.25-mmol/l dialysate calcium will result in a nearly negligible efflux of calcium at a 1.5% dextrose, and a greater efflux of 112 mg (2.8 mmol) per day at a serum ionized calcium level of 1.15 mmol/l. However, even in patients with a negative dialysate calcium balance, concomitant use of calcium-containing phosphate binders, especially when coupled with vitamin D metabolites, will result in an overall positive calcium balance. As pointed out by Moe [39], many different factors need to be taken into consideration when choosing the appropriate calcium dialysate concentration for a given PD patient: dietary intake, serum calcium concentration, patient’s age and growth status, PTH level, use of calcium versus non-calcium phosphate binders, concomitant vitamin D, and use of hormone replacement therapy in postmenopausal women (estrogen increases intestinal calcium absorption). All hypercalcemic patients (K/DOQI definition, ⬎10.2 mg/dl or 2.54 mmol/l) should be on a 1.25-mmol/l or lower calcium dialysate. Patients who are hypocalcemic (K/DOQI definition, ⬍8.4 mg/dl or 2.10 mmol/l) should receive vitamin D, and if needed, an oral calcium supplement if PTH is elevated. For those patients with serum calcium between 8.4 and 10.2 mg/dl, more individualization is needed.

Phosphorus Balance in PD Patients

Without phosphate binding therapy, all patients undergoing PD are in a positive phosphorus balance, unless they are severely malnourished.

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The choice of binder will depend largely on the patient’s preference, the calcium balance, and the availability and affordability of alternative phosphate binders. In most patients compliance is the best predictor of the binder efficacy, and usually the number of capsules and side effects of the phosphate binder will dictate compliance. We recently confirmed, in a blinded study comparing calcium carbonate and sevelamer, that HD patients refuse to take more than an average of 10 capsules per day, regardless of the type of binder [49].

Control of Calcium and Phosphate in PD Patients

Noordzij et al. [1], reporting data from the NECOSAD study, compared calcium and phosphate levels of HD and PD patients. Mean phosphate levels were elevated in both groups (5.79 ⫾ 1.78 and 5.37 ⫾ 1.51 mg/dl, respectively), corrected calcium were 9.64 ⫾ 1.02 and 10.0 ⫾ 0.98 mg/dl, and Ca ⫻ P product 55.6 ⫾ 17.5 and 53.7 ⫾ 16.2 mg2/dl2. In this interesting study, 3 months after the onset of dialysis treatment, HD patients had significantly greater plasma P concentrations and Ca ⫻ P product then PD patients. Conversely, PD patients had greater plasma Ca concentrations. Indeed, the majority of patients had plasma Ca concentrations greater than the range prescribed by K/DOQI. Forty percent of HD patients and 29% of PD patients met the guideline for Ca levels. Conversely, the percentage of HD patients that reached the P target (39%) was significantly less than that of PD patients (50%). The target for Ca ⫻ P product was met by 54% of HD and 58% of PD patients. Finally, more than half the patients had plasma iPTH concentrations less than the proposed target range, and 21% of HD and 22% of PD patients reached the iPTH target. When targets were combined, at 3 months after the start of dialysis treatment, 16% of HD and 15% of PD patients met both calcium and phosphorus targets. Only 4.7% of HD and 5.9% of PD patients reached all four targets. In a multicenter study of Italian PD patients, we studied the main parameters of mineral metabolism [50]. Serum P, albumin corrected total Ca, and PTH were measured over a 6 months period in 490 PD patients (CAPD 56%, APD 42%). Most patients (68%) had dialysate Ca levels of 1.25 mmol/(1.5 mmol/l: 2%; 1.75 mmol/l: 30%), and 89% of them were treated with P binders (Ca salts: 62%; Sevelamer: 36%; Al salts: 32%), 60% were treated with calcitriol and 30% with statins. Mean levels of total Ca were 9.37 ⫾ 0.75 mg/dl; CaAlb 9.80 ⫾ 0.77: P 5.1 ⫾ 1.1 mg/dl; CaxP 49.9 ⫾ 11.2; intact PTH 329 ⫾ 309 pg/ml. Mineral metabolism parameters were outside the recommended range in many pts: Ca ⬎ 9.5 mg/dl: 66%; Ca ⬎ 10 mg/dl: 33%; P ⬎ 5.5 mg/dl: 33%; P ⬎ 6 mg/ dl: 22%; Ca ⫻ P ⬎ 60: 18%; PTH ⬎ 400 pg/ml: 27%; PTH ⬍ 100 pg/ml: 25%

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of patients. Despite the better levels of P, compared to the Dutch patients [1], a significant number of patients is still outside the limits suggested by clinical practice guidelines. In particular, more than 50% of patients has PTH levels indicating either excessive suppression or increased bone turnover. Data from both studies suggest that more vigorous efforts to reduce the prevalence of these factors in PD patients should be considered.

Effect of Metabolic Acidosis on Bone Metabolism in PD Patients: Are Bicarbonate Based Solutions the Answer?

There is clear evidence that bone mineral metabolism is altered by acute and chronic metabolic acidosis, especially in patients affected by renal insufficiency [51]. Hydrogen ions are buffered by bone bicarbonate, exchanging sodium and potassium for protons. Decreases in pH directly release calcium from bone and stimulates osteoclast mediated bone resorption. Although PD patients seem to have a less pronounced acidosis compared to HD patients, in most patients the average bicarbonate level is lower than in the general population. Conventional, lactate-based PD solutions do not fully correct metabolic acidosis, and they determine a loss of bicarbonate into the dialysate [52]. The development of new bicarbonate-based PD solutions should improve treatment and prevention of renal bone disease, by better correcting metabolic acidosis [53].

Conclusions

Hyperphosphatemia is an independent risk factor for higher incidence of cardiovascular events in patients with chronic kidney disease. In addition, increased phosphorus and calcium–phosphate product levels are important contributors to vascular calcifications in these patients. Also, it is well known how hyperphosphatemia accelerates the progression of secondary hyperparathyroidism, the concomitant bone loss and consequent calcium–phosphate precipitation. The control of serum phosphorus levels may reduce vascular calcification by decreasing calcium–phosphate product and reducing the active process through regulation of specific genes. Consequently, more efficient phosphate removal by dialysis, along with new calcium-free and aluminum-free phosphate binders have been proposed for the control of hyperphosphatemia in chronic renal failure. Recent studies have shown that new therapeutical tools may be useful to prevent vascular calcifications in animals and humans. Additional investigations are necessary to examine the relative effect of different phosphate-binders on mortality for cardiovascular events.

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Mario Cozzolino, MD Renal Unit, Ospedale San Paolo, Azienda Ospedale San Paolo Via A. di Rudinì, 8 IT–20142 Milano (Italy) Tel. 0039 02 818 44723, Fax 0039 02 891 29989 E-Mail [email protected]

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Peritoneal Dialysis: A Therapy for Uremia and Beyond Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 226–234

Integration of Peritoneal Dialysis in the Treatment of Uremia Claudio Ronco, Roberto Dell’Aquila, Maria Pia Rodighiero, Pierluigi Di Loreto, Emilia Spanò Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy

Abstract The real integration of a specific therapy into the renal replacement program is represented by the possibility of easy and free patient transfer from one treatment to another without restrictions. In the case of peritoneal dialysis we feel that its integration in the therapeutic approach of uremia represents an ethical obligation for the physician, a clinical opportunity for the patient and a good cost/benefit solution for care givers. A full conviction that peritoneal dialysis represents a real therapeutic option for ESRD patients is necessary to achieve a real integration of this therapy in the uremia treatment program. A positive cost benefit ratio, both from the clinical and the economical points of view must also be seeked. The patient indirectly, must receive the same positive conviction, based on solid data and clinical results, comparable to those achievable in hemodialysis. Furthermore the patient must know that such treatment will provide an equal opportunity for kidney transplant compared to other therapies. Such a kind of feeling and knowledge must include information on patient’s survival, rate of complications, treatment adequacy, availability of different techniques within the treatment and complete summary of advantages and disadvantages. Copyright © 2006 S. Karger AG, Basel

The search for an adequate renal replacement therapy has spurred new interest in all different dialysis techniques that may provide an effective treatment for disparate patients. In this view, peritoneal dialysis (PD) and hemodialysis (HD) are not considered opposite realities any further, but they represent, together with the renal transplantation, different options in the common field of renal replacement therapy. A real integration of PD in the active treatment of uremia should be therefore achieved to provide the wider spectrum of therapies to our patients and to

benefit from the organizational advantages of treating patients with different therapeutic strategies. The real integration of different techniques into the renal replacement program, is obtained when easy and free transfer of the patient from one treatment to another is made possible without restriction. Therefore, PD must be considered, together with HD and transplantation, one of the possibilities for the ESRD patient. Effective integration of PD includes, in our view, several aspects, which will be briefly reviewed in this chapter.

The Peritoneal Dialysis Program

At similar levels of clinical indication, the possibility of offering a free choice of the renal replacement technique is a real obligation to the patient for the nephrologist. The patient must be correctly informed and educated throughout the period of progression of his renal disease. During periodic hospitalization or day hospital activities, adequate information should be coupled with accurate clinical and social evaluation. With this program of staff interventions, the patient will choose the technique with knowledge, freedom and safety. The main message is the concept that different techniques are interchangeable with possibility of free access to all of them (if clinically possible) and a free flux among them. Patient information and education can be adequate only when the staff (both nurses and doctors) is fully convicted that PD should be considered at the same level of other techniques. Furthermore, family collaboration and contacts with other patients with positive experiences should be encouraged. Once the patient has been informed on advantages and disadvantages, and the family support has been assessed, the patient will be helped in his choice by a reliable hospital team, and will be accompanied by a good feeling of freedom and safety. At this point, from the ethical point of view, all efforts have been done to achieve an effective integration of PD in the treatment of uremia.

Organizational Aspects

When organizational issues are concerned, PD may represent a mean for a correct allocation of the available resources. PD represents an important buffer that avoids further expansion of the dialysis center. In fact, while in the eighties we were previewing a plateau of the dialysis patients growth for the mid nineties, today, this forecast has been shown to be totally wrong. Hard data collected in the nineties [1], show that an average increase of HD patients of 8.2% and of PD patients of 10.3% was recorded in the period 1993–1994 worldwide and the trend seemed to be maintained in the last years although a tendency to a plateau has

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been shown in some cases for PD. This is due to a better survival on dialysis, wider criteria of acceptance and development of some countries. With such a continuous growth, in the absence of the possibility of using PD as a parallel therapy, HD centers would become insufficient to provide adequate therapy to all patients. Using PD, the number of HD stations can be maintained within physiological limits, and medical and nursing staffs can remain sufficient. Finally, PD permits to maintain alive the program and concept of home dialysis that has been partially abandoned for HD although a new interest for daily HD seems to be growing. Additionally, while in the past PD was representing a limitation for patients candidate to kidney transplant, today PD patients are well accepted in any transplant list without restrictions. The PD patient is continuously dialyzed being the ideal candidate in a waiting list. Furthermore a late removal of the catheter has been shown to be safe and without specific complications [2].

Clinical Parameters of Adequacy

Several patients may encounter potential hazards or logistic problems related to extracorporeal treatments. Among them, elderly patients, newborn and children may find in PD a real opportunity of treatment [3]. Short term candidates to kidney transplant may be easily treated without need of creating a vascular access. Self care and home dialysis patients might find in PD the solution for their logistic problems. Finally, HIV infected patients, may maintain their privacy without exposure to dangerous contamination or social and human discrimination. The previously claimed advantages in diabetic patients seem to be less important today and the mortality in diabetic PD and HD patients is in any case higher compared to non-diabetic patients. As a requirement however, PD necessitates dedicated medical and nursing staffs, dedicated spaces and rooms inside the department and adequate evaluation of the social and clinical conditions of the candidate. Again, to identify PD as a clinical opportunity, we should emphasize the central role of the staff and its capacity of information and education of the patients. A step-by-step protocol for patients admittance to the treatment, a description of possible complications and a clear statement that ‘PD is more than CAPD’, and therefore that PD techniques other than CAPD can be used, will further increase the positive attitude of the patient. In this field, future application of continuous flow PD may further expand the spectrum of therapies for the PD candidate. A positive attitude of the patient and a deep knowledge of the technique will prevent drop outs and treatment failure. For example, the patient must be aware that the steady state condition will be different from the initial phases of the therapy. On the other hand the staff must consider that different cultural

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patterns will permit a different level of understanding of the disease. In this matter it is important to achieve a distinction between illusions and real targets that can be achieved. A good patient motivation will permit a strict adherence to dietary guidelines and drug therapy. The social and family support will permit to switch the patient attitude from dependence into sense of freedom. Finally, doctors and nurses must be aware that the attempt of increasing treatment dose, will decrease patient’s compliance to restrictions and technical guidelines. In conclusion, patients and doctors must be aware of the potential of the therapy and the possible results achievable with the treatment. To seek for targets the treatment cannot achieve may result in a complete failure of the treatment.

The Search for Patient Rehabilitation

The final target of renal replacement therapy is to obtain a full social and physical rehabilitation of the patient. In this case, PD can offer specific advantages such to become a good chance for effective rehabilitation. Patient’s social and working life may benefit from an effective integration of PD in the renal replacement therapy program. PD is a out-of-hospital treatment, machineless in most of cases, with procedures that reduce stress at the minimum. It is an self care treatment in which the patient has the possibility to plan holidays and travelling. Based on these features, and on a continuous staff support, the patient experiences a unique sense of safety and freedom. This feeling is further accompanied by the certainty that, when possible or when needed, HD will always be available and kidney transplant is not precluded.

Technical Issues

PD may also become a technical need and may represent the unique solution in certain clinical or logistic conditions. In the case of excessive distance from the hospital, the percentage of patients treated with PD may increase from 10 to 60% of the referred population. When transportation problems are present, the percentage can further increase. Temporary or permanent lack of HD stations may render PD a unique option for ESRD patients of that area. In the mean time, if a continuous bidirectional flux of patients is maintained between PD and HD, the best utilization of the available spaces will be obtained. In case of total absence of vascular access, and when temporary access cannot be placed for clinical or technical reason, PD becomes a must to provide effective blood purification. The same situation can be experienced in patients

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with absolute intolerance to HD. In this case the transfer to PD can be temporary or permanent depending on the evolution of the clinical pattern.

Peritoneal Dialysis is a Full Treatment for ESRD

A full conviction that PD represents a real therapeutic option for ESRD patients is necessary to achieve a real integration of this therapy in the uremia treatment program. A positive cost benefit ratio, both from the clinical and the economical points of view must also be seeked. The patient indirectly, must receive the same positive conviction, based on solid data and clinical results, comparable to those achievable in HD. Furthermore the patient must know that such treatment will provide an equal opportunity for kidney transplant compared to other therapies. Such a kind of feeling and knowledge must include information on patient’s survival, rate of complications, treatment adequacy, availability of different techniques within the treatment and complete summary of advantages and disadvantages. From the literature [4], PD and HD do not seem to differ in respect to morbidity and mortality rates. CAPD patients have a greater need for hospitalization mainly due to peritonitis, while HD patients have a greater incidence of intra- and peridialytic cardiovascular instability, arrhythmias and extracellular fluid volume expansion. Diabetes negatively affects survival both in CAPD and in HD and no significant differences in the evolution of diabetes have come out. Method survival is worse in CAPD, but there is a strong influence of patients selection criteria and a definite ‘center effect’. All things considered patient survival does not differ for the two methods, but for older patients it seems to be better in CAPD. Incidence of peritonitis affects the risk of death in PD patients. This is an important complication that has however been dramatically reduced in the last 5 years. The advent of the Y set and the adjusted analysis of peritonitis incidence have shown an average rate of 1 episode/30 pts month. This incidence is the average of two populations: the peritonitis free patients and the frequent relapsers. If a correct clinical evaluation of the causes inducing frequent relapses of peritonitis is done, the incidence of such complication can probably further reduced. The nineties have represented a period in which, after peritoneal transport was studied and reduction of peritonitis rate was achieved, adequacy of treatment has become a main issue to define a therapy completely reliable. Recent studies [5] have demonstrated that despite a lower Kt/V compared to HD, CAPD can provide adequate treatment. In particular, early studies showed that a weekly Kt/V of 1.7 could be enough to provide adequate treatment in CAPD patients.

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Analyzing a fully rehabilitated population, we could confirm that weekly Kt/V was in the range of 1.77 for urea [6]. In the same study we could achieve an exponential correlation between weekly Kt/V and protein catabolic rate, such to suggest that when a certain level of therapy is provided, protein intake reaches a plateau becoming dependent only on the free choice of the patient. A simple calculation can therefore be performed in CAPD to assess the number of liters of dialysis solution required in a totally anuric patient, to achieve the desired weekly Kt/V, assuming a complete dialysate/plasma equilibration. Reports from the CANUSA study, had however suggested that a higher level of efficiency should be pursued and values between 1.9 and 2.1 of Kt/V should be definitely obtained to increase patient’s survival. As suggested by authors [7, 8], a careful analysis of the prescribed dose should be carried out in such conditions, mostly when higher efficiency levels are chosen as a target. In fact, it is evident that as long as the target Kt/V is increased, and the patient body weight increases, exchange volumes and number of daily bags should be increased as well. We must be careful, however, that high volumes are claimed to increase complications and discomfort, while increased number of exchanges per day may reduce drammatically the compliance of the patient and his feeling of freedom, with possible treatment failure and poor rehabilitation. In conclusion, we may speculate that we should probably avoid to seek for a given treatment, results and objectives that can only seldom be achieved. These difficult attempts, may in some cases result in negative effects such to cause a complete failure of the therapy. The availability of different PD techniques is today a reality. CCPD, different forms of APD, nightly treatments and so on must be available in the dialysis center. For an effective utilization, dedicated rooms and staff for training and teaching are definitely required. On the other hand, an accurate evaluation of the patient and his peritoneal membrane characteristics is fundamental to provide the bases for the correct indication of the technique. When urea clearance is plotted against the dialysate flow rate, the relationship presents three specific regions: (a) the first region is including the dialysate flow rates typical for CAPD (3–5 exchanges/day). In this region the correlation is very steep and clearance displays significant changes even in presence of minimal changes of the dialysate flow. We should however remember that minimal variations of the dialysate flow like 1.2 ml/min may require moving from 4 to 5 exchanges/day. This region is therefore dialysate flow dependent or flow limited, since the volume of the dialysate per day is the factor that mostly limits the clearance value. In this region it would be theoretically simple to increase dialysate flow by few ml/day to achieve clearances much higher and consequently significant increases in Kt/V. However, while theoretically possible, practically this would become unfeasible since it would mean to carry out 6–10 exchanges/day. While this can be done in a critically ill patient admitted to the hospital, it is absolutely impossible in patients on ambulatory regimen. For an

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acceptable rehabilitation in fact, the patient should not spend most of his time performing dialytic exchanges. In conclusion, typical CAPD technique is basically dialysate flow limited. When an attempt is done to overcome flow limitations, social and patient-related limitations take over and efficiency cannot be increased. The only possible way to increase dialysate flow without increasing the number of the exchanges is to increase the volume of solution per exchange. This approach has been underestimated in the past years and we must probably take it into consideration as a standard for the coming years. To achieve the same fractional clearance in patients weighing 60 and 90 kg, one must schedule 4 exchanges/day with 2 and 3 l bags respectively. The impact of possible intraperitoneal pressure rises must be carefully checked, to avoid middle-long term complications such as hernias, respiratory problems or decreased ultrafiltration. Increasing the dialysate flow rate, the relationship with clearance enters the typical region of automated PD. The dialysate flows may vary significantly due to a variation of the dwell time from 30 to 0 min, and on the number of exchanges per day. Assuming a 30 min dwell and 20 min for influx and outflux, twelve 2-l exchanges can be performed overnight for an overall duration of 10 h. The clearance will be 19 ml/min or 11.4 l/day. When the dwell time is reduced to 0 and the dialysate flow is therefore increased, the clearance raises over 30 ml/min with a total clearance per day of 18 l. This would figure out a rise of the weekly Kt/V in a 60 kg patient from 2.21 to 3.50. This treatment, which could be defined high flux automated PD would however, require 60 l of dialysis solution. Such quantity is much higher compared to what today’s cyclers can handle and the cost for such treatment may become excessive. A good compromise could be the use of a tidal volume of solution that may contribute to artificially increase the dialysate volume and to a better utilization of the surface area available for the exchanges. Further increases in dialysate flow rate, demonstrate a plateau of the relationship between urea clearance and dialysate flow rate. In this region, further increases in dialysate flow rates do not result in parallel increases in clearance. This region has been experimentally explored utilizing high speed cyclers and double lumen intraperitoneal catheters in continuous flow PD mode [6]. The plateau has been also studied with computerized models, based on mass transferarea coefficient calculation. The value of the mass transfer coefficient is a function of the product of the overall permeability of peritoneum times the available surface area of the membrane. This parameter is based on the calculation made for each single subject, of the maximal clearance theoretically achievable at infinite blood and dialysate flow rates i.e. at constantly maximal gradient for diffusion. Kinetically speaking, the clearance value tends to decrease over time within the duration of one exchange and this is due to a progressive dialysate/ plasma equilibration with a parallel reduction of the gradient for diffusion. The mass transfer-area coefficient is than mathematically calculated as the intersection

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Survival

High dose region (low correlation) Practice/case mix dependent

Low dose region (high correlation) Treatment dependent Efficiency (Kt/V units)

Fig. 1. The correlation between PD efficiency and survival displays a curvilinear function. In the low dose region the correlation is steep while in the high dose region the correlation is lost and the survival rate is affected by other factors such as environment, genetics, case mix and practice pattern.

of the clearance curve with the y axis at the zero time of one exchange, where the gradient for diffusion is maximal. In rapid PD exchanges and intermittent dialysis techniques, the limitations imposed by the peritoneal MTC should be carefully considered. Whether these limitations are imposed by the permeability of the membrane or by the blood flow rate in the peritoneal capillary network as suggested by the ‘nearest capillary hypothesis’ [9], it is not clarified yet. It should however be remembered that clearances limitations are specifically linked to different dialysis techniques and optimization of the therapy means to identify the more suitable therapy for each patient. Residual renal function, patient’s dietary intake and effective treatment efficiency should be periodically controlled for this purpose. When for whatever reason a transfer to HD, temporary or permanent, becomes mandatory, doctors, nurses and patients, should be aware that this is a natural event when a real integration among treatments has been operated. Recent data provided by the ADEMEX [10] study seem to suggest an exponential relationship between efficiency (Kt/V) and survival in PD. Our interpretation of the data provide the following explanation. In any treatment, the relationship between dose and survival is extremely steep in the low dose region while the relationship tends to plateau in the high dose region (fig. 1). The level of the plateau is achieved when the dose of therapy is such to prevent complications, comorbidity and high mortality related to underdialysis. At this point the level of plateau will be different in different centers or countries, depending on

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environmental or genetic risk factors and clinical practice patterns. This area represents the concept of adequacy beyond Kt/V. Cost Issues

To achieve a complete integration of PD in the treatment of uremia, a detailed analysis of costs should be undertaken. However, while differences can be found in the costs of single techniques, the correct approach to the problem should probably imply an overall evaluation of the costs of the entire renal replacement therapy program in a given area or population. In this view, the analysis of the cost of uremia treatment/million of population will include preventive measures, replacement therapies, the transplant program related drug therapy and hospitalization. References 1 2

3 4 5

6

7

8

9 10

Ronco C, La Greca G: Integration of peritoneal dialysis in active uremia treatment. Perit Dial Int 1997;17(suppl 2):S155–S160. Chiaramonte S, Bragantini L, Scalco G, Feriani M, Conz P, Ronco C, Brendolan A, Crepaldi C, Dell’Aquila R, Milan M, Segato G, La Greca G: Late removal of the peritoneal catheter in transplanted CAPD patients; in Ota K (ed): Current Concepts in Peritoneal Dialysis. Proceedings of the Fifth Congress of the ISPD, 1990. Kyoto, Excerpta Medica, 1992, pp 753–756. McDonald M, McPhee PD, Walker RJ: Successful self-care home dialysis in the elderly. A single center experience. Perit Dial Int 1995;15:33–36. Maiorca R, Cancarini G: Outcome of peritoneal dialysis: comparative studies; in Nolph KD, Gokal R (eds): Textbook of peritoneal dialysis. Dordrecht, Kluwer Academic Publishers, 1994, pp 699–734. Keshaviah PR, Nolph KD, Van Stone JC: The peack urea concentration hypothesis: a urea kinetic approach to comparing the adequacy of continuous ambulatory peitoneal dialysis (CAPD) and hemodialysis. Perit Dial Int 1989;9:257–260. Ronco C, Bosch JP, Lew SQ, Feriani M, Chiaramonte S, Conz P, Brendolan A, La Greca G: Adequacy of continuous ambulatory peritoneal dialysis: comparison with other dialysis techniques. Kidney Int 1994;46(suppl 48):S18–S24. Misra M, Nolph KD, Khanna R, Prowant BF, Moore HL: Retrospective evaluation of renal kt/V (urea) at the initiation of long-term peritoneal dialysis at the University of Missouri: relationships to longitudinal nutritional status on peritoneal dialysis. ASAIO J 2003;49:91–102. Wang T, Lindholm B: Beyond CANUSA, DOQI, ADEMEX: what’s next? Adequacy of peritoneal dialysis in Mexico, Canada USA. Dialysis outcomes quality initiative. Perit Dial Int 2002;22: 555–562. Ronco C: The nearest capillary hypothesis. A novel approach to peritoneal transport physiology. Perit Dial Int 1996;16:121–125. Prichard S: ADEMEX and HEMO Trials: where are we going? Blood Purif 2003;21:42–45.

Claudio Ronco, MD Divisione di Nefrologia e Dialisi, Ospedale San Bortolo Via Rodolfi IT–36100 Vicenza (Italy) Tel. ⫹39 444 993869, Fax ⫹39 444 920693, E-Mail [email protected]

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The Role of Chronic Peritoneal Dialysis in the Management of the Patient with Chronic Kidney Disease Fredric O. Finkelstein, Susan H. Finkelstein, Laura K. Troidle Yale University, St. Raphael’s Hospital, Renal Research Institute, New Haven, Conn., USA

Abstract The role of chronic peritoneal dialysis (CPD) in the management of patient with chronic kidney disease is being reexamined. There has been a decline in CPD utilization in the United States, which has been attributed to a variety of factors. It is important that these factors be understood and addressed, since nephrologists feel that about 30% of end-stage renal disease patients should be maintained on CPD and patients are more satisfied with CPD and feel that CPD has a less negative impact on their lives than hemodialysis. The present chapter discusses some of the reasons for decline in CPD utilization in the United States. Copyright © 2006 S. Karger AG, Basel

The role of chronic peritoneal dialysis (CPD) in the comprehensive management of the patient with chronic kidney disease (CKD) is in the process of being reexamined. This is due to a variety of factors, which include (1) the decline in peritoneal dialysis utilization in some countries, such as the United States; (2) concerns with the relative mortality risks of CPD compared to hemodialysis (HD), and (3) increasing interest in patients’ perceptions of their satisfaction with care and their quality of life, independent from the impacts of these therapies on morbidity and mortality. The decline in CPD utilization has been most striking in the United States; the percentage of prevalent end-stage renal disease (ESRD) patients maintained on CPD therapy has declined from 14% in 1995 to 8% in 2002 [1]. This decline has been puzzling since it has occurred despite a variety of advances in CPD therapy during this time period [2, 3]. Peritonitis rates, i.e. have declined to less than one episode every 24 months of therapy [4]. A variety of new solutions

40

% patients

35 30 25 20 15 10 5 0 USA

Canada

United Kingdom

New England

Fig. 1. The percentage of patients that nephrologists feel should be maintained on CPD therapy (taken from [9–12]).

have been introduced, such as icodextrin in the United States and amino acid based as well as newer, more biocompatible solutions in many other countries [5, 6]. Furthermore, the new generation of automated cycling machines has permitted easy utilization of large volume cycling to maximize clearances [7]. Blake and Finkelstein [8] speculated on the reasons for the decline in CPD utilization in the United States and Canada. These authors suggested that a variety of factors perhaps contributed to this decline, such as the increased age of patients, the increased severity of illness, the increased availability of HD facilities, the challenges of running a CPD unit with a limited number of patients, a lack of focus on the education of the patient with CKD, and the inadequate training of nephrologists in CPD therapy. This decline in CPD utilization has occurred despite the fact that nephrologists in many countries, such as the United States, Canada and the United Kingdom, all report that about 35% of ESRD patients should be maintained on CPD therapy, as shown in figure 1 [9–12]. For example, Mendelssohn et al. [9] examined the attitudes of American nephrologists toward CPD therapy and noted that they felt that CPD therapy was dramatically underused. Furthermore, these authors suggested, as have others, that the modality selection decision should be based largely on patient preference. The reasons for the discrepancies between what the nephrologists thought should be happening with CPD utilization and the realities was investigated by Troidle et al. [12] by asking nephrologists in New England what they thought were the barriers to CPD utilization. As summarized in table 1, this study

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Table 1. Barriers to Growth of CPD Therapy (from [12]) Poor physician training in CPD Technique failure and long term viability of the therapy Problems with CKD education Poor organization of CPD centers and support systems Institutional barriers from established dialysis centers

focused attention on the following: (1) poor physician training in CPD; (2) problems with lack of support for the proper education of the CKD patient; (3) the lack of adequate infrastructure and poor organization and support for many CPD centers; (4) institutional barriers from established dialysis centers, and (5) the problems with technique failure and long term viability of CPD therapy. The importance of CKD education has been emphasized by several researchers, since recent studies have suggested that if patients are given a choice of modality therapy, about 40% of new dialysis patients will choose CPD [13, 14]. Thus, in the Netherlands, where CKD education is generally widely established, 38% of incident ESRD patients started CPD and 62% started HD between 1997 and 2001 [13]. And, in New Haven, 40% of incident patients who completed our CKD education program between 2002 and 2005 started CPD [14]. Problems related to poor physician training in CPD have been discussed elsewhere [15]. The difficulties revolve around providing training for patients who are monitored in an outpatient setting and return to dialysis centers only monthly for follow-up appointments. Developing adequate training programs for nephrology trainees, thus, presents particular challenges. Institutional barriers to CPD are of concern. It is generally felt to be easier for physicians to start new dialysis patients on HD rather than CPD, since uniform standards of care govern the functioning of HD units [8]. Furthermore, it presents certain advantages for dialysis facilities to incorporate new patients onto HD if dialysis slots are available. The incremental costs of starting HD is minimal if the physical plant is already established, machines are functional and nursing and technical staffs are already in place. On the other hand, the positive aspects of CPD therapy, from a nephrologists’ standpoint, are often ignored. For example, CPD facilities are generally run on a primary nursing care model with nurses assuming the primary care of patients and interfacing primarily with the patients; thus, physician input is focused and efficient, visits are monthly at best, and therefore physician time is freed up to pursue other activities. The problem of the relative mortality risks of CPD therapy compared to HD therapy has been closely examined by several investigators. Of particular

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concern, is the recent publication from the CHOICE study which suggested a significantly higher mortality rate for patients maintained on CPD compared to those on HD, particularly so for patients with underlying cardiovascular disease [16]. The results of this study appear to contradict the results of several national registries, as well as the detailed review of data from the USRDS published by Vonesh et al. [17]. This latter article, examining the USRDS database, stressed the higher mortality rates in HD patients with no comorbidities [17]. But, what factors are important to patients in deciding what modality of ESRD therapy to choose? Certainly, relative morbidity and mortality rates are significant. But, recent work has focused attention of patient satisfaction with therapy, the impact of the therapy on the lifestyle of the patient, and the quality of life of the patient undergoing the treatment. The CHOICE study carefully examined the notion of patient satisfaction by defining those factors that patients felt were important from their perspective, gleaned from focus group discussions with patients, and then interviewing incident HD and CPD patients 7 weeks after the start of dialysis therapy [18]. Patients on CPD therapy were more satisfied than HD patients with their care in all domains studied. Juergensen in our group also interviewed about 145 prevalent HD and CPD patients and extended these observations by examining the impact of the dialysis therapy on patients’ lives. CPD patients were not only more satisfied with their care and but they also felt that the impact of the CPD therapy on their lives was significantly less than for the HD patients [19]. CPD patients noted less impact of therapy on 15 of 16 domains examined. In addition, HD patients were much more likely to cite the negative aspects of their therapy than the CPD patients [19]. These studies focus attention on the patients’ perception of their care and emphasize that the patients are in general more satisfied with CPD than HD therapy and that CPD has a less negative impact on their lives than HD. The importance of these observations in terms of providing education to patients concerning modality selection needs to be emphasized. In conclusion, it seems that the nephrologists as well as patients feel that if there were no barriers to CPD therapy, 30–40% of incident ESRD patients would choose CPD as their initial therapeutic modality. For this to be realized, there must be adequate CKD education provided to patients with progressive kidney disease. This education should discuss not only the problems concerning the relative risks of morbidity and mortality with HD and CPD therapy, but the issue of patient satisfaction with therapy and the impact of the therapy on patients’ lives. Furthermore, the barriers that exist to CPD therapy must be discussed and addressed, including the problems with education of nephrology trainees and the organization and structure of CPD centers.

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References 1 2

3 4 5

6 7

8 9 10 11 12 13

14

15 16

17 18 19

U.S. Renal Data System: USRDS 2004 Annual Data Report. Bethesda, MD, National Institutes of Health, Department of Health and Human Services, 2004. Kiernan L, Kliger A, Gorban-Brennan N, Juergensen P, Tesin D, Vonesh E, Finkelstein F: Comparison of continuous ambulatory peritoneal dialysis-related infections with different ‘Y-tubing’ exchange systems. J Am Soc Nephrol 1995;5:1835–1838. Gokal R: Introduction: advances in peritoneal dialysis. Adv Ren Replace Ther 2000;7:269–270. Peritoneal dialysis-related infections recommendations: 2005 update. Perit Dial Int 2005;25:107–131. Dombros N, Dratwa M, Feriani M, Gokal R, Heimbürger O, Krediet R, Plum J, Rodriquez A, Selgas R, Struijk D, Verger C: European best practice guidelines for peritoneal dialysis. 5. Peritoneal dialysis solutions. Nephrol Dial Transplant 2005;20(suppl 9):ix16–ix20. Frampton JE, Plosker GL: Icodextrin: a review of its use in peritoneal dialysis. Drugs 2003;63: 2079–2105. Juergensen PH, Murphy AL, Pherson KA, Kliger AS, Finkelstein FO: Tidal peritoneal dialysis: comparison of different tidal regimens and automated peritoneal dialysis. Kidney Int 2000;57: 2603–2607. Blake PG, Finkelstein FO: Why is the proportion of patients doing peritoneal dialysis declining in North America? Perit Dial Int 2001;21:107–114. Mendelssohn DC, Mullaney SR, Jung B, Blake PG, Mehta RL: What do American nephrologists think about dialysis modality selection? Am J Kidney Dis 2001;37:22–29. Jung B, Blake PG, Mehta RL, Mendelssohn DC: Attitudes of Canadian nephrologists toward dialysis modality selection. Perit Dial Int 1999;19:263–268. Jassal SV, Krishna G, Mallick NP, Mendelsshohn DC: Attitudes of British Isles nephrologists towards modality selection: a questionnaire study. Nephrol Dial Transplant 2002;17:474–477. Troidle LK, Kliger AS, Finkelstein FO: Barriers to CPD Utilization in Network #1, 10. New England, Perit Dial Int in press. Jager KJ, Korevaar JC, Dekker FW, Krediet RT, Boeschoten EW, Netherlands Cooperative Study on Adequacy of Dialysis Study Group: The effect of contraindications and patient preference on dialysis modality selection in ESRD patients in the Netherlands. Am J Kidney Dis 2004;43:891–899. Rodd K, Wuerth D, Finkelstein S, Kliger AS, Finkelstein FO: More chronic kidney disease patients choose peritoneal dialysis vs hemodialysis after receiving CKD education. Perit Dial Int 2006; in press. Mehotra R, Blake P, Berman N, Nolph K: An analysis of dialysis training in the United States and Canada. Am J Kidney Dis 2002;40:152–160. Jaar BG, Coresh J, Plantinga IC, Fink NE, Klag MJ, Levey AS, Levin NW, Sadler JH, Kliger A, Powe NR: Comparing the risk for death with peritoneal dialysis and hemodialysis in a national cohort of patients with chronic kidney disease. Ann Intern Med 2005;143:174–183. Vonesh E, Snyder JJ, Foley EN, Collins AJ: The differential impact of risk factors on mortality in hemodialysis and peritoneal dialysis. Kidney Int 2004;66:2389–2401. Rubin HR, Fink NE, Plantinga LC, Sadler JH, Kliger AS, Powe NR: Patient ratings of dialysis care with peritoneal dialysis vs hemodialysis. J Am Med Assoc 2004;291:697–703. Juergensen E, Juergensen P, Wuerth DW, Finkelstein SH, Finkelstein FO: Peritoneal dialysis vs. hemodialysis: comparing satisfaction with treatment. Perit Dial Int 2006; in press.

Fredric O. Finkelstein Yale University, St. Raphael’s Hospital, Renal Research Institute 136 Sherman Avenue New Haven, CT 06511 (USA) Tel. ⫹1 203 787 0117, Fax ⫹1 203 777 3559 E-Mail [email protected]

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Peritoneal Dialysis Is Appropriate for Elderly Patients Isaac Teitelbaum Division of Renal Disease and Hypertension, Department of Internal Medicine, University of Colorado Health Sciences Center, Denver, Colo., USA

Abstract Background/Aims: The utilization of peritoneal dialysis decreases with age. A number of concerns have been raised regarding the suitability of peritoneal dialysis for elderly patients. The purpose of this review is to determine whether these concerns are medically valid. Methods: Literature review and synthesis. Results: Most elderly patients possess the manual and cognitive skills necessary to perform peritoneal dialysis. Elderly patients on peritoneal dialysis exhibit excellent compliance with their treatment regimen and display no increase in the rate of infectious complications though they may have a slight increase in hospital days. They easily achieve adequacy targets, experience good technique survival and their nutritional status is at least as good as that of their hemodialysis counterparts. Patient survival varies around the world but is overall comparable to that of age-matched patients on hemodialysis. Quality of life may be somewhat superior to that of older hemodialysis patients. Conclusion: Elderly patients with end-stage renal disease are appropriate candidates for peritoneal dialysis. It is not medically justifiable to exclude them from consideration for this therapeutic modality. Copyright © 2006 S. Karger AG, Basel

As of 2003, the last year for which data is available, there were over 1.1 million end-stage renal disease patients worldwide. Of those on dialysis, approximately 10% overall were being treated with peritoneal dialysis (PD). The frequency of PD utilization varies widely from country to country. Yet, with the exception of New Zealand, an obvious trend emerges: the utilization of PD for end-stage renal disease therapy diminishes drastically with age. For example, in the United States, PD is utilized by 12.7% of patients below age 19. This falls to 5.8% in the 45–64 year old age group and to only 4.0% in patients above age 75; in contrast, PD utilization is 60% in the ⬎75 age group in New Zealand [1]. Many factors – social, economic, geographic and others – could play a role in

Table 1. Potential medical reasons for the underutilization of peritoneal dialysis in elderly end-stage renal disease patients

Poor manual and mechanical skills Decreased neuropsychiatric function Poor compliance Higher infection rates Higher frequency of hospitalization Worse nutrition Poor dialysis adequacy Poor technique survival Increased mortality rate

this age-related decrease of PD utilization. The question I would like to address is: are there valid medical reasons to justify a decrease in PD utilization in the elderly? A number of medical concerns have been raised regarding the suitability of PD for elderly patients (see table 1). I will briefly review each of these in an effort to determine whether these concerns are valid. Please note that the definition of ‘elderly’ utilized in the various studies reviewed varies somewhat, but it is generally above age 60–70. Manual Dexterity and Neuropsychiatric Function

Elderly patients are more likely than their younger counterparts to require assistance in the performance of PD. Yet, nearly two-third of patients above age 60 are still capable of performing PD independently [2]. When observed annually for 5 years, young and elderly PD patients exhibit a similar Karnofski Index score at each time point. Though not studied specifically in the elderly, neuropsychometric testing shows that PD patients perform significantly better on number connection and digit span tests than do pre-treatment hemodialysis (HD) patients [3]; post-treatment HD patients still perform slightly worse than PD patients but not significantly so. Depression is, of course, a problem in the elderly. However, upon examining dialysis patients over age 65 Iordanidis et al. [4] found no difference in the frequency or severity of depression in those on HD or PD. If anything, there was a trend toward greater severity of depression in the HD patients. Thus, for most of the elderly, neither manual dexterity nor neuropsychiatric function limits the ability to perform PD. Compliance

Concerns regarding increased rates of non-compliance with the dialysis regimen in the elderly are unfounded as well. Blake et al. [5] performed a multicenter

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study of CAPD compliance in 14 dialysis programs in the US and Canada. Overall, the rate of non-compliance decreased with age falling from 23% in those below age 45 to 13% in patients aged 45–65. Non-compliance was only 5% in patients above age 65. Another study by Kutner et al. also showed improved compliance with age for patients performing either HD or PD. It should be noted that use of automated PD may result in further improvement in compliance [6].

Hospitalization

There is very little data on the relative rates of hospitalization for HD and PD patients stratified by age. In general, PD does appear to be associated with slightly higher hospitalization rates than is HD [7]. Yet, the excess risk appears to diminish with age. In a study by Habach et al. [8] in which data was stratified by age, the relative risk for hospital admission per year at risk (PD:HD) was lower in patients age 65 or above (1.11) compared to those in other age brackets (RR ranging from 1.12 to 1.35).

Infectious Complications

A number of authors have examined the frequency of PD-related infections in the elderly. Holley et al. [9] conducted a case control study of 103 patients over age 60 (mean 67) comparing them to a population of patients below age 50 (mean 37). Patients were matched for gender, race, percent diabetics, duration of PD, and connection devices. There was no difference in the frequency of peritonitis in these two patient groups; of note, the frequency of both exit-site and tunnel infections were significantly decreased in the older population. McDonald et al. [10] also examined the frequency of peritonitis in older patients (average age 64.4) compared to that of the general PD population and found no difference. Tabulating data from these two studies along with several others (table 2) demonstrates clearly that there is no increased risk of peritonitis in the elderly.

Dialysis Adequacy and Nutrition

There is very little data comparing dialysis adequacy in young and elderly PD patients. It is noteworthy, however, that in each of three studies no significant difference in weekly Kt/V between these two populations could be demonstrated [11–13]. Similarly, there are relatively few studies examining the nutritional status of elderly PD patients. While Perez-Contreras et al. [13]

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Table 2. Peritonitis rates in young and old peritoneal dialysis patients (episodes/year) Author

Young

Old

DeVecchi Holley McDonald Mooraki Nebel Perez-Contreras Suh

0.37 0.89 0.57 0.80 0.73 0.55 0.75

0.52 0.95 0.42 1.20 0.54 0.72 0.55

Average

0.67 ⫾ 0.18

0.70 ⫾ 0.28

p ⫽ NS

demonstrated modestly decreased nutritional status in the elderly compared to younger PD patients other authors have not corroborated this finding [14, 15]. Nolph et al. [15] reported no difference when plotting protein catabolic rate as a function of Kt/V in the young and elderly. In addition, several authors have demonstrated adequate serum albumin concentrations in elderly patients undergoing PD [11, 12, 14]. It should also be noted that the likelihood of malnutrition (as assessed by SGNA score) is, if anything, higher in HD patients over age 65 than it is in age-matched PD patients [14]. Overall, therefore, it appears that the nutritional status of elderly PD patients is comparable to that of both their younger counterparts and that of elderly HD patients. Technique Survival

Technique survival in elderly PD patients has been variably reported to be either slightly inferior (not surprisingly) or equivalent to that of younger PD patients. Of greater importance, however, is the comparison of technique survival for elderly patients treated with PD compared to elderly patients treated with HD. While data are somewhat limited, there appears to be no significant difference in technique survival by dialysis modality in the elderly [10, 16]. In fact, it is noteworthy that PD has been successfully performed even in octo- and nonagenarians [17]. Patient Survival

Data regarding patient survival of the elderly utilizing different dialysis modalities is more complex and more controversial. Studies from several

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countries including Canada, Denmark, Italy and the United Kingdom [16, 18–20] demonstrate no effect of dialysis modality on survival of elderly patients treated with either HD or PD. In contrast, recent data from the United States does suggest an increase in mortality for elderly patients treated with PD. However, this increase in mortality is restricted to elderly diabetics; elderly non-diabetic patients with no baseline comorbidity actually enjoy superior survival with PD while for elderly non-diabetic patients with baseline comorbidity there is no difference in survival between the two dialysis modalities [21]. The reason(s) for the difference between the US and other countries is not immediately apparent. Possibilities include: the lower percentage of AfricanAmericans (who enjoy better survival on dialysis than do Caucasians) treated with PD in the US, a higher percentage of women (who have been shown to have poorer access to cardiac care than do men), the higher percentage of diabetics on dialysis in the US, the lack in the US (until very recently) of nonglucose based peritoneal dialysate, and poorer training of American nephrologists in the area of PD overall [22]. Nevertheless, it should be recognized that even in the US the excess mortality risk for elderly patients treated with PD is relatively minor, no greater than 20%. Overall, therefore, concerns regarding heightened mortality in elderly patients treated with PD are at most modest. Finally, it must be recognized that longevity is neither the only, nor necessarily the most important, clinical endpoint. For many patients, particularly the elderly, quality of life is at least as important, if not more so, than quantity. PD has been shown to be associated with a higher degree of patient satisfaction than is HD [23] and offers several other advantages of particular relevance to the elderly. These include: increased cardiovascular stability with a lower frequency of arrhythmias, decreased travel requirements, marked decrease in needle sticks, lowered likelihood of GI bleeding, and lowered risk of bacteremia.

Conclusion

Most elderly patients possess the manual and cognitive skills necessary to perform PD. For those who do not, use of a properly trained partner or assistant is a ready alternative. Elderly patients on PD exhibit excellent compliance with their treatment regimen and display no increase in the rate of infectious complications though they may have a slight increase in hospital days. They easily achieve adequacy targets, experience good technique survival and their nutritional status is at least as good as that of their HD counterparts. Patient survival varies around the world but is overall comparable to that of age-matched patients on HD. Quality of life may be somewhat superior to that of older HD

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patients. Elderly patients with end-stage renal disease are appropriate candidates for PD. It is not medically justifiable to exclude them from consideration for this therapeutic modality. References 1 2 3

4

5

6

7

8 9 10 11

12

13

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United States Renal Data System 2005 Annual Data Report. Nebel M, Finke K: CAPD in patients over 60 years of age: review from 1984–1989. Adv Perit Dial 1990;6(suppl):56–60. Buoncristiani U, Alberti A, Gubbiotti G, Mazzotta G, Gallai V, Quintaliani G, Gaburri M: Better preservation of cognitive faculty in continuous ambulatory peritoneal dialysis. Perit Dial Int 1993; 13(suppl 2):S202–S205. Iordanidis P, Alivanis P, Iakovidis A, Dombros N, Tsagalidis I, Balaskas E, Derveniotis V, Ierodiakonou C, Tourkantonis A: Psychiatric and psychosocial status of elderly patients undergoing dialysis. Perit Dial Int 1993;13(suppl 2):S192–S195. Blake PG, Korbet SM, Blake R, Bargman JM, Burkart JM, Delano BG, Dasgupta MK, Fine A, Finkelstein F, McCusker MX, McMurray SD, Zabetakis PM, Zimmerman SW, Heidenheim P: A multicenter study of noncompliance with continuous ambulatory peritoneal dialysis exchanges in US and Canadian patients. Am J Kidney Dis 2000;35:506–514. Juergensen PH, Gorban-Brennan N, Finkelstein FO: Compliance with the dialysis regimen in chronic peritoneal dialysis patients: utility of the pro card and impact of patient education. Adv Perit Dial 2004;20:90–92. Murphy SW, Foley RN, Barrett BJ, Kent GM, Morgan J, Barre P, Campbell P, Fine A, Goldstein MB, Handa SP, Jindal KK, Levin A, Mandin H, Muirhead N, Richardson RM, Parfrey PS: Comparative hospitalization of hemodialysis and peritoneal dialysis patients in Canada. Kidney Int 2000;57: 2557–2563. Habach G, Bloembergen WE, Mauger EA, Wolfe RA, Port FK: Hospitalization among United States dialysis patients: hemodialysis versus peritoneal dialysis. J Am Soc Nephrol 1995;5:1940–1948. Holley JL, Bernardini J, Perlmutter JA, Piraino B: A comparison of infection rates among older and younger patients on continuous peritoneal dialysis. Perit Dial Int 1994;14:66–69. McDonald M, McPhee PD, Walker RJ: Successful self-care home dialysis in the elderly: a single center’s experience. Perit Dial Int 1995;15:33–36. Mooraki A, Kliger AS, Juergensen P, Gorban-Brennan N, Finkelstein FO: Selected outcome criteria and adequacy of dialysis in diabetic and elderly patients on CAPD therapy. Adv Perit Dial 1994;10:89–93. De Vecchi AF, Maccario M, Braga M, Scalamogna A, Castelnovo C, Ponticelli C: Peritoneal dialysis in nondiabetic patients older than 70 years: comparison with patients aged 40 to 60 years. Am J Kidney Dis 1998;31:479–490. Perez-Contreras J, Miguel A, Sanchez J, Rivera F, Olivares J: A prospective multicenter comparison of peritonitis in peritoneal dialysis patients aged above and below 65 years. Adv Perit Dial 2000;16:267–270. Cianciaruso B, Brunori G, Kopple JD, Traverso G, Panarello G, Enia G, Strippoli P, De Vecchi A, Querques M, Viglino G, Vonesh E, Maiorca R: Cross-sectional comparison of malnutrition in continuous ambulatory peritoneal dialysis and hemodialysis patients. Am J Kidney Dis 1995;26:475–486. Nolph KD, Moore HL, Prowant B, Meyer M, Twardowski ZJ, Khanna R, Ponferrada L, Keshaviah P: Age and indices of adequacy and nutrition in CAPD patients. Adv Perit Dial 1993;9:87–91. Ismail N, Hakim RM, Oreopoulos DG, Patrikarea A: Renal replacement therapies in the elderly; Part 1. Hemodialysis and chronic peritoneal dialysis. Am J Kidney Dis 1993;22:759–782. Sunder S, Taskapan H, Jojoa J, Krishnan M, Khandelwal M, Izatt S, Chu M, Subramanian P, Chinthalapalli H, Lobbedez T, Jassal SV, Bargman JM, Oreopoulos DG: Chronic peritoneal dialysis in the tenth decade of life. Int Urol Nephrol 2004;36:605–609.

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Krishnan M, Zhu N, Badovinac K, Oreopoulos DG, Fenton SSA: Outcomes in the elderly on dialysis: Canadian results differ again. J Am Soc Nephrol 2003;14:497a. Heaf JG, Lokkegaard H, Madsen M: Initial survival advantage of peritoneal dialysis relative to haemodialysis. Nephrol Dial Transplant 2002;17:112–117. Harris SAC, Lamping DL, Brown EA, Constantinovici N: Clinical outcomes and quality of life in elderly patients on peritoneal dialysis versus hemodialysis. Perit Dial Int 2002;22:463–470. Vonesh EF, Snyder JJ, Foley RN, Collins AJ: The differential impact of risk factors on mortality in hemodialysis and peritoneal dialysis. Kidney Int 2004;66:2389–2401. Mehrotra R, Blake P, Berman N, Nolph KD: An analysis of dialysis training in the United States and Canada. Am J Kidney Dis 2002;40:152–160. Rubin HR, Fink NE, Plantinga LC, Sadler JH, Kliger AS, Powe NR: Patient ratings of dialysis care with peritoneal dialysis vs. hemodialysis. J Am Med Assoc 2004;291:697–703.

Dr. Isaac Teitelbaum Medical Director, Home Dialysis Program University of Colorado Health Sciences Center 4200 E. 9th Ave. Denver, CO 80262 (USA) Tel. ⫹1 303 372 6753, Fax ⫹1 303 315 4852 E-Mail [email protected]

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The Impact of Peritoneal Dialysis Upon Quality of Life and Mortality of Patients with End-Stage Congestive Heart Failure Lazaro Gotloib, Roberto Fudin Department of Nephrology, Ha’Emek Medical Center, Afula, Israel

Abstract Background: Aged patients affected by congestive heart failure refractory to pharmacologic therapy, coupled with severe comorbidities that preclude heart transplantation have a gloomy prognosis. Use of automated peritoneal dialysis resulted in a significantly improved quality of life and survival. Methods: Twenty patients (mean age: 65.7 ⫾ 7.7 years) with severe congestive heart failure (Class IV-NYHA) and a high Charlson comorbidity index (7.8 ⫾ 1.8) were treated by means of automated peritoneal dialysis (3 sessions/week, 8 h each). The period of follow-up ranged between 7 and 35 months (19.8 ⫾ 7.4 months). Results: After 1 year of follow-up, all patients showed functional (Class I-NYHA) and hemodynamic improvement: left cardiac work index increased from 2.33 ⫾ 0.69 to 2.59 ⫾ 0.47 kg/min/m2 (p ⬍ 0.01); systolic times ratio was significantly reduced (from 61.14 ⫾ 12.57 to 39.18 ⫾ 13.44%, p ⬍ 0.01); and the thoracic fluid contents was substantially reduced (from 0.04 ⫾ 0.005 to 0.003 ⫾ 0.0001 ⍀). A marked drop of hospitalization days was observed. Conclusions: Automated peritoneal dialysis appears as a promising tool for treating patients suffering from refractory, end stage congestive heart failure. Improvement of cardiac function may result from clearing the blood from middle molecular weight myocardial depressant substances, including atrial natriuretic peptide. Results of this investigation are a call for a prospective multicenter study in order to confirm these promising observations. Copyright © 2006 S. Karger AG, Basel

‘If a man lives many years, let him have joy throughout them all’ Ecclesiastes XI

Congestive heart failure (CHF) emerged as a continuously increasing pandemics killing, at least in the USA, around 300,000 patients each year [1]. The affected population includes some 5 million patients in the USA, with

around 500,000 new cases identified per year. Besides the high morbidity and mortality, the burden of treating heart failure upon the continuously squeezed health care facilities is also increasing. Some 6.5 million-hospital days/year are devoted in the US to care of patients affected by CHF (80% of them older than 65 years) [1]. Older patients having a severe cardiac condition are usually affected by additional comorbidities. Under these circumstances, application of some therapeutic strategies and/or pharmacological interventions fails to cut short the gloomy progression of the disease. Then, physicians face the problem of the patient dying from CHF refractory to optimal pharmacological therapy. This short review will be focused on this specific group of patients showing a mortality rate of around 74% due to CHF during the first year of follow up [2], or 85% mortality in those having a Charlson comorbidity score higher than 5 [3]. And, specifically, use of peritoneal dialysis (PD) will be proposed as a life saving and quality of life improving procedure.

Recommended Therapeutic Strategies

Pharmacological therapy, including intermittent intravenous infusion of inotropic drugs, vasodilators, diuretics, calcium and ␤-blocking agents, digitalics, angiotensin-converting enzyme inhibitors or antagonists alone or in combination with low dose spironolactones have been widely recommended [1, 4, 5]. However, some of the aforementioned therapeutic schedules appear to be unsafe in patients with compromised renal function, basically spironolactones alone, or in combination with angiotensin-converting enzyme [6]. For patients in whom these pharmacological interventions fail, heart transplantation, cardiomyoplasty and other surgical procedures represent the only possibility to keep them alive and, of course, enjoying an acceptable quality of life. However, heart transplantation is available to a quite relatively low number of eligible patients [1]. Besides, not every patient refractory to optimal pharmacological treatment is suitable for heart transplantation. The long list of contraindications identified by currently accepted guidelines includes: diabetes with evidence of end organ damage, irreversible pulmonary hypertension, active peptic ulcer disease, severe COPD, peripheral or cerebro-vascular disease and age over 65 years. For this kind of patients, end of life options that include hospice care and/or inactivation of implantable defibrillators are, at the present time, proposed [2]. This hopeless prospect stimulated nephrologists to find an alternative and perhaps an unconventional approach, in order to improve quality of life and survival of patients with end stage CHF.

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Therapy Based on Extra Corporeal Blood Purification Techniques

Nephrologists have to face the challenge of critically ill, Class III, IV (NYHA), overhydrated and oligo-anuric terminal cardiac patients quite frequently. Some investigators applied continuous renal replacement therapies (veno-venous, slow continuous or slow daily hemofiltration) in order to obtain a favorable turn upon the deteriorated fluid balance. However, besides the considerable costs derived from long term – daily hemofiltration, results in terms of survival were poor. After treating a heterogeneous group of Class IV-NYHA patients, Canaud et al. [7] found that only 13 showed a partial recovery (Class IINYHA), 13 died within 1 month of ultrafiltration therapy, and only 18 survived for periods longer than 3 months. Iorio et al. [8] treated 16 Class IV-NYHA refractory patients, with on line bicarbonate daily hemofiltration. Only 6 patients remained alive, on dialysis, after 18–52 weeks of therapy. So far, it may be concluded that hemofiltration and hemodialysis were effective as an acute rescue therapy, but ineffective as a long-term treatment.

The Hope of PD

More than 50 years ago Schneierson [9] published the first case report using PD as a successful rescue therapy in a patient affected by severe CHF. After this contribution, the literature shows that PD has been applied to around 300 overhydrated cardiac patients both, as an acute rescue therapy or as a longterm maintenance treatment [10]. Even though most reports deal with small numbers of patients, it seems evident that both, intermittent and continuous ambulatory peritoneal dialysis, substantially contributed to the quality and length of life otherwise of dying patients [11, 12]. We recently reported a prospective and not controlled study done in 20 patients affected by refractory CHF. Mean age was 65.7 ⫾ 7.6 years, all of them having compromised renal function (MDRD GFR: 14.8 ⫾ 3.8 ml/min). Fifteen out of the 20 patients were diabetics, with end organ damage (type I ⫽ 10; type II ⫽ 5). The zero time mean ejection fraction, evaluated by echocardiography, was lower than 35% (31.2 ⫾ 4.7%). The mean Charlson comorbidity index was 7.8 ⫾ 1.8. According to currently accepted criteria, none of these patients would have been considered as a candidate for heart transplantation [13]. Initially, 2–5 sessions of hemofiltration were performed in order to reach dry weight. Then, after surgical implantation of a Tenckhoff catheter, automated PD was started. Patients underwent 3 sessions/week (8 h each), using 15–20 l of standard-lactated buffered PD solutions (mean: 10.35 ⫾ 3.05 l of 1.5% and 8.95 ⫾ 2.95 l of 4.25% glucose concentration respectively).

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Normal⫽ 3.3–5.3kg ⫻ min/m2 Zero time versus first year Mann–Whitney test **

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Fig. 1. a, b and c represent mean ⫾ SD of hemodynamic parameters obtained at zero time (open bar) and after the first year of follow-up (black bar). d Survival curves. The upper curve (dying patients) indicates the period of treatment before death. The lower curve (surviving patients) points at the length of time on treatment at the end of the study. **p ⬍ 0.01 and ***p ⬍ 0.001.

Evaluation of hemodynamic parameters and thoracic fluid contents was performed by means of transthoracic cardio-bio-impedance (Cardioscreen Version 3/1 – Medizinisch Mesteenik, Ilmenau, Germany) and corroborated by clinical examination. Mean ultrafiltration rate was 2,102 ⫾ 505 ml/session. All patients showed substantial improvement, sustained by the fact that at the end of the first year of follow-up, their functional capabilities were defined as Class 1 (NYHA). Additionally, left ventricular function appeared significantly invigorated. Mean left cardiac work index was substantially higher (fig. 1a), whereas the mean

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systolic times ratio showed a marked reduction (fig. 1b). This evidence is well grounded, considering the demonstrated interrelation between systolic times ratio and ejection fraction, estimated by echocardiography [14]. This marked recovery of systolic left ventricular function was concomitant with a significant reduction of thoracic fluid contents (fig. 1c), testifying for correction of the intra and extravascular water overload. The mortality during the first year was 10%, substantially lower than the 85% expected according to the Charlson comorbidity index. The overall mortality in the 20 patients during the 396 months of follow-up was 30%. The median survival time of patients who died was 22 months (fig. 1d). Since mean (21 months) and mode (20 months) were quite close, it may be assumed that in spite of the small size of the sample, the Gaussian distribution of data related to survival, raises the possibility that these results could be reproducible, if applied to a larger population of similar patients. The total number of hospitalization days due to CHF and during 1 year before starting automated PD was 157, whereas the corresponding figures for the whole period of dialytic therapy were only 13 (p ⬍ 0.001).

Why Can PD Be so Effective in Refractory CHF?

Clinical and hemodynamic improvement seen in 4 non-compliant patients (basically unrestricted fluid intake) supports the contention that fluid overload may well be more the result rather than the cause behind progression and tenacity of refractory CHF. Published evidence indicates that cytokines and other humoral factors are involved in the development and progression of CHF. Some of them have specific myocardial depressant activity. Atrial natriuretic peptide, tumor necrosis factor-␣, interleukins (IL-1 and IL-6) induce apoptosis of cardiac myocytes and/or have also negative inotropic influence upon the heart muscle [15]. Blood levels of atrial natriuretic peptide are linked to the left ventricular mass and function, and are considered useful markers to predict mortality [16]. Molecular weight of myocardial depressant factors oscillates between 500 and 30,000 Da [17]. Since the peritoneum is permeable to solutes of middle molecular size [18] it is not surprising that tumor necrosis factor-␣ and atrial natriuretic peptide can be cleared from blood by means of PD [19, 20]. This information suggests that blood depuration of the aforementioned middle molecular size substances may well explain both, the better quality of life and the more extended survival observed in this group of severely ill cardiac patients. We cannot rule out the eventual additional effect of removing from blood, by means of PD, other still unidentified substances with negative

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effects upon cardiac myocytes. This hypothesis finds support in the already reported evidence showing failure of anticytokines as a monotherapy in patients with compromised left ventricular systolic function [21].

Conclusions

The observations presented in this study shed some hope for patients affected by refractory CHF. These results should be confirmed by a larger, perhaps multi centric study that, in our opinion, needs not to have a control group. The literature offers well-grounded evidence pointing at the gloomy prognosis of the disease. Even heart transplantation, as a life saving procedure, was never compared in controlled studies with any of the aforementioned conventional medical therapies [2]. Finally, if additional clinical research will eventually corroborate the positive effect of PD in end stage CHF, new efforts should be directed to design a new PD solution, having in mind the intricate challenges posed by cardiac decompensated patients.

References 1

2 3 4

5

6

7

8 9 10

Hunt SA, Baker DN, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Woble RJ, Parker M, Silver MA, Stevenson LW: ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2001;104:2996–3007. Jessup M, Brozena S: Heart failure. N Engl J Med 2003;348:2007–2018. Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383. Klein L, O’Connor CM, Gattis WA, Zampino M, de Luca L, Vitarelli A, Fedele F, Gheorghiade M: Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations. Am J Cardio 2003;91:18F–40F. Pitt B, Zaunad F, Remme WJ, Cody R, Cataigne A, Perez A, Palensky J, Wittes J: The effect of spironolactone on morbidity and mortality in patients with severe heart failure: randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–717. Juurlink DN, Mandani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier AA: Rates of hyperkalemia after publication of the randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543–551. Canaud B, Leblanc M, Leray-Moragnes H, Delmas S, Klouche K, Beraud JJ: Slow continuous and daily ultrafiltration for refractory congestive heart failure. Nephrol Dial Transplant 1998;13(suppl 4): S51–S55. Iorio L, De Santo LS, Violi F: Hemodialytic treatment of cardiac failure. Semin Nephrol 2001;21: 278–281. Schneierson SJ: Continuous peritoneal irrigation in the treatment of intractable edema of cardiac origin. Am J Med Sci 1949;218:76–79. Gotloib L, Fudin R, Yakubovich M, Vienken J: Peritoneal dialysis in refractory end-stage congestive heart failure: a challenge facing a no-win situation. Nephrol Dial Transplant 2005;20(suppl 7):32–36.

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11

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13 14

15 16

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Tormey V, Conlon PJ, Farrell J, Horgan J, Walshe JJ: Long-term successful management of refractory congestive heart failure by intermittent ambulatory peritoneal ultrafiltration. Q J Med 1996;88: 681–683. Ryckelink JP, Lobbedez T, Valette B, Le Goge C, Mazouz O, Levaltier B, Potier JC, Hurault de Ligny B: Peritoneal ultrafiltration and treatment-resistant heart failure. Nephrol Dial Transplant 1998;13(suppl 4):56–59. Costanzo MR, Augustine S, Bourge R, Bristow M, O’Connell JB, Driscoll D, Rose E: Selection and treatment of candidates for heart transplantation. Circulation 1995;92:3593–3612. Boudoulas H, Geleris P, Bush CA, Lewis RP, Fulkerson PK: Assessment of ventricular function by combined non-invasive measures: factors accounting for methodological disparities. Int J Cardiol 1983;2:493–506. Diwan A, Tran T, Misra A, Mann DL: Inflammatory mediators and the failing heart: a translational approach. Curr Mol Med 2003;3:161–182. Zoccali C, Mallamaci F, Benedette FA, Triperi G, Parlongo S, Cataliotti S, Cutrupi A, Giacone G, Bellanuova I, Cottini E, Malatino LS: Cardiac natriuretic peptides are related to left ventricular mass and function and predict mortality in dialysis patients. J Am Soc Nephrol 2001;12:1508–1515. Horl WH, Riegel W: Cardiac depressant factors in renal disease. Circulation 1993;87(suppl 5): IV77–IV82. Babb AL, Johansen PJ, Strand MJ, Tenckhoff H, Scribner BH: Bi-directional permeability of the human peritoneum to middle molecules. Proc Eur Dial Transplant Assoc 1973;10:247–262. Zemel D, Imholz AL, de Waart DR, Dinkla C, Strujik DG, Krediet RT: Appearance of tumor necrosis factor-alpha and soluble TNF receptors I and II in peritoneal effluent. Kidney Int 1994;46: 1422–1430. Fincker ME, Campbell HT, Sklar AH, Carvana RJ, Lightfoot BD, Cheek PL, Smith KL, Hess CP: Atrial natiuretic peptide (ANP) is removed by peritoneal dialysis in humans. Adv Perit Dial 1989; 5:16–19. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT: Anti-TNF therapy against congestive heart failure. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–3140.

Lazaro Gotloib, MD Department of Nephrology Ha’Emek Medical Center IL–18101 Afula (Israel) Tel./Fax ⫹972 4 6591537, E-Mail [email protected]

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Transplantation and Peritoneal Dialysis Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 254–258

The Impact of the Pre-Transplant Renal Replacement Modality on Outcome After Cadaveric Kidney Transplantation: The Ghent Experience W. Van Biesen, N. Veys, R. Vanholder, N. Lameire Department of Nephrology, University Hospital Ghent, Ghent, Belgium

Abstract For suitable patients, renal transplantation is still the most preferable renal replacement modality, offering the best outcome in terms of survival and quality of life [Meier-Kriesche, H.U. et al: Semin Dial 2005;18:499–504]. The shorter the period on dialysis, the better the outcome after transplantation seems to be [Meier-Kriesche, H.U. et al: Transplantation 2002;74: 1377–1381]. However, for most patients, a pre-emptive transplantation is not an option by lack of a suitable organ. Therefore, most people have to undergo hemodialysis or peritoneal dialysis (PD) while awaiting a donor kidney. There is evidence that PD positively impacts on the outcome after transplantation [Van Loo, A.A. et al: J Am Soc Nephrol 1998;9:473–481], an effect that could be attributed to a more stable fluid homeostasis, but also to an independent effect of biocompatibility of the dialysis membrane [Van Biesen, W. et al: Transplantation 2000;69:508–514], which is by definition better in PD. Based on these findings, since 1999, all hemodialysis patients at the university of Ghent are dialyzed on a low complement activating dialyzer, and dialysis and especially ultrafiltration in the 24 h preceding the transplantation are avoided as much as possible. A recent re-analysis of the data of the outcome of our transplant program showed that this approach resulted in a reduction of delayed graft function in the hemodialysis patients, allowing to reach an outcome level comparable to that of the PD patients. However, the long-term patient survival still is slightly superior in the PD patients. Copyright © 2006 S. Karger AG, Basel

Immediate Post-Transplant Graft Function

Acute renal failure (ARF) and delayed graft function (DGF), defined, respectively, as the need for dialysis and as delayed decrease of serum creatinine,

are common complications of kidney transplantation, with a reported incidence of up to 70%. Several secondary problems, such as fluid overload, retention of uremic solutes, hyperkalemia, and metabolic acidosis, are induced directly by ARF or DGF, and all these factors affect immediate morbidity and mortality after renal transplantation [3]. The differences in renal functional capacity between kidneys with immediate and DGF may persist up to 1 year after transplantation. Grafts with delayed function have been reported to have 10–15% lower 1-year graft survival rates compared with grafts with immediate function. DGF, especially if it was linked to rejection, was also linked to worse long-term graft outcome [5, 6]. The most common cause of DGF is acute tubular necrosis as a result of either ischemic damage to the kidney before or renal hypoperfusion during and after engraftment. The latter can be induced by many factors, such as vaso-active agents (cyclosporin, non-steroidal anti-inflammatory drugs, vasopressors) or unrecognized hypovolemia. Several studies demonstrated that peritoneal dialysis (PD) as pretransplantation dialysis modality has a protective effect on recovery of renal function after renal transplantation [3, 7, 8]. In a recent analysis of the USRDS data base, Goldfarb-Rumyantzev et al. [9] also confirmed that the previous use of hemodialysis (HD) as renal replacement therapy (RRT) modality had a negative impact on graft outcomes. As PD patients have a more stable fluid status than HD patients, this was hypothesized to be the responsible factor for this observation. However, in a multivariate analysis, Van Biesen et al. [4] were able to show that, besides factors related to volume status and cold ischemia time, PD on itself seemed to have an independent beneficial impact on immediate graft recovery. It was hypothesized that this effect was due to the lower grade of exposure to bio-incompatibility in PD patients, an hypothesis supported by the observation that in HD patients, those using cuprophane membranes had a worse outcome as compared to those treated with less leukocyte and complement activating membranes [3]. Based on these findings, the treatment policy for HD patients in the University Hospital Ghent was altered. All patients were placed on noncomplement activating membranes. The strategy to perform systematically an extra dialysis session immediately before transplantation, formerly introduced to avoid the immediate need for dialysis after the transplantation in case of DGF, was abolished. If an extra dialysis session was unavoidable e.g. because of severe hyperkalemia, no ultrafiltration was performed. Five years after implementation of these new guidelines, a reanalysis of the transplant outcome was performed. In total, 455 patients (350 HD, 105 PD) were included. PD patients were more likely to be female (57/105 versus 48/350, p ⫽ 0.006) and had been on RRT for a shorter period of time (708 ⫾ 432 versus 1,054 ⫾ 849 days, p ⫽ 0.0001). There was no difference in age, cold ischemia time, or prevalence of diabetes. Time to reach a serum creatinine value half that of the pre-transplant

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value was not different anymore between PD and HD patients (Log rank: p ⫽ 0.76) in the subgroup of patients transplanted after 1999. In the HD patients, the fact of being transplanted before 1999 was a risk factor for DGF, whereas it was not in the PD patients. This pointed to an impact of ‘biocompatibility’ on immediate graft recovery after transplantation.

PD before Combined Kidney Pancreas Transplantation

There has always been concern about the use of PD before combined simultaneous pancreas kidney (SPK) transplantation, as it was thought that it might increase the risk for infectious complications. Some early reports indeed warned for increased infection rates in patients with SPK [10]. This study was however only published as an abstract, and was multi-centric, so that interaction of centre experience with PD and SPK might also have played a role. Recently, Kim et al. [11] reported no difference in infectious complications between PD and HD patients after SPK in an investigation comprising 120 patients. Out of these 120, abdominal infection developed in 5 PD and 6 HD patients (p ⫽ 0.88). The time of diagnosis of intra-abdominal infection and the spectrum of organisms cultured were similar in the two groups of patients. Age, duration of dialysis, and way of exocrine drainage did not have a significant impact on infection rate. Patient and pancreas graft survival rates were 92.3 and 88.4% in the PD group and 95.5 and 92% in the HD group (p ⫽ NS) after a mean follow-up of 42 ⫾ 27 months and 39 ⫾ 27 months, respectively. There seems thus no need to withhold PD in patients on the waiting list for SPK.

Long-Term Graft and Patient Survival

Whereas DGF might increase the morbidity of the immediate posttransplant period, long-term outcome is of course a main concern for most patients and physicians. However, it seems not unlogical to accept a relation between DGF and long-term graft outcome. As ARF may result in irreversible loss of a number of nephrons, the hyperfiltration in the reduced number of nephrons after the initial insult may result in progressive loss of the grafted kidney function later on. In addition, ARF may trigger acute rejection, hence further jeopardizing long-term kidney function. Fontan et al. [12] demonstrated that DGF and early acute rejection had a definite additive impact on late graft survival and on the presence of markers of late graft dysfunction after 6 years of followup. Giral-Classe et al. [13] found that this negative impact on long-term graft

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outcome can best be predicted by the evolution of creatinine clearance in the first 7 days after transplantation. Goldfarb-Rumyantzev et al. [9] studied allograft and recipient survival by using US Renal Data System records from 1 January 1990 to 31 December 1999, with a follow-up period through 31 December 2000. Compared with HD, a Cox model showed that PD immediately before transplantation predicts a 3% lower risk for overall graft failure (p ⬍ 0.05) and a 6% lower risk for recipient death (p ⬍ 0.001). When the predominant RRT modality was analyzed (modality used for ⬎50% of the RRT time), PD had a protective effect on graft survival compared with HD. Better recipient survival was also associated with PD (HR, 0.96; p ⬍ 0.05). Increased number of RRT modalities during the ESRD course was associated with increased risk for graft failure (HR, 1.04 per additional modality used; p ⬍ 0.005) and recipient death (HR, 1.11 per additional modality used; p ⬍ 0.001). In our Ghent experience, we observed that long-term patient survival was better in the PD patients as compared to the HD patients (p ⫽ 0.04). Once again however, being transplanted before 1999 had an impact on long-term survival in HD, but not in PD patients. Long-term graft survival appeared not to be different between HD and PD (p ⫽ NS). When transplant success was analysed (patient alive with functioning graft), outcome was again superior in the PD patients as compared to HD patients (p ⫽ 0.04).

Conclusion

The previously reported difference in short-term outcome between PD and HD patients was abolished by implementation of new HD philosophies strategies, at least in our hands. In our group, there was no difference in long-term graft survival, but this seems to be different in the USRDS database. Long-term patient survival after transplantation was however superior in PD patients, as it was also in the USRDS dabates. PD as the first dialysis modality is thus not contra-indicated in patients on the waiting list for transplantation, and very likely offers a survival advantage. In patients waiting for SPK transplantation, recent reports show no increased infection risk.

References 1 2

Meier-Kriesche HU, Schold JD: The impact of pretransplant dialysis on outcomes in renal transplantation. Semin Dial 2005;18:499–504. 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;74:1377–1381.

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3

4

5 6

7 8

9

10 11

12 13

Van Loo AA, Vanholder RC, Bernaert PR, Vermassen FE, Van Der Vennet M, Lameire NH: Pretransplantation hemodialysis strategy influences early renal graft function. J Am Soc Nephrol 1998;9:473–481. Van Biesen W, Vanholder R, Van Loo A, Van Der Vennet M, Lameire N: Peritoneal dialysis favorably influences early graft function after renal transplantation compared to hemodialysis. Transplantation 2000;69:508–514. 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. Troppmann C, Gillingham KJ, Benedetti E, Almond PS, Gruessner RW, Najarian JS, Matas AJ: Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The multivariate analysis. Transplantation 1995;59:962–968. Bleyer AJ, Burkart JM, Russell GB, Adams PL: Dialysis modality and delayed graft function after cadaveric renal transplantation. J Am Soc Nephrol 1999;10:154–159. Van Biesen W, Vanholder R, Lameire N: Impact of pretransplantation dialysis modality on patient outcome after renal transplantation: the role of peritoneal dialysis revisited. Perit Dial Int 1999;19: 103–106. Goldfarb-Rumyantzev AS, Hurdle JF, Scandling JD, Baird BC, Cheung AK: The role of pretransplantation renal replacement therapy modality in kidney allograft and recipient survival. Am J Kidney Dis 2005;46:537–549. Malaise J, Squifflet JP, Van Ophem D: Influence of the type of renal replacement therapy on peritonitis rate after simultaneous pancreas kidney transplantation. Transplant Proc 2002;34:2823. Kim RD, Oreopoulos DG, Qiu K, McGilvray ID, Greig PD, Wright E, Grant DR, Cattral MS: Impact of mode of dialysis on intra-abdominal infection after simultaneous pancreas-kidney transplantation. Transplantation 2005;80:339–343. Fontan M, Rodriguez-Carmona A, Falcon T, Moncalian J, Oliver J, Valdes F: Renal transplantation in patients undergoing chronic peritoneal dialysis. Perit Dial Int 1996;16:46. Giral-Classe M, Hourmant M, Cantarovich D, Dantal J, Blancho G, Daguin P, Ancelet D, Soulillou JP: Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys. Kidney Int 1998;54:972–978.

W. Van Biesen Department of Nephrology, University Hospital Ghent De Pintelaan 185 BE–9000 Ghent (Belgium) Tel. ⫹32 9 240 4402, Fax ⫹32 9 240 4599, E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 259–270

Transplantation Outcome in Patients on PD and HD Giovanni C. Cancarini, Silvio Sandrini, Gisella Setti, Nicola Bossini, Silvia Cassamali, Nicoletta Pertica, Paolo Maiorca Section of Nephrology, Department of Experimental and Applied Medicine, University of Brescia and Division of Nephrology, Spedali Civili Brescia, Brescia, Italy

Abstract In the past, peritoneal dialysis (PD) has been considered a second choice dialysis modality for many aspects and that negative attitude has been extended also to possible negative effects on renal transplantation. In the last years, many papers have faced the question whether PD could attain similar results in renal transplantation as hemodialysis and there is sufficient evidence to answer that question. On the short time after transplantation, patients coming PD have lower prevalence of delayed graft function than hemodialysis patients, but higher prevalence of renal vascular thrombosis, above all in children. Incidence of acute graft rejection is not different between the two dialysis modalities. The long-term outcome of renal transplantation is similar in patients coming from either PD or hemodialysis. Copyright © 2006 S. Karger AG, Basel

The past negative attitude towards peritoneal dialysis (PD) as a dialysis modality before kidney transplantation has progressively disappeared, in the last years, and PD is no more considered as a risk factor in renal transplantation as previously suggested [1, 2]. On the other hand, PD has peculiar features, different from hemodialysis (HD), which must be taken into consideration when kidney transplantation is considered. Other chapters, in this volume, face some major clinical problem: suitability of PD patients for transplant, use of PD after kidney transplantation in the case of delayed graft function, and return to PD after failed renal transplant. This chapter will focus on the outcome of renal transplantation in PD patients comparing it, when possible, to that of HD patients.

Factors Affecting the Comparison Between PD and HD

PD Penetration and PD Technique Survival PD penetration is very different worldwide and its average is about 12% in western countries. This means that the physicians involved in renal transplantation programs have 8 times more experience in treating HD patients than PD patients, in other words they should be more confident with HD patients. Another point that could affect the comparison is the different time of stay in the two methods. PD has a definitely worse technique survival than HD, so those PD patients remaining for long time in the waiting list, risk to be transferred to HD before being transplanted, overall in the countries with low transplantation rate. On the other hand there is the observation of Snyder et al. [3] on the 22,776 Medicare and Medicaid transplanted patients in the years 1995–1998; after 5 years, the 31.7% of PD patients have been transplanted against only the 15.7% on HD (p ⬍ 0.001). After adjustments were made for the differences in PD and HD patients, the relative likelihood of receiving a kidney transplant was 1.39 (95% CI: 1.35–1.43; p ⬍ 0.0001) times greater for PD than for HD patients. Those authors refer that ‘There may be a perception among patients and their physician that peritoneal dialysis is the treatment of choice for transplant candidates . . . transplant candidates were more likely to be placed on PD than HD.’ In our center the probability to be transplanted is higher for PD patients (after 5 years: 46 versus 37%) but does not reach the statistical significance [4]. Out of the 155 PD patients in our waiting list, only 6% are still on PD after 5 years, the remaining 58% having been transplanted or dead or cancelled from the list and the 36% having been shifted to HD (unpublished data). The French Collaborative Group [5] found that, even if the kidney allocation in France is blind to dialysis modality, the probability to be transplanted was higher in PD patients with an RR of 0.71 (p ⬍ 0.0001). However, they found that the median waiting time was inversely related to the proportion of PD patients on waiting list, i.e. the centers with higher PD use were also those with shorter waiting time. Yet, it must be highlighted that they found that the length on dialysis at registration was significantly shorter for PD patients than for HD patients (11.4 ⫾ 11.8 versus 19.5 ⫾ 34.8 months; p ⬍ 0.0001). In a little series of 42 dialyzed patients who received living-donor kidney transplantation, the transfer rate from PD to transplantation was significantly higher than that of HD (4.7 versus 1.9%; p ⫽ 0.0036) [6]. Those authors suggest that the reason for the high transplant rate of PD patients might be cooperation with their family and the provision of relevant information by nephrologists during PD. All this suggests a center effect, but one could also hypothesize that the physician involved in PD programs are more efficient in putting their patients in the waiting

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list. According to those authors, the center-effect is a potential bias that could have affected the publications demonstrating shorter waiting time of PD patients [5]. Patient Selection for the Dialysis Modalities A recent paper on end stage renal disease (ESRD) patients in five European countries/regions examined how co-morbidity had affected access to transplantation and computed the relative risk of receiving a first transplant within 4 years after the start of RRT [7]. That paper showed that the prevalence of co-morbidities increased according to patient age and differed among the countries. The probability to be transplanted within 4 years (Reference Austria set ⫽ 1) was as low as 0.26 (95% CI: 0.21–0.23) in Italy and as high as 4.10 in Norway (95% CI: 3.43–4.91) in patients without co-morbidity, while in those with co-morbidity the same figures were 0.12 (95% CI: 0.08–0.17) and 3.19 (95% CI: 2.51–4.04). Among the dialyzed patients without co-morbidity 21.4% were on PD and 78.6% on HD; the percentage of patients with one or more comorbid condition were, respectively, 17.2 and 82.8%, whereas in the group with more than 2 co-morbid conditions they were 14.4 and 85.6%. That supports a positive selection for PD patients, which could partly contrast the effect of different penetration. This hypothesis could be the explanation why, on 22,776 patients from Medicare, PD patients were more likely to be transplanted than HD patients (p ⬍ 0.0001) [3]. The French Collaborative Group [5] compared the characteristics of 647 PD and 5,190 HD patients on kidney waiting list and found that the PD group had a significant prevalence of women (41.3 versus 36.8; p ⫽ 0.004) and younger patients (age: 44.8 ⫾ 13.2 versus 46.2 ⫾ 12.8; p ⫽ 0.04). By comparing the data of transplanted patients, age was not different between PD and HD, but the former one kept on a higher prevalence of women (39 versus 35%). Cold Ischemia Time One advantage for PD patients consists on the fact that they are always ready for the transplant operation thanks to both the continuous blood purification offered by this daily dialysis modality and to the short time needed for flushing out the peritoneal solution. HD patients generally need to be dialyzed, for 3–4 h before the operation and this could increase the cold ischemia time. The data from the French Collaborative study [5] confirm this assumption in favour of PD: 20.5 ⫾ 8.1 versus 22.4 ⫾ 8.3 h (p ⬍ 0.001). However, other authors have reported cold ischemia time not significantly different or significantly different even if probably not so clinically relevant (e.g. 21.2 versus 21.6 h in reference [8]).

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Short-Term Outcome

The main clinical problems shortly after transplantation are delayed renal function and surgical complications. Delayed graft function (DGF) could depend on many factors related to donor (e.g. age, non-heart-beating donor, clinical status just before operation), kidney (e.g. cold ischemia time, difficulty in perfusion, ischemia-perfusion injury), recipient (fluid, vascular and cardiac status, ability to metabolize immunosuppressive drugs) and kind of immunosuppressive therapy [9–12]. Unfortunately, DGF could depend on either acute tubular necrosis or acute rejection, which could be easily differentiated only when renal biopsy is done; unfortunately, many papers report all those data together. Bleyer et al. [8] showed that the percentage of patients who did not produce urine in the first 24 h post-transplant was 8.3% in the PD group versus 11.9% in that on HD (p ⬍ 0.001). A summary of the results reported by other papers is shown in the table 1. The paper of Bleyer et al. reported also that the good results of PD did not change if only patients who had been on dialysis for 2 years were considered; this selection was made to exclude a possible confounding effect by residual renal function, more frequent in PD patients. On the other hand, the lack of effect of that possible confounder was demonstrated by the requirement of dialysis in the first week: the OR for HD versus PD was 1.395 (95% CI: 1.214–1.600; p ⫽ 0.0001) [8]. Snyder et al. [3] found an odd ratio for delayed renal function of 0.74 (0.68–0.81; p ⬍ 0.0001) for PD patients against HD patients after adjustment for prognostic differences. Some hypothesis has been suggested to explain those differences between PD and HD. The reduced cold ischemia time could play a role, since that time is inversely related to the probability of early graft function; other hypotheses bases on the shorter length of dialysis before transplantation in PD patients, their extra-cellular volume status as well as on inflammatory stimulation induced by HD performed shortly before transplant. Van Loo et al. [13] have shown that the evolution of serum creatinine, in HD patients, was markedly influenced by the kind of membrane and the use of ultrafiltration in the 24 h before transplantation. The time to reach one half of the baseline serum creatinine in the group treated with biocompatible dialysis membranes and without ultrafiltration was 1.7 ⫾ 0.8 days versus 9.3 ⫾ 9.1 days (p ⬍ 0.01) in the group treated with bio-incompatible membranes and ultrafiltration. Ultrafiltration could negatively affect renal function thanks to the relative extra-cellular volume reduction and consequent graft hypo-perfusion. Many authors claimed that PD patients are more ECV expanded than HD patients and this could be the cause of the different prevalence of DGF. However, Van Biesen et al. [14] demonstrated a protective role of PD per se, independent of

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Table 1. Percentages of delayed graft function and acute renal failure post-transplantation, according to different authors Reference

PD

HD

p

Shapira et al. [15] Cardella et al. [16]* Triolo et al. [17] Koch and Halloran [18] Cacciarelli et al. [19] Pérez Fontán et al. [20] Escuin et al. [21] Vanholder et al. [22] Bleyer et al. [8] Van Biesen et al. [14] (DGF) Van Biesen et al. [14] (ARF) Vats et al. [23]** Joseph and Jindal [24] Snyder et al. [3] Cancarini et al. [4] Fontana et al. [25] (DGF)** Fontana et al. [25] (ARF)**

40 35 23 19 26 22 16 23 20 15 0 11 31 12 16 24 14

55 35 27 58 36 39 33 50 29 34 18 12 50 16 31 22 16

NS NS NS ⬍0.01 NA ⬍0.05 ⬍0.001 ⬍0.0001 ⬍0.001 0.03 ⬍0.01 NS ⬍0.01 NA ⬍0.05 NS NS

ARF ⫽ Acute renal failure; DGF ⫽ delayed graft function; NA ⫽ not available; NS ⫽ not significant. * ⫽ Only patients over 50 years of age; ** ⫽ only children.

the body weight gain, the fluid administration in the first 72 h, and the cold ischemia time. Since DGF is associated with a 2.8 (p ⬍ 0.0001) times greater risk of death, a 2.9 times risk of graft failure (p ⬍ 0.0001) [3], the beneficial effect of PD could be expected as a favourable prognostic factor for the outcome of renal transplantation. Two of the papers, quoted in the table 1, were addressed to study this topic in children and both of them found no difference in the prevalence of DGF between PD and HD [23, 25]. One of them [25] showed, by Cox regression analysis, no effect by modality, whereas, in one of the two models tested, the fluid load had a significant effect (p ⫽ 0.037), but, its weight can not be defined due to the unit chosen (ml/h) and the low number of digits reported in the paper. Many years ago, some papers suggested that PD could grant a higher immune response than HD; this could be risky for favouring the appearance of graft rejection [1]. About all the following studies focusing this topic and reported in the table 2 did not support that suggestion.

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Table 2. Percentages of rejection post-transplantation according to different authors Reference

PD

HD

p

Cardella et al. [16] Escuin et al. [21] Pérez Fontán et al. [20] Vanholder et al. [22] Joseph and Jindal [24] Snyder et al. [3] Cancarini et al. [4]

48 45 48 68 49 30 67

41 45 41 52 44 31 67

NS NS NS ⬍0.05 NS NS NS

NS ⫽ Not significant.

Bartosh et al. [26] found an increased graft failure rate among those SLE cadaveric transplant recipients receiving PD before transplant compared with controls and compared with SLE patients receiving HD (63 versus 29%; p ⫽ 0.019). To explain that difference, the authors quote the altered T-cell subset ratios found by Guillou et al. [1] and hypothesize a possible detrimental interaction occurring in SLE patients receiving PD. However, this explanation does not apply to another result of the same paper, e.g. the percentage of graft failure in recipients from living donors that was 17% for PD and 32% for HD. In another study, the PD patients had a higher frequency of, biopsy proved, acute rejection (37.5 versus 9.1% in HD; p ⫽ 0.034) [27]. PD patients had an earlier increases of CD3, CD19, CD4 and CD4⫹ CD28⫹ cells than in the HD patients and the numbers of these cells in the PD group were higher than those in the HD between days 3 and 28 after transplantation, most significantly on day 7. These findings suggest that the PD patients could potentially have a higher immunocompetence and immune responsiveness associated with a higher rate of acute rejection in the early stage of renal transplantation when compared with the HD patients [27]. Graft Vascular Thrombosis Vascular thrombosis of the graft is a very dangerous complication for the graft function and its prevalence seems to be higher among patients coming from PD (table 3). Ojo et al. [28] found that the relative risk of early allograft thrombosis was for PD patients versus HD patients after the first (RR: 1.87; p ⫽ 0.001), and even more after the following transplantations (RR: 12.95; p ⬍ 0.001). The Cox analysis done by Snyder et al. [3] showed that PD patients had a 23% increase

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Table 3. Risk of allograft vascular thrombosis in transplanted patients coming from PD and HD Reference

No of PD patients

PD versus HD (%)

p

Murphy et al. [36] Escuin et al. [21] Bakir et al. [37] van der Vliet et al. [38] Pérez Fontán et al. [20] Ojo et al. [28] Vats et al. [23]* McDonald et al. [29]*

97 138 126 303 127 502 1090 7247

9.2 versus 0 2.2 versus 3.5 8.7 versus 6.0 7.3 versus 3.6 4.7 versus 6.1 – 3.3 versus 1.7 3.4 versus 1.9

⬍0.01 NS NS ⬍0.02 NS ⬍0.001 ⫽0.04 ⬍0.005

* ⫽ Transplantation in children. NS ⫽ Not significant.

in the probability of graft failure during the first 3 months (RR: 1.23; 1.09–1.39; p ⬍ 0.001) which further increased if one censored death (1.33; 1.16–1.53; p ⬍ 0.0001). After the third months the prevalence of graft failure was not significantly different between PD and HD: RR ⫽ 0.96 (95% CI 0.87–1.05) as well the risk of death (RR: 0.91; 95% CI: 0.80–1.04). Among the causes for the earliest failures, the only significant difference between PD and HD was the prevalence of graft thrombosis which accounted for 64/156 versus 106/349 failures (41% versus 30%; p ⫽ 0.0192) [3]. Graft failure due to vascular thrombosis is frequent in paediatric renal transplantation programs; it occurred in 2.7% of 7,247 paediatric renal transplants performed between 1987 and 2001 and was the third most common cause of graft loss; but, looking at the later cohort (1996–2001), it became the most common cause of graft failure (21%), possibly due to the decreased incidence of acute rejection [29]. Graft loss because of vascular thrombosis accounted for the 3.4% in the PD group versus 1.9% in the HD group, 2.4% in the pre-emptive transplant group, and 4.1% among patients who received both dialysis modalities [29]. A possible risk factor for vascular thrombosis could be the obesity, since graft loss due to this reason was more common in obese as compared with nonobese (19% versus 10%) [30]. Obesity could affect the outcome of renal transplantation also because of its independent effect on progression of proteinuria in renal transplant recipients [31]. Immunosuppressive therapy could increase the obesity since, in that study, 9% of the renal transplant recipients were obese pre-transplantation compared to 30% at baseline (p ⬍ 0.001) and follow-up. At this regard, one has to keep in mind that PD is more risky for obesity than HD [32].

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Table 4. Patient and graft survival in different studies comparing PD and HD Reference

Follow-up (years)

Lambert et al. [41] Cosio et al. [42] Vats et al. [23]* Snyder et al. [3] Joseph and Jindal [24] Cancarini et al. [4] Chalem et al. [5]

4 7 3 5 5 10 2

Patient survival

Graft survival

PD

HD

p

PD

HD

p

92 83 – 85 79 88 NA

88 77 – 85 81 83 NA

NA NS – NS NS NS NS

92 – 82 – 61 74 91

77 – 82 – 64 76 89

NA – NS – NS NS NS

* ⫽ Children. NA ⫽ Not available; NS ⫽ not significant.

An association between a significantly decreased risks of graft failure due to thrombosis with use of IL-2 receptor blockade as induction therapy (1.07 versus 2.40%; OR 0.44, 95% CI 0.23–0.84, p ⫽ 0.014) has been recently reported by the North American Pediatric Renal Transplant Cooperative Study [33]. This finding requires a prospective randomized study to exclude a possible association by chance. In our center the low occurrence of vascular thrombosis is anecdotic, probably thanks to the prophylactic use of low-molecular-eight heparin. Both this approach and the higher prevalence of thrombosis in PD patients found in literature could have a theoretical basis on the fact that some kind of thrombophilia has been suggested for PD either for increased platelet count or for increased fibrinogen concentration like in nephrotic syndrome [34–35].

Long-Term Outcome

Some recent data on patient and graft survival are shown in Table 4 and update our previous reports [4, 39, 40]. Goldfarb-Rumyantzev et al. [43] found that a longer duration of ESRD is associated with both a worsening graft outcome and a worsening recipient survival. The former became significant after 6 months passed on dialysis, and after 1 year the risk did not increased further; the latter became significant after 1 year of ESRD duration and continues to increase over time. Searching for an explanation about the different trends of graft and patient survival, the authors speculated that predictors of the graft survival (e.g. oxidative stress, loss of

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residual renal function, aberrant T, B cell and cytokine production) might be peaking at 1 year, whereas additional factors affecting recipient survival (e.g. cardiovascular calcification) continue to accumulate after 1 year of dialysis therapy. The association between ESRD duration and graft survival was similar between HD (HR: 1.02 per year, p ⬍ 0.001) and PD (HR: 1.03 per year, p ⬍ 0.001) as well as patient survival HD (HR: 1.04, p ⬍ 0.001) and PD (HR: 1.07, p ⬍ 0.001) when dialysis duration was evaluated as continuous variable. When dialysis duration was evaluated as categorical variable, HD showed a significant increase in the hazard risk at each time interval versus 0–14 days, whereas PD had a trend in the same direction, but not statistically significant, for both graft and patient survival. In a following paper, the same authors focused their attention on the different effect of HD and PD on long-term survival [44] and found that, compared with HD, PD was associated with reduced risks for graft failure and recipient death in all the following models: RRT modality immediately before transplantation (HR for graft failure: 0.97, p ⬍ 0.05; HR for patient survival: 0.94, p ⬍ 0.001) or as a predominant RRT modality during the ESRD course (HR for graft failure: 0.97, p ⬍ 0.05; HR for patient survival: 0.96, p ⬍ 0.05), or used alone (HR for graft failure: 0.93, p ⬍ 0.0001; HR for patient survival: 0.90, p ⬍ 0.001). Increased number of RRT modalities used during the ESRD course was associated with worsening of graft and recipient survival. Flaws of both those studies is the ratio 3:1 between HD and PD patients, the attribution of patients to the modality group according to the predominant RRT modality during the ESRD course, lack of information about residual renal function, anthropometric characteristics, cardiovascular status. Moreover, as all the multivariate statistical analyses, the Cox method adjusts only for the variables entered the model and, among them only for those associated with a sufficient number of the end points considered. Chakkera et al. [45] did a study to define the reasons of the inferior outcomes after kidney transplantation among African Americans; they confirmed, at the univariate analysis, the negative effect of dialysis duration pretransplant (RR: 1.04 per year; 95% CI: 1.04–1.05) as well as the positive effect of PD either when dialysis modality at ESRD initiation was considered (HR: 0.91; 95% CI: 0.88–0.93) or when dialysis modality pre-transplantation was considered (HR: 0.92; 95% CI: 0.85–1.00). A previous report from our group showed that the 10-year patient survival was 88% for PD and 83% for HD (p: NS) and the causes of death were similar in both groups [4]. After 10 years 74% of PD and 76% of HD patients (p: NS) had a functioning kidney and, at the last follow-up (79 ⫾ 43 and 84 ⫾ 44 months after transplantation) serum creatinine was no different (1.5 ⫾ 0.5 mg/dl in both groups) as well as the percentage of patients with urine protein excretion higher than 1 g/day (16%).

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Vanholder R, Heering P, Van Loo A, et al: Reduced incidence of acute renal graft failure in patients treated with peritoneal dialysis compared with hemodialysis. Am J Kidney Dis 1999;33: 934–940. Vats AN, Donaldson L, Fine RN, Chavers BM: Pretransplant dialysis status and outcome of renal transplantation in north american children: a NAPRTCS study. Transplantation 2000;69: 1414–1419. Joseph JT, Jindal RM: Influence of dialysis on post-transplant events. Clin Transplant 2002;16: 18–23. Fontana I, Santori G, Ginevri F, et al: Impact of pretransplant dialysis on early graft function in pediatric kidney recipients. Transplant Int 2005;18:785–793. Bartosh SM, Fine RN, Sullivan EK: Outcome after transplantation of young patients with systemic lupus erythematosus: a report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation 2001;72:973–978. Satoh S, Tsuchiya N, Sato K, Ohtani H, Komatsuda A, Habuchi T, Kato T: Influence of pretransplant dialysis modality on the change of lymphocyte subset populations and acute rejection rates after renal transplantation. Int J Urol 2004;11:825–830. Ojo AO, Hanson JA, Wolfe RA, et al: Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients. Kidney Int 1999;55:1952–1960. McDonald RA, Smith JM, Stablein D, Harmon WE: Pretransplant peritoneal dialysis and graft thrombosis following pediatric kidney transplantation: a NAPRTCS report. Pediatr Transplant 2003;7:204–208. Hanevold CD, Ho PL, Talley L, Mitsnefes MM: Obesity and renal transplant outcome: a report of the north American pediatric renal transplant cooperative study. Pediatrics 2005;115: 352–356. Armstrong KA, Campbell SB, Hawley CM, David L, Nicol DL, Johnson DW, Isbel NM: Obesity is associated with worsening cardiovascular risk factor profiles and proteinuria progression in renal transplant recipients. Am J Transplant 2005;5:2710–2718. Heimbürger O: Obesity on PD patients: causes and management. Contrib Nephrol 2003;140: 91–97. Smith JM, Stablein D, Singh A, Harmon W, McDonald RA: Decreased risk of renal allograft thrombosis associated with interleukin-2 receptor antagonists: a report of the NAPRTCS. Am J Transplantation 2006;doi:10.1111/j.1600–6143.2005.01213.x Assouad M, Eknoyan G: Does the choice of renal replacement therapy adversely affect hypercoagulability associated with renal disease? Perit Dial Int 2000;20:375–383. Kobayashi M, Yorioka N, Yamakido M: Hypercoagulability and secondary hyperfibrinolysis may due to abnormal lipid metabolism in patients treated with continuous ambulatory peritoneal dialysis. Nephron 1997;76:56–61. Murphy BG, Hill CM, Middleton D, et al: Increased renai allograft thrombosis in CAPD patients. Nephrol Dial Transplant 1994;9:1166–1169. Bakir N, Surachno S, Sluiter WJ, et al: Peritonitis in peritoneal dialysis patients after renal transplantation. Nephrol Dial Transplant 1998;13:3178–3183. van der Vliet JA, Barendregt WB, Hoitsma AJ, Buskens FGM: Increased incidence of renal allograft thrombosis after continuous ambulatory peritoneal dialysis. Clin Transplantation 1996;10: 51–54. Maiorca R, Sandrini S, Cancarini GC, et al: Kidney transplantation in peritoneal dialysis patients. Perit Dial Int 1994;14(suppl 2):S162–S168. Maiorca R, Sandrini S, Cancarini GC, et al: Integration of peritoneal dialysis and transplantation programs. Perit Dial Int 1997;17(suppl 2):S170–S174. Lambert MP, Bernaert P, Vijt D, De Smet R, Lameire N: CAPD – a risk factor in renal transplantation? ARF after transplantation. Perit Dial Int 1996;16(suppl 1):S495–S498. Cosio FG, Alamir A, Yim S, et al: Patient survival after renal transplantation. I. the impact of dialysis pre-transplant. Kidney Int 1998;53:767–772. Goldfarb-Rumyantzev A, Hurdle JF, Scandling J, et al: Duration of end stage renal disease and kidney transplant outcome. Nephrol Dial Transplant 2005;20:167–175.

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Goldfarb-Rumyantzev AS, Hurdle JF, Scandling JD, Baird BC, Cheung AK: The role of pretransplantation renal replacement therapy modality in kidney allograft and recipient survival. Am J Kidney Dis 2005;46:537–549. Chakkera HA, O’Hare AM, Johansen KL, et al: Influence of race on kidney transplant outcomes within and outside the department of veterans affairs. J Am Soc Nephrol 2005;16:269–277.

Prof. Giovanni C. Cancarini Sezione di Nefrologia-Dipartimento Medicina Sperimentale ed Applicata – Università di Brescia U.O. Nefrologia – Spedali Civili di Brescia, Piazza Spedali Civili, 1 IT–25123 Brescia (Italy) Tel. ⫹39 030 3995626/1, Fax ⫹39 030 307218 E-Mail [email protected]

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Transplantation and Beyond Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 271–277

Peritoneal Dialysis after a Failed Transplant Biju John, Lily Mushahar, Simon J. Davies Department of Nephrology, University Hospital of North Staffordshire, Stoke-on-Trent and Institute for Science and Technology in Medicine, School of Medicine, Keele University, Keele, UK

Abstract Failed transplantation is an increasingly common cause for starting dialysis treatment. As with all patients approaching dialysis there is a need for adequate physical and psychological preparation and yet whilst by definition these individuals are known to health professionals this is not always achieved. It is likely that given adequate information, a significant proportion of these patients would prefer PD on lifestyle grounds. There is increasingly strong evidence that patients commencing PD after transplant failure enjoy overall survival and technique survival that is no different to those new to dialysis, even when other risk factors such as age, comorbidity, race, gender and membrane function are taken into account. The risk of peritonitis is also not different. These patients tend to lose residual renal function more rapidly but this does not translate into worse outcomes. The role and benefit in modulating immune suppressive drugs before and after commencing PD is not clear. Copyright © 2006 S. Karger AG, Basel

Peritoneal Dialysis Following Transplant Failure: What are the Issues?

Graft failure is now becoming one of the more important causes of patients entering the dialysis programme. It is estimated that 2–3% of transplants fail each year necessitating a return to dialysis, and although the number of grafts failing per 1,000 patients per year dropped in the 1990s from 50 to 40, the absolute number has increased due to the cumulative increase in the size of transplant programmes [1]. The choice of dialysis modality after allograft

failure depends on patient and physician preferences and there is evidence that this is left too late with inadequate time for preparation. The available evidence presented in this article would suggest that choice of peritoneal dialysis (PD) is associated with a survival risk that is equivalent to that experienced by new patients to this modality, after adjustment for confounding factors such as age and comorbidity. A further issue in the management of the patient with the failing graft is the approach to reducing immune suppression, to ensure where possible preservation of residual renal function without increasing infection risk.

Haemodialysis or Peritoneal Dialysis?

There is increasing evidence that preparation and education prior to commencing dialysis is associated with a greater likelihood of choosing PD and with higher levels of patient satisfaction [2, 3]. This preparation should include both medical and psycho-social considerations, and for most patients choice of modality will be governed largely by life-style issues where practicable. Many patients will have bad memories of dialysis and have concerns that are now out of date. For example, new dialysis alternatives, such as APD or more frequent, short hours haemodialysis (HD) might have become available. It is also often the case that patients with failing grafts are managed by clinicians who have little or no first hand experience of these options if there is separation of the transplant and dialysis programmes. There is evidence that medical, let alone psychological preparation for dialysis following transplant failure is less than adequate. In a study of these patients commencing dialysis anaemia management in particular was suboptimal, as judged by an average haematocrit of 27.5% and poor erythropoietin usage [4]. On multivariate analysis this was less serious in patients choosing PD than HD, although this was probably a function of socio-economic factors rather than a treatment effect. There is, however, some evidence to suggest that HD patients with failed grafts need higher doses of erythropoietin [5]. Whatever the reason, it is certainly clear that despite the fact these patients are known to nephrologists, significant improvements in management could be achieved. One of the first studies to report on patients commencing PD following transplant failure was associated with a particularly high death rate [6]. Forty two patients with transplants that had lasted at least 6 months and on average 7.4 years, were compared with the 43 randomly selected from the new PD patient population. Despite a relatively young mean age of 45 years, the patients with failing graft had a shorter time to peritonitis and first catheter removal and a

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higher death rate (12 deaths verses 3 in the comparator group). This has led to concern that PD is a poor modality choice following graft failure. To explore this possibility, a sub-analysis of the Stoke PD Study was undertaken to compare patient and technique survival between 28 patients commencing PD following graft failure with 17 who stared with HD during the same time-period (1989–2000) [7]. Age, length of transplant function and comorbidity was not different between these groups. If anything, PD was associated with better early survival, but this was not significant and the cohort was not large enough to address differences in comorbidity (5 year actuarial survival HD: 68%, PD: 83%, p ⫽ 0.1). When survival in the same 28 patients was compared to all new patients commencing PD during the same time period (n ⫽ 469), actuarial survival was better, but once this was adjusted for age and comorbidity there was no difference. More recent studies have supported the view that PD after transplantation in not inherently risky. Duman et al. [8] compared 34 failed transplants with 82 failed native kidneys on PD and showed similar patient and technique survival. Report of patient survival in a large incident US cohort also reported good outcomes in PD patients with failed grafts, with better survival in patients commencing with PD as opposed to HD, but this was not adjusted for age or comorbidity [9]. All these studies, however, either lack sufficient power to exclude a type 2 errors or adequate adjustment for comorbidity. Badve et al. [10] exploiting the ANZDATA registry, addressed these concerns in a recent large, multi-centre study. They showed comparable outcomes in 309 patients commencing PD after failed allografts when compared with 13,638 new PD patients with failed native kidneys who had never been transplanted. The failed transplant group were younger but had a worse GFR and longer duration of ESRD. On multivariate analysis the predictors of death were age, racial origin, comorbidity, body mass index and high membrane transport status.

Technique Failure Following a Failed Transplant

PD is undoubtedly associated with worse technique failure that HD, and it might be anticipated that this would be a particular problem following transplant failure. In the comparison with new PD patients in the Stoke Study whilst actuarial patient survival was better, there was no difference in the overall technique failure rate [7]. Concerns have been expressed that transplantation is associated with abnormal peritoneal membrane function (high transport) on recommencement of PD [11], but this has not been supported by other studies [7, 12]. The ANZDATA study found no differences in membrane function in the failed transplant group compared to native kidney failure, whereas risk of

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technique failure was greater in high transport patients across the board [10]. In the Stoke Study there was a tendency for a more rapid increase in solute transport to occur in these patients during the first 12 months of PD treatment [7]. The explanation for this is not entirely clear, but the most striking difference between patients with graft failure and new PD patients in this study was the rate of loss of residual renal function. Despite similar residual Kt/Vurea at the commencement of dialysis, as a group their rate of loss was twice as fast during the first 12 months of therapy, after which it declined in parallel. Increased glucose exposure needed to obtain ultrafiltration might have been responsible for the relative increase in solute transport observed, as this was found in the whole cohort [13]. The other concern in using PD is the relative risk of peritonitis in patients who have previously been exposed to immune-suppression. A retrospective study of 185 PD patients of whom 39 had previously been on immunesuppressive treatment for a mixture of transplantation, vasculitis and SLE found that these patients experienced higher infection rates [14]. Peritonitis tended to be more severe, was more likely to result in catheter loss and was associated both with current and previous immune-suppressive load. In addition to the higher peritonitis rate observed by the Toronto group, the study by Duman also found that PD patients with failed grafts experienced more peritonitis episodes, although technique failure was not increased [8]. The ANZDATA group examined the risk of developing peritonitis specifically [10]. They found on multivariate analysis that the risk factors for peritonitis included age, race – with an increased risk found in aboriginal, Maori, Samoan, Tongan and Pacific and Cook islanders, but reduced risk in Asians increased body mass index and high membrane transport status. Failed transplant, however, was not a risk factor.

Balancing the Risk of Preservation of Renal Function and Immune-Suppression

Preservation of residual renal function is one of the clear advantages of PD as a dialysis option. The sudden stopping of immune-suppression on recommencing dialysis is one possible reason for the more rapid decline in residual renal function that these patients appear to experience, but continuing immunesuppression has its own inherent risks. Firstly, it may increase the risk of infection; second, it might in itself be nephrotoxic at this stage of the transplants life. The clinician is therefore faced with a dilemma: should immune-suppression be stopped on re-commencement of dialysis?

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Currently there is little hard evidence upon which clinicians can base their decision. This has led Jassal et al. [15] to perform a decision analysis based on the assumptions that continuing immune-suppression will indeed maintain residual renal function for a longer period and that this will confer the same survival benefit as it does when associated with native kidney function. Taking reported risks for malignancy and infection into account and making the unlikely assumption that these risks will revert to those of the general population if immune-suppression is stopped, they conclude that there may well be a net survival advantage to continuing therapy. The opposite view has been expressed however. In an analysis of 197 failed transplants from Rotterdam [16, 17], non-randomised continuation of immune-suppression was associated with significantly higher infection and death rates, the latter both from infection and cardiovascular disease, with no advantage in preventing clinical rejection episodes. The study included HD and PD patients but no information on preservation of residual renal function. Another approach to the problem is the optimisation of immune-suppressive treatment prior to graft failure. There is increasing evidence that reducing or stopping calcineurin inhibitors in the presence of allograft nephropathy or chronic rejection in conjunction with mycophenolate is associated with better graft function [18, 19]. This combined with the use of calcium antagonists and ACE inhibitors early during graft failure that should be continued after commencement of dialysis may help preserve residual renal function [20, 21].

Conclusion

Patients with failing transplants represent a group with particular risks. Despite being known to nephrologists their medical care can be sub-optimal, they have increased accrued cardiovascular risk, increased infection risk and if they choose PD a more rapid decline in residual renal function. Despite this latter concern there is no evidence that the technique survival on PD is worse and overall survival is at least as good as for patients starting PD due to failed native kidneys. Despite concerns from smaller studies that peritonitis rates are higher, this does not translate into higher technique failure due to this complication. Patients should be enabled to engage with the pre-dialysis education and information programme as early as possible and immune-suppression tailored to optimise graft function and reduce infection risk. Dialysis should be commenced in a timely manner, avoiding temporary HD and acute illnesses that might cause volume depletion. There is a potential advantage to maintaining residual renal function after dialysis commencement by continuing a modified

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dose of immune-suppression although this approach requires evaluation from a randomised trial.

References 1 2

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Schaubel DE, Jeffery JR, Mao Y, Semenciw R, Yeates K, Fenton SS: Trends in mortality and graft failure for renal transplant patients. CMAJ 2002;167:137–142. Jager KJ, Korevaar JC, Dekker FW, Krediet RT, Boeschoten EW: The effect of contraindications and patient preference on dialysis modality selection in ESRD patients in The Netherlands. Am J Kidney Dis 2004;43:891–899. Rubin HR, Fink NE, Plantinga LC, Sadler JH, Kliger AS, Powe NR: Patient ratings of dialysis care with peritoneal dialysis vs hemodialysis. JAMA 2004;291:697–703. Gill JS, Abichandani R, Khan S, Kausz AT, Pereira BJ: Opportunities to improve the care of patients with kidney transplant failure. Kidney Int 2002;61:2193–2200. Almond MK, Tailor D, Marsh FP, Raftery MJ, Cunningham J: Increased erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme. Nephrol Dial Transplant 1994;9:270–273. Sasal J, Naimark D, Klassen J, Shea J, Bargman JM: Late renal transplant failure: an adverse prognostic factor at initiation of peritoneal dialysis. Perit Dial Int 2001;21:405–410. Davies SJ: Peritoneal dialysis in the patient with a failing renal allograft. Perit Dial Int 2001;21: S280–S284. Duman S, Asci G, Toz H, Ozkahya M, Ertilav M, Sezis M, Ok E: Patients with failed renal transplant may be suitable for peritoneal dialysis. Int Urol Nephrol 2004;36:249–252. Guo A, Mujais S: Patient and technique survival on peritoneal dialysis in the United States: evaluation in large incident cohorts. Kidney Int Suppl 2003:S3–S12. Badve SV, Hawley CM, McDonald SP, Mudge DW, Rosman JB, Brown FG, Johnson DW: Effect of previously failed kidney transplantation on peritoneal dialysis outcomes in the Australian and New Zealand patient populations. Nephrol Dial Transplant 2005;9:9. Wilmer WA, Pesavento TE, Bay WH, Middendorf DF, Donelan SE, Frabott SM, McElligott RF, Powell SL: Peritoneal dialysis following failed kidney transplantation is associated with high peritoneal transport rates. Perit Dial Int 2001;21:411–413. Tobe S, Chu MG, Bargman JM: Characterization of peritoneal transport in patients with failed renal allografts receiving CAPD. Adv Perit Dial 1991;7:39–43. Davies SJ: Longitudinal relationship between solute transport and ultrafiltration capacity in peritoneal dialysis patients. Kidney Int 2004;66:2437–2445. Andrews PA, Warr KJ, Hicks JA, Cameron JS: Impaired outcome of continuous ambulatory peritoneal dialysis in immunosuppressed patients. Nephrol Dial Transplant 1996;11:1104–1108. Jassal SV, Lok CE, Walele A, Bargman JM: Continued transplant immunosuppression may prolong survival after return to peritoneal dialysis: results of a decision analysis. Am J Kidney Dis 2002;40:178–183. Smak Gregoor PJ, Zietse R, van Saase JL, op de Hoek CT, JN IJ, Lavrijssen AT, de Jong GM, Kramer P, Weimar W: Immunosuppression should be stopped in patients with renal allograft failure. Clin Transplant 2001;15:397–401. Gregoor PJ, Kramer P, Weimar W, van Saase JL: Infections after renal allograft failure in patients with or without low-dose maintenance immunosuppression. Transplantation 1997;63:1528–1530. Mourad G, Vela C, Ribstein J, Mimran A: Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy. Transplantation 1998;65:661–667. Weir MR, Ward MT, Blahut SA, Klassen DK, Cangro CB, Bartlett ST, Fink JC: Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int 2001;59:1567–1573.

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Rahn KH, Barenbrock M, Fritschka E, Heinecke A, Lippert J, Schroeder K, Hauser I, Wagner K, Neumayer HH: Effect of nitrendipine on renal function in renal-transplant patients treated with cyclosporin: a randomised trial. Lancet 1999;354:1415–1420. Li PK, Chow KM, Wong TY, Leung CB, Szeto CC: Effects of an angiotensin-converting enzyme inhibitor on residual renal function in patients receiving peritoneal dialysis. A randomized, controlled study. Ann Intern Med 2003;139:105–112.

Prof. Simon J. Davies Department of Nephrology, University Hospital of North Staffordshire Princes Road, Hartshill Stoke-on-Trent ST4 7LN, UK Tel. ⫹44 1782 554164, Fax ⫹44 1782 620759 E-Mail [email protected]

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Automated Peritoneal Dialysis – Indications and Management Dana Negoi, Karl D. Nolph Department of Medicine, Division of Nephrology, University of Missouri, Columbia, Mo., USA

Abstract Automated peritoneal dialysis (APD) use has increased considerably in the last decade, and its growth has been mainly driven by patient preference and development of new, simpler cyclers. Careful management of the APD prescription can result in adequate solute and fluid removal in vast majority of patients, even anuric and large patients. So far, there are no convincing data that peritonitis rates, decline in residual renal function, protein losses, patient and technique survival, are different for APD and continuous ambulatory peritoneal dialysis (CAPD). APD has the major advantage of allowing positive changes in the life-style of end stage renal disease patients. Copyright © 2006 S. Karger AG, Basel

Automated peritoneal dialysis (APD) is a general term used to describe all types of peritoneal dialysis (PD) performed with the help of a cycler. It is well recognized that APD has been increasingly utilized as a form of renal replacement in many countries. The growth of APD has been driven by several factors. First, from the physician’s perspective, in an era when small solute clearances were considered of major importance in terms of adequacy, APD was viewed as a technique that could achieve higher small solute clearances by using higher dialysate volumes. This applied mainly to patients with above average transport via the peritoneal equilibration test in whom small solute clearances are dialysate flow limited. Patient choice had probably the highest impact on APD growth in countries where there is no economical barrier. Young patients and those who maintain an active life style prefer APD, because they are free of the need for a manual daytime exchange (even with the long day time dwell).

The development of newer cyclers, which are easier to use made the growth of APD also possible. In 2003 there were 145,000 patients on PD, worldwide. Twenty-nine percent of them were on APD. There has been a steady increase in APD utilization over the years: in 1998 only 21% of the global PD patients were on APD. This percentage has increased yearly by 1–2% (data from Jose Diaz-Buxo, Fresenius Medical Care). At the end of 2004, there were 1,371,000 dialysis patients worldwide, and 11% of them were on PD. Thirty percent of the 149,000 global PD patients were on APD. In the USA, 60% of PD patients were on APD [1]. There are now different ways to deliver dialysis using a cycler: • CCPD – continuous cycling peritoneal dialysis consists of several cycles (usually 4–5) done at night, over 9–10 h and a long daytime dwell. • NIPD – nightly intermittent PD, is dialysis done every night with the use of a cycler, 4–5 night exchanges with a dry peritoneal cavity during the day. • IPD – classical intermittent PD is not usually done currently because of poor clearances and high morbidity and mortality. It involves APD treatments done several times a week, but usually not every day. • TPD – tidal PD is also rarely utilized. An initial fill volume is introduced in the peritoneal cavity, after which a tidal volume is drained and introduced during each cycle, leaving a reserve volume in the peritoneal cavity after drainage. It can be performed nightly tidal peritoneal dialysis (NTPD) or continuous tidal peritoneal dialysis (CTPD). The comments below relate mainly to APD with intermittent exchanges (draining as completely as possible) and not to tidal techniques.

Indications

Both continuous ambulatory peritoneal dialysis (CAPD) and APD can be used successfully in end stage renal disease patients who want to be treated with PD, but there are instances when one form of therapy is preferred over the other. First and foremost, the choice between APD and CAPD has to belong to the patient, so that dialysis is less disruptive to his life and permits patient adaptation to the logistics of therapy. Some patients will view the use of the cycler at home as being invasive, and will not accommodate well to the procedure. A recent retrospective analysis of incident cohorts (1999–2001 cohorts) managed on PD in the USA, suggested that in the first year of PD there were more failures on CAPD than APD [2]. There was no difference in technique survival after the first year. Catheter malfunction and psychosocial factors were the two major causes of technique failure in the first year in patients on CAPD.

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One can speculate that catheter malfunction and leaks occur early in the course of PD and might not be such a big problem in patients performing PD in the supine position. It also might be that the patients adapt easier to the logistics of the therapy in APD versus CAPD. The findings of this study also suggest that APD patients survive longer than the CAPD patients. The authors corrected for age and diabetes, but note that residual effects of age in the older CAPD population could still have been present. Also, they mention that the type of patients allocated to APD may have certain characteristics that are not adjusted for, such as a more active lifestyle, better compliance and better ultrafiltration (UF) with short cycles. However, to date, there are no large scale, randomized, prospective studies to establish that patient survival, technique survival, catheter survival, peritonitis rates, exit site infection rates, the decline in renal function or protein losses are significantly different for APD and CAPD. Physicians will most probably recommend APD in one of the following situations: • Patients with high peritoneal transport status, especially those with decreased residual renal function, who will not be able to maintain euvolemia using the longer average dwell times of CAPD, due to rapid glucose absorption and low UF. • As a rescue therapy for long-term CAPD patients who cannot achieve fluid balance. • For patients who need higher volume therapy to achieve adequate small solute clearances (large patients and those with decreasing residual renal function): a fill volume which is higher than 2–2.5 l is better tolerated in the supine position at night and can be coupled with more frequent exchanges. • For patients who cannot tolerate high intraperitoneal pressure or are at risk of developing abdominal wall hernias. • In children where freedom during the day from performing multiple exchanges allows them to have a lifestyle closer to their peers. • For elderly and patients who need assistance during the day and are dependent on other caregivers to do their dialysis for them. • TPD might be indicated in patients who have drain problems or patients who have pain at the beginning of inflow or at the end of the drain [3, 4]. • Possibly for patients with frequent episodes of peritonitis on CAPD, although, as mentioned above, to date it is not universally accepted that APD is associated with decreased rates of peritonitis. Results of various studies looking at the incidence of peritonitis in APD versus CAPD are contradictory. As long as we do not have better studies, APD cannot be firmly indicated just for better prevention of peritonitis. RRF is an important predictor of survival among end stage renal disease and PD patients. As mentioned, there is no conclusive data that APD has any

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advantages over CAPD in terms of preservation of residual renal function, and it cannot be indicated or contraindicated on the basis of preservation of residual renal function. Also, since there is no good evidence that protein losses in dialysate differ between APD and CAPD, APD cannot be chosen to reduce protein losses.

Management

Reaching Adequacy Targets Current PD guidelines have undergone intense scrutiny in the recent years. Discussion about adequacy targets is beyond the scope of this article. Previously published KDOQI guidelines have different small solute clearance targets for CAPD and APD with and without day dwells [5]. There are also different targets for high and low transporters. Whether weekly urea clearance in liters/liters total body water (Kt/V) or creatinine clearance in l/week/1.73 m2 BSA (Cr Cl) is a better target remains debatable. Cr Cl might reflect better RRF, which is without doubt directly associated with better outcomes. New, revised KDOQI guidelines are expected to be published soon. The available data to support them is mainly based on studies in CAPD patients [6, 7]. These guidelines will probably decrease the weekly Kt/Vurea target to 1.7, and the same target will be extended for APD patients. Cr Cl is not going to be used. Randomized trials to assess different targets in APD patients are needed. The Caring for Australians with Renal Impairment Guidelines were recently published [8]: they recommend that for CAPD and APD patients, the weekly Kt/V target should be greater or equal to 1.6 per week. The minimum weekly-corrected creatinine clearance target would be 60 l/week in high and high-average transporters and 50 l/week in low- average and low transporters. The European Best Practice Guidelines were also just published [9] and they also recommend the same Kt/V target for both CAPD and APD patients: a weekly value of 1.7 is suggested. For slow transport APD patients, an additional target of 45 l/week/1.73 m2 for peritoneal creatinine clearance should be sought in addition to achieving the Kt/Vurea target of 1.7. Although APD was considered a technique that can increase treatment dose and meet higher adequacy targets and expectations for improved quality of life, the PD – clinical performance project showed that in the US, only 60% of the APD patients achieved Kt/V targets of greater or equal to a weekly Kt/V of 2.1 in the year 2000, compared with 65% of the CAPD patients [10]. Encouraging is the fact that each year, more and more patients achieved these targets. Decreasing the small solute clearance targets for APD will have a great impact on the way the APD is prescribed and especially will put less pressure

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on the patients, who are frequently overwhelmed by the challenges of reaching the targets. With the lower targets, it might be also easier to prescribe APD to low transporters who are well known to be the most difficult group of patients to manage with APD. Whenever needed, careful management of the PD prescription can result in increased small solute clearance and this can be achieved by: • Increasing fill volume (higher intraperitoneal fill volumes are better tolerated in the supine position). • Increasing the number of cycles at night (limited due to increase in the inefficient time of draining and filling). • Increasing the time spent on the cycler, but most patients will not tolerate more than 9–10 h per night. • Adding a midday exchange (PD plus). Ultrafiltration Ultrafiltration (UF) and control of extracellular volume is an important part of the PD prescription. The Adequacy of PD in Mexico Trial (ADEMEX) showed that by increasing the small solute clearances above the Kt/Vurea of approximately 1.6–1.7 per week or creatinine clearance of 46–50 l/week, there are no additional survival benefits in CAPD patients [7]. Adequate UF is probably more important to survival after these threshold values for small solute clearances are obtained. The European APD Outcome Study (EAPOS) demonstrated the importance of UF as an outcome parameter: baseline UF, not Cr Cl or membrane permeability, was associated with survival in anuric patients on APD [11]. More recently, analysis of data from The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) showed again, that lower peritoneal UF volumes were associated with increased risk of death in anuric PD patients [12]. The European Best Practice Guidelines is the first document to set a minimum peritoneal UF target for anuric patients: 1.0 l/day [9]. New KDOQI guidelines are also expected to deal with volume status in PD. In APD there is potential for enhanced UF since the osmotic gradient between the dialysate and systemic circulation is better preserved at night when the hypertonic dialysate is replaced at short time intervals. The higher osmotic gradient during the short night-time dwells will allow a higher UF rate during each exchange. However, at the end of short, less than 2 h dwells, the dialysate can contain electrolyte free water due to the movement of water through aquaporins and result in hypernatremia. Longer dwells provide time for sodium diffusion through intercellular channels and the dialysate nears electrolyte equilibrium with extracellular fluid at the end of a dwell. The short, night-time dwells should be at least 2 h in duration to afford balanced water and sodium

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removal (relative to extracellular sodium concentration) unless electrolyte free water removal is desired (as in hyponatremia). If an increase in the number of short dwells during the night is attempted in order to increase UF, this might mandate higher exchange frequencies and shorter dwell times, because the majority of patients will not accept being connected to the cycler for more than 9–10 h. This maneuver risks increasing the ‘dead dialysis time’ because of increased drain and fill time and there may be detrimental effects on clearances and even UF. Utilization of tidal flow techniques may allow greater flow rates without the ‘dead dialysis time’. Management of the long day dwell is the most important aspect of the UF management. Some patients can have back filtration and negative UF during the day, but the long day dwell cannot be eliminated, especially in patients without residual renal function, because it has a great contribution to the total small solute clearance and most importantly, to the middle molecule clearances. Use of icodextrin can significantly improve the total UF and salt removal during the daytime long dwell. Icodextrin provides sustained UF during a 12–14 h dwell, decreasing the daily peritoneal membrane exposure to the glucose and glucose degradation products and has the potential for better preservation of the peritoneal membrane function. In conclusion, APD seems to be an advantageous modality for many end stage renal disease patients who are treated with PD. The growth of APD is primarily patients driven due to positive changes in their life style. The variety of APD techniques is evolving and excellent results can be obtained with this modality. References 1

2 3

4 5 6

7

Grassmann A, Gioberge S, Moeller S, Brown G: ESRD patients in 2004: global overview of patient numbers, treatment modalities and associated trends. Nephrol Dial Transplant 2005;20: 2587–2593. Guo A, Mujais S: Patient and technique survival on peritoneal dialysis in the United States: evaluation in large incident cohorts. Kidney Int 2003;64(suppl 88):S3–S12. Kathuria P, Twardowski ZJ: Automated peritoneal dialysis; in Gokal R, Khanna R, Krediet R, Nolph K (eds): Textbook of Peritoneal Dialysis, ed 2. Dordrecht/Boston/London, Kluwer Academic Publishers, 2000, pp 435–463. Ronco C, Kliger A, Amici G, Virga G: Automated peritoneal dialysis: clinical prescription and technology. Perit Dial Int 2000;20(suppl 2):s70–s76. National Kidney Foundation: NKF-K/DOQI clinical practice guidelines for peritoneal dialysis adequacy: update 2000. Am J Kidney Dis 2001;37(suppl):s65–s136. Szeto CC, Wong TY, Chow KM, et al: Impact of dialysis adequacy on the mortality and morbidity of anuric Chinese patients receiving continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 2001;12:355–360. Paniagua R, Amato D, Vonesh E, et al: Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13:1307–1320.

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9 10 11 12

Johnson D, Brown F, Lammi H, et al: Dialysis adequacy (PD) guidelines. The CARI guidelines. Acceptance into dialysis, dialysis adequacy, haemoglobin, deceased kidney donor suitability, and evaluation of renal function guidelines. Nephrology 2005;10:S81–S107. The European Best Practice Guideline Working Group on Peritoneal Dialysis: Adequacy of peritoneal dialysis. Nephrol Dial Transplant 2005;20(suppl 9):ix24–ix27. Flanigan M, Rocco M, Prowant B, et al: Clinical performance measures: the changing status of peritoneal dialysis. Kidney Int 2001;60:2377–2384. Brown E, Davies SJ, Rutherford P, et al: Survival of functionally anuric patients on automated peritoneal dialysis: the European APD outcome study. J Am Soc Nephrol 2003;14:2948–2957. Jansen A, Termorshuizen F, Korevaar JC, et al: Predictors of survival in anuric peritoneal dialysis patients. Kidney Int 2005;68:1199–1205.

Dana Negoi, MD Assistant Professor of Medicine, Division of Nephrology University of Missouri, Columbia, One Hospital Drive, MA 436 Columbia, MO 65212 (USA) Tel. ⫹1 573 882 7992, Fax ⫹1 573 884 4820 E-Mail [email protected]

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APD Schedules and Clinical Results Pierre-Yves Durand ALTIR and Nephrology Department, University Hospital of Nancy, Nancy, France

Abstract This chapter exposes the clinical effects of different APD schedules. Clinical studies have shown that Na removal is lower with APD compared to CAPD. Therefore the loss of residual renal function requires continuous therapy with long day-dwell of polyglucose dialysate. Peritoneal small molecule clearances are closely determined by the hourly dialysate flow rate (and not the dwell time, which is a concept coming from equilibrium PD techniques as CAPD) with a maximum reached by 3 l/h for average transporter patients. On the other hand, the optimal intraperitoneal volume should be 1500 ml/m2 of BSA, and less if the hydrostatic intraperitoneal pressure is higher than 18 cm H2O. The optimization of the nocturnal APD session depends on the knowledge of the individual drain flow profile. A new schedule, called ‘BreakPoint-APD’ is based on the automatic adaptation to the drain profile for each patient and for each cycle. It increases clearances by about 10% compared to tidal and CCPD, though reducing the number of nocturnal alarms. The future of APD is likely to continue thanks to further simplification in the machine use, i.e. with improvements in cycler technology. Copyright © 2006 S. Karger AG, Basel

APD is the most powerfull peritoneal dialysis (PD) technique. It can provide adequate dialysis for anuric patients with body surface area above 1.73 m2 [1]. In addition, APD offers the possibility of adapting regimen to the patient’s individual needs with respect to private life. Individualization of APD requires the knowledge of peritoneal transport characteristics in order to choose the optimal schedule. But first of all, the prescription of APD should fulfill the new adequacy targets, which could be defined by recent literature data. APD and Adequacy Targets

Small molecule clearances should no longer be considered as major adequacy indexes. Despite international guidelines still focusing on urea and creatinine

clearances [2], two large and recent prospective studies, ADEMEX [3] and EAPOS [1] have demonstrated that small molecule clearances were not predictive factors for patients’ survival. Consequently, in addition to Kt/V or creatinine clearance, other adequacy indexes should be emphasized, such as fluid balance, Na removal, nutritional state, residual renal function, quality of life, and others. Fluid balance should be now considered as critical for adequacy and longterm success of PD treatment. In the EAPOS study, multivariate analysis identified daily ultrafiltration as an independent factor in survival for anurics [1]. APD may produce adequate fluid removal, but the Na removal rate seems to be lower than with CAPD [4]. In a Spanish study, average Na removal was 192 mmol/day in CAPD and 92 mmol/day in APD without icodextrin long dwell, and 148 mmol/day with icodextrin long dwell [4]. EAPOS study confirmed the long-term adequacy of Na-fluid balance for anurics, at the condition to use an icodextrin day dwell. The poor Na extraction with APD is due to the Na sieving during short-dwell phase of APD. It confirms the necessity of diurnal long day dwell with glucose polymers when the diuresis declines. Icodextrin significantly increases Na removal because it does not induce Na sieving and it increases the daily ultrafiltration volume.

APD Schedules: Individualizing the Therapy

For a given patient, it could appear sometimes difficult to choose the good APD schedule amongst the multiple choices permitted by APD. The patient’s characteristics would help to decide the precise therapy. These characteristics are mainly: residual renal function, corpulence, peritoneal transport, hydrostatic intraperitoneal pressure and catheter drain flow rate. They can be considered as tools to determine the individual APD schedule: regimen, duration of nocturnal session, total fill volume, intraperitoneal volume, dwell time and cycles characteristics. APD Schedules for Anuric Patients Intermittent regimens (‘dry day’) are possible only for patients with significant residual renal function. For anurics, PD regimen should be continuous. It is admitted that 2 daytime exchanges in addition to nocturnal APD can achieve adequate dialysis either for clearances [1, 5, 6], or for Na-fluid balance [4] in most patients. Data are missing for low-transporter patients. However that may be, a continuous APD regimen for anuric patients should use polyglucose as long day-dwell in order to enhance salt removal, concordant with dietary salt restriction. The use of low-sodium containing dialysate could theoretically be efficient, but these solutions are not commercially available.

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APD Schedules with Various Total Fill Volumes Small molecule peritoneal clearances directly depend on the total amount of dialysate used during the nocturnal session [5, 7, 8]. They are closely determined by the hourly dialysate flow rate [7]. For average to high transporter patients, the dialysate flow rate providing the best creatinine clearances is about 3 l/h [9]. Under such conditions, it is easy to reach small molecule clearance targets required by the DOQI guidelines [2] as long as a sufficient amount of dialysate is prescribed, involving a dramatic increase in the cost. However the larger the molecule, the smaller the increase in clearances with high volumes compared to those of small molecules, especially for low and low-average transporter patients [9]. Notably for all, peritoneal ␤2-microglobulin clearances could not be improved with elevated flow rates. Therefore, small molecule clearances do not reflect larger molecules clearances. That confirms the poor value of urea Kt/V as dialysis dose index when using high volume APD. The EAPOS study included 177 anuric patients on a 2-year observation period [1]. Choosing the PD Plus concept approach [6], good survival was observed when using median dialysate flow rates of less than 1.5 l/h (13 l/9-h APD sessions) in addition to 2 large-volume day dwells. However in this study some patients required larger overnight dialysate volumes (28.7 l, i.e. 3.2 l/h). To summarize, the prescription of the total fill volume should be determined by three main factors: the residual renal function, the peritoneal transport and a corpulence index (BSA, V or BMI). For anurics low-transporter and large-sized patients, APD (and all PD techniques) is unable to provide adequate dialysis. Anuric APD patients with BSA superior to 2 m2 often require more than 20 l. But for most of average-transporter and medium-sized patients, total fill volumes of 15 l seem to be enough to provide adequate dialysis.

APD Schedules with Various Dwell Volumes The prescription of the dwell volume should fulfill a double goal: to be large enough for an efficient dialysis, and small enough to be well tolerated. Too large dwell volumes can induce a bad quality of sleep, because of subclinical sleep disorders due to the reduction of pulmonary indexes [10]. That is due to a decrease in the diaphragmatic compliance secondary to an increase in the intraperitoneal hydrostatic pressure in the supine position. Each additional liter of intraperitoneal volume increases the intraperitoneal hydrostatic pressure of about 2 cm H2O in supine position, causing a decrease in the total pulmonary vital capacity ranging from 9 to 20% according to studies [10]. The intraperitoneal hydrostatic pressure, easy to measure, is very helpful to determine the maximal intraperitoneal fill volume, which is well tolerated. Values up to 18 cm H2O

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(zero level at mid-axillary line, patient in supine) lead to only minor respiratory disturbances compatible with a good quality of sleep. Too small dwell volumes result in poor dialysis efficiency. This is essentially due to three factors: (1) a dialysate volume insufficient to be in contact with the entire peritoneal surface; (2) a slow drainage subsequent to a relatively large residual volume with respect to the fill volume, and (3) the necessary multiplication of the cycles to deliver the total fill volume, increasing the total drain-fill time. Studies on the mass transfer coefficient for small solutes (KoA) have shown that the dwell volume should preferably be normalized for the BSA, because BSA is supposed to be related to the peritoneal functional surface area [10]. Dwell volume of 1500 ml/m2 of BSA was described as being optimal. To summarize, intraperitoneal fill volume should be 1500 ml/m2 of BSA. But, if it generates an intraperitoneal hydrostatic pressure above 18 cm H2O, fill volume should be reduced, otherwise special attention to the quality of sleep is required. CCPD, Tidal and BreakPoint-APD: How to Manage the Drain Profile When using new-technology based cyclers, in fact CCPD automatically switches to a tidal-PD with 10–20% of reserve volume. In consequence, CCPD was shown logically as efficient as tidal. Therefore, tidal is now reserved for indications excluding power of dialysis, as inflow/outflow pain or mechanical outflow problems [9]. However studies on individual drain flow profiles could highlight a new form of tidal PD, called ‘BreakPoint-APD’ [11]. Drain Flow Profile in APD (fig. 1) The drain phase flow rate in a supine position is biphasic: a first phase of constant rapid flow (⬎200 ml/min) suddenly followed by a second phase of constant slow flow (⬍50 ml/min) (table 1). These 2 phases follow one another without transition, separated by a ‘breakpoint’ (fig. 1) [11]. The breakpoint depends on a residual intraperitoneal volume averaging 500 ml, but showing wide interindividual variations (ranging from 0 to 1,200 ml [11]). In APD session with many repeated cycles, the time spent for draining after the breakpoint can be characterized by very low clearances. Avoiding this phase should improve the efficiency of APD. This notion is at the origin of the concept of the BreakPoint-APD. Clinical Results BreakPoint-APD is a tidal PD characterized by a variable reserve volume determined by the breakpoint. It is an individual prescription which requires the knowledge of the drain flow profile for each patient. AMICI studied 8 patients

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25 l

Breakpoint

Intraperitoneal volume

w id flo Rap

x

Slow

0

flow

10

20

Drain time (mn)

Fig. 1. The characteristic drain flow profile in supine position (the volume ‘x’ determines the moment of the Breakpoint).

Table 1. Drain flow profile studies in supine position

Brandes et al. [12] Durand et al. [13] Amici and Thomaseth [11] Scanziani et al. [14]

IP volume at breakpoint (ml)

Rapid drain flow rate (ml/min)

Slow drain flow rate (ml/min)

381 ⫾ 280 425 ⫾ 239 538 ⫾ 220 422 ⫾ 258

380 ⫾ 98 206 ⫾ 28 337 ⫾ 32 267 ⫾ 36

36 ⫾ 21 43 ⫾ 24 16 ⫾ 4 40 ⫾ 7

IP ⫽ Intraperitoneal.

comparing NIPD, 50% tidal-PD with BreakPoint-APD [11]. Clearances were improved of about 10% with BreakPoint-APD compared to tidal. We performed a cross-over randomized trial in 12 patients comparing BreakPoint-APD with CCPD (unpublished data). BreakPoint-APD showed drain period reduced by 55% (theoretical saved time: 2 h/session), an increase in urea clearance by 8% (p ⫽ 0.007) compared to CCPD. In this study, the quality of the sleep was improved during BreakPoint-APD, probably by reducing the nocturnal alarms. To summarize, these news findings could promote a new generation of cyclers, which automatically individualize the schedule according to patient’s

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characteristics in order to improve their quality of life while increasing the efficacy of the therapy.

References 1

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6 7 8 9 10

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Brown EA, Davies SJ, Rutherford P, Meeus F, Borras M, Riegel W, Divino Filho JC, Vonesh E, Van Bree M, EAPOS Group: Survival of functionally anuric patients on automated peritoneal dialysis: the European APD Outcome Study. J Am Soc Nephrol 2003;14:2948–2957. National Kidney Foundation: NKF-DOQI clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis 1997;30(3 suppl 2):S67–S136. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, et al, for the Mexican Nephrology Collaborative Study Group: Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13:1307–1320. Rodriguez-Carmona A, Fontan MP: Sodium removal in patients undergoing CAPD and automated peritoneal dialysis. Perit Dial Int 2002;22:705–713. Juergensen PH, Murphy AL, Kliger AS, Finkelstein FO: Increasing the dialysis volume and frequency in a fixed period of time in CPD patients: the effect on Kpt/V and creatinine clearance. Perit Dial Int 2002;22:693–697. Diaz-Buxo JA: Enhancement of peritoneal dialysis: the PD Plus concept. Am J Kidney Dis 1996;27:92–98. Durand PY, Freida P, Issad B, Chanliau J: How to reach optimal creatinine clearances in automated peritoneal dialysis. Perit Dial Int 1996;16(suppl 1):S167–S170. Perez RA, Blake PG, McMurray S, Mupas L, Oreopoulos DG: What is the optimal frequency of cycling in automated peritoneal dialysis? Perit Dial Int 2000;20:548–556. Vychytil A, Lilaj T, Schneider B, Hörl WH, Haag-Weber M: Tidal peritoneal dialysis for hometreated patients: should it be preferred? Am J Kidney Dis 1999;33:334–343. Durand PY, Balteau P, Chanliau J: Dwell volume prescription in automated peritoneal dialysis and its assessment; in Ronco C, Amici G, Feriani MP, Virga G (eds): Automated Peritoneal Dialysis. Contributions to Nephrology. Karger, 1999, vol 129, pp 90–97. Amici G, Thomaseth K: Role of drain and fill profile in automated peritoneal dialysis; in Ronco C, Amici G, Feriani MP, Virga G (ed): Automated Peritoneal Dialysis. Contributions to Nephrology. Karger, 1999, vol 129, pp 44–53. Brandes JC, Packard WJ, Watters SK, Fritsche C: Optimization of dialysate flow and mass transfer during automated peritoneal dialysis. Am J Kidney Dis 1995;25:603–610. Durand PY, Balteau P, Chanliau J, Kessler M: Analysis of drain flow rates in supine position measured by continuous data acquisition. Perit Dial Int 1998;18(suppl 2):S1. Scanziani R, Dozio B, Baragetti I, Maroni S: Intraperitoneal hydrostatic pressure and flow characteristics of peritoneal catheters in automated peritoneal dialysis. Nephrol Dial Transplant 2003;18:2391–2398.

Pierre-Yves Durand ALTIR and Nephrology Department University Hospital of Nancy, BP 149 FR–54504 Vandoeuvre Cedex (France) Tel. ⫹33 3 83 15 37 12, Fax ⫹33 3 83 15 37 32 E-Mail [email protected]

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Evolution of Technology for Automated Peritoneal Dialysis Claudio Roncoa, Richard Amerlingb, Roberto Dell’Aquilaa, Maria Pia Rodighieroa, Pierluigi Di Loretoa a

Nephrology Department, St. Bortolo Hospital, Vicenza, Italy; bDivision of Nephrology and Hypertension, Beth Israel Medical Center, New York, N.Y., USA

Abstract Automated peritoneal dialysis (APD) is important for the further penetration of PD in the dialysis marketplace. Long dwell, equilibration PD (CAPD) has limited applicability in many patients due to inadequate solute clearance or fast membrane transport characteristics. Providing large volumes of dialysate over circumscribed hours is highly labor intensive without an automated system. Early attempts at APD were crude but effective in reducing labor, which was generally provided by nursing staff. Later evolution of PD technology has been greatly accelerated by the microchip, and by miniaturization of components. Current generation machines allow individualized fill volumes, variable tidal volumes and additional daytime automated exchanges, teledialysis, memorized delivery control, and full portability. The ideal machine should not only be able to perform all treatment schedules, but it should also optimize the performance of a selected treatment strategy. Biocompatible solutions, improved osmotic agents, and sorbent technology are all adaptable to APD. The eventual evolution toward continuous flow PD will resolve many of the current problems with both CAPD and APD. Copyright © 2006 S. Karger AG, Basel

Automated peritoneal dialysis (APD) is the fastest growing dialysis treatment in the world at present time. The rapid evolution of this treatment modality has been facilitated by the development of new technology and by recent advances in prescription and monitoring. Since 1960, machines have been developed to perform semiautomatic or fully automatic PD treatment. Back then, PD was intermittent (IPD) with 24–72 h per week divided into three or more sessions. The technology was relatively primitive. The slow peritoneal transport with low solute clearance using

rapid exchanges yielded poor efficiency, and limited the application of these techniques [1]. In the 1970s, long-dwell, or equilibration PD along with the availability of sterile dialysate in plastic bags [2] led to continuous ambulatory peritoneal dialysis (CAPD). These advances made PD treatment in chronic patients a real therapeutic option, and the modality grew rapidly. Over the next decade knowledge derived from the peritoneal equilibration test together with a better understanding of adequacy limitations of CAPD, led to a renaissance of APD techniques. Today, APD is a daily home treatment with automated nightly exchanges and the possibility for additional daytime dwells (CCPD) [3, 4]. The development of user-friendly machines, made possible by the microchip [1], was a key factor in this evolution. The incorporation of microchips and software allowed for greater programming flexibility. It is now possible to prescribe individualized fill volumes, variable tidal volumes and additional daytime automated exchanges, teledialysis and memorized delivery control. Miniaturization of all components allows full portability [5]. Today in the USA, APD is utilized by 31.9% of all PD patients, including daytime dwell mode, daytime empty mode and schedules with one or more additional manual exchange [6]. Plans to lower adequacy targets for PD notwithstanding (Burkhart; personal communication), we believe that higher solute clearances will be needed if PD is to grow as a modality. Newer APD techniques are the answer to these requirements. Higher adequacy targets, as well as a better quality of life, will be more easily delivered by APD. Improved dialysis solutions and continuous flow techniques are further steps in the evolution of APD.

History and Development of APD

Before the advent of CAPD, PD was performed intermittently with various schedules. Peritoneal fluid was prepared and stored in 10 l containers. These were suspended above the patient; inflow and outflow was by gravity inflow, outflow, and dwell times were determined manually by clamping and unclamping the lines. A bed scale was used to monitor the inflow and drainage volumes, and a nurse was frequently required. The process was labor-intensive and the need for automation became evident. Several machines were then designed to perform IPD based on semi-automatic or fully automatic principles (fig. 1). Semi-automatic machines were based on a simple layout in which at every cycle the fluid was drawn from 10 l plastic tanks, heated and pumped to a bag suspended above the patient. In and outflow were then gravity-driven. Machines using this simple design were the AMP 80/2 (American Medical product Corporation), the Peritonium IV (B. Braun), the PD 700 (Jungner

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a

b

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Fig. 1. Schematical representation of three different methods utilized in the 1970s to deliver IPD. a Manual system, b semiautomatic device, c completely automatic system.

Instrument A.B.), the PD 10 (Gambro), the SIF 901 (Sifra), the Peritokomb IIIA (Fresenius). We developed in Vicenza our own semi-automatic machine, as did many of the groups involved in PD. A further step in the evolution of APD was the preparation of dialysate from reverse osmosis-treated (RO) water, concentrated salts and glucose. These units could prepare solution in various amounts and deliver it using pumps with or without gravity. Machines with this capability were the PDS 300 and PDS 400 (Physio-Control), the APD system (Cobe), the Drake Willock 6001 (Drake Willock), The ‘Vicenza’ Automatic Apparatus (never commercialized) and the Ariane (Bernas Medical) (fig. 2). Because commercially prepared solutions in 10 l tanks was not available in the USA, these machines were preferred. In Europe, semiautomatic machines were more frequently utilized. With the advent of CAPD in the late 1970s, IPD was left by the wayside. The technical simplicity of CAPD was weighed against the limited efficiency of IPD, the complexity of the machines, the limited reliability as a home-base modality, the absence of adequate monitoring, and was widely preferred. In addition, our poor understanding of individual membrane characteristics resulted in inadequate selection of patients for rapid exchange schedules. CAPD became the dominant form PD in subsequent years with IPD being used in only a few centers. Over time, the limitations of CAPD in patients with hyperpermeable membrane, poor dexterity, or a large muscle mass began to emerge. Improvements in technology

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a

b

c

Fig. 2. Three different machines for intermittent peritoneal dialysis from the 1970s–1980s: the Gambro PD 10, the Drake Willock 6001 and the Vicenza automatic apparatus. a Manual, b Semiautomatic, c Automatic.

for APD and better understanding of membrane physiology together with concerns about adequacy spurred a new interest in APD. Chronic cycling PD (CCPD) and nightly intermittent PD (NIPD) started to grow as alternative techniques. These were also perceived by patients as offering an improved quality of life. The rapid growth of APD led industry to pursue new devices and to develop new cyclers with enhanced capabilities and user-friendliness. The New Generation of Cyclers

In the early 1980’s, Baxter Healthcare introduced the APD home system, PAC-X™, which gave patients the ability to perform their dialysis exchanges during the night. PAC-XTRA™ replaced PAC-X and was both quieter and more reliable. PAC-XTRA continues to be utilized worldwide for pediatrics and in emerging markets. This machine (fig. 3) was designed to be utilized at home and to make the patient self-sufficient. The tubing set was loaded at the beginning of the treatment and plastic bags were connected to create a closed system. Different volumes and dwell times could be programmed for a overnight treatment.

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Fig. 3. The Baxter Pac-Xtra.

The Home Choice and the Home Choice Pro In an effort to refine APD technology, a more patient-friendly system was developed in 1994 by Baxter. The Home ChoiceTM system is easy to set-up, operate, and troubleshoot. Its small size and non-medical appearance adapts well to the home environment. The device uses non-gravity-based technology to move and measure solution. Dialysis efficiency is optimized through continuous monitoring of flow rates which detect when a patient is empty and by eliminating idle time in the drain and fill phases. The system features a disposable cassette and auto-reset alarms. Tabletop design makes it a truly portable home dialysis system with a weight of 25 pounds and dimensions of 7⬘H ⫻ 18.6⬘W ⫻ 15.7⬘D. The newest APD system available from Baxter Healthcare is the Home Choice PROTM with PD LinkTM software. It adds a 2-MB data card and an optional modem to send information on the home dialysis treatment to the

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Fig. 4. The Baxter Home Choice pro.

center. This system provides a means to monitor therapy and compliance, and creates a database of therapy information. Skipped treatment days, shortened treatment time, manually changed therapy parameters, bypassed therapy phases or cycles, or reduced fill volumes are readily detected. The data card calculates and records ultrafiltration levels, total volume, fill volume, drain time and cycle times. It has the capacity to store up to 60 days of treatment data. The patient simply brings the data card into the unit. The data is extracted to assess therapy results and patient compliance, and lists problems the patient may have experienced while operating the system. The data card can be reprogrammed by the physician or nurse with any prescription changes. Once the prescription changes are entered via the PD Link software, the patient simply inserts the card back into the system and all of the settings are updated. This device eliminates the need for patients to program and manually record therapy data. In addition, the PD team benefits by simplifying data collection and management. This may shorten training time with new patients due to the simplicity of the new system (fig. 4). With the modem feature, therapy data can be retreived on demand, as often as needed. The PD Night and the Sleep Safe A significant contribution to the evolution of APD technology came from Fresenius Medical Care with the creation of the PD NightTM machine. The Fresenius PD Night is a cycler specificaly designed for APD (fig. 5). The structure and functions are perfectly integrated in a easy-to-use interface. The central unit is suspended by a vertical support. The interface is a simple display with basic messages and can be programmed by the trained personnel and patients. There is a code-protected program to prevent unwanted changes in the prescription. The machine stores data from the last dialysis session and has the option for a teledialysis program. The line connection system is based on the Andy-plus® technology and includes the use of a recycled bag as a drainage

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6

1

2 3 1

3

4

5

5

Fig. 5. The Fresenius PD Night.

container. Flows are gravity-controlled and there is a capability of handling up to 25 l per session and more. The last bag option is utilized for CCPD schedules. The Sleep SafeTM machine includes further enhancements (fig. 6). It is equipped with an interface based on icons rather than written messages. A touchscreen allows for intuitive programming while the built-in software provides for a teledialysis connection. There are various levels of access to code protected programs so that only scheduled changes can be programmed by the operator. The system allows for storage of up to 3 months of treatment data on a card. Tubing connection is via Stay Safe®. The machine is equipped with a system for automatic detection of the type of bag and connection. Bags made of Biofine® material are employed and steam sterilization for bags and lines is utilized. Flows are hydraulically controlled with in- and outflow rates up to 400 ml/min. Pressures and flow rates are monitored to ensure effective delivery of prescribed regimens. Warming of dialysis solution is performed on-line. There is the ability to profile glucose concentratrion throughout treatment. The last bag option and the possibility to perform different CCPD schedules (Plus Therapy) complete the features of this machine.

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Fig. 6. The Fresenius Sleep Safe.

The PD 100T, PD101 and the PD 200 The PD 100T and PD 101 are pump-driven systems capable of handling more than 50 l of fluid. There is a built-in option for the last bag fill for patients on CCPD. Fluid inflow and drainage are pneumatically driven (simulated gravitycontrolled flow by a membrane pump). Volume/cycle, number of cycles, inflow and dwell time, outflow time can all be programmed. The system permits storage of the last 15 treatments (fig. 7). The PD 200 machine is the latest stage in the evolution of Gambro equipment. A clear graphical user interface is displayed on a large, high-resolution, full-colour touch screen. Operation is simplified by the use of icons and intuitive software, and the screen can easily be adapted to different languages and user groups. A line set casette ensures quick start-up and the treatment settings can be downloaded from a patient card. The machine operates silently with long alarm-free periods. The patient can plan the treatment, including a pause, and operate the machine at home without any problem. The PD 200, like its predecessor, is a pump-driven machine, which incorporates a pressure chamber in which the heater bag as well as the drain bag are placed (fig. 8). It can therefore operate with a stroke volume equal to the entire

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Fig. 7. The Gambro PD 100-T and PD 101.

Fig. 8. The Gambro PD 200.

exchange volume. This enables flow rates up to 400 ml/min, which adds valuable dwell time. Greater patient comfort may result from the gradually increased inflow rate. The PD 200 incorporates scales, which continuously weigh the solution. These are used to control ultrafiltration, which is very accurate. The PD 200 allows prescription of all presently described modalites, and has potential to be programmed for future alternatives. The software can optimize prescription delivery by taking the available treatment time and fluid volume into account. The continuous flow rate measurement is particularly useful when tidal modes are preferred. The PD 200 machine can also benefit from the new customized solutions with low concentration of glucose degradation products (GDPs) and a nearly physiological pH [7]. Biocompatible fluid is considered especially valuable for APD patients, as they are exposed to larger fluid volumes than patients on CAPD.

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The Ideal PD Machine

For a machine designed for home use, ease of troubleshooting and service is more important than for a hospital product. From the patients’ perspective the most important requirements are a user-friendly, intuitive interface and unobtrusive, portable hardware. The medical team would want to individualize prescriptions and be able to monitor the treatment to ensure compliance, preferably in real time. For safety considerations, the software should be ‘intelligent’ and not allow errors. Problems with in or outflow, over and underfilling, and temperature variance should trigger alarms and clearly indicate what the problem is. It is a constant challenge to balance what is technically possible and clinically desirable against what is practically achievable. Patient satisfaction must also be balanced against the desire of the medical team to control everything. Flexibility in the choice of modes and solution composition should be built-in to allow the incorporation of new concepts. Lastly, for any therapy to be successful in the marketplace, its operating costs need to be reasonable. Machine design is a dynamic process moving towards a future into which medical and technical events are continually integrated. The ideal machine should not only be able to perform all treatment schedules, but it should also optimize the performance of a selected treatment strategy. For example, on-line pressure and flow sensors should be integrated to provide accurate information on patient response to a given treatment regimen. Catheter malfunction or excessive intraabdominal pressure should be immediately detected and an appropriate solution proposed or even attempted by the machine. Integrated sensors could also be used to determine optimal tidal volume in tidal PD. Real time detection of net ultrafiltration could be linked to provide feedback for the next cycle fluid composition. This would require on-line fluid preparation. Similar innovations have been made attempted in hemodialysis with the primary target clinical tolerance to ultrafiltration. In PD these efforts should be oriented towards decreasing dialysate toxicity and maximizing utilization of the peritoneal membrane. Individual treatment variables in PD include membrane permeability and blood flow, behavior of the abdominal cavity, biological response to dialysate, and flow characteristics of the catheter. All other variables should be controlled by the machine.

Prescription and Delivery of APD

Fill volume optimized for body size and intraperitoneal pressure [8, 9], membrane transport characteristics [10, 11] and total dialysate volume per

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session are the most important parameters influencing efficiency and limiting APD adequacy. With nocturnal tidal PD, only patients with a 4-h D/P creatinine (Cr) ratio ⬎0.65 and total volumes between 25 and 30 l per session can reach a peritoneal creatinine clearance (CrCl, normalized to 1.73 m2) above 50 l/week [12]. This is confirmed by Twardowski et al. [13] who found an average CrCl of 47 l/week in nocturnal tidal PD patients with a mean D/PCr of 0.66. Adding two diurnal dwells (CTPD2) in anuric patients, only those with a D/PCr ⬎ 0.65 can reach both DOQI targets (weekly Kt/V ⬎ 2.1 and CrCl ⬎ 63 l/week) and this requires dialysate volumes of more than 20 l per session [14]. Using NIPD with a mean of 14 l per session, average CrCl of 27 l/week was obtained in 7 patients (74 kg, 1.8 m2) with a mean D/PCr of 0.68 [15]. Another study demonstrated a CrCl of 42.5 l/week and a Kt/V of 1.55 in 9 patients on NIPD (75 kg mean body weight) with average per session volume of about 10 l [16]. Both studies confirm that volumes less than 20 l per session in NIPD yields inadequate results. The tidal modality with tidal volume at 50% of dwell volume has demonstrated equal or superior clearances to non-tidal modalities using the same dialysis time and volume [17, 18]. The major advantage of this method is increased dialysate flows with shorter exchange times which makes higher delivered volumes possible. There is also less membrane ‘down time’ [12, 17, 19, 20]. A rational approach to increase clearance in APD is tailored dwell and tidal volumes. Because intra-abdominal pressure is lower in the supine position [21], larger intraperitoneal volumes are possible during nocturnal APD. Increased dwell volumes, individualized to patient size and intraabdominal pressure, allows for better results in patients with low peritoneal permeability. Common dwell volumes in APD are 40 ml/kg [19] or 2.5 l/1.73 m2 [8, 22]. The recommended maximal intraabdominal pressure is 18 cm H2O [9]. Increased intra-abdominal pressure can lead to reduced ultrafiltration which lowers the clearance [23]. Another approach to an optimal APD prescription is computer-assisted kinetic modeling [24]. Programs are available from Baxter (PD Adequest), Fresenius (Pack PD), and Gambro (PDC). All have in common a reliable mathematical model for the PD prescription using individual peritoneal function tests [25–32]. All these programs enable simulations of different APD regimens with total clearance results to predicted accurately for each patient.

Treatment Monitoring

In PD, the prescribed dose only occasionally equals the delivered dose. Catheter malfunction, changes in membrane transport and (mostly) poor patient

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compliance are the main causes. Catheter malfunction is detected by periodically measuring inflow and outflow times. Alteration in peritoneal transport is suspected when blood chemistry changes in a patient on a constant PD regimen. Changes in D/P Cr on the peritoneal equilibration test will confirm changes in transport characteristics of the membrane. Cycler function and patient compliance can be monitored either electronically or with frequent home visits. As previously mentioned, newer cyclers have the ability to record treatment data on flash memory cards, or transmit this information to the center via modem. For the moment, data cards are a more practical solution. But with expansion of high-speed internet access, real time tele-monitoring is increasingly attractive and feasible. Another approach we find useful in assessing compliance is to look at the difference between measured and predicted creatinine excretion. Non-compliant patients typically perform a full treatment only when kinetics are measured, which changes the steady state and transiently results in more creatinine appearing in the dialysate. If the measured creatinine excretion is significantly higher than that predicted by body size and gender, non-compliance is very likely. Others, while confirming the underlying hypothesis, have not endorsed this method for assessment of compliance (need reference from Gotch [33, 34]). The direct measurement of clearances normalized to body surface area and body water volume, expressed on a weekly basis, is crucial in the assessment of treatment adequacy. Creatinine and urea clearance are the most widely used adequacy indices in PD and APD. In a steady-state, the calculation of clearance, i.e. the ratio between dialytic (and renal) solute removal and the blood solute concentration, requires quantitation of solute removed by total collection of drained dialysate. Blood and dialysate solute concentrations are measured by standard assays. The ratio of dialysate to blood solute concentration multiplied by the dialysate volume equals the clearance [35]. In APD, the intermittency or variable intensity of the therapy causes a modest compartmental disequilibrium with fluctuation of plasma concentrations between the predialytic (evening) and postdialytic (morning) values [14, 16]. This difference is more marked for urea than for creatinine [16]. The use of a postdialytic plasma value in clearance measurement significantly overestimates Kt/V by 6.3% [16] up to 14% [14]. The overestimation increases with efficiency of APD. Ideally, the blood sample is taken during the day at a time equidistant from the end of the previous and the beginning of the subsequent nocturnal APD sessions [36]. This value should be roughly equivalent to the average of pre- and post-blood concentrations, but this assumption has not been thoroughly tested. Adequacy targets reflect intermittency or variable intensity and are higher in NIPD (Kt/V ⱖ 2.2 and CrCl ⱖ 66 l) than in CCPD (Kt/V ⱖ 2.1 and

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CrCl ⱖ 63 l), and both are higher than CAPD (Kt/V ⱖ 2.0 and CrCl ⱖ 60 l) [37]. These different adequacy targets are due to the effect of different blood solute concentrations on the calculation of clearances. This also explains the differing targets for HD vs. PD [35]. Intermittent treatments present blood profiles that may not reflect total body solute concentration due to dynamic compartmental disequilibrium [35, 38–40]. Based on the ‘Peak Concentration Hypothesis’, Keshaviah proposed the solute removal index as an adequacy index that takes into account compartmental disequilibrium. With the solute removal index, removed solute mass is normalized to predialysis compartment (body) content. Predialysis levels of solute, distant from the end of the previous treatment, can be assumed fully equilibrated [38–41]. At that moment blood solute concentration fully reflects total body water volume. The solute removal index is very seldom used but has the same rationale as creatinine or urea Kt/V because they share the same distribution compartment (total body water) [42–44]. Using a double index (Kt/Vurea, CrCl), target discrepancies (i.e. one above and the other below the target value) can present a problem. Target discrepancies have been reported in several papers, both in APD [14, 43] and in CAPD [44, 45]. The most common finding is that Kt/Vurea more easily reaches adequacy targets than CrCl. Factors affecting this discordance are the intermittent nature of APD treatment [43], the degree of residual renal function [44], different rates of solute transport for the two molecules and membrane characteristics [13, 45]. We recommend that in cases of discordance between the two indices, the Kt/Vurea should be given primacy [37, 46]. There is considerable day-to-day variability in adequacy indices derived from 24 h collections in PD, which affects the evaluation of dialysis adequacy in any PD modality. Consequently, when single measurements are close to adequacy targets, it is advisable to repeat them to reduce the variability [47, 48]. The CANUSA study went a long way towards the determination of optimal indices and targets in CAPD, though groups were not randomized to different doses, and APD patients were not studied [49]. The ADEMEX trial did prospectively study randomized groups of CAPD patients at different dose levels and found no difference in survival by intent to treat analysis. Treatment failures were more frequent in the low dose group [50]. Nevertheless, based largely on this study, adequacy targets for PD are likely to be lower in the next K/DOQI recommendations (Burkhart, personal communication). APD was compared prospectively to CAPD in a Danish study of 34 patients over only 6 months. While quality of life was significantly better in the APD group, sleep disorders were also more common. The study was not powered to detect differences in mortality or dialysis-related hospitalizations [51]. Another prospective, but nonrandomized study of over 100 patients on CAPD and APD for a year demonstrated

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significantly lower ultrafiltration volumes and sodium removal for APD. There was a significantly faster decline in residual renal function in the APD group, but no differences in cardiovascular morbidity and mortality [52].

Current and Future Trends in APD

New Solutions The utilization of new biocompatible solutions in APD with alternative osmotic agents, nutritional integration, reduced sodium content and alternative buffers is attractive, particularly because of the higher fluid volumes and peritoneal contact with APD [53, 54]. Amino acids together with glucose in APD allow for the simultaneous absorption of calories and nitrogen for protein anabolism. The optimal proportion glucose:amino acids in the mixture of 7:1, gives an approximate intake of 1 g of nitrogen with every 112 kcal. This mixture was used in a long-term study on children with favourable results [55]. Combining amino acids and bicarbonate buffered solutions provides better acid buffering and enhanced protein anabolism. In a short-term metabolic balance study, 19 malnourished CAPD patients were able to establish positive net nitrogen balance with 1–2 exchanges/day of PD solution containing 1.1% amino acids rather than dextrose [56]. Glucose-free APD using a mixture of glycerol and amino acids during the night and icodextrin during the daytime for ultrafiltration is an interesting concept. Small osmotic agents like glycerol and amino acids should produce adequate ultrafiltration in short dwells, while better ultrafiltration during daytime dwell could be obtained with icodextrins [57]. Moreover, a period of glucosefree PD could allow the recovery of the membrane with type I ultrafiltration failure (reduction, exaustion or glycosylation of aquaporins). In a study on stable CAPD patients a solution of 0.6% glycerol and 1.4% amino acids in 2 of 4 exchanges there were no significant differences in blood chemistries or ultrafiltration compared with standard dialysate. Glucose absorption decreased markedly from 84 to 1 g/day, and dialysate CA-125 levels increased in the glycerol/amino acid group [58]. Glycerol is readily absorbed and has been reported to produce hyperosmolality and hypertriglyceridemia in CAPD and has not been widely used as an osmotic agent [59]. Bicarbonate as a buffer in CAPD and APD is available with on-line mixing of dialysate to avoid calcium and magnesium carbonate precipitation. Studies performed in continuous renal replacement therapies, where PD solutions are often used, show that a bicarbonate solution with electrolytes and glucose is stable without precipitation up to 72 h [60]. In a crossover study of 14 APD patients, standard dialysate was compared with lactate/bicarbonate solutions. In

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addition to less inflow pain with the neutral pH dialysate, effluent IL-6 and advanced glycation endproducts were lower. Effluent CA-125 was higher in the lactate/bicarbonate group, suggesting better mesothelial cell integrity [61]. Another study looked at the inflammatory response of rat peritoneum when exposed to standard solutions, bicarbonate-buffered solutions (also low in GDP), and glucose-free solutions (icodextrin, amino acid, amino acid/glycerol). Conventional solutions and the amino acid-based solutions abolished leukocyte recruitment induced by lipopolysaccharides, while the bicarbonate solutions had no effect. Icodextrin partially suppressed this response. The authors conclude that the negative effects of lactate-buffered solutions on immune response is greater than that of high glucose concentrations and negates the benefit of glucose-free dialysate [62]. Biosensors Intraperitoneal pressure can be measured continuously for on-line optimization of fill volume. Closely linked to pressure, dialysate flow speed can be measured for on-line optimization of exchange times. Peritoneal pO2, pCO2, and pH can be measured both for on-line bicarbonate mixing and acid-base and oximetry monitoring, possibly useful also for sleep apnea syndrome cases. Urea can be monitored on-line, together with dialysate conductivity (with on-line fluid production), permitting real time assessment of clearance. Optical or sound-based sensors could detect white blood cells or fibrin in dialysate for the early diagnosis of peritonitis [63]. On-Line Preparation of Solutions for APD When residual renal function deteriorates many CAPD patients are switched to APD so that a larger dose of dialysis can be prescribed and conveniently administered. However, the volumes of PD solution required for optimal APD are considerably larger than for CAPD. The cost of the solution and the practical problems in transporting, storing and handling large volumes, maybe 20–25 l/day, severely limits the use of APD. On-line preparation of dialysate by mixing water with appropriate electrolyte and osmolytes addresses these limitations. Stepwise ultrafiltration under controlled conditions is a well-established technique to prepare large volumes of sterile and pyrogen-free fluid for use in hemodiafiltration and hemofiltration [64, 65]. The accumulated long-term experience in HDF and HF has created an open attitude among regulatory authorities in many countries. As long as certain conditions are fulfilled, on-line ultrafiltration is considered an acceptable technique (FDA, reclassification notice of 15.3.99). The published clinical experience of on-line prepared fluids for PD is limited to a few technical reports [66, 67], as appropriate equipment is not yet available.

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On-line generation of fluid would permit individualization of electrolyte and osmotic agent concentrations. The glucose concentration could be varied beyond the present fixed concentrations, and even be adjusted to the length of the dwell, based on membrane permeability characteristics. Bicarbonate could be used without extra expense and complexity and at the concentration required to achieve acid-base correction in each individual case. GDP production could be minimized, as none of the conditions promoting their formation prevails [68]. Compact machines capable of dialysate preparation have been designed for home hemodialysis; this should not be an obstacle for APD patients, who have already accepted a machine into their home. Evolution Toward Continuous Flow Perfection of peritoneal double lumen catheters will pave the way for continuous flow peritoneal dialysis, which is the logical extension of APD. Continuous flow peritoneal dialysis, with external regeneration of peritoneal dialysate by external dialysis, addresses many of the limitations of CAPD and APD. Significantly higher clearances, bicarbonate buffers, no GDPs, minimal protein losses, and low cost are some of the potential advantages [69–74].

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Fusshoeller A, Plail M, Grabensee B, Plum J: Biocompatibility pattern of a bicarbonate/lactatebuffered peritoneal dialysis fluid in APD: a prospective, randomized study. Nephrol Dial Transplant 2004;19:2101–2106. Mortier S, Faict D, Gericke M, Lameire N, De Vriese A: Effects of new peritoneal dialysis solutions on leukocyte recruitment in the rat peritoneal membrane. Nephron Exp Nephrol 2005;101:e139–e145. Epub 2005 Aug 30. Steele M, Kwan JT: Potential problem: delayed detection of peritonitis by patients receiving home automated peritoneal dialysis. Perit Dial Int 1997;17:617. Ledebo I: Principles and practice of hemofiltration and hemodiafiltration. Artif Organs 1998;22:20–25. Ghezzi PM: Hemodiafiltration with endogenous reinfusion (HFR): evolution of the method. G Ital Nefrol 2005;22(suppl 31):S105–S110. Yu AW, Manahan FJ, Filkins JP, Mohammed MS, Soundararjan R, McShane AP, Gandhi VC, Ing TS: Peritoneal dialysis using bicarbonate-containing solution sterilized by ultrafiltration. Int J Artif Organs 1991;14:463–465. Brunkhorst R, Fromm S, Wrenger E, Berke A, Petersen R, Riede G, Westphale J, Zamore E, Ledebo I: Automated peritoneal dialysis with ‘on-line’-prepared bicarbonate-buffered dialysate: technique and first clinical experience. Nephrol Dial Transplant 1998;13:3189–3192. Wieslander A, Kjellstrand P, Rippe B: Heat sterilization of glucose-containing fluids for peritoneal dialysis biological consequences of chemical alterations. Perit Dial Int 1995;15:52–60. Amerling R, Glezerman I, Savransky E, Dubrow A, Ronco C: Continuous flow peritoneal dialysis: Principles and applications. Semin Dial 2003;16:335–340. Ronco C, Dell’Aquila R, Bonello M, Gloukhoff A, Amerling R, Cruz C, Levin N: Continuous flow peritoneal dialysis: A new double lumen catheter. Int J Artif Organs 2003;26:984–990. Twardowski ZJ: Peritoneal dialysis glossary II. Perit Dial Int 1988;8:15–17. Durand PY, Slingeneyer A, Benevent D, Chanliau J: CAPD: peritoneal clearances with a 5th nocturnal automated exchange (Baxter Quantum). Perit Dial Int 1997;17(suppl 1):S15 (abstract). Diaz-Buxo JA: Enhancement of peritoneal dialysis: the PD Plus concept. Am J Kidney Dis 1996;27:92–98. Korbet SM, Vonesh EF, Firanek CA: Peritonitis in an urban peritoneal dialysis program: an analysis of infecting pathogens. Am J Kidney Dis 1995;26:47–53.

Dr. Claudio Ronco Department of Nephrology, St Bortolo Hospital Viale Rodolfi IT–36100 Vicenza (Italy) Tel. ⫹39 0444 993869, Fax ⫹39 0444 920693 E-Mail [email protected]

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New Technologies Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 310–320

Continuous Flow Peritoneal Dialysis: Current State-of-the-Art and Obstacles to Further Development Claudio Roncoa, Richard Amerlingb a

Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy; bDivision of Hypertension and Nephrology, Beth Israel Medical Center, New York, N.Y., USA

Abstract Peritoneal dialysis (PD) is still underutilized as home based renal replacement therapy and in-patient treatment of acute renal failure. Hindering the expansion of PD is poor solute clearance, which is a result of the intermittent dwell technique. Continuous flow PD is an old concept that has demonstrated urea clearances from 2–5 times higher than standard PD. It relies on a 2–3 l dwell volume and continuous dialysate flow at 100–300 ml/min. This high flow rate dictates the need for an efficient dual lumen catheter, or two separate catheters with ports separated maximally, as well as a means to generate or regenerate large volumes of fluid. A modified hemodialysis system can easily be adapted to regenerate sterile peritoneal dialysate, and a dual lumen catheter with excellent flow characteristics has been designed. Ultrafiltration control and a means to accurately balance transperitoneal with external ultrafiltration persist as technical challenges. Continuous flow PD remains an attractive modality for daily home dialysis and treatment of acute renal failure. Copyright © 2006 S. Karger AG, Basel

We recently considered the question ‘Is there a need for CFPD?’ [1]. One could easily respond with another question: ‘Is there a need for PD?’ We feel the answer to both questions is an unequivocal ‘Yes!’ If we are to continue to embrace PD, we need to make it more efficient, more attractive to patients as a home therapy, and more suitable for a larger cross-section of patients. There are compelling reasons to expand PD use in renal replacement therapy (RRT). PD is attractive in regions with low per capita income, as it is generally cheaper then HD and requires less infrastructure to provide and maintain. CFPD in this setting could be reserved for those with excessive fluid requirements due to large body size and lack of residual renal function. Since sterile

peritoneal dialysate could be regenerated by dialysis against fluid manufactured online from treated tap water, the cost savings in sterile dialysate would eventually overcome equipment costs. Home based therapies maintain a competitive advantage economically because of the low manpower requirements. PD remains a reliable method for the treatment of acute renal failure and is easily applied in developing countries. Acute PD treatment centers could be developed with minimal investments of money and staffing to bring acute RRT to areas of the world where none presently exists [2]. Here one can envision adapting CFPD in a single-pass mode in certain patients with hypercatabolic acute renal failure using dialysate formulated and sterilized locally. Interest in home hemodialysis is growing. This modality could expand considerably if the daily dialysis study currently getting underway shows a significant benefit of more frequent treatments. Such a result would almost certainly lead to legislation authorizing payment for more than three treatments per week. At least three manufacturers have produced attractive home hemodialysis machines. Yet the proliferation of home HD brings concern about serious dialysisrelated accidents occurring at home, such as hemorrhage, air embolism, errors associated with dialysate composition, and sepsis. A home therapy using the peritoneal membrane is simply inherently safer. There is increasing concern about the long-term negative hemodynamic effects of arteriovenous shunts used for dialysis and their possible impact on cardiovascular mortality [3, 4]. Until intravenous hemodialysis catheters are much less infection-prone, PD and CFPD offer RRT without hemodynamic compromise. ‘PD First,’ as opposed to ‘fistula first,’ could have a major beneficial impact on cardiovascular mortality if widely applied. It has proven difficult to expand the population treated with peritoneal dialysis beyond a certain limit [5–12]. A new PD technique might lead to an increased enrollment of patients in PD as well as provide an alternative mode to those already treated with PD. CFPD might allow patients to stay longer on PD before emigrating to a blood based technique. CFPD might represent a first choice technique in some large, anephric, or hyperpermeable patients. K/DOQI adequacy targets are a bridge too far for many patients [13–18]. Increasing exchange number and volume in continuous ambulatory peritoneal dialysis (CAPD) can only go so far before other strategies must be pursued. Reaching adequacy targets in automated peritoneal dialysis (APD) requires large amounts of fluid or prolongation of sessions to the point of intolerability and non-compliance [19–30]. CFPD would be a new option for patients with limited chances in standard CAPD or APD schedules. Furthermore, CFPD may reveal potential beneficial effects of high dose PD treatment [31–35]. One interpretation of the ADEMEX study [36] is that both treatment arms were in the inadequate domain. What effect would a weekly Kt/V of 3 or more, achievable

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Fig. 1. Solution of the steady state Kpe equation over a wide range of values for mass transfer coefficient (MTC) and Qp/Kd. Dialyzer clearance Kd is limited by peritoneal dialysate flow rate (Qp), thus Kd Qp. As Kd increases, peritoneal clearance (Kpe) approaches the MTC. Based on published experience with CFPD, MTC is in the 40–70 ml/min range, with peritoneal urea clearances of 25–60 ml/min, depending on dialysate flow rate (Frank Gotch, personal communication).

with CFPD, have on morbidity and mortality, not to mention technique survival? Figure 1 displays two regimens of continuous flow PD in the standard Kt/V domain map of Gotch [37]. These treatment schedules allow values of Kt/V that are among the highest achievable with current therapies. With CFPD it is possible to explore the region of clearance in which neither dialysate flow rate nor blood flow rate are limiting factors. This region identifies values of clearance which approximate the mass transfer coefficient (MTC). In CFPD, higher levels of efficiency require large amounts of fluid. Several approaches can be used to provide the large volumes and high dialysate flows (200–300 ml/min) required for CFPD. One is to use commercially prepared fluid in single pass mode, but this would imply an enormous increase in cost, huge protein losses, and a major storage problem. Another possibility would be to use a moderately sized batch of prepared fluid and recirculate it until fully saturated. This would reduce the cost of dialysate, but would also limit efficiency and solute removal. Yet another approach involves preparation of ultrapure, sterile dialysate from water and concentrate with online ultrafiltration. This approach is already used in hemodiafiltration and has been clinically validated in Europe. It could allow individualization of

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dialysate as well as intra-treatment variations in response to measurements of ultrafiltration and intraperitoneal pressure. The major problem with this technique is the potentially devastating protein losses with such high flow rates in single-pass mode. The last method would use an initial fixed volume of 2–3 l of commercial dialysate for priming followed by continuous extracorporeal regeneration of the spent dialysate. This would be performed either by a hemodialysis filter or by adsorption. Complete regeneration by adsorption is hard to achieve, but the two processes could be combined (see article elsewhere in this issue on use of sorbents in PD by Winchester et al.). The external regeneration of dialysate is in our view the most promising method and the one requiring the least investment in new technology. Two areas remain as technical challenges and are limiting the widespread application of CFPD: catheter design and ultrafiltration control. The requirement for simultaneous in and outflow dictates either two catheters or a double lumen catheter. Two separate catheters were used by Shinaberger et al. [38], the originator of CFPD. He obtained in some cases urea clearances over 100 ml/min. Cruz et al. [39] and Amerling et al. [40] have also used two separate catheters. While there is a concern about increasing chances of exit site or tunnel infections with two PD catheters, this has not emerged as a significant problem with the Tesio-Canaud two-catheter system for hemodialysis. With two catheters, one should be in the pelvis and the other oriented towards the diaphragm, to achieve maximal port separation. Ideally, the pelvic catheter should have a coiled tip and a preformed bend to produce an exit site below the insertion site. A short, straight Tenckhoff catheter pointing cephalad and exiting near the pelvic catheter can be placed adjacent to the latter using a single incision [40]. A properly designed dual lumen catheter would be advantageous and should not increase patient discomfort. The real challenge is to find a design with minimal intraperitoneal recirculation, or streaming. This is possible when the two tips of the catheter are positioned such that a maximal exposure of the peritoneal surface to the fluid is guaranteed. We have recently developed a new catheter designed to prevent intraperitoneal recirculation and maximize dialysate/membrane contact. This catheter displays minimal recirculation and no discomfort for the patient. It consists of a curled-tip silicone catheter reaching down to drain the pelvis and a sub-peritoneal ‘shower head’ to disperse regenerated dialysate towards the diaphragmatic peritoneum [41]. Early clinical results are encouraging and more studies are planned (fig. 2). A more perplexing problem in CFPD is the assessment and control of ultrafiltration during treatment. This dictates the need for accurate, real time measurement of intraperitoneal volume. Increases in volume reflect transperitoneal

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Diaphragms

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Fig. 2. Anatomic ‘Ideal’ catheter design for CFPD resulting in uniform flow? (Gotch, F).

ultrafiltration, which would need to be matched by extracorporeal fluid removal. A mismatch would lead to either abdominal over-distension or underfilling, with discomfort or loss of efficiency, respectively. Pressure curves have displayed limited accuracy in and other techniques are still inaccurate or experimental. Pressure-volume relationships within the peritoneal cavity are not linear. Software would need to filter variations due to respiration and movement. Segmental bioimpedance has been shown to measure intraperitoneal volume with a fair degree of accuracy and this technique is being examined as a possible adjunct to CFPD [42]. Ultrafiltration in the external circuit is readily accomplished with existing volumetric dialysis machines and the rate would simply need to be coupled to the internal rate. As of now, dextrose is the osmotic agent of choice in CFPD and the concentration required for ultrafiltration will need to be individualized for each patient’s transport characteristics. CFPD methodology offers distinct advantages over current PD techniques regarding the use of dextrose. Since the intraperitoneal dextrose can be held constant by the extracorporeal system, a lower concentration can be used. Also, a dextrose-containing fluid made online would have few, if any glucose degradation products, which may lead to peritoneal toxicity [42]. Other important problems and technical challenges include monitoring of pressure and flow rates, monitoring of the catheter function and establishing

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safety limits relevant to the structure of the abdominal cavity. New ultrafiltration technologies and more precise sensors, recalibrated to the range of intraperitoneal pressure, may provide the required margin of safety. Further safety issues concern non-bacterial peritonitis, biocompatibility and long-term peritoneal membrane preservation. Albumin losses, a problem when high dialysate flows are employed in single-pass mode, are virtually eliminated in CFPD by recirculating the same fluid volume and returning the final effluent to the peritoneal cavity after maximal volume reduction by ultrafiltration. This may lead to a loss of middle molecule clearance associated with protein binding. The answer to this problem rests on future clinical studies, particularly with sorbent technology [43]. Safety issues include the prevention of infections and peritonitis. The fact that CFPD is closed system water should help prevent most instances of accidental contamination associated with multiple connections. Furthermore, since CFPD can accomplish approximately twice as much small solute clearance and ultrafiltration as conventional PD, the dialytic session can be shortened to 8 h, allowing an extended daily period free of exchanges. Several studies have shown beneficial effects of long ‘dry abdomen’ cycles on host defenses [44–46]. Peritoneal cell counts increase as a function of dwell and can exceed 100 cells/mm3 in non-infected patients after 12–14 h of dwell. Peritoneal macrophage phagocytic function and opsonic activity of the effluent are affected by prolonged dwell times [37, 44]. More recent investigations have confirmed these finding and also shown that long dry periods allow for additional peritoneal macrophage differentiation [46]. The proportion of mature monocytes increased after an exchange-free interval of 12–14 h. The cytokine response to lipopolysaccharides and the interleukin-1 receptor antagonist content of macrophage lysate also significantly increased after the exchange-free interval. Of interest is the fact that no changes were observed between NIPD and CCPD patients, strongly suggesting that the beneficial effect of the prolonged exchange-free period is independent of the presence or absence of dialysate in the peritoneal cavity. Recent studies have validated the kinetic constructs of CFPD and generated new enthusiasm for CFPD [37, 39, 47, 48]. Cruz et al. [39] studied five patients with two separate catheters using fresh commercial dialysate with 1.5% dextrose, an exchange volume of 2 l and a dialysate flow rate of 200 ml/min. They observed mean peritoneal clearances for urea and creatinine of 42 and 33 ml/min, respectively and an impressive ultrafiltration rate of 16 ml/min. Raj et al. [47] used a recirculation system using hemodialysis technology, a single lumen catheter with a ‘Y’ adapter and a single needle device to control inflow and outflow [47]. The average glucose concentration of the solution was 0.729 0.562% and the dialysis solution flow rate was 141.3 23.7 ml/min. They observed mean peritoneal clearances for urea and creatinine of 26.5 and

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24.1 ml/min, respectively and an estimated ultrafiltration rate of 3 ml/min. Although these clearances are definitely better than those observed with conventional PD, they are lower than those of Cruz et al. and other investigators. The differences most likely reflect the lower effective dialysate flow rate with the use of the single needle device. Mineshima et al. [48] performed CFPD in clinical studies using a double lumen catheter, regeneration with a hemodialyzer, exchange volumes of 1 l and peritoneal solution flow rates of only 100 ml/min. Once again their urea clearance averaged 14.1 4.4 ml/min, which is better than with conventional PD, but much lower than the mean for CFPD. The best explanation for their findings is the extremely low exchange volume, modest peritoneal dialysate flow rates and ‘streaming’ of regenerated dialysate from port to port in their side-by-side dual lumen catheter. Freida and Issad performed single pass CFPD using two catheters (one permanent, one temporary) and flow rates of 100–150 ml/min. They achieved urea clearances of 21–36 ml/ min and ultrafiltration with 1.36% dextrose ranged from 2 to 8 ml/min [49]. In our experiences with two catheters and flow rates of 200–300 ml/min we have seen urea clearances of 25–75 ml/min [40]. In CFPD, as in all forms of home dialysis, there is a constant challenge to balance what is technically possible and clinically desirable with what is practically achievable [50–59]. Patient satisfaction should therefore be the most important design criterion for a CFPD machine. The second goal is the capability to individualize the prescription and measure delivered dialysis dose and patient compliance. There should be flexibility in the choice of modes and solution composition in order to accommodate new ideas and medical progress. The basic requirement of safety according to local and global standards is a mandatory characteristic of any medical device and must also apply to CFPD machines. Most important, treatment cost must also be contained. A design philosophy is a dynamic vision towards a future goal, into which medical and technical events and demands are continually integrated [60–63]. Based on this consideration, the ideal machine should not only be able to perform all treatment schedules, but it should also optimize the performance of a selected treatment strategy. Segmental bioimpedance might provide the technology for this purpose. Sodium and glucose concentrations could be instantaneously varied by such a feedback loop, providing fine control of net ultrafiltration.

Conclusion

CFPD was one of the first techniques of PD performed [38]. When a technique is conceived as a first solution to a problem there is good chance that this solution is the best.

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The rationale for using CFPD was to eliminate the non-dialytic down time and maximize the transperitoneal solute gradient. Conventional PD modalities are based on intermittent techniques, with efficiency declining exponentially with dwell time. As dialysate flow increases, the dialytic downtime represented by the inflow and outflow phases becomes highly important and detracts from overall treatment efficiency. CFPD was developed as a technique in which fluid was constantly present in the abdomen, continuously replenished by fresh or regenerated fluid via two indwelling catheters. CFPD reportedly achieved urea clearances in the range of 40–50 ml/min [31–33]. Technical problems related to fluid handling, inadequate peritoneal access systems, poor quality of sorbents used for regeneration, unreliable flow/pressure monitoring systems and high costs compared to other techniques hampered the development of CFPD and it was abandoned. There are many reasons for the renewed interest in CFPD [64]. One is the improvement in PD technique survival by providing adequate clearances or ultrafiltration when other techniques fail. New technologies have made possible accurate fluid handling, reliable monitoring of pressures and flows in the circuit and double lumen catheters for CFPD. Techniques for generating on-line PD fluid, or to regenerate a recirculating batch have become feasible [34, 35]. We hope to continue to develop this technique, which has demonstrated its great potential as a home renal replacement therapy, as well as in the treatment of ARF. We see it as a safer alternative to home hemodialysis, and as a way to avoid the hemodynamic insult of an arteriovenous shunt.

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Shinaberger JH, Shear L, Barry KG: Peritoneal-extracorporeal recirculation dialysis: a technique for improving efficiency of peritoneal dialysis. Invest Urol 1965;2:555–565. Cruz C, Melendez A, Gotch F, Folden T, Levin NW, Crawford T, Diaz-Buxo JA: Continuous flow peritoneal dialysis (CFPD): preliminary clinical experience. Perit Dial Int 2000;20(supp 1):S6. Amerling R, Glezerman I, Savransky E, Dubrow A, Ronco C: Continuous flow peritoneal dialysis: principles and applications. Semin Dial 2003;16:335–340. Ronco C, Dell’Aquila R, Bonello M, Gloukhoff A, Amerling R, Cruz C, Levin N: Continuous flow peritoneal dialysis: a new double lumen cathether. Int J Artif Organs 2003;26:984–990. Zhu F, Hoenich NA, Kaysen G, Ronco C, Schneditz D, Murphy L, Santacroce S, Pangilinan A, Gotch F, Levin NW: Measurement of intraperitoneal volume by segmental bioimpedance analysis during peritoneal dialysis. Am J Kidney Dis 2003;42:167–172. Winchester JF, Brady JA, Salsberg JA, Mok W, Quartararo PJ: Potential for sorbents in continuous flow peritoneal dialysis. Contrib Nephrol 2003;140:305–308. Vlaanderen K, de Fijter CW, Bos HJ, van der Meulen J, Beelen RH, Oe PL, Verbrugh HA: The effect of dwell time on peritoneal phagocytic defense of chronic peritoneal dialysis patients. Adv Perit Dial 1989;5:151–153. de Fijter CWH, Verbrugh HA, Oe PL, Peters EDJ, van der Meulen J, Donker AJM, Verhoef J: Peritoneal defenses in continuous ambulatory versus continuous cyclic peritoneal dialysis. Kidney Int 1992;42:947–950. Wrenger E, Baumann C, Behrend M, Zamore E, Schindler R, Brunkhorst R: Peritoneal mononuclear cell differentiation and cytokine production in intermittent and continuous automated peritoneal dialysis. Am J Kidney Dis 1998;31:234–241. Raj DSC, Self M, WorkJ: Hybrid Dialysis: recirculation peritoneal dialysis revisited. Am J Kidney Dis 2000;36:58–67. Mineshima M, Suzuki S, Sato Y, Ishimori I, Ishida K, Kaneko I, Agishi T: Solute removal characteristics of continuous recirculating peritoneal dialysis in experimental and clinical studies. ASAIO J 2000;46:95–98. Freida P, Issad B: Continuous flow peritoneal dialysis: assessment of fluid and solute removal in a high-flow model of ‘fresh dialysate single pass.’ Perit Dial Int 2003;23:348–355. Twardowski ZJ, Prowant BF, Nolph KD, Martinez AJ, Lampton LM: High volume, low frequency continuos ambulatory peritoneal dialysis. Kidney Int 1983;23:64–70. Freida PH, Issad B, Allouache M: Relationships between fill volume, small solute clearances, and net ultrafiltration during a standardized APD program. Perit Dial Int 1998;18:124 (abstract). National Kidney Foundation: Computer-assisted kinetic modeling approach to achieving target doses of peritoneal dialysis: NKF-DOQI clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis 1997;30(suppl 2):S90–S92. Vonesh EF, Lysaght MJ, Moran J, Farrell P: Kinetic modeling as a prescription aid in peritoneal dialysis. Blood Purif 1991;9:246–270. Vonesh EF, Burkart J, McMurray SD, Williams PF: Peritoneal dialysis kinetic modeling: validation in a multicenter clinical study. Perit Dial Int 1996;16:471–481. Rippe B, Stelin G, Haraldsson B: Computer simulations of peritoneal fluid transport in CAPD. Kidney Int 1991;40:315–325. Haraldsson B: Assessing the peritoneal dialysis capacities of individual patients. Kidney Int 1995;47:1187–1198. Gotch FA, Keen ML: Kinetic modeling in peritoneal dialysis; in Nissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis, ed 3. Norwalk, Appleton & Lange, 1996, pp 343–375. Gotch FA, Lipps BJ, Keen ML, Panlilio F: Computerized urea kinetic modeling to prescribe and monitor delivered Kt/V (pKt/V, dKt/V) in peritoneal dialysis. Adv Perit Dial 1996;12:43–45. Amici G, Mastrosimone S, Da Rin G, Bocci C, Bonadonna A: Clinical validation of PD Adequest software: modeling error assessment. Perit Dial Int 1998;18:317–321. Verrina E, Amici G, Perfumo F, Trivelli A, Canepa A, Gusmano R: The use of the PD Adequest mathematical model in pediatric patients on chronic peritoneal dialysis. Perit Dial Int 1998;18: 322–328. Struijk DG, Douma CE: Future research in peritoneal dialysis fluids. Semin Dial 1998;11: 207–212.

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Ash SR, Janle EM: Continuous flow-through peritoneal dialysis (CFPD): comparison of efficiency to IPD, TPD, and CAPD in an animal model. Perit Dial Int 1997;17:365–372. Ronco C, Brendolan A, Zanella M: Evolution of machines for automated peritoneal dialysis. Contrib Nephrol 1999;129:142–161. Amerling R: The rediscovery of continuous flow peritoneal dialysis. Int J Artif Organs 2004;27: 165–167. Passlick-Deetjen J, Lage C, Jorres A: Continuous flow peritoneal dialysis: solution formulation and biocompatibility. Semin Dial 2001;14:384–387.

Claudio Ronco, MD Department of Nephrology, St. Bortolo Hospital Viale Rodolfi IT–36100 Vicenza (Italy) Tel. 39 0444 993869, Fax 39 0444 920693, E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 321–325

Continuous Flow Peritoneal Dialysis: Ideal Peritoneal Dialysis or Second-Rate Hemodialysis? Joanne M. Bargman Staff Nephrologist and Professor of Medicine, University Health Network and University of Toronto, Toronto, Canada

Abstract Background: Since the original description of continuous flow PD (CFPD) by Shinaberger, there has been interest in the utility of this modality to augment small solute clearances in those on PD. Methods/Results: The clinical and theoretical treatment of CFPD regimens and the changing views of small solute clearance and outcome in dialysis since the publication of several important randomized, controlled trials are reviewed. Conclusion: There is little justification to promote CFPD solely on the basis of increased small solute clearance, given the lack of robust association between this measure and outcome in PD patients. Furthermore, leaving the abdomen empty between CFPD sessions may seriously compromise removal of middle molecular weight uremic toxins, one of the presumed strengths of conventional PD. Copyright © 2006 S. Karger AG, Basel

Despite all the advances in the last few decades in both peritoneal and hemodialysis, nephrologists continue to be vexed by the impressive death rate in patients undergoing dialysis. The incremental risk of death in patients on dialysis, compared to the general population, varies from several-fold to over an order of magnitude in the younger dialysis patients [1]. It is to the credit of our sub-specialty that, instead of remaining stagnant and patting ourselves on the back that we can stop patients from dying of kidney failure, we continue to look for ways to mitigate the mortality rates in our chronic dialysis patients. The National Cooperative Dialysis Study [2] ushered in an era where adequacy of hemodialysis was measured almost exclusively by small solute kinetics in general, and urea kinetics in particular. The NCDS suggested that more

dialysis (measured by urea kinetics) was associated with reduced chance of hospitalization. Although the analysis of this data by Gotch and Sargent [3] suggested a ‘step function’ whereby once the Kt/V urea reached a critical value, there was no further benefit to more dialysis, others suggested that this was not the case, and that more Kt/V urea was associated with a better outcome [4]. This era of adequacy defined by urea kinetics also held that ‘more is better’, i.e. the higher the Kt/V, the better for the patient. Unfortunately, the use of Kt/V urea for the measurement of adequacy of dialysis was adopted with little hesitation by those taking care of patients on peritoneal dialysis (PD). The appropriation of a small, easily-diffusible solute for the quantification of a long, slow dialytic process such as PD gained widespread acceptance. Both the utility of small-solute kinetics for PD and the assumption that ‘more is better’ was strengthened by the findings of the CANUSA study [5]. In this observational study of 680 incident PD patients in Canada and the United States, higher total (renal and peritoneal) small solute clearance was associated with reduction in mortality. In an effort to reduce mortality rates, therefore, one approach would be to augment small solute clearance. The advent and popularization of automated PD (APD) was one way to increase small solute clearance. (In fact, a large study of anuric APD patients was unable to demonstrate an association between small solute clearance and survival [6].) Another consideration was to augment the small solute clearance through a technique called continuous flow PD (CFPD). In this technique, the intraperitoneal dialysate is constantly being replenished by a matched inflow and outflow of fluid or by the recirculation of a single large exchange through an external apparatus.

Benefits of CFPD

The putative advantages of CFPD are (i) there is no wasted time during inflow and drain, as with conventional PD, and (ii) there is a continuous concentration gradient generating solute flux during the whole dwell time. It has been suggested that there are other benefits as well. For example, the flow-through system continuously adds glucose to the intraperitoneal dialysate. Therefore the osmotic gradient between the peritoneal fluid and the blood remains intact, and so ultrafiltration will be enhanced. In fact, because of the decreased opportunity for glucose absorption compared to more ‘stagnant’ systems, there might be more ultrafiltration with less glucose absorption. Another potential advantage to CFPD is that the dialysis fluids could be generated by an on-line mixing apparatus, and so allow for more biocompatible fluids to be produced when not having to deal with modifications of the PD fluids needed

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for storage in conventional CAPD and APD. Therefore, in a manner similar to current hemodialysis technology, the bedside generation of dialysis fluid would allow for bicarbonate-based dialysate and obviate the need for acidic, lactatebased solutions currently in use. Finally, it was considered that if the small solute clearance could be packaged and compressed into just a few hours, the abdomen could remain dry for the remainder of the day and allow for repair of intraperitoneal structures, such as the mesothelium. The initial experience with a rudimentary CFPD system was reported 40 years ago [7]. Two PD catheters were inserted in the abdomen, and dialysate flow rates ranged between 120 and 300 ml/min. With this system, urea clearance went as high as 125 ml/min. Subsequent modifications to the technique include the use of dual-lumen catheters in lieu of a second implanted PD catheter, and the use of either single-pass sterile dialysate or externally-regenerated dialysate [8]. A recent study using a temporary second catheter showed that the mean creatinine clearance was more than twice the value during APD and, interestingly, 5 times greater than during CAPD. The CFPD technique also increased the mass transfer-area coefficient for creatinine [9].

The Faulty Rationale for CFPD

As described above, the NCDS and CANUSA studies ushered in and consolidated the belief that ‘more dialysis’, as measured by small solute clearance parameters, led to improved patient survival. In that context, there would be ample justification to tolerate the complexity and expense engendered by the CFPD set-up, if it led to increased Kt/V urea. However, subsequent studies, including randomized controlled studies, in both peritoneal and hemodialysis patients, refuted the concept that ‘more is better’ [10–13]. Indeed, it appears that there is a minimum clearance requirement in both modalities, and values greater than these do not translate into improved survival. If that is the case, then the CFPD system cannot be justified on the basis that the increase in small solute clearance will benefit the patient. It is clear that PD treats renal failure in a manner different from hemodialysis. Although the weekly Kt/V urea in PD is usually just a little more than half as much as that on hemodialysis, survival of PD patients is more or less identical to that of those on hemodialysis [14]. Therefore PD must be helping the patient in a way that is not measured by these small solute parameters. Some of the benefits of PD likely relate to the preservation of residual renal function afforded by this modality [10], clearance of middle molecular weight toxins via the peritoneal membrane, and the intrinsic ‘continuousness’ of the CAPD/APD regimen, as opposed to the seesaw effect of intermittent hemodialysis.

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The latter point may have an important lesson to teach us about CFPD. Some have advocated that since the small solute clearance is so high, the CFPD procedure could be done for only part of the day, and the patient could be left dry until the next CFPD session. Unfortunately, that kind of regimen will turn a continuous dialysis process into an intermittent one. In that case, the strength of PD, i.e. the continuousness, will be lost, and the process would resemble instead intermittent hemodialysis, but with lower small solute clearance during the time on dialysis. Furthermore, removal of middle-molecules is time-dependent and therefore proportional to the total number of hours on dialysis. Using CFPD for part of the day and leaving the patient dry will likely impair, not enhance, removal of middlemolecular weight toxins. A recent theoretical analysis using 8 h of CFPD in addition to CAPD for the rest of the day showed only a trivial increase in middle molecule clearance (stdKt/V for ␤2-microglobulin 3.63 on CFPD and 3.56 for CAPD) [15]. It follows that if the patient were instead dry for the time of day not on CFPD that middle-molecule clearance would seriously deteriorate.

Conclusion

The use of CFPD to increase small solute clearance had a rational underpinning when it was thought that greater small solute clearance would be associated with improvement in patient survival. Recent studies, however, have shown that this is not the case. While there may be other theoretical advantages to this modality, such as enhanced ultrafiltration per glucose absorbed, it cannot be promoted on the basis of the augmented small solute parameters. Furthermore, it would be a mistake to compress PD into a rapid-flowing 8-h period and leave the abdomen dry for the rest of the time. This regimen would be akin to intermittent hemodialysis but with even less small solute removal, hence ‘second-rate’ hemodialysis. It is important to remember that PD works in a way that is not quantifiable by small solute kinetics.

References 1 2 3 4

Foley R, Parfrey P, Sarnak M: Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998;9:S16–S23. Lowrie E, Laird N, Parker T, Sargent J: Effect of the hemodialysis prescription on patient morbidity: report from the National Cooperative Dialysis Study. N Engl J Med 1981;305:1176–1181. Gotch F, Sargent J: A mechanistic analysis of the National Cooperative Dialysis Study. Kidney Int 1985;28:526–534. Owen W, Lew N, Liu Y, Lowrie E, Lazarus J: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993;329: 1001–1006.

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The Canada-USA (CANUSA) Peritoneal Dialysis Study Group: Adequacy of dialysis and nutrition in chronic peritoneal dialysis: association with clinical outcomes. J Am Soc Nephrol 1996;7:198–207. Brown E, Davies S, Rutherford P, Meeus F, Borras M, Riegel W, Divino Filho J, Vonesh E, van Bree M: Survival of functionally anuric patients on automated peritoneal dialysis: the European APD outcome study. J Am Soc Nephrol 2003;14:2948–2957. Shinaberger J, Shear L, Barry K: Increasing efficiency of peritoneal dialysis: experience with peritoneal-extracorporeal recirculation dialysis. Trans Am Soc Artif Intern Organs 1965;11:76–82. Amerling R, Glezerman I, Savransky E, Dubrow A, Ronco C: Continuous flow peritoneal dialysis: principles and applications. Semin Dial 2003;16:335–340. Freida P, Issad B: Continuous flow peritoneal dialysis: assessment of fluid and solute removal in a high-flow model of ‘fresh dialysate single pass’. Perit Dial Int 2003;23:348–355. Bargman J, Thorpe K, Churchill D: Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001;12:2158–2162. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, Mujais S: Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13:1307–1320. Lo WK, Ho YW, Li CS, Wong KS, Chan TM, Yu AW, Ng FS, Cheng IK: Effect of Kt/V on survival and clinical outcome in CAOD patients in a randomized prospective study. Kidney Int 2003;64: 649–656. Eknoyan G, Beck G, Cheung A, Daugirdas J, Greene T, Kusek J, et al: Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 2002;347:2010–2019. Fenton S, Schaubel D, Desmeules M, Morrison HI, Mao Y, Copleston P, Jeffery J, Kjellstrand C: Hemodialysis versus peritoneal dialysis: a comparison of adjusted mortality rates. Am J Kidney Dis 1997;30:334–342. Leypoldt J, Burkart J: Small-solute and middle-molecule clearances during continuous flow peritoneal dialysis; in Khanna R (ed): Advances in Peritoneal Dialysis, Peritoneal Dialysis Publications, pp 26–31.

Joanne M. Bargman, MD, FRCPC University Health Network and University of Toronto 200 Elizabeth Street, 8N-840 Toronto, Ontario M5G 2C4 (Canada) Tel. ⫹1 416 340 4804, Fax ⫹1 416 340 4999, E-Mail [email protected]

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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 326–335

A New Home Based Bioimpedance System for PD Roberto Dell’Aquilaa, Maria Pia Rodighieroa, Pierluigi Di Loretoa, Emilia Spanòa, Sandra Brendolana, Carlo Crepaldia, Federico Nalessoa, Valentina Corradia, Massimo De Cala, Paolo Braganòb, Claudio Roncoa a

Department of Nephrology, Dialysis and Transplantation, St. Bortolo Hospital, Vicenza, bMedical Science Department, Estor S.p.A, Pero, Italy

Abstract Fluid overload and uncontrolled hypertension may be considered important mortality risk factors in peritoneal dialysis (PD) population. Even malnutrition is highly prevalent in PD patients. It is now well established that lower levels of serum markers of nutrition such as albumin, creatinine, and prealbumin are associated with increased mortality in PD patients [Fein, P.A. et al: Adv Perit Dial 2002;18:195–199]. Moreover cardiovascular disease is a leading cause of death in patients with end-stage renal disease, and hypertension and volume expansion are highly prevalent in long-term PD patients. Many studies in hemodialysis and in PD have demonstrated that phase sensitive bioelectrical impedance analysis is a widely used and proven method for evaluating patient’s body composition. The vectorial bioimpedance analysis is a validated system to evaluate the hydration and nutritional state of hemodialysis and PD patients with acceptable sensitivity and specificity. The aim of this study is to evaluate the reliability and accuracy of the new multifrequency BodyComp® bioimpedance analyzer as a home based tool versus traditional Bia Vector®. Copyright © 2006 S. Karger AG, Basel

Cardiovascular disease is a leading cause of death in patients with endstage renal disease [2], and hypertension and volume expansion [3, 4], highly prevalent in long-term peritoneal dialysis (PD) patients, may be considered the principal determinants. Wang et al. [5] demonstrated that fluid overload is the major determinant of uncontrolled hypertension (fig. 1); also malnutrition may be considered an important mortality risk factors in a PD population [1]. Bioelectrical impedance analysis (BIA) is a widely used and proven method for evaluating patient’s body composition [6–15].

16 15

Males ⫽ Females

14

nECW (l/m)

13 12 11 10 9 8 7 6 Normotension

Controlled hypertension

Uncontrolled hypertension

Healthy controls

Fig. 1. Volume status (nECW) in male and female CAPD patients and in healthy controls. Modified from [5].

BIA is a relatively inexpensive, easy to use, safe, non-invasive method to evaluate the body composition specific for the assessment of soft tissue hydration. Body impedance is generated as the opposition to the flow of an injected alternating current and is measured from skin electrodes positioned on hand and foot. Impedance Z, is represented by a complex number i.e. a combination of resistance R, the opposition to the flow of the injected current at any current frequency trough intra and extra-cellular ionic solutions, and reactance Xc, the capacitive component of cell membranes and tissue interfaces. The arc tangent of the proportion of between the two components is called phase angle. The vectorial bioimpedance analysis (BiaVector) is a validated system able to interpret the measured single components of impedance vector Z at 50 kHz, and to represent them in a probabilistic graph (fig. 2) of vector BIA, i.e. a stand alone method of body composition analysis, where the continuous, bivariate, vector of impedance is evaluated trough an ordinal scale of deviation from a reference population. Correct hydration and nutritional state of patients are detected with acceptable sensibility and specificity. Because of its cost, this technology is not available to everyone and furthermore the patient needs the operator aid to take the measure. The aim of this

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Deh

ath le

te

ydra

lar

⫺3

Mu

s cu

95% 75%

⫺1

0

Obe

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50%

⫺2 Lea n

Xc/H (Ohm/m)

tion

che ctic

⫹2

Ca

⫹1

⫹3

Ana

sarc

a

R/H (Ohm/m)

Fig. 2. RXc graph of vector BIA.

study is to assess the possibility to follow the hydration state at home with impedance analyser specifically designed for a personal use. The personal impedance analyzer (PIA) (fig. 3) is a multiple frequency device that measures upper body impedance simply holding the device in the hands. In fact, it seems reasonable to let the patient able to make an impedance measure by himself to monitor his hydration state. This solution is very useful in patients on CAPD treatment. By using this device the medical staff can monitor the hydration state of the patient taking measure by BIA and, at same time with the PIA instrument: this allows to evaluate the correct hydration state of the patient but, above all, the presence of luid overload. In this case, the clinician detects an impedance value with the PIA instrument that corresponds to a BIA value. He could furthermore establish a threshold value of PIA impedance that the patient, after his dismissing from the hospital, should not trespass. It is important to evaluate if there is a correlation between the two different instruments.

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Fig. 3. PIA instrument BODYCOMP MF (Akern, Florence).

If this correlation exists, PIA could become a new method for monitoring hydration state of patients after dismission by the hospital. Aim of this study is to assess the reliability and accuracy of PIA as a home based method compared to BIA.

Patient and Methods We carried out a 2 months study on 20 CAPD selected patients (12 males, mean age 53 ⫾ 16 years, and 8 females, mean age 51 ⫾ 17 years); all patients were undergoing CAPD for at least 6 months; no diabetic patients were enrolled in the study and no episodes of peritonitis occurred during the study period. All the patients were measured by validated phase sensitive 50 KHz BIA analyzer (BIA 101, Akern). Hand to hand PIA assessment concurrently was taken (BodyComp®, Akern). Such device is a multiple frequency instrument sensing the impedance modulus at 5, 50 and 100 KHz. The correspondence between the impedance module obtained by BIA and the impedance module obtained at 50 KHz by the personal device was evaluated. Furthermore it is reasonable to assume the reactance to be a strong hydration indicator. Formers studies indicate that reactance is a sensible index of hydration changes (fig. 4). Therefore it appears possible to demonstrate a correlation between the reactance measured by BIA and a computed reactance obtained by PIA instrument. In practical terms it is realistic to assume that the low Z frequency to high Z frequency, relationship measured by the PIA instrument, correlates with the reactance measured by conventional phase sensitive BIA.

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60

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95% D

75% Xc/H (Ohm/m)

40

30

B

20 C A

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0 100

200

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500

R/H (Ohm/m)

Fig. 4. Hydration state variation of a patient in the RXc graph.

Results

The first step has been to evaluate on all patients the agreement between the impedance module obtained by both devices at 50 kHz. In spite of the fact that two different body regions are measured, since conventional BIA is appraising the right ipsilateral side of the body in a recumbent position, and the PIA is measuring the upper half body in a standing position, a linear correlation between BIA impedance and PIA impedance was observed (fig. 5). On each patient, the correlation between the measures of the two instruments appears very strong (fig. 7, table 1). Afterwards, for each patient was found a correlation factor between the impedances found with the two instruments. The correlation between BIA and PIA values of the measures on all patients becomes stronger if a personal scale factor is found for each patient (fig. 6). On individual, basis strong correlation between the impedance modulus obtained with the two instruments was found (table 1, figs. 6, 7). The individual correlation factor between BIA and PIA was obtained. Absolute values are different, but relative variations are consistent within the two methods.

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800

Z BIA/Z PIA

Ohm

600

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200 200

300

400

500

600

700

800

Ohm

Fig. 5. Correlation diagram between BIA impedance and PIA one on all patients.

Z BIA/Z PIA

800

Ohm

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Ohm

Fig. 6. Dispersion diagram between BIA impedance and PIA impedance scaled for each patient.

750

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Ohm

700 650 600 550 500 500

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Ohm

Fig. 7. Correlation curve of impedances on patient #1.

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Table 1. Example of values obtained by means BIA and PIA method on 1 patient Patient #1

BIA impedance

PIA impedance

Measure 1 Measure 2 Measure 3 Measure 4 Measure 5

630 687 625 701 605

571 661 606 696 554

Impedance correlation factor r ⫽ 0.96418, p ⫽ 0.033.

Table 2. Reactance measured by BIA and calculated reactance by PIA on patient #1 Patient #1

BIA reactance

PIA reactance

Measure 1 Measure 2 Measure 3 Measure 4 Measure 5

50 70 56 78 57

47 55 46 62 39

Ohm

Reactance correlation factor r ⫽ 0.854212, p ⫽ 0.01.

Xc/ZL-ZH

120 100 80 60 40 20 0 0

20

40

60

80

100

Ohm

Fig. 8. Dispersion diagram of reactance measured by BIA and reactance calculated by means impedances PIA.

On individual, a strong correlation between the reactance measured by BIA and the calculated one by PIA was found (table 2, figs. 8, 9). Discussion

Malnutrition is highly prevalent in PD patients and is associated with higher mortality and lower serum levels of markers of nutrition such as

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Xc/ZL-ZH

80 Ohm

60 40 20 0 0

20

40

60

80

100

Ohm

Fig. 9. Dispersion diagram of reactance by BIA and calculated one by PIA on patient #1.

albumin, creatinine, prealbumin, and total cholesterol is important risk factors in PD patients. Fein et al. [1] demonstrated that reactance was directly correlated with albumin and total protein. Capacitance was directly correlated with body mass index, albumin and blood urea nitrogen and inversely correlated with body weight. Phase angle was directly correlated with all of the biochemical markers of nutrition, such as albumin, total protein, creatinine and blood urea nitrogen. The BIA indices reflect nutrition status in PD patients, and may be useful in monitoring nutrition interventions. Several reports in the literature used BIA to analyze body composition in evaluating the nutrition status of dialysis patients [16–18]. Passadakis et al. [19] reported that BIA phase angle seems to be a simple method for the routine assessment of nutrition status in CAPD patients. Ikizler et al. [20] showed that reactance values by BIA are a reliable indicator of hospitalization in HD patients. Chertow et al. [21, 22] reported that body cell mass and total body water derived from BIA were in excellent agreement with those determined by dual energy X-ray absorptiometry. Recently Wang et al. demonstrated that PD patients with uncontrolled hypertension are more volume overloaded (fig. 1) and their blood pressure may be difficult to control by antihypertensive therapy alone; long-term volume expansion will lead to the structural remodelling of arterial system which is characterized by diffuse dilation, hypertrophy and stiffing of the aorta and major arteries. These changes may in turn increase the volume sensitivity of blood pressure and enhance the difficulties in blood pressure control. These findings indicate that volume control should be intensified in hypertensive CAPD patients, being overhydration an important factor in the pathogenesis of hypertension in dialysis patients. Furthermore Gotloib et al. [23] focuses on the use of PD applied to congestive heart failure (CHF) patients [New York Heart Association (NYHA), class IV] with or without renal impairment with clinical functional improvement. Author demonstrated that after 1 year of follow-up, all patients showed haemodynamic improvement: significant

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improvement of left cardiac work index, lower thoracic fluid contents as well as a regression from NYHA class IV to class I. Need for hospitalization for CHF decreased from 157 to 13 days. They concluded that PD appears to be a promising therapeutic tool for patients affected by refractory CHF. Many other authors have published about the use of PD as a continuous peritoneal ultrafiltration in the treatment of CHF [24–27]. All these situations such as malnutrition, hypertension, overhydration and CHF have the same lowest common denominator: the management and monitoring of body composition with particular regard to fluid status. PIA appears adequate to self assess fluid changes. The use of a validated home based hand-held device affordable, easy to use could be a fundamental tool in self controlling fluid balance: clinician could find a reference threshold value of impedance or reactance that the patient should not trespass after his dismission by the hospital; this gives the medical staff a further chance to strictly control critical PD patients but at the same time give the steady patient the possibility to be remotely controlled by physicians, saving time and improving quality of life: for all dialysis patients to improve long-term survival. It’s also reasonable to think that in the future the patient could dispose of a reactance personal analyzer able to measure only the reactance component.

References 1

2 3

4

5 6 7 8 9 10

Fein PA, Gundumalla G, Jorden A, Matza B, Chattopadhyay J, Avram MM: Usefulness of a bioelectrical impedance analysis in monitoring nutrition status and survival of peritoneal dialysis patients. Adv Perit Dial 2002;18:195–199. Khandelwal M, Oreoppoulos DG: Is there a need for low sodium dialysis solution for peritoneal dialysis patients? Adv Perit Dial 2004;20:156–162. Koc M, Toprak A, Tezcan H, Bihorac A, Akoglu E, Ozener IC: Uncontrolled hypertension due to volume overload contributes to higher left ventricular mass index in CAPD patients. Nephrol Dial Transplant 2002;17:1661–1666. Wong PN, Mak SK, Lo KY, Tong GMW, Wong AKM: Factors associated with poorly-controlled hypertension in continuous ambulatory peritoneal dialysis patients. Singapore Med J 2004;45: 520–524. Wang X, Axelsson J, Lindholm B, Wang T: Volume status and blood pressure in continuous ambulatory peritoneal dialysis patients. Blood Purif 2005;23:373–378. Piccoli A, Rossi B, Pillon I, Bucciante G: A new method for monitoring body fluid variation by bioimpedance analysis: the RXc graph. Kidney Int 1994;46:534–539. Piccoli A, Negrelli S, Caberlotto A: Bivariate normal values of the bioelectrical impedance vector in adult and elderly populations. Am J Clin Nutrit 1995;61:269–270. Lukaski H, Bolonchuk W, Hall CB, Siders W: Validation of tetrapolar bioelectrical impedance method to assess human body composition. J Appl Phys 1986;60:1327–1332. Segal KR, Van Loan M, Fitzgerald P, Hodgdn JA, Van Itallie TB: Lean body mass estimation by bioelectrical impedance analysis: four site cross-validation study. Am J Clin Nutr 1988;47:7–14. Lichtenbelt W, Westerterp K, Wouters L, Luijendijk S: Validation of bioelectrical impedance measurements as a method to estimate body water compartments. Am J Clin Nutr 1994;60:159–166.

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Brown B, Karatzas T, Nakielny R, Clarke R: Determination of upper arm muscle and fat areas using electrical impedance measurements. Clin Phys Physiology 1988;9:47–55. Stall S, Ginsberg N, DeVita M, Zabetakis P, Lynn R, Gleim G, Wang J, Pierson R, Michelis M: Comparison of five body composition methods in peritoneal dialysis patients. Am J Clin Nutr 1996;64:125–130. Piccoli A: Body fluid overload and bioelectrical impedance analysis in renal patients. Miner Electrolyte Metab 1996;22:76–78. Maggiore Q: Non invasive monitoring of hemodynamic parameters during hemodialysis. Int J Artif Organs 1995;18:499–503. Edefonti A, Carcano A, Damiani B, Ghio L, Consalvo G, Picca M: Changes in body composition assessed by bioimpedance analysis in the first six months of chronic peritoneal dialysis. Adv Perit Dial 1997;13:267–270. Kushner RF, de Vries PM, Gudivaka R: Use of bioelectrical impedance analysis measurements in the clinical management of patients undergoing dialysis. Am J Clin Nutr 1996;64:S503–S509. Oe B, de Fijter CW, Oe PL, Stevens P, de Vries PM: Four-site skinfold anthropometry (FSA) versus body impedance analysis (BIA) in assessing nutritional status of patients on maintenance hemodialysis: which method is to be preferred in routine patient care? Clin Nephrol 1998;49: 180–185. Dumler F: Use of bioelectric impedance analysis and dual-energy X-ray absorptiometry for monitoring the nutritional status of dialysis patients. ASAIO J 1997;43:256–260. Passadakis P, Sud K, Dutta A, et al: Bioelectrical impedance analysis in the evaluation of the nutritional status of continuous ambulatory peritoneal dialysis patients. Adv Perit Dial 1999;15: 147–152. Ikizler TA, Wingard RL, Harvell J, Shyr Y, Hakim RM: Association of morbidity with markers of nutrition and inflammation in chronic hemodialysis patients: a prospective study. Kidney Int 1999;55:1945–1951. Chertow GM, Lowrie EG, Wilmore DW, et al: Nutritional assessment with bioelectrical impedance analysis in maintenance hemodialysis patients. J Am Soc Nephrol 1995;6:75–81. Chertow GM, Lazarus JM, Lew NL, Ma L, Lowrie EG: Development of a population-specific regression equation to estimate total body water in hemodialysis patients. Kidney Int 1997;51: 1578–1582. Gotloib L, Fudin R, Yakubovich M, Vienken J: Peritoneal dialysis in refractory end-stage congestive heart failure: a challenge facing a no-win situation. Nephrol Dial Transplant 2005;20: vii32–vii36. Elhalel-Dranitzki M, Rubinger D, Moscovici A, Haviv YS, Friedlaender MM, Silver J, Popovtzer MM: CAPD to improve quality of life in patients with refractory heart failure. Nephrol Dial Transplant 1998;13:3041–3042. Stegmayr BG, Banga R, Lundberg L, Wikdahl AM, Plum-Wirell M: PD treatment for severe congestive heart failure. Perit Dial Int 1996;16:S231–S235. Ryckelynck JP, Lobbedez T, Valette B, Le Goff C, Mazouz O, Levaltier B, Potier JC, Hurault de Ligny B: Peritoneal ultrafiltration and treatment-resistant heart failure. Nephrol Dial Transplant 1998;13:56–59. Mehrotra R, Khanna R: Peritoneal ultrafiltration for chronic congestive heart failure: rationale, evidence and future. Cardiology 2001;96:177–182.

Roberto Dell’Aquila, MD Department of Nephrology, Dialysis and Transplantation St. Bortolo Hospital IT–36100 Vicenza (Italy) Tel. ⫹39 0444 753650, Fax ⫹39 0444 753949, E-Mail [email protected]

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The Potential Application of Sorbents in Peritoneal Dialysis James F. Winchestera, Richard Amerlinga, Nicolas Harborda, Vincent Capponib, Claudio Roncoc a

Beth Israel Medical Center, New York, N.Y., bMedaSorb Technologies, Inc., Monmouth Junction, N.J., USA; cDepartment of Nephrology, San Bortolo Hospital, Vicenza, Italy

Abstract Sorbents have been designed to remove small and middle molecular weight toxins, including low molecular weight proteins, peptides, cytokines and chemokines in patients undergoing renal replacement therapy. Sorbents assist the process of peritoneal dialysate regeneration and have the potential to improve the efficiency of continuous flow peritoneal dialysis. Copyright © 2006 S. Karger AG, Basel

In the ADEMEX study [1] the demonstration of lack of difference in survival between the two groups with clearly separated peritoneal dialysis prescriptions for small molecule removal, has resulted in a reassessment of the importance of middle molecules and low molecular weight proteins (LMWP) in peritoneal dialysis. Techniques to improve the efficiency [2, 3] of continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have led to continuous flow peritoneal dialysis [4]. Sorbents in line with improved dialysis catheters [5, 6], have the potential to reduce the cost of dialysis fluid-by-fluid regeneration, and to remove toxic products, offer the major prospect of increasing the efficiency of peritoneal dialysis. Uremia is mediated by the retention of nitrogenous products and other molecules with significantly different properties. While the nitrogenous metabolites are relatively homogenous, the others are very heterogeneous, with respect to MW and other characteristics, such as protein binding and hydrophobicity. The European Uremic Toxin (EUTox) Work Group subdivided the

remainder of molecules into two categories: protein-bound solutes and middle molecules [7]. The uremic toxins which are highly protein bound, include p-cresol [7], homocysteine [8], advanced glycation end-products [9], and hippuric acid [10]; these are poorly removed by all dialytic approaches but may be amenable to sorbent removal. EUTox proposes that middle molecules have a MW range of 500–60,000 Da, a classification that includes many toxins identified since the original middle molecule hypothesis [11] (upper MW limit 2,000 Da). Low-molecular weight proteins and peptides (LMWPs) make up almost all of these toxins. LMWPs that have been identified as putative uremic toxins [12], include ␤2-microglobulin (␤2M) [13], certain advanced glycation end-products [14, 15], adrenomedullin [16], leptin [17, 18], complement proteins [19], and pro-inflammatory cytokines [20, 21]. Recently the free adducts of advanced glycation end-products have been shown to be removed by peritoneal dialysis [22].

Activated Carbon

Hemoperfusion in uremia has utilized activated carbons, ion-exchange resins or non-ionic macroporous resins [23, 24]. For all sorbents adsorptive capacity is enhanced by inducing a high surface porosity and large surface area. Non-polar solutes are better adsorbed from aqueous solution than are polar solutes. With traditional uncoated carbon, small toxins (creatinine, uric acid, hippuran, and vitamin B12) are removed. Theoretically, modern carbon sorbents are capable of removing middle molecular weight toxins. Biologically important small solutes may be adsorbed onto carbon (glucose, calcium, amino acids, vitamin D, and hormones), as has been demonstrated in hemoperfusion [25, 26].

Novel Sorbents

Several novel sorbents have been used in the treatment of renal disease. Most have been used in blood contacting devices [27, 28], and some have been used in plasma contacting devices [29]. All are capable of removing toxic LMWPs. It is possible to create resin beads with a large adsorptive surface area [30]. Such a resin (BetaSorb™, MedaSorb Technologies) has a pore size distribution capable of removing molecules from 8–30 kDa, such as ␤2-microglobulin, leptin, IL-6, IL-18, angiogenin and others (table 1).

Potential Application of Sorbents in Peritoneal Dialysis

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Table 1. Clinical and experimental sorbents Sorbent

Manufacturer

Solute removed

Direct blood contact

Approved and investigated uses

Enteral sorbents Renagel (sevelamer)

Genzyme

Phosphorous

No

Uremic toxins

No

Bile acids Bile acids

No No

Chronic kidney disease Chronic kidney disease progression Dyslipidemia Dyslipidemia

Small MW solutes

Yes

HemoCleanse

Small MW solutes

Yes

HemoCleanse

Unbound (DT) Yes and bound (PF); bilirubin, creatinine Small MW solutes No

Kremezin Kureha, Japan (AST-120) Ocera, USA (charcoal) Colestid (colestipol) Pharmacia Questran (cholestyramine) Bristol-Myers squibb Kayexelate Activated carbon Charcoal Liver dialysis system/unit HemoCleanse (charcoal and cation exchanger) 1st generation PF-liver dialysis (powdered sorbent around plasmafilters) BioLogic-DT/PF (charcoal ⫾ silica) 2nd generation MARS (charcoal and cation exchanger clear albumin dialysate) Hemosorba Adsorba (charcoal with cellulose coating) PlasmaFlo Hemokart, Alukatt-Adult Resins Ion-exchange resins Kayexelate (Sodium polstyrene sulfonate) (cation exchange resin)

Gambro

Drug overdose (acetaminophen, TCA’s), Hepatic coma and encephalopathy Drug overdose, Hepatic coma and encephalopathy SIRS, sepsis

Drug overdose, Hepatic coma and encephalopathy

Asahi Medical

Yes

Gambro

Yes

Asahi Medical National Medical Care, NJ

Yes Yes

Drug overdose Drug overdose, aluminum

No

Hyperkalemia

Potassium, lithium

Winchester/Amerling/Harbord/Capponi/Ronco

Porphyria, paraquat, drug overdose Drug overdose

338

Table 1. (continued) Sorbent

AmSorb (not yet available) Resins Nonionic/macroporous resins Prometheus (combined anion exchange and neutral BetaSorb (divinylbenzene) (not yet available) Styrosorb Alizarin, Albumin-MPHEMA (not yet available) Amberlite XAD-7 Acrylic ester (not yet available) Selecta plus Immunosorbents Lixelle Type S-15 and S-35 (cellulose beads ⫹ hydrophobic hexadecyl alkyl chain) Immusorba TR (polyvinyl alcohol gel immobilized with tryptophan) Immusorba pH (polyvinyl alcohol gel immobilized with phenylalanine) Prosorba (silica and protein A) CF-X (not yet available) Ig-Therasorb Medisorba MG Selesorb Miro

Manufacturer

Solute removed

HemoCleanse

Ammonium

Fresenius

Bilirubin, cholic acid, tryptophan

MedaSorb

‘Middle-molecules,’ e.g. BMG

Direct blood contact

Approved and investigated uses Uremia, liver failure

No (albumin circuit) Yes

Hepatic coma & encephalopathy

Russian ‘Middle-molecules’ Hacettepe University, Turkey

No

Aluminum, Bilirubin

Rohm and Haas

TNF-␣, IL-6

Yes

Arsenic

Bellco

BMG

Yes

Uremia

Kaneka

BMG, IL-1b, IL-6, LPS, ET

Yes

Dialysis-related amyloidosis, SIRS

Asahi

Antibodies

No

Myasthenia gravis Guillain-Barre

Asahi

Antibodies

No

GBS, MS, RA, SLE

Fresenius Ube Industries

IgG, and IgG complexes Cytokines

No (upstream RA cell separator) No

Baxter Kuraray Kaneka Fresenius

Antibodies Antibodies Antibodies Antibodies

No No No No

Potential Application of Sorbents in Peritoneal Dialysis

Xenotransplant Myasthenia gravis Lupus C1q antibodies

339

Post-peritoneal sorbent (dialysate regeneration) Dialysate heater and reservoir

Pump or gravity

Pre-peritoneal sorbent cartridge (removal of glucose degradation products)

Peritoneal cavity

Fig. 1. Schema of sorbent assisted peritoneal dialysis

Dialysate Regeneration

Hydrophobic solutes are removed by carbon and non-ionic macroporous resins, while adsorption through chemical affinity requires ion exchange resins and chemisorbents [31, 32]. A combination of zirconium, charcoal and urease, have been used to regenerate dialysate [33, 34]. Since charcoal and other sorbents have no capacity for water, acid moieties and urea, they must be used in combination with other techniques such as hemodialysis, hemofiltration, peritoneal dialysis, and hemodiafiltration.

Peritoneal Dialysis

The resin can be placed in line in a device designed for flow-through or continuous flow peritoneal dialysis (fig. 1). Most likely is the application of sorbents in a continuous flow peritoneal dialysis system. Sorbents offer singularly unique attributes for enhancing peritoneal dialysis as they do in hemodialysis. In addition they can be designed to remove toxic glucose degradation products and aldehydes from heat sterilized dialysis fluid [35]. Sorbents have been investigated for their role in enhancing solute removal [36, 37]. Recently this has been applied to peritoneal dialysis with large increments in urea and creatinine clearances. Sorbents offer the theoretical advantage of increasing ultrafiltration, and the removal of protein-bound metabolic toxins [38].

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340

Conclusions

To improve the efficiency of APD and in particular, continuous flow through peritoneal dialysis, sorbents offer a practical and inexpensive approach. Sorbent devices of sufficient capacity to adsorb molecules in the range 8–20 kDa may be a welcome addition to the peritoneal dialysis regimen. Nonspecific sorbents, with a wide range of LMWP removal, are desirable in removing toxins which are poorly or inefficiently mobilized by peritoneal dialysis alone.

References 1

2

3 4 5 6

7

8

9

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Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, Mujais S, Mexican Nephrology Collaborative Study Group: Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 2002;13:1307–1320. Amerling R, DeSimone L, Inciong-Reyes R, Pangilinan A, Folden T, Ronco C, Gotch FA, Levin N: Clinical experience with continuous flow and flow-through peritoneal dialysis. Semin Dial 2001;14:388–390. Amerling R, Glezerman I, Savransky E, Dubrow A, Ronco C: Continuous flow peritoneal dialysis: current perspectives. Contrib Nephrol 2003;140:294–304. Dell’Aquila R, Rodighiero MP, Bordoni V, D’Intini V, Ronco C: APD prescription: achieving the adequacy goals. Semin Dial 2002;15:397–402. Diaz-Buxo JA: Streaming, mixing, and recirculation: role of the peritoneal access in continuous flow peritoneal dialysis (clinical considerations). Adv Perit Dial 2002;18:87–90. Ash SR, Sutton JM, Mankus RA, Rossman J, de Ridder V, Nassvi MS, Ross J: Clinical trials of the T-fluted (Ash Advantage) peritoneal dialysis catheter. Adv Ren Replace Ther 2002;9: 133–143. Vanholder R, De Smet R, Glorieux G, et al, for the European Uremic Toxin Work Group: Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 2003;63:1934–1943. Bostom AG, Shemin D, Lapane KL, et al: Hyperhomocysteinemia and traditional cardiovascular risk factors in end-stage renal disease patients on dialysis: a case-control study. Atherosclerosis 1995;114:93–103. Henle T, Deppisch RM, Beck W, et al: Advanced glycation end-products during haemodialysis treatment: discrepant results with different methodologies reflecting the heterogeneity of AGE compounds. Nephrol Dial Transplant 1999;14:1968–1975. Farrell PC, Gotch FA, Peters JH, et al: Binding of hippurate in normal plasma and in uremic plasma pre- and postdialysis. Nephron 1978;20:40–46. Babb AL, Ahmad S, Bergström J, Scribner BH: The middle molecule hypothesis in perspective. Am J Kidney Dis 1981;1:46–50. Clark WR, Gao D: Low-molecular weight proteins in end-stage renal disease: potential toxicity and dialytic removal mechanisms. J Am Soc Nephrol 2002;13:S41–S47. Gejyo F, Yamada T, Odani S, Nakagawa Y, Arakawa M, Kunitumo T, Kataoka H, Suzuki M, Hirasawa Y, Shirahama T, Cohen A, Schmid K: A new form of amyloid protein associated with chronic hemodialysis was identified as beta2-microglobulin. Biochem Biophys Res Commun 1985;129:701–706. Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman AM, Korbet SM, Barth RH, Winston JA, Fuh H, Manogue KR, Cerami A, Vlassara H: Reactive glycosylation endproducts in diabetic uremia and treatment of renal failure. Lancet 1994;343:1519–1522.

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Bohlender JM, Franke S, Stein G, Wolf G: Advanced glycation end products and the kidney. Am J Physiol Renal Physiol 2005;289:F645–F659. Ishimitsu T, Nishikimi T, Saito Y, et al: Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure. J Clin Invest 1994;94: 2158–2161. Sharma K, Considine RV, Michael B, et al: Plasma leptin is partly cleared by the kidney and is elevated in hemodialysis patients. Kidney Int 1997;51:1980–1985. Matsubara K, Kiyomoto H, Moriwaki K, Hara T, Kondo N, Shokoji T, Hitomi H, Aki Y, Aono M, Nishiyama A, Ohmori K, Kohno M: Leptin kinetics during peritoneal dialysis in acutely uraemic rats. Nephrology 2004;9:256–261. Deppisch RM, Beck W, Goehl H, Ritz E: Complement components as uremic toxins and their potential role as mediators of microinflammation. Kidney Int 2001;78(suppl):S308–S314. Pereira BJ, Shapiro L, King AJ, et al: Plasma levels of IL-1p, TNF, and their specific inhibitors in undialyzed chronic renal failure, CAPD, and hemodialyzed patients. Kidney Int 1994;45: 890–896. Kaizu Y, Kimura M, Yoneyama T, et al: Interleukin-6 may mediate malnutrition in chronic hemodialysis patients. Am J Kidney Dis 1998;31:93–100. Agalou S, Ahmed N, Thornalley PJ, Dawnay A: Advanced glycation end product free adducts are cleared by dialysis. Ann N Y Acad Sci 2005;1043:734–739. Winchester JF: Hemoperfusion; in Horl W, Koch KM, Lindsay RM, Ronco C, Winchester JF (Editor in Chief) (eds): Replacement of Renal Function by Dialysis, ed 5. Dordrecht, Kluwer Academic Publishers, 2004, pp 725–738. Mikhalovsky SV: The detoxication with bioselective carbon sorbents. Biomater Artif Cells Artif Organs 1989;17:157–160. Winchester JF, Ratcliffe JG, Carlyle E, Kennedy AC: Solute, amino acid, and hormone changes with coated charcoal hemoperfusion in uremia. Kidney Int 1978;14:74–81. Kokot F, Pietrek J, Seredynski M: Influence of haemoperfusion on plasma levels of hormones and B-methyldigoxin. Proc Eur Dial Transplant Assoc 1978;15:604. Winchester JF, Silberzweig J, Ronco C, Kuntsevich V, Levine D, Parker T, Kellum JA, Salsberg JA, Quartararo P, Levin NW: Sorbents in acute renal failure and end stage renal disease: middle molecule and cytokine removal. Blood Purif 2004;22:73–77. Gejyo F, Kawaguchi Y, Hara S, Nakazawa R, Azuma N, Ogawa H, Koda Y, Suzuki M, Kaneda H, Kishimoto H, Oda M, Ei K, Miyazaki R, Maruyama H, Arakawa M, Hara M: Arresting dialysisrelated amyloidosis: a prospective multicenter controlled trial of direct hemoperfusion with a beta2-microglobulin adsorption column. Artif Organs 2004;28:371–380. Bellomo R, Tetta C, Ronco C: Coupled plasma filtration adsorption. Intensive Care Med 2003;29: 1222–1228. Davankov V, Pavlova L, Tsyurupa M, Brady J, Balsamo M, Yousha E: Polymeric adsorbent for removing toxic proteins from blood of patients with kidney failure. J Chromatogr Biomed Sci Appl 2000;739:73–80. Ash SR, Baker K, Blake DE, Carr DJ, Echard TG, Sweeney KD, Handt AE, Wimberly AL: Clinical trials of the BioLogic-HD. Automated single access, sorbent-based dialysis. ASAIO Trans 1987;33:524–531. Patzer JF 2nd, Yao SJ, Wolfson SK Jr: Zeolitic ammonium ion exchange for portable hemodialysis dialysate regeneration. ASAIO J 1995;41:221–226. Gordon A, Maxwell MH, Lewin AJ: Sorbent regeneration of peritoneal dialysate: an approach to ambulatory dialysis. J Dial 1976–77;1:145–164. Ash SR: The allient dialysis system. Semin Dial 2004;17:164–166. Ishikawa N, Miyata T, Ueda Y, Inagi R, Izuhara Y, Yuzawa H, Onogi H, Nishina M, Nangaku M, Van Ypersele De Strihou C, Kurokawa K: Affinity adsorption of glucose degradation products improves the biocompatibility of conventional peritoneal dialysis fluid. Kidney Int 2003;63: 331–339. Lang HL, Nolph KD, McGary TJ: Enhancement of clearances by activated charcoal in an in vitro model of peritoneal dialysis. Clin Exp Dial Apheresis 1982;6:85–95.

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37

38

Blumenkrantz MJ, Lewin AJ, Gordon A, Roberts M, Pecker EA, Coburn JW, Maxwell MH: Development of a sorbent peritoneal dialysate regeneration system – a progress report. Proc Eur Dial Transplant Assoc 1978;15:213–219. Roberts M, Ash SR, Lee DB: Innovative peritoneal dialysis: flow-thru and dialysate regeneration. ASAIO J 1999;45:372–378.

James F. Winchester Beth Israel Medical Center 350 East 17th Street, 18BH20 New York, NY 10003 (USA) Tel. ⫹1 212 420 4070, Fax ⫹1 212 420 4117 E-Mail [email protected]

Potential Application of Sorbents in Peritoneal Dialysis

343

Author Index

Amerling, R. 291, 310, 336 Avesani, C.M. 144, 166 Axelsson, J. 144, 166

Finkelstein, S.H. 235 Flessner, M.F. 28, 156, 174 Fudin, R. 247

Bargman, J.M. 321 Bossini, N. 259 Braganò, P. 326 Brancaccio, D. 214 Brendolan, S. 326

Gallieni, M. 214 Garosi, G. 62 Gotloib, L. 54, 247

Cancarini, G.C. 259 Cappelletti, F. 62 Capponi, V. 336 Carrero, J.J. 144, 166 Cassamali, S. 259 Chiarelli, G. 214 Cnossen, N. 111 Corradi, V. 326 Cozzolino, M. 214 Crepaldi, C. 326 Davies, S.J. 271 De Cal, M. 326 Dell’Aquila, R. XI, 226, 291, 326 De Vriese, A. 70, 84 Di Loreto, P. 226, 291, 326 Di Paolo, N. 62 Durand, P.-Y. 285 Finkelstein, F.O. 42, 235

Harbord, N. 336 Heimbürger, O. 97, 144, 166 Ismail, N.A. 129 John, B. 271 Jörres, A. 48 Khrizman, V. 54 Kitzler, T. 119 Konings, C.J. 111 Kooman, J.P. 111 Kotanko, P. 119 Krediet, R.T. 104 Lameire, N. 37, 70, 84, 254 Leunissen, K.M. 111 Levin, N.W. 119 Lindholm, B. 144, 166 Lo, W.-K. 90, 152

Macdougall, I.C. 202 Maiorca, P. 259 Misra, M. 20 Mortier, S. 70, 84 Mushahar, L. 271 Nalesso, F. 326 Negoi, D. 278 Nolph, K.D. 20, 135, 278 Pertica, N. 259 Piraino, B. 181 Raymond, N. 129 Rodighiero, M.P. XI, 226, 291, 326 Ronco, C. XI, 1, 226, 291, 310, 326, 336 Sandrini, S. 259 Schwenger, V. 77 Setti, G. 259 Shahab, I. 135 Shostak, A. 54 Spanò, E. 226, 326 Stenvinkel, P. 144, 166 Teitelbaum, I. 187, 240 Thijssen, S. 119

344

Tobe, S.W. 129 Troidle, L.K. 235 Twardowski, Z.J. 13, 195

van der Sande, F.M. 111 Van Der Tol, A. 37 Vanholder, R. 37, 254 Veys, N. 37, 254

Van Biesen, W. 37, 70, 84, 254

Wajsbrot, V. 54 Winchester, J.F. 336

Author Index

Witowski, J. 48 Wystrychowski, G. 119 Zhu, F. 119

345

Subject Index

Acidosis, see Metabolic acidosis Activated carbon, sorbents 337 Adipokines adipose tissue and systemic inflammation 169 functions 167–169 prospects for study in renal patients 171 Adiponectin, functions 168 Advanced glycation end products (AGE) animal models of peritoneal dialysis 72, 73 formation 78, 79, 91 malnutrition-inflammation-atherosclerosis syndrome prevention 140 peritoneal dialysis accumulation 49–51, 77 receptor, see RAGE Albumin, serum levels and mortality risks 152, 153 Anemia etiology 205 prevalence in peritoneal dialysis 202 treatment dialysis adequacy 206 erythropoiesis-stimulating therapy administration route 208, 211 darbepoetin alfa 207, 208 epoetin alpha 207, 208 epoetin beta 207, 208 expected response 208 poor response 209, 210 initiation 203

iron replacement 206, 207 nutrition 206 peritonitis patients 210, 211 target hemoglobin concentration 203–205 Angiogenesis, see Vascular endothelial growth factor Angiotensin II, peritoneal dialysis induction and fibrosis 74 Angiotensin-converting enzyme (ACE) inhibitors malnutrition-inflammation-atherosclerosis syndrome prevention 141 mesothelial cell effects 163 renal function preservation after failed kidney transplant 275 Antibiotics malnutrition-inflammation-atherosclerosis syndrome prevention 141, 142 peritonitis management 183 Aquaporin-1, peritoneum 33, 34, 98, 99 Atherosclerosis, see Malnutritioninflammation-atherosclerosis syndrome; Vascular calcification Automated peritoneal dialysis (APD) adequacy targets 281, 282, 285, 286 cyclers Home Choice 295 Home Choice Pro 295, 296 ideal criteria 300 overview 294 PD 100T 298

346

PD 101 298 PD 200 298, 299 PD Night 296, 297 Sleep Safe 297 historical perspective 292–294 indications 279–281 modes 279, 294 popularity 278, 279 prospects biosensors 305 continuous flow 306 dialysis fluids composition 304, 305 on-line preparations 305, 306 schedules anuric patients 286 BreakPoint automated peritoneal dialysis 288, 289 computer-assisted kinetic modeling 301 drain profile management 288, 289 dwell volume prescription 287, 288, 301 total fill volume prescription 287, 300, 301 treatment monitoring 301–304 ultrafiltration 282, 283 Balance solution, clinical studies 91, 92 Beta-blockers, sclerosis risks in peritoneal dialysis 66, 67 Bioimpedance analysis, see also Multifrequency bioimpedance analysis 50-kHz bioimpedance vector analysis 123, 124 fluid volume estimation 122 hydration indicator 123 peritoneal dialysis patient studies 124–127, 332–334 principles 120, 327 single-frequency bioimpedance analysis 122 whole-body versus segmental bioimpedance analysis 120–122 Body mass index (BMI), outcome correlation in dialysis patients 170, 171 Bone morphogenetic protein-7 (BMP-7), vascular calcification prevention 216, 217

Subject Index

Calcium handling calcium balance in peritoneal dialysis 219, 220 control in peritoneal dialysis 221, 222 phosphorus balance in peritoneal dialysis 220, 221 renal osteodystrophy 218, 219 serum levels and mortality risks 214 vascular calcification impact in dialysis patients 217, 218 pathogenesis 215–217 risks 215 Cardiovascular disease, chronic kidney disease 144, 145 Catheters, see also Tenckhoff catheter continuous-flow peritoneal dialysis 313 designs 198 double-lumen catheters for continuousflow peritoneal dialysis 199 historical perspective 195–197 Cbfa-1, vascular calcification role 216 Cloudy dialysate diagnostic algorithm 192, 193 infection 187 noninfectious causes eosinophils 190 fibrin 192 malignant cells 191 monocytes 190, 191 overview 187–189 polymorphonuclear leukocytes 189, 190 red blood cells 191 triglycerides 192 Congestive heart failure comorbidity 248 epidemiology 130, 247 fluid overload 129 hemodialysis treatment 132, 249 hemofiltration therapy 249 medical management 131 mortality 248 pathophysiology 130, 131 peritoneal dialysis treatment of refractory disease 132, 133, 249–252, 333, 334 pharmacotherapy 248 stages 130

347

Continuous cycling peritoneal dialysis, see Automated peritoneal dialysis Continuous flow peritoneal dialysis (CFPD) catheter design 313 dextrose as osmotic agent 314 dialysis adequacy 311–313 monitoring 314, 315 rationale 310, 311, 317, 322–324 safety 315 scheduling 323, 324 ultrafiltration control 313, 314 urea kinetics 315, 316 Convection hemodialysis 1–3 interference with diffusion 6 C-reactive protein (CRP) cardiac event prediction 153 inflammation marker 136, 145–147 mortality prediction 153, 158 Darbepoetin alpha, see Anemia Dialysate cloudy, see Cloudy dialysate regeneration with sorbents 340 Dialysis fluids automated peritoneal dialysis composition 304, 305 on-line preparations 305, 306 bicarbonate-based solutions in bone disease treatment and prevention 222 combinations of biocompatible fluids 94, 95 glucose-containing biocompatible fluids Balance 91, 92 Gambrosol Trio 91 Physioneal 92, 93 inflammation prevention 147, 148 low glucose degradation product solutions and biocompatibility 162, 163 malnutrition-inflammation-atherosclerosis syndrome prevention 140 mesothelial cell phenotype and peritoneal dialysis response 159, 160 non-glucose-containing biocompatible fluids Extraneal 94 Nutrineal 93, 94

Subject Index

pH effects on inflammation 160 Diffusion hemodialysis 1–3 interference with convection 6 solute transfer in peritoneal dialysis 15, 16 Dry body weight assessment 105, 106 definition 105 Elderly patients prevalence of chronic peritoneal dialysis utilization 240 prospects 244, 245 underutilization of chronic peritoneal dialysis reasons compliance 241, 242 dialysis adequacy and nutrition 242, 243 hospitalization 242 infectious complications 242 manual dexterity and neuropsychiatric function 241 overview 240, 241 patient survival 243, 244 technique survival 243 Eosinophils, cloudy dialysate 190 Epoetin , see Anemia Extraneal, clinical studies 94, 140 Fetuin, vascular calcification prevention 216, 217 Fibrin, cloudy dialysate 192 Fibrosis, peritoneum angiotensin II role 74 clinical correlates and mechanisms 178 hydrostatic pressure effects on avascular matrix 179 inflammation association 176 RAGE role 73, 74, 81 sclerosis etiology and pathogenesis 66, 67 solute clearance effects 179 sub-peritoneal compact zone alterations 176–178 transforming growth factor-␤ role 73

348

Gambrosol Trio, clinical studies 91 Glitazone, malnutrition-inflammationatherosclerosis syndrome prevention 141 Glucose degradation products (GDPs) compounds 91 dialysis fluid as source 77 inflammation induction 146 mesothelial cell phenotype and peritoneal dialysis response 161 peritoneal membrane accumulation and effects 50, 51, 78, 79 Heart failure, see Congestive heart failure Hemodialysis blood compartment 4, 5 congestive heart failure management 132 convection 1–3, 6 dialysate compartment 5 diffusion 1–3, 6 kidney transplant outcome effects, see Kidney transplant membrane permeability 3, 4 peritoneal dialysis integration in uremia treatment, see Uremia solute clearance factors 2 solute diffusivity and sieving 3–5 urea kinetics modeling, see Urea kinetics Home Choice, automated peritoneal dialysis cycler 295 Home Choice PRO, automated peritoneal dialysis cycler 295, 296 Hyaluronan, peritoneal transport effects 162 Hyperphosphatemia, see Phosphate handling Icodextrin, peritoneal dialysis use metabolism 100 overview 45, 94, 97 peritoneal transport with solutions clinical studies 101 high transporter patient use 101, 102 long-term effects 102 ultrafiltration 100, 101 structure 100 Inflammation, see also Malnutritioninflammation-atherosclerosis syndrome

Subject Index

adipose tissue and systemic inflammation 169 etiology in peritoneal dialysis 145, 146, 167 genetic susceptibility 147 glucose degradation product induction 146 markers 136, 145, 153, 167 pathophysiology in peritoneal dialysis 160, 161 peritoneal dialysis failure role 156 prevention in peritoneal dialysis 147–149 Interleukin-6 (IL-6), gene polymorphisms 47, 158 Intravital microscopy, peritoneum acute effects of peritoneal dialysis fluid perfusion 86, 87 chronic dialysis fluid exposure studies 87, 88 glucose effects in diabetic rat model 86 technique 86 Iron, anemia management 206, 207 Kidney transplant failure rate 271, 272 patient selection for renal replacement therapy mode 261 peritoneal dialysis after failed transplant hemodialysis comparison 272, 273 immunosuppressive therapy 274, 275 recommendations 275, 276 residual renal function preservation 274, 275 technique failure 273, 274 peritoneal dialysis penetration and technique survival 260, 261 renal replacement therapy mode effect on outcomes cold ischemia time 261 combined kidney and pancreas transplantation after peritoneal dialysis 256 immediate post-transplant graft function 254–256, 262–264 long-term graft and patient survival 256, 257, 266, 267 vascular thrombosis 264–266

349

Knockout mouse, see RAGE Kt/V, see Urea kinetics Leptin, functions 167, 168 Macrophage, adipocyte interactions 169 Malnutrition-inflammation-atherosclerosis (MIA) syndrome atherosclerosis 137 inflammation markers 136 malnutrition 136, 137 metabolic acidosis 138 overview 135 peritoneal transport 137 residual renal function 137, 138 treatment angiotensin-converting enzyme inhibitors 141 antibiotics 141, 142 biocompatible peritoneal dialysis solutions 140 glitazone 141 inflammation nutrition 139 volume control 139 lifestyle modification 142 malnutrition acidosis 138, 139 appetite stimulants 139 dialysis adequacy 138 nutritional support 138 nonsteroidal anti-inflammatory drugs 141 statins 141 thalidomide 142 vitamin C 141 vitamin E 141 Matrix GLA protein (MGA), vascular calcification prevention 216, 217 Mesothelial monolayer animal model of peritoneal dialysis effects dialysis solution studies of repopulation and repair 57–59 homeostatic repopulation 57 preparation 55 cell phenotype and peritoneal dialysis response 49, 156, 157, 159–161

Subject Index

glucose degradation product effects 78, 79 Metabolic acidosis bicarbonate-based solutions in treatment and prevention 222 bone metabolism effects in peritoneal dialysis 222 malnutrition-inflammation-atherosclerosis syndrome 138 Monocytes, cloudy dialysate 190, 191 Multifrequency bioimpedance analysis (MF-BIA), see also Bioimpedance analysis dry body weight assessment 105, 106 personal impedance analyzer applications 332–334 overview 328, 329 study design 329 validation 330, 332 principles 122 Nonsteroidal anti-inflammatory drugs (NSAIDs), malnutrition-inflammationatherosclerosis syndrome prevention 141 Normalized protein equivalent of nitrogen appearance (nPNA), calculation and urea clearance relationship 20, 21 Nutrineal, clinical studies 93, 94, 140 Osteopontin, vascular calcification prevention 216 Overhydration causes 113 diagnosis 112, 113 peritoneal dialysis complication 111, 112 prevalence 112 treatment hypertonic glucose 114 peritoneal ultrafiltration 114, 115 residual renal function and diuresis effects 114, 115 sodium restriction 113, 114 Patient On Line (POL), peritoneal function testing 39 PD 100T, automated peritoneal dialysis cycler 298

350

PD 101, automated peritoneal dialysis cycler 298 PD 200, automated peritoneal dialysis cycler 298, 299 PD-Adequest, peritoneal function testing 39 PD Night, automated peritoneal dialysis cycler 296, 297 Peritoneal dialysis, see also Automated peritoneal dialysis; Continuous flow peritoneal dialysis access, see Catheters animal models acute models 72 ANIMOD collaboration 70, 71 chronic models 72–74 clinical relevance 71, 72 prospects 74 dialysis solutions, see Dialysis fluids failure rate 45 initiation 42–46 kidney transplant outcome effects, see Kidney transplant long-term effects on peritoneal function glucose degradation product accumulation 48–51 mesothelium effects, see Mesothelial monolayer overview 17 sclerosis, see Sclerosis, peritoneum lymphatic absorption 16 modes 43 solute transfer convection 16 diffusion 15, 16 solute transport factors dialysate compartment 6–8 membrane properties 8, 9 microcirculation 9–11 sorbents, see Sorbents urea kinetics modeling, see Urea kinetics Peritoneal equilibration test (PET) chronic peritoneal dialysis findings 157 peritoneal function testing 37, 38, 40 Peritoneum anatomy 13, 14, 31–33 aquaporin-1 33, 34 cellular immune response 158, 159

Subject Index

fibrosis, see Fibrosis, peritoneum function 14 interstitium structure 175 transport role 175, 176 membrane function testing 17, 37–40 properties 8, 9 vascular bed studies, see Intravital microscopy, peritoneum microcirculation 9–11, 33 resistance to solute and water transport 14, 15 sclerosis, see Sclerosis, peritoneum ultrafiltration, see Ultrafiltration, peritoneum Peritonitis anemia management 210, 211 catheter removal 184, 185 causes 182, 183 clinical presentation 182 cloudy dialysate, see Cloudy dialysate epidemiology 181, 182 fungal peritonitis 183, 184 management 183 mortality 181 mycobacterial peritonitis 184 peritoneal dialysis risks 45, 50, 51 sclerosis etiology 66 Personal Dialysis Capacity test (PDC), peritoneal function 39, 40 Personal impedance analyzer (PIA) applications 332–334 overview 328, 329 study design 329 validation 330, 332 Phosphate handling calcium balance in peritoneal dialysis 219, 220 control in peritoneal dialysis 221, 222 phosphorus balance in peritoneal dialysis 220, 221 serum levels and mortality risks 214, 215 vascular calcification impact in dialysis patients 217, 218 pathogenesis 215–217 risks 215

351

Physioneal, clinical studies 92, 93, 140 Pit-1, vascular calcification role 216 Polymorphonuclear leukocytes, cloudy dialysate 189, 190 RAGE knockout mouse studies peritoneal angiogenesis 80, 81 peritoneal fibrosis 81 peritoneal inflammation 80 ligands 79, 80 mesothelial cell effects 78, 79 peritoneal fibrosis role 73, 74 signal transduction 79, 80 structure 79 Red blood cells, cloudy dialysate 191 Residual renal function (RRF) kidney transplant failure and preservation with peritoneal dialysis 274, 275 malnutrition-inflammationatherosclerosis syndrome 137, 138 overhydration treatment effects 114, 115 prognostic value 153 Resistin, functions 168, 169 Sclerosis, peritoneum animal models 65 etiology and pathogenesis 66, 67 frequency in peritoneal dialysis 63 pathology 63–65 simple sclerosis versus sclerosing peritonitis 62, 63, 67 Shear rate value blood 4 solute transfer in peritoneal dialysis 16 Sleep Safe, automated peritoneal dialysis cycler 297 Sodium dietary intake recommendations 108 removal in peritoneal dialysis mortality relationship 108 target 106, 107 Sorbents activated carbon 337 dialysate regeneration 340 peritoneal dialysis utilization 340, 341

Subject Index

targets 337 types 337–339 Standardized peritoneal membrane assessment (SPA), peritoneal function testing 38, 39 Statins, malnutrition-inflammationatherosclerosis syndrome prevention 141 Tenckhoff catheter development 197 modifications for complication avoidance 197–199 Thalidomide, malnutrition-inflammationatherosclerosis syndrome prevention 142 Transforming growth factor-␤ (TGF-␤) glucose degradation product induction 78 peritoneal dialysis induction and fibrosis 73 peritoneal membrane effects 85 Triglycerides, cloudy dialysate 192 Ultrafiltration, peritoneum automated peritoneal dialysis 282, 283 continuous flow peritoneal dialysis control 313, 314 fluid loss measurement 31 intraperitoneal hydrostatic pressure 31 lymph flow measurement 31 membrane model 29 net ultrafiltration equation 28 osmosis and fluid loss 29, 30 prospects for study 34, 35 overhydration treatment effects on residual renal function and diuresis 114, 115 overview 16 transport process 98–100 Urea kinetics blood urea versus blood urea nitrogen 23 clearance in normal kidney 21, 22 continuous flow peritoneal dialysis 315, 316 hemodialysis overview 22 simplified model peritoneal dialysis comparison 26

352

principles 23, 24 time-averaged blood urea nitrogen calculation 25, 26 time requirement to achieve Kt/V ⫽ 1 25 indicators 20 normalized protein equivalent of nitrogen appearance calculation and urea clearance relationship 20, 21 peritoneal dialysis efficiency and survival 233, 234 overview 22 simplified model hemodialysis comparison 26 principles 23, 24 steady state blood urea nitrogen calculation 25 time requirement to achieve Kt/V ⫽ 1 24 urea clearance needed to achieve Kt/V ⫽ 2/week 24, 25 Uremia, peritoneal dialysis integration in treatment clinical parameters of adequacy 228, 229 education aspects 237 elderly patients, see Elderly patients full-treatment studies 230–234 institutional barriers 237 modes of peritoneal dialysis 231

Subject Index

mortality studies 237, 238 organizational aspects 227, 228 overview 226, 227 patient preferences 238 prevalence and trends of chronic peritoneal dialysis utilization 235–237 program 227 rehabilitation 229 technical issues 229, 230 Vascular calcification impact in dialysis patients 217, 218 pathogenesis 215–217 risks 215 Vascular endothelial growth factor (VEGF) chronic peritoneal dialysis fluid exposure effects in rats 87, 88 glucose degradation product induction 78, 81 peritoneal membrane effects 85 Vitamin C, malnutrition-inflammationatherosclerosis syndrome prevention 141 Vitamin E, malnutrition-inflammationatherosclerosis syndrome prevention 141 Water aquaporin-1 transport 33, 34, 98, 99 overhydration, see Overhydration removal target in peritoneal dialysis 106

353

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Proteomics in Nephrology: Towards Clinical Applications (Contributions to Nephrology)

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Manual of Clinical Dialysis

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Nutrition and Kidney Disease: A New Era (Contributions to Nephrology)

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A Practical Manual of Renal Medicine: Nephrology, Dialysis and Transplantation

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