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
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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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Fig. 1. Factors affecting solute clearances in extracorporeal treatments.
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
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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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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)
Approach to Understand Peritoneal Dialysis and Hemodialysis
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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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31
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
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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
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7 8 9 10 11 12 13
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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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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
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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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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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2.0
*
1.5 RAGE
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0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
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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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References 1
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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.
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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
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UF with Convective icodextrin Na transport
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Almost no transport
Pore:
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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
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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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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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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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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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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 111–118
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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fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial. J Am Soc Nephrol 2003;14:2338–2344. Woodrow G, Oldroyd B, Stables G, Gibson J, Turney JH, Brownjohn AM: Effects of icodextrin in automated peritoneal dialysis on blood pressure and bioelectrical impedance analysis. Nephrol Dial Transplant 2000;15:862–866. 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 Suppl 2002;81:S23–S33. Davies S, Plum J, Heimbürger O: Increasing our understanding of the mechanism of action of icodextrin. Abstract F-PO407 ⭈ ASN 2004. Plum J, Gentile S, Verger C, Brunkhorst R, Bahner U, Faller B, Peeters J, Freida P, Struijk DG, Krediet RT, Grabensee B, Tranaeus A, Filho JC: Efficacy and safety of a 7.5% icodextrin peritoneal dialysis solution in patients treated with automated peritoneal dialysis. Am J Kidney Dis 2002;39:862–871. le Poole CY, van Ittersum FJ, Weijmer MC, Valentijn RM, ter Wee PM: Clinical effects of a peritoneal dialysis regimen low in glucose in new peritoneal dialysis patients: a randomized crossover study. Adv Perit Dial 2004;20:170–176. Konings CJ, Kooman JP, Gladziwa U, van der Sande FM, Leunissen KM: A decline in residual glomerular filtration during the use of icodextrin may be due to underhydration. Kidney Int 2005;67:1190–1191. Gunal AI, Kirciman E, Guler M, Yavuzkir M, Celiker H: Should the preservation of residual renal function cost volume overload and its consequence left ventricular hypertrophy in new hemodialysis patients? Ren Fail 2004;26:405–409. Chang ST, Chen CL, Chen CC, Lin FC, Wu D: Enhancement of quality of life with adjustment of dry weight by echocardiographic measurement of inferior vena cava diameter in patients undergoing chronic hemodialysis. Nephron Clin Pract 2004;97:c90–c97.
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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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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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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Ronco C, Dell’Aquila R, Rodighiero MP (eds): Peritoneal Dialysis: A Clinical Update. Contrib Nephrol. Basel, Karger, 2006, vol 150, pp 144–151
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.
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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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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
PGs, interleukins hyaluronan, CA MCP-1, RANTES CA-125, VEGF
Hyaluronan collagen
Endothelial cells
IL-1, TNF-␣ Macrophage
NOS
Vascular recruitment
Fibrinogen fibronectin albumin, lgs chemokines PGs
HA Col
Intersitial matrix
TGF-1 bFGF
H2O2 PD solution (glucose, GDPs)
? Muscle cells
Basement membrane
Peritoneal cavity
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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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.
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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
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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 s
