Nolph and Gokal's Textbook of Peritoneal Dialysis [4 ed.] 3030620867, 9783030620868, 9783030620875

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Ramesh Khanna Raymond T. Krediet Editors

Nolph and Gokal’s Textbook of Peritoneal Dialysis Fourth Edition

Nolph and Gokal’s Textbook of Peritoneal Dialysis

Ramesh Khanna • Raymond T. Krediet Editors

Nolph and Gokal’s Textbook of Peritoneal Dialysis Fourth Edition

With 132 Figures and 105 Tables

Editors Ramesh Khanna University of Missouri Columbia, MO, USA

Raymond T. Krediet Dept. Medicine Div. Nephrology University of Amsterdam Academic Medical Center Amsterdam, The Netherlands

ISBN 978-3-030-62086-8 ISBN 978-3-030-62087-5 (eBook) https://doi.org/10.1007/978-3-030-62087-5 1st edition: © Springer Science+Business Media Dordrecht 1994 2nd edition: © Springer Science+Business Media Dordrecht 2000 3rd edition: © Springer Science+Business Media, LLC 2009 © Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface to the Fourth Edition

The 4th edition of the Nolph and Gokal’s Textbook of Peritoneal Dialysis covers an update of our current knowledge on peritoneal dialysis, mainly as renal replacement therapy. More than ten years have passed since the publication of the third edition in 2009. In this period, the number of patients treated with peritoneal dialysis has increased, especially in some underdeveloped countries, making peritoneal dialysis the third mode of chronic renal replacement therapy after hemodialysis and kidney transplantation. Dr. Karl Nolph, one of the pioneers of modern peritoneal dialysis and editor of the first two editions of the Nolph and Gokal’s Textbook of Peritoneal Dialysis, passed away on June 16, 2014. Dr. Ramesh Khanna and Dr. Raymond T. Krediet, who were already editors of the 3rd edition, have taken the responsibility to be editors for the present 4th edition. The last decade has been characterized by increased use of automated peritoneal dialysis and the more widespread application of more biocompatible dialysis solutions, like those containing icodextrin as an osmotic agent and solutions with a neutral pH and a reduced content of glucose degradation products. Also, the focus on adequacy based on the quantity of small solute clearances has changed to more attention to the total patient management including hydration status of patients, blood pressure control, anemia control, and bone health, including in the elderly. The current edition provides an extensive review of the “state of the art” of peritoneal dialysis. It contains 32 chapters, 9 of which are completely new. These include urgent start peritoneal dialysis, incremental dialysis, patientcentered prescription, blood pressure control, electrolyte management, encapsulating peritoneal sclerosis, acute kidney injury, kidney transplantation in peritoneal dialysis, and translational research. All other chapters except two have been updated or completely rewritten. All authors are highly qualified in the subject of their chapter. Therefore, the book in its current fully updated form should be useful for medical students, residents, nephrology fellows, clinical and academic nephrologists, researchers, nurses, dieticians, social workers, bioengineers, pharmacologists, epidemiologists, and many others. The 4th edition of Nolph and Gokal’s Textbook of Peritoneal Dialysis is published at a time, in which the world is gradually recovering from the

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COVID pandemic, which also critically affected the available time of many authors. Although the publication is later than foreseen originally, the editors hope that this 4th fully updated edition will be as useful as the previous ones for all those involved in peritoneal dialysis and will be beneficial for all patients treated with peritoneal dialysis. Columbia, USA Amsterdam, The Netherlands March 2023

Ramesh Khanna Raymond T. Krediet Editors

Preface to the Second Edition

The Textbook of Peritoneal Dialysis, in its 2nd edition, covers the advances made in the field over the past 25 years. In the past two decades, the time during which the therapy has been increasingly utilized, this book has been recognized as a major source of the discipline’s base knowledge. The evolution of this text from its previous independent volumes parallels the growth of peritoneal dialysis from continuous ambulatory peritoneal dialysis in the eighties to the current therapies that encompass manual and automated therapies with full emphasis on adequacy of dialysis dose. Peritoneal dialysis represents an intracorporeal technique for blood purification. This unique dialysis system represents one of man’s several attempts to manipulate nature for sustenance of life. The past few years of advances have focused on further improvement of the technique. The areas that have fueled the interest of researchers include adequacy of dialysis doses, further improvement in catheter technology, automated techniques, further definition of indications and the ideal time to initiate dialysis. Newer insights into the hostdefense mechanisms have also made the past decade of advances in the field more meaningful for the clinicians. The second edition of the Textbook of Peritoneal Dialysis is in a way a compilation of all the explosive new knowledge in the field. It cites and describes in great detail all the new discoveries on a background of prior understanding of the subjects. These advances have made the therapy better in terms of diagnosis and management of patient care. The current group of Editors has worked with the experts in the field to attain balance between the new inventions and contentious issues. An attempt has been made to update bibliographies as recently as possible. To that end, the contributions of Advances in Peritoneal Dialysis, the annual publication of selected papers from the Annual Conference of Peritoneal Dialysis, and Peritoneal Dialysis International, the official publication of the International Society for Peritoneal Dialysis, have been enormous and can be judged by their frequent citation in the book. As in the past edition, we have not edited the overlaps between chapters, since we feel the readers might benefit by exposure to different perspectives of complex material. The Editors have tried in this text to sustain a balance between clinical and theoretical knowledge. We would like to credit our devoted authors for expending their busy time on writing and proofreading their respective vii

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chapters. We offer our heartfelt thanks to all the authors for their hard work, extraordinary contributions, and superb cooperation in editing this monumental work. To the many individuals at Kluwer Academic Publishers, we acknowledge their professionalism and intense Iabor. We appreciate the fine editorial assistance provided by Peggy Gray. We hope that readers will find this text a useful resource for both clinical and research problems when dealing with patients on peritoneal dialysis. January 2000

The Editors

Preface to the First Edition

In 1986, the first edition of Continuous Ambulatory Peritoneal Dialysis, edited by R. Gokal, was published. In 1989, the third edition of Peritoneal Dialysis, edited by K. D. Nolph, was published. Rather than edit new editions of each of these books separately, we have decided to combine our efforts to edit this single book which is called The Textbook of Peritoneal Dialysis. Peritoneal dialysis represents an internal technique for blood purification. In this dialyzer, the blood path, the membrane and the dialysate compartment are provided by nature. Interest in and utilization of peritoneal dialysis has been stimulated by the developments of chronic peritoneal catheters, automated cycling equipment, manipulations of transport, experiences with continuous ambulatory peritoneal dialysis, experiences with peritoneal dialysis using cyclers, decreases in peritonitis rates with new connection approaches and better definitions of adequate peritoneal dialysis. New advances in our understanding of the physiology of peritoneal dialysis (including the role of peritoneal lymphatics) and peritoneal dialysis kinetics are examples of the dynamic nature of the field. Publications related to peritoneal dialysis usually exceed 400 annually. Peritoneal Dialysis International, the official journal of the International Society for Peritoneal Dialysis, is a journal solely devoted to peritoneal dialysis experiences and development. The Sixth Congress of the International Society for Peritoneal Dialysis was held in Thessaloniki, Greece, in 1992. The next meeting of this international society will be held in Stockholm, Sweden, in 1995. The 13th Annual Peritoneal Dialysis Conference was held in San Diego, California, in 1993 and attracted 2,500 participants from 40 countries. At this time, more than 70,000 patients are estimated to be maintained on chronic peritoneal dialysis worldwide. This book is meant to provide an overview of the state of the art of peritoneal dialysis. Many clinicians are making extensive commitments to peritoneal dialysis. Nephrologists, anatomists, physiologists, pharmacologists, biomedical engineers, and even physicists are involved in studies to better understand peritoneal dialysis. The complexities of peritoneal dialysis and the peritoneal membrane are becoming apparent. Studies of peritoneal dialysis increase understanding of the anatomy and physiology of biological membranes and the factors influencing the paths for movement of solutes across the microcirculation and related structures. Peritoneal dialysis provides a “window” to the visceral microcirculation in animals and in humans. ix

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Peritoneal dialysis may be useful to treat problems other than renal failure. Beneficial effects in the treatment of dysproteinemia, psoriasis, hypothermia and metabolic problems have been reported. The intraperitoneal administration of chemotherapeutic agents draws upon and contributes to our understanding of peritoneal dialysis. This book contains a chapter dealing with the concepts of intraperitoneal chemotherapy. The editors feel fortunate to have been involved in peritoneal dialysis research and development for over 50 years of combined experience. New ideas and new developments have been an almost daily occurrence. Yet, our understanding of this dialysis system is still in its infancy. The authors of the chapters in this book have been actively investigating and writing about their respective topics for many years. Most are individuals with whom we have had the good fortune to have had frequent contacts. Many coauthors of chapters have somewhat different opinions, and yet, they have made an effort to combine their thoughts in a single chapter. As in our previous books, each chapter is an extensive review of a given topic. We have not edited out all overlap between chapters since we feel the reader benefits by exposure to slightly different perspectives of complex material, and this allows each author to deal with all issues that relate to his respective topics. We hope that this book will serve as a reference text for all those with more than a casual interest in peritoneal dialysis. August 1993

Ram Gokal Karl D. Nolph

Acknowledgments

We thank the authors for their perseverance during the COVID-19 pandemic. We acknowledge the teachings we received from our teachers, nurses, students, and patients. We wish to thank the support staff for the ever-ready help. We are ever grateful to our families for their indulgence, support, inspiration, and bearing with us.

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Contents

1

History of Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . D. Negoi and Ramesh Khanna

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2

Current Status and Growth of Peritoneal Dialysis . . . . . . . . Fahad Aziz and Ramesh Khanna

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Patient Survival Comparisons Between Peritoneal Dialysis and Hemodialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marlies Noordzij and Peter G. Blake

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Peritoneal Structure and Changes as a Dialysis Membrane After Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . Rafael Selgas, Kazuho Honda, Manuel López-Cabrera, Chieko Hamada, and Lázaro Gotloib

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The Physiology and Pathophysiology of Peritoneal Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Raymond T. Krediet, S. Furgeson, and I. Teitelbaum

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Peritoneal Dialysis Program Organization and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Maria Luongo, B. Prowant, L. Burrows, J. Neumann, and L. Ponferrada

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Peritoneal Dialysis Access and Exit-Site Care Including Surgical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 P. Kathuria, Z. J. Twardowski, and W. K. Nichols

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Automated Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . 285 P. Kathuria and Z. J. Twardowski

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Incremental Peritoneal and Hemodialysis . . . . . . . . . . . . . . . 323 Rafia I. Chaudhry, Tushar Chopra, Natalie Nesmith McCall, and Thomas Golper

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Urgent-Start Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . 341 Arshia Ghaffari and Jim Hung Nguyen

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Monitoring the Functional Status of the Peritoneum Dirk G. Struijk and Ramesh Khanna

. . . . . . 361

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New Peritoneal Dialysis Solutions and Solutions on the Horizon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 D. W. Johnson and Raymond T. Krediet

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Blood Pressure Control in Peritoneal Dialysis . . . . . . . . . . . . 417 Panagiotis I. Georgianos and Rajiv Agarwal

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Peritoneal Infections in Peritoneal Dialysis (PD Peritonitis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 Hariharan Regunath, Kyle Ludwig, and Ramesh Khanna

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Noninfectious Complications of Peritoneal Dialysis Claire Kennedy and Joanne M. Bargman

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Protein-Energy Wasting During Peritoneal Dialysis . . . . . . . 511 Angeles Espinosa-Cuevas, Ailema González-Ortiz, Bengt Lindholm, Kamyar Kalantar-Zadeh, and Juan Jesus Carrero

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Calcium, Phosphate, and Renal Osteodystrophy . . . . . . . . . . 537 A. Vardhan and A. J. Hutchison

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Cardiovascular Disease and Inflammation . . . . . . . . . . . . . . 575 Magdalena Jankowska, Bengt Lindholm, and Peter Stenvinkel

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Vascular Calcification and Calciphylaxis in Peritoneal Dialysis Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Ignacio A. Portales-Castillo, Preethi Yerram, and Sagar Nigwekar

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Electrolyte Management in Peritoneal Dialysis . . . . . . . . . . . 619 Kunal Malhotra and Ramesh Khanna

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Management of Anemia in Peritoneal Dialysis Patients . . . . 631 Nupur Gupta and Jay B. Wish

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Peritoneal Dialysis in Diabetic End-Stage Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653 M. Misra and Ramesh Khanna

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Peritoneal Dialysis in Children . . . . . . . . . . . . . . . . . . . . . . . . 675 Bradley A. Warady, Alicia Neu, and Franz Schaefer

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PD in the Older Person . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737 Richard W. Corbett and Edwina A. Brown

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Ultrafiltration Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Watske Smit and Raymond T. Krediet

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Long-Term Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . 781 S. J. Davies and Raymond T. Krediet

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Encapsulating Peritoneal Sclerosis . . . . . . . . . . . . . . . . . . . . . 799 E. J. Goffin and Raymond T. Krediet

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Role of Peritoneal Dialysis in Acute Kidney Injury . . . . . . . . 811 Fahad Aziz and Kunal Chaudhary

. . . . . . . 467

Contents

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Kidney Transplant and Peritoneal Dialysis . . . . . . . . . . . . . . 837 Lee Anderson, Preethi Yerram, and Venkatesh Kumar Ariyamuthu

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Basic Science and Translational Research in Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849 Joanna Stachowska-Pietka, Jacek Waniewski, and Michael Flessner

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Animal Models for Peritoneal Dialysis Research . . . . . . . . . . 883 M. M. Zweers and P. J. Margetts

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Intraperitoneal Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . 899 Michael F. Flessner

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927

About the Editors

Ramesh Khanna University of Missouri Columbia, MO, USA Dr. Ramesh Khanna is a tenured Professor of Medicine, Director of the Karl D. Nolph, MD, Division of Nephrology at the School of Medicine, University of Missouri, Columbia, Missouri, USA. Dr. Khanna has been actively involved in the field of nephrology for the past 50 years. He is fully engaged in patient care, teaching nephrology, translational research, and administration. His primary research interest is in applied physiology of solute and water transport across peritoneal membrane. In collaboration with Drs. Karl Nolph†, Dimitrios Oreopoulos†, and Zbylut Twardowski, Dr. Khanna’s research inventions resulted in clinical management guidelines and several patents. Dr. Khanna has consistently received the highest honors in the field both nationally and internationally. He is the current organizing chair of the successful “Annual Dialysis Conference,” which is in its 43rd year of consecutive existence. Dr. Khanna has authored/coauthored numerous papers in top journals, book chapters, abstracts, letters to the editor, and two books, the Textbook of Peritoneal Dialysis, 4th edition, and the very popular beginner’s guide book The Essentials of Peritoneal Dialysis. In addition, he has presented in numerous conferences/workshops across the world. He has been the editorial board member of about 12 journals, and Section Editor of Clinical Nephrology, along with editor of Advances in Peritoneal Dialysis, PD News (Newsletter of the International Society xvii

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About the Editors

for Peritoneal Dialysis), and Peritoneal Dialysis Today (Highlights of the Annual Conference on Peritoneal Dialysis). Raymond T. Krediet Raymond (Ray) Krediet graduated in 1973 at the University of Amsterdam. In 1978 he completed his training as an internist-nephrologist and became Head of Nephrology at the Binnengasthuis, Amsterdam in 1979 where he introduced treatment with continuous ambulatory dialysis (CAPD). In 1986 he was promoted on a PhD thesis, entitled “Peritoneal permeability in continuous ambulatory peritoneal dialysis patients.” In 1999 he became Professor and Head of the Department of Nephrology at the Academic Medical Centre, University of Amsterdam. Professor Krediet supervised the research of 29 PhD students and is the author of 576 publications in scientific journals, of which 82% were on Nephrology. He was promotor of 31 PhD theses. His h-index is 72 (WoS). He is, among others, former chairman of the Dialysis Group Netherlands, the International Society for Peritoneal Dialysis, and the Nephrology Section of the European Union for Medical Specialists. He retired in October 2010, but is still involved in research and a number of academic and organizational activities. He was a member of the Scientific Advisory Board of the European Renal Association from 2012 to 2018. In 2011 he became an honorary member of the Netherlands Federation of Nephrology and in May 2012 he was awarded the International Distinguished Medal from the National Kidney Foundation in the USA. He contributed to the first edition of The Textbook of Peritoneal Dialysis and is co-editor of the three subsequent editions.

Contributors

Rajiv Agarwal Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA Lee Anderson Division of Nephrology, Department of Medicine, University of Texas Southwestern, Dallas, TX, USA Venkatesh Kumar Ariyamuthu Associate Professor of Medicine (Clinical Scholar Track), Division of Nephrology, Medical Director of Kidney Transplant Program - Banner University Medical Center – Tucson, AZ, USA Fahad Aziz Division of Nephrology, University of Wisconsin, Madison, WI, USA Joanne M. Bargman Division of Nephrology, University Health Network, Toronto, ON, Canada Peter G. Blake Western University, London, OT, Canada London Health Sciences Centre, London, OT, Canada Edwina A. Brown Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK L. Burrows Branson Nephrology and Dialysis, Branson, MO, USA Juan Jesus Carrero Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Kunal Chaudhary Division of Nephrology, University of Missouri, Columbia, MO, USA Rafia I. Chaudhry University of California San Francisco, San Francisco, CA, USA Tushar Chopra University of Virginia Health System, Charlottesville, VA, USA Richard W. Corbett Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK xix

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S. J. Davies Faculty of Medicine and Health Sciences, Keele University, Newcastle-under-Lyme, UK Angeles Espinosa-Cuevas Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico, Mexico Michael F. Flessner University of Mississippi Medical Center, Jackson, MS, USA S. Furgeson University of Colorado-Anschutz Medical Campus, Aurora, CO, USA Denver Health Hospital, Denver, CO, USA Panagiotis I. Georgianos Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece Arshia Ghaffari Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA E. J. Goffin Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium Thomas Golper Vanderbilt University Medical Center, Nashville, TN, USA Ailema González-Ortiz Laboratory of Experimental Surgery, Instituto Nacional de Pediatría, Mexico, Mexico Lázaro Gotloib Department of Nephrology, Ha’Emek Medical Center, Afula, Israel Nupur Gupta Indiana University School of Medicine, Indianapolis, IN, USA Chieko Hamada Juntendo University, Tokyo, Japan Kazuho Honda Department of Anatomy, Showa University School of Medicine, Tokyo, Japan Jim Hung Nguyen California Kidney Specialists, Los Angeles, CA, USA A. J. Hutchison Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester, UK Magdalena Jankowska Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland D. W. Johnson Nephrology, Princess Alexandra Hospital, Brisbane, Australia Kamyar Kalantar-Zadeh University of California Irvine, Orange, CA, USA P. Kathuria University of Oklahoma College of Medicine, Tulsa, OK, USA Claire Kennedy Division of Nephrology, Kingston Health Sciences Center, Kingston, ON, Canada

Contributors

Contributors

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Ramesh Khanna School of Medicine Department of Medicine, Division of Nephrology, Health Sciences Center, Columbia, MO, USA Raymond T. Krediet Division of Nephrology, Academic Medical Center – University of Amsterdam, Amsterdam, The Netherlands Manuel López-Cabrera Centro de Biologia Molecular “Severo Ochoa”, Madrid, Spain Bengt Lindholm Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Kyle Ludwig Clinical Pharmacy Specialist – Medical Intensive Care Unit, University of Missouri Hospital and Clinics, Columbia, MO, USA Maria Luongo Boston, MA, USA Kunal Malhotra School of Medicine, Division of Nephrology, University of Missouri, Columbia, MO, USA P. J. Margetts Divison of Nephrology, Department of Medicine, St. Joseph’s Hospital, McMaster University, Hamilton, ON, Canada Natalie Nesmith McCall Vanderbilt University Medical Center, Nashville, TN, USA M. Misra University of Missouri School of Medicine, Columbia, MO, USA D. Negoi Cayuga Medical Associates, Ithaca, NY, USA Alicia Neu Johns Hopkins Children Hospital, Baltimore, MD, USA J. Neumann Satellite Healthcare, Inc, San Jose, CA, USA W. K. Nichols School of Medicine, University of Missouri, Columbia, MO, USA Sagar Nigwekar Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Marlies Noordzij Clinical Epidemiologist, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands L. Ponferrada University of Missouri, Columbia, MO, USA Ignacio A. Portales-Castillo Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA B. Prowant Columbia, MO, USA

Maria Luongo: Retired. B. Prowant: deceased.

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Hariharan Regunath Department of Medicine – Divisions of Infectious Diseases and Pulmonary & Critical Care Medicine, University of Missouri, Columbia, MO, USA Clinical Microbiology Lab, University of Missouri Hospital and Clinics, Columbia, MO, USA Department of Pulmonary and Critical Care Medicine, University of Maryland-Baltimore Washington Medical Center, Glen Burnie, MD, USA Franz Schaefer University Hospital for Children and Adolescents, Heidelberg, Germany Rafael Selgas Hospital Universitario La Paz, IdiPAZ, Universidad Autonoma de Madrid, Madrid, Spain Watske Smit Department of Internal Medicine, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands Joanna Stachowska-Pietka Nalecz Institute of Biocybernetics and Biomedical Engineering, Warsaw, Poland Peter Stenvinkel Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden Dirk G. Struijk Division of Nephrology, Dianet, Location AmsterdamUMC, Amsterdam, The Netherlands I. Teitelbaum University of Colorado-Anschutz Medical Campus, Aurora, CO, USA Z. J. Twardowski Emeritus Professor, MU School of Medicine, Columbia, MO, USA A. Vardhan Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester, UK Jacek Waniewski Nalecz Institute of Biocybernetics and Biomedical Engineering, Warsaw, Poland Bradley A. Warady Pediatric Nephrology, Children’s Mercy Kansas City, Kansas City, MO, USA Jay B. Wish Division of Nephrology, Indiana University School of Medicine, IU Health University Hospital, Indianapolis, IN, USA Preethi Yerram Division of Nephrology, University of Missouri-Columbia, Columbia, MO, USA Nephrology Section, Harry S Truman Veterans Administration Hospital, Columbia, MO, USA Division of Nephrology and Hypertension, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA M. M. Zweers Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Contributors

1

History of Peritoneal Dialysis D. Negoi and Ramesh Khanna

Contents The Discovery of Principles of Dialysis: Diffusion and Ultrafiltration. Thomas Graham and Henri Dutrochet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

The Peritoneal Cavity and the Peritoneal Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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The Birth of Clinical Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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First Attempts at Peritoneal Dialysis: Georg Ganter (1923) . . . . . . . . . . . . . . . . . . . . . . . . .

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Early Experience in Peritoneal Dialysis (1923–1950) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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The Modern Era of Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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First Step in Long-Term Peritoneal Dialysis: Intermittent Peritoneal Dialysis . . . .

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The Tenckhoff Catheter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 The Growth of and Disappointment with Intermittent/Periodic Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Continuous Ambulatory Peritoneal Dialysis (CAPD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 CAPD with Plastic Bags . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 The Y-Set and “Flush Before Fill” Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Automated Peritoneal Dialysis (APD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

This contribution was authored by D. Negoi and K.D. Nolph in the previous edition. D. Negoi (*) Cayuga Medical Associates, Ithaca, NY, USA R. Khanna School of Medicine Department of Medicine, Division of Nephrology, Health Sciences Center, Columbia, MO, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 R. Khanna, R. T. Krediet (eds.), Nolph and Gokal's Textbook of Peritoneal Dialysis, https://doi.org/10.1007/978-3-030-62087-5_1

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D. Negoi and R. Khanna Peritoneal Dialysis Catheters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Peritoneal Dialysis Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Current State of Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Abstract

The Discovery of Principles of Dialysis: The concept of the uremic syndrome caused by Diffusion and Ultrafiltration. Thomas blood and tissue accumulation of toxic sub- Graham and Henri Dutrochet stances normally excreted in the urine was an established idea in the middle of nineteenth century. In the late 1800s, renal insufficiency and concurrent uremic intoxication were treated only by simple and ineffective measures such as blood-letting, dietary changes, digitalis, infusion of normal saline followed by forced diuresis, purgation, and diaphoresis. The period of time surrounding the beginning of the twentieth century was marked by intense research and growth in scientific knowledge that allowed the birth of clinical dialysis, a lifesaving therapy for patients with renal failure. The following items will be discussed: The discovery of principles of dialysis; peritoneal permeability and the peritoneal membrane; the birth of clinical dialysis; first attempts at peritoneal dialysis; early experience in peritoneal dialysis; the modern era of peritoneal dialysis; first step in long-term peritoneal dialysis; the Tenckhoff catheter; the growth of and disappointment with intermittent peritoneal dialysis; continuous ambulatory peritoneal dialysis; CAPD with plastic bags; the Y-set and “flush before fill” system; automated peritoneal dialysis; peritoneal dialysis catheters; peritoneal dialysis solutions; current state of peritoneal dialysis. Keywords

Peritoneal dialysis · Peritoneal cavity · Continuous ambulatory peritoneal dialysis · Peritoneal dialysis patient · Peritoneal lavage

The development of peritoneal dialysis in early 1900s as a form of renal replacement therapy was made possible by remarkable progress in science and medicine that took place in the eighteenth and nineteenth centuries [1–3]. In the field of physical chemistry, it was Thomas Graham (1805–1869) who completed vast work that included the discovery of laws of diffusion of gases (Graham’s law: the rate of diffusion of a gas is inversely proportional to the square root of its molecular weight), investigation of osmotic force, and separation of chemical or biological fluids by dialysis [4–8]. His work represents the theoretical foundation upon which clinical dialysis could later develop. Graham was born in Glasgow, Scotland; his father wanted him to study theology and enter the Church of Scotland. He became a student at the University of Glasgow in 1819, where he was attracted by the field of chemistry and attended lectures in chemistry against his father’s wishes. His passion and dedication for this science caused him later to alienate his father. Graham became professor of chemistry at numerous colleges, his lectures being attended by aspirants in chemistry and medicine, as their training was similar during that time. Between 1846 and 1861, he published an important series of papers in the Philosophical Transactions of the Royal Society: “The motion of gases” in 1846, followed by “The motion of gases part II” 3 years later, “The Bakerian lecture on osmotic force” in 1854, and “Liquid diffusion applied to analysis” in 1861 [4]. His studies led him to the innovative distinction between “crystalloids” and “colloids,” which he defined based

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on their ability to diffuse through a semipermeable membrane and crystallize. He introduced the concept of “semipermeable” membrane and redefined the term dialysis. In his experiments, he separated solutions containing sugar or gum arabic from water, using sheets of vegetable parchment impregnated with starch, acting as a “dialytic septum.” He noted that sugars can cross the semipermeable membrane and called them crystalloids, as opposed to gum arabic, which did not cross the vegetable, semipermeable membrane, and called these types of substances colloids. He wrote: “The molecules are moved by force of diffusion. . . It may perhaps be allowed to me to apply the convenient term dialysis to the method of separation by the method of diffusion through a system of gelatinous matter” [4]. As mentioned by Gottschalk, prior to this new meaning given to the term dialysis, this was used “to describe dissolution of strength or weakness of the limbs, coming from the Greek, to part asunder” [4]. Graham also suggested that animal tissue could be used as a functioning semipermeable membrane and showed that the rate of diffusion of different molecules is inversely related to the molecular size. He also demonstrated that urea, which is present in the urine, can be dialyzed through semipermeable membranes. Because of these brilliant discoveries that proved that solutes can be “dialyzed” or separated from a fluid using a semipermeable membrane, he is considered to be the “father of modern dialysis.” Prior to Graham, it was René Henri Joachim Dutrochet (1776– 1846) who introduced the term osmosis to describe the movement of water through membranes that hamper the passage of solutes but

allow the passage of water down concentration gradients of salts [5]. This is an early description of osmotic induced ultrafiltration. Some authors consider Dutrochet as being the “grandfather of dialysis” because he discovered the principle that explains osmotic ultrafiltration [5].

The Peritoneal Cavity and the Peritoneal Membrane Egyptian morticians observed the peritoneal cavity as early as 3000 B.C. and recorded their observation in the Ebers papyrus [9, 10]. They described it as a “definite entity in which the viscera were somehow suspended” [9]. In the Roman times it was Galen, the Greek physician, who made thorough descriptions of the peritoneal cavity and peritoneum, which he observed by treating injuries of the gladiators [10]. Extensive knowledge of the peritoneal cavity started to accumulate in the last half of the nineteenth century, as the abdomen was often explored due to developments in abdominal surgery (see Table 1). In the early 18 s, von Recklinghausen [11, 12] comprehensively described the peritoneal cavity, even proposing it was lined entirely by mesothelial cells and noting the lymphatic drainage. In 1877, Georg Wegner – from the Surgical Clinic of the University of Berlin – published his “surgical comments on the peritoneal cavity” [13]. His observations were the results of experiments in rabbits where he injected hypertonic solutions of sugar, salt, or glycerin in an animal’s peritoneal cavity and found that intraperitoneal fluid volume increased. When hypotonic

Table 1 Pioneering animal studies of the peritoneal membrane Investigator Recklinghausen [11, 12] Wegner [13] Beck [14] Kolossow [14] Starling and Tubby [15] Cunningham [9, 16] Putnam [17] Engel [18]

Findings Described mesothelium and lymphatic drainage Transport of solutes and water across the peritoneum Described mesothelium Described intermesothelial paths Transport of solutes and water across the peritoneum Peritoneal transport and structure Described the peritoneum “as a dialyzing membrane” Peritoneal transport

Date 1862–1863 1877 1893 1893 1894 1920–1926 1923 1927

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solutions were injected in the peritoneum, their volume decreased. In 1893, Beck described the peritoneal mesothelium and possible connections of the peritoneal cavity with lymphatics [14] and Kolossow described paths between the mesothelial cells, which he did not believe were connected with the lymphatic system [14]. The famous English physiologist E.H. Starling and his collaborator from Guy’s Hospital in London, A.H. Tubby, specifically studied the transport of fluids and solutes across the peritoneal membrane and published their result at the end of nineteenth century [15]. They determined that solute exchange was primarily between solutions in the peritoneal cavity and blood, lymphatic transport being considered negligible. They reproduced Wegner’s results and also studied the transport of indigo carmine and methylene blue and concluded that, as with water, they can cross the peritoneal membrane in both directions. Further insight into peritoneal physiology was acquired in the early years of the twentieth century. Some of the most well-known works during that period of time are those published by Cunningham, Putnam, and Engel. Cunningham [9, 16] studied the absorption of glucose from the peritoneal cavities of rats in 1920 and reviewed extensively the peritoneal structure and function in 1926. At the same time, Putnam described the dog peritoneum “as a dialyzing membrane” and brought more evidence that the peritoneum was a semipermeable membrane that allowed bidirectional water and solute transport on the basis of the principles of osmosis and diffusion. His experiments were complex, including observations on dwell time, flow rate, fluid removal, and exchange of various solutes [17, 18]. Advanced animal studies were done by Engel, who published his conclusions in 1927 [18]. He showed that animals could not tolerate extensive ultrafiltration and that solute clearance is directly proportional with its molecular size, the flow rate of the intraperitoneal fluid, peritoneal surface area, and blood flow. These were the times when the first attempts of therapeutic peritoneal dialysis were done in humans.

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The Birth of Clinical Dialysis In 1913–1914, Abel, Rowntree, and Turner developed a device they called the “artificial kidney” or “vivi-diffusion apparatus” using semipermeable collodium membranes specifically designed to substitute the role of the kidneys in eliminating toxic substances when these organs are failing [4, 19]. Although they experimented with this apparatus only in animals, their intention was to develop a method of extracorporeal dialysis that could be used in humans. Their work was terminated in 1914 because of World War I. The first human hemodialysis was done in 1924 in Germany by Georg Haas, who apparently was unaware of Abel’s work in the United States [6]. Also in Germany, Heinrich Necheles had great interest in “external” dialysis, and was searching for a better dialysis membrane for his dialyzers [20]. His work with goldbeater’s skin, which was a commercial preparation of visceral peritoneum from calves’ abdomen, must have stimulated Ganter to perform peritoneal dialysis [20].

First Attempts at Peritoneal Dialysis: Georg Ganter (1923) Georg Ganter from Würtzburg, Germany, is credited with the first publication regarding application of peritoneal dialysis to treat uremia. He was aware of the hemodialysis attempts of his contemporaries, and was captivated by the idea of using a patient’s own natural membranes for dialysis. He considered that application of external dialysis at the bedside would be complicated due to difficulties in establishing the extracorporeal circuit and toxic effects of the hirudin, which was used as anticoagulant [21]. In 1923, Ganter published the result of his investigations in humans and animals in his only paper, entitled “On the elimination of toxic substances from the blood by dialysis” [22]. He described his 1918 attempt to remove uremic toxins in a young man with glomerulonephritis using pleural lavage. He removed a pleural

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effusion and replaced the fluid with a single infusion of 750 mL of a sodium chloride solution and noted clinical improvement. The patient still died a few days after discharge, probably because Ganter did not recognize that uremic toxins will build up again [8]. He then carried out experiments on rabbits and guinea pigs made uremic by ligation of ureters and found that intraperitoneal instillation of saline solution improved the symptoms of uremia and blood urea nitrogen levels. In order to perform fluid exchanges, he used drainage tubes implanted in the peritoneal cavity and instilled saline solutions in volumes of approximately 50 mL, which were left in the peritoneal cavity for about 3 h. After this period of time the fluid was drained, with an average volume of 10–30 mL being recovered. The procedure was then repeated up to four times. He found that, after each exchange, there was almost complete equilibration of nonprotein nitrogen in the dialysate with blood concentrations and that some of the instilled fluid was absorbed. He also noted improvement in the animal’s uremic symptoms after peritoneal lavage: their appetite and activity level were improved after each exchange. Ganter used this procedure in a woman with acute uremia from bilateral ureteral obstruction due to uterine carcinoma: her condition improved transiently after a single intraperitoneal infusion of 1.5 L of physiologic saline. In another patient with a coma due to diabetic ketoacidosis, he instilled 3 L of saline intraperitoneally, and the patient’s mental status improved transiently. His unprecedented clinical experience with intermittent peritoneal dialysis was limited, but he envisioned that this procedure could become a new form of therapy and recognized a few aspects of primary importance in its applicability: adequate access is extremely important to maintain good inflow and outflow, peritoneal infection is the most common complication and the use of sterile solutions can help prevent this complication, a large volume of dialysate is necessary in order to remove the uremic toxins, and he suggested 1–1.5 L per exchange. Dwell time also influences solute clearance and it was considered necessary that the fluid remain in the peritoneal cavity until the equilibrium between the

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blood and dialysate is reached. Additionally, he recommended the use of hypertonic solutions to promote fluid as well as toxin removal. Unfortunately, Ganter did not continue research in the field of peritoneal dialysis, which evolved very slowly in the following years, probably because most of the attempts were unsuccessful in saving the life of patients.

Early Experience in Peritoneal Dialysis (1923–1950) In 1950, Odel and his colleagues [23] summarized and analyzed the published experience with peritoneal lavage (dialysis) between 1923 and 1948 and formulated some recommendations based on published results and their own experience. They found only five papers published on this topic from 1923 to 1938 (including Ganters’ paper) and as many as 33 papers between 1946 and 1948. No papers were published during World War II (1939–1945), but the number of fatal renal failure cases caused by trauma in both civilian and military patients brought this problem to the center of attention and stimulated research. They identified 101 reported patients treated by peritoneal lavage, including three patients treated by the authors. Sixty-three of the patients had reversible causes of renal failure, 32 had irreversible renal lesions, and two had an indeterminate diagnosis. Of the 101 patients reported in that 25-year period, only 36 survived: 32 patients with reversible uremia, two of the patients considered to have irreversible renal lesions, and two of those with indeterminate renal diagnosis. The most common causes of death were pulmonary edema (40%), uremia (33%), and peritonitis (15%). The peritoneal dialysis technique was applied in a very diverse way: 22 of the reported patients received intermittent treatments, with 1–6 lavages for exchanges of 15 min to 6 h duration and 75 of the patients received continuous treatment of 1 to 21 days duration. In four cases the type of intraperitoneal lavage was unknown. There was also a great variety of solutions used for peritoneal lavage with 14 different types reported: different

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concentrations of sodium chloride and dextrose solutions, Ringer’s, Rhoads’, Hartmann’s two modified Tyrode’s, “A,” “P,” modified “P” solutions, Kolff’s and two unknown. Rubber catheters introduced in the peritoneal cavity with the help of trocars, as well as glass or stainless steel tubes with multiple perforations, were used for inflow of the dialysis fluid into the peritoneal cavity, while mushroom-tip catheters of large bore, or stainless steel sump drains “similar to those perforated suction tubes used in operating rooms” were used for drainage of the peritoneal fluid from the peritoneal cavity. Catheter complications were very common and difficult to deal with: these included leakage of fluid, especially around the rigid tubes, bacterial contamination of the tubes, outflow obstruction caused by pocketing of the omentum, visceral perforation caused by the rigid tubes, and intra-abdominal hemorrhage. Other complications were noted: depletion of plasma proteins, sometimes to critical levels, in addition to derangements of the acid– base, electrolytes, and water balance. Odel and his colleagues were convinced that composition of the fluid used for dialysis was of the greatest importance and the main cause of experimental and clinical peritoneal dialysis failure was related to the imbalance of water and electrolytes. They advocated the use of a solution that would not change the normal electrolyte composition of the plasma, would permit maximal diffusion of waste products from the blood, would permit mild dehydration (moderately hypertonic solution), and would not irritate the peritoneum (the solution needs to have a pH close to that of the plasma). It is worth noting that the early investigators were aware of the fact that peritoneal lavage aided in removal of metabolic waste products, but the concept of adequate dialysis had yet to be discovered. Frequently, the duration of dialysis was too short, or if time of dialysis was longer, the amount of dialysis fluid was not sufficient to achieve sufficient removal of waste products. Although mortality with peritoneal lavage was high, it offered hope for effective therapy in some patients, especially in patients with reversible causes of renal failure, who were able to recover

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renal function before the peritoneal dialysis procedure failed. Of the papers published after World War II, the most important are considered to be those of doctors Howard Frank, a surgical intern, Arnold Seligman, trained in chemistry, and Jacob Fine, their mentor and chief of service at Beth Israel Hospital in Boston. They worked under contract with the “Office of Scientific Research and Development” (OSRD), the federal agency created by President Franklin D. Roosevelt in 1941 to promote research for military purposes in medicine and weapons technology [7]. Their task was to work on treatments for acute renal failure in trauma patients, and because they wanted to avoid the use of anticoagulants they opted for peritoneal lavage as a good possibility. As the literature regarding the use of natural membranes was limited at the time they embarked on their project, the team began by doing very elegant studies of peritoneal irrigation in non-nephrectomized and nephrectomized uremic dogs [24]. They calculated the optimal flow rate and volume of peritoneal irrigation fluid in order to obtain the maximum urea clearance and to prevent uremia, compared the blood urea clearance by peritoneal irrigation with clearance through the kidneys, and experimented with irrigation of various parts of the gastrointestinal tract and pleural cavity, which proved to be ineffective means of urea removal. The irrigation fluid used was Ringer’s solution containing glucose, which was later changed to a Tyrode’s solution, in their search for the right solution. Their uremic, nephrectomized dogs survived for 3–10 days with peritoneal dialysis and none of them died of uremia, but rather of peritonitis. Their method involved the use of two catheters introduced into the peritoneal cavity, one of them used for inflow of irrigation fluid and the other one for drainage. Continuous irrigation of the peritoneal cavity was done for 20 h daily for 2 days and 8–12 h daily thereafter, with the outflow rate being modified in order to prevent overdistension of the peritoneal cavity. Encouraged by the results of their experimental work in dogs, in 1945 they decided to try the treatment on a patient who presented to the

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emergency room at Beth Israel Hospital with acute renal failure from sulfathiazole administration [7, 25]. Their treatment was successful and the patient recovered after 7 days of dialysis, using the same technique as described before. This technique can be called an “intermittently continuous irrigation,” because the fluid was introduced in the peritoneal cavity by continuous irrigation, but there were periods of time when the irrigation was stopped and so peritoneal dialysis did not take place. It is interesting that their papers do not make any reference to the first successful use of continuous peritoneal dialysis in a patient with urinary tract obstruction by Wear, Sisk, and Trinkle, and they were probably unaware of this achievement [23, 26]. Fine’s group’s success became known immediately and gave an impulse to others to use their technique. Motivated by their own accomplishment, they continued work on peritoneal dialysis and tried to perfect their work. They treated 18 more patients, but only four survived [23]. They found that peritonitis was the greater risk associated with the procedure, and the main reason for considering this method

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was still in the investigational phase [27]. They improved the irrigation fluid by decreasing the sodium chloride concentration to 0.74% to reduce the risk of hyperchloremia, added gelatin, and increased the glucose concentration to increase the fluid tonicity so they were able to control edema. Bicarbonate was used in the irrigation fluid to combat acidosis. The bicarbonate solution was sterilized separately and added to the solution before irrigation was initiated. Their closed system was bulky and seemed complicated, and the procedure required the constant attendance of a nurse (see Figs. 1 and 2). The dialysis solution was sterilized and administrated from special 20-L Pyrex bottles, which required a large autoclave and were difficult to manipulate. The access was somewhat improved by introduction of a flexible sump drain that could be used as a two-way system if a separate inflow tube was not available. Most of the patients were treated with continuous flow technique, but they also used intermittent peritoneal lavage in some of the patients, with 0.5–2-L fill volumes depending on patient tolerability and 15 min to

Fig. 1 Schematic representation of closed system used by Frank, Seligman, and Fine. (From Annals of Surgery 1948, with permission)

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D. Negoi and R. Khanna

Fig. 2 Closed system used by Frank, Seligman, and Fine. (From Annals of Surgery, 1948 with permission)

3 h dwell time [27]. After finishing his internship, Frank remained at Beth Israel Hospital as a thoracic surgeon and member of the faculty at the Harvard Medical School and Arnold Seligman went to John Hopkins University School of Medicine, where he followed both a surgical and chemistry career [7]. The next major step in the development of peritoneal dialysis was the work done by Arthur Grollman, from Southwestern Medical School in Dallas, Texas [28]. It is interesting that, in reality, Grollman did not believe in the value of peritoneal dialysis for treatment of acute renal failure, which he thought could be managed by conservative

measures if they were properly applied [28]. His main interest was actually to find a simple way to prolong life of nephrectomized dogs, which he used to study the role of kidneys in hypertension [29]. His procedure involved the instillation by gravity of the irrigating fluid in the peritoneal cavity of the dogs, using a needle introduced in the peritoneal cavity through the flank [28]. The fluid was left in the abdomen for variable periods of time, and then removed using the same size needle connected by an adapter to a rubber tube. The drainage was followed by refilling. The procedure was carried out twice daily in the morning and late afternoon and kept the dogs alive for

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30–70 days after bilateral nephrectomy, compared to the previously reported average of 10 days. Although he called this technique an intermittent peritoneal lavage, it was actually a continuous type of peritoneal dialysis in the way we classify it today, because he did not have periods of a “dry” abdomen. He called it intermittent because it did not involve continuous instillation of the dialysis fluid, but rather the fluid was left to dwell in the peritoneal cavity for various periods of time. He considered that more frequent exchanges were not necessary to prolong a dog’s life, but could further decrease the level of urea and other catabolites. His kinetic studies showed that urea reaches equilibrium in 2 h after filling the peritoneal cavity of dogs with 1 L of fluid containing different concentrations of glucose. He also paid attention to the volume of fluid removed with peritoneal lavage using various concentrations of glucose in the dialysis solutions and using variable periods of time. In humans, he found equilibrium time for urea, electrolytes, creatinine, and glucose after 2 h, using 2–3 L instillation volumes of dialysis solution. He described the use of his method in five human patients. The dialysis fluid composition was modified based on patient needs and “intermittent” exchanges of 2 h duration were done for 16–48 h. The access used was for the first time a plastic tube, “to which omentum does not attach itself” [28]. The single plastic catheter was kept in place for the entire procedure and was used for both inflow, when it was attached through a needle to the infusion bottle, and outflow, when it was connected to an adapter and rubber tube for drainage. One of his patients survived, two others had some improvement in their clinical condition but died after peritoneal dialysis was stopped, and the other two did not improve at all with peritoneal dialysis. He did not have any peritonitis in humans; there was one episode in a dog dialyzed for 70 days, due to a break in the aseptic technique. Grollman considered his method superior to the continuous lavage previously described because of its simplicity and possibly increased efficiency in removal of the waste products. His technique did not require “the complex apparatus, multiple incisions, and constant attention necessary when one

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utilizes a constant perfusion technique as advocated by previous investigators” [28]. Additionally, he considered that continuous irrigation can create a “channeling” of the fluid between the inflow and outflow and be less efficient in urea removal due to decrease in available surface for exchange.

The Modern Era of Peritoneal Dialysis The modern era of peritoneal dialysis started with Morton Maxwell in 1959 [30]. Maxwell started training in renal physiology with Homer Smith at the New York University School of Medicine in 1948. After he joined the staff of the VA Hospital in Los Angeles, California, he purchased a Kolff twin-coil kidney machine and started using it. He found this procedure “formidable” and expensive, with narrow applicability due to necessity of dedicated medical staff with special training, who had to work long hours to prepare the machine, deliver the treatment, and clean up after a 6-h-long session [31]. He turned his attention to peritoneal dialysis and found Grollman’s technique promising in its simplicity and worked on refining it. One of the obstacles he wanted to eliminate was the laborious way of extemporaneous preparation of dialysis solutions. Access-related complications were also a great limiting factor in peritoneal dialysis and he started experimenting with different catheters. Maxwell introduced a semirigid nylon catheter with a curved tip and numerous tiny distal perforations, which, similar to plastic catheters, caused less omental reaction than the rubber and metal tubes. Because it was semirigid, it did not have the tendency to kink as did other plastic catheters developed in the early 1950 s, and, by decreasing the diameter and increasing the number of very small perforations in the distal end, he prevented portions of the omentum from entering the catheter and this resulted in better performance. He convinced the Don Baxter Company of Glendale, California, and Cutter Laboratories of Berkeley, California, to produce a standard dialysis solution in 1-L sterile glass bottles, special Y-type administration tubing, and the new type of catheter [29, 30]. The peritoneal

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dialysis procedure involved insertion of the catheter into the peritoneal cavity through an incision of the abdominal wall, below the umbilicus, using a 17 French Duke trocar set [31]. Then the catheter was attached to the Y-tubing, previously connected to 2 L of warmed dialysis solution (see Fig. 3). The paired bottles were hung above the bed level and the dialysis fluid was allowed to flow into the peritoneal cavity. The tubing was clamped when the bottles were empty with some

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fluid still present in the administration tubing, and the bottles were then lowered onto the floor. After 1 h dwell time, the clamps were removed and the fluid was permitted to flow out of the peritoneal cavity. When the drainage was complete, a new pair of dialysate bottles was connected to the catheter using new tubing. This “intermittent” procedure was continued for 12–36 h as required by the clinical situation and proved to be “mechanically successful” in 76 instances [31].

Fig. 3 Maxwell’s paired bottle technique. (From JAMA 1959, with permission)

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Maxwell and his colleagues specifically reported only six cases in their classical paper, with five survivors and one death after transient improvement with dialysis. Those patients who recovered had acute renal failure, barbiturate poisoning, intractable edema, hypercalcemia, and acute on chronic renal failure due to ureteral blockage. The new dialysis solution contained sodium in a concentration of 140 mEq/L, chloride 101 mEq/L, calcium 4 mEq/L, magnesium 1.5 mEq/L, dextrose 15 g/L, and, for the first time, lactate 45 mEq/ L. The lactate was replacing bicarbonate in the dialysis solution, eliminating the problem of precipitation of calcium salts. Potassium was excluded from the commercial dialysis solution because most of the patients with acute renal failure had hyperkalemia, but, if needed in patients with low serum potassium levels, it could be added to one of the bottles using a hypodermic syringe. The 1-L bottles were much easier to handle than the large carboys introduced by Fine’s group and generally used up to that point. If there was need for addition of other substances to the dialysis solution (potassium, dextrose, prophylactic antibiotics, heparin), they were added to one of the two bottles used for each exchange, a maneuver that, from their perspective, decreased the risk of peritonitis. Actually, they reported that in their experience peritonitis never occurred, although in fact the risk of contamination was still increased because the system was disconnected with each exchange. Their experience in patients with chronic renal failure was unsatisfactory, but they imagined that with further improvement of the technique, peritoneal dialysis could become more efficient so that it could be applied for shorter sessions of 6– 8 h duration. Theoretically, chronic patients could be admitted to the hospital at certain intervals and receive the peritoneal dialysis treatment, “in the same manner patients with refractory anemia are given transfusions at the present time” [31]. Although the procedure was still not ready for use in the treatment of chronic uremia, the fact that now it became a simpler nursing procedure and the dialysis solution was commercially available in 1-L bottles allowed it to be accepted and used more commonly as a treatment for acute

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renal failure. The new catheter used by Maxwell seemed to have fewer complications than previously used catheters and became widely used. At the same time, at the US Navy Hospital in Oakland, California, Paul Doolan and his team started research in dialysis, being stimulated once more by war casualties due to acute renal failure and hyperkalemia in the Korean War (1950–1953) [32]. Their goal was again to find a simple way to dialyze patients on the battle field or at the bedside, and found that peritoneal dialysis applied using Grollman’s intermittent flow technique was most appropriate. In the same year, 1959, they published their experience with the use of intermittent peritoneal lavage in ten patients [33]. They used dialysis solutions that were prepared in the hospital, with a lower content of sodium (128 meq/L), glucose used as an osmotic agent, and bicarbonate 28 mmol/L added as a buffer and, to avoid precipitation of calcium salts, they administered calcium parenterally. Potassium was added to the dialysis fluid as required by the clinical situation. Doolan and Murphy developed a polyvinyl chloride catheter with a straight intra-abdominal segment with multiple side holes, transverse ridges, and spiral grooves to avoid kinking and omental obstruction. William Murphy was the president of the Cordis Corporation and manufactured this catheter, but it did not become widely used because it was difficult to insert, sometimes even requiring laparotomy. Nevertheless, Doolan and his group used the catheter to successfully carry out intermittent flow peritoneal dialysis. The work of Maxwell and Doolan and the introduction of plastic catheters and commercially available “rinsing” solutions contributed to the widespread acceptance of peritoneal dialysis in the early 1960 s as a clinically feasible technique.

First Step in Long-Term Peritoneal Dialysis: Intermittent Peritoneal Dialysis The first chronic renal failure patient treated with long-term peritoneal dialysis was Mae Stewart, a 33-year-old black woman from San Francisco who had complications from a recent childbirth

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[32, 34]. In late 1959, she was referred to see Dr. Richard Ruben at Mt. Zion Hospital in San Francisco for management of her renal failure. Previously that year, Ruben had worked with Doolan at Oakland Naval Hospital, where he acquired the skills necessary to perform peritoneal dialysis. He started Stewart on peritoneal dialysis with the help of his colleagues, doctors A.E. Lewis and E. Hassid. She improved after the first dialysis session, with a decrease in serum creatinine form 20 to 13 mg/dL, but after a week her condition deteriorated again. They decided to leave the catheter in place in case they might need to use it again. As it turned out, the patient had small, shrunken kidneys and chronic renal failure due to glomerulonephritis, so her uremic symptoms returned after several days. She continued to receive in-hospital, weekly peritoneal dialysis treatments, using the same catheter left in place, so the Murphy-Doolan catheter was the first one used for chronic peritoneal dialysis. She was allowed to go home between treatments, where she was able to continue to take care of her family. Sometimes during treatments, she was disconnected from the closed system after inflow and was allowed to ambulate. She was kept on intermittent or “periodic” peritoneal dialysis for 7 months, and the catheter was replaced only once at 3 months after starting the treatment. Intraperitoneal antibiotics were administered occasionally to prevent the occurrence of peritonitis. Later during the treatment, the patient developed pericarditis, refused to continue further treatments, and died. Mae Stewart was the first patient maintained on chronic dialysis; she started treatment in January 1960 several months before Clyde Shields started chronic hemodialysis in Seattle in March 1960. Ruben and his collaborators wrote a report of this case and submitted it to the New England Journal of Medicine, but the manuscript was rejected for publication. During the early 1960 s, many centers were trying to use intermittent peritoneal dialysis in patients with end-stage renal failure. The results were disappointing mainly because of frequent episodes of peritonitis due to access infection or contamination during the repeated maneuvers of

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changing the bottles [35]. Survival was commonly limited to only few months. As the nylon catheters were found to be unsatisfactory for longterm use, many attempts in different centers were being made to design a safe and easy method to insert an access device that would permit reliable dialysate flow and limit the infectious and mechanical complications. During that time, significant results in chronic dialysis were accomplished at the University of Washington in Seattle, where Belding Scribner and Wayne Quinton were able to maintain end-stage renal disease patients on chronic hemodialysis. However, the number of patients was much higher than what they could accommodate, and also some of the patients were running out of sites for hemodialysis access, requiring other forms of chronic therapy. Scribner, the same as others during that time, thought that peritoneal dialysis could be a good alternative to hemodialysis and invited Dr. Fred Boen, a Dutch physician from Indonesian origin, educated and working in The Netherlands, to come to Seattle and work on peritoneal dialysis [36, 37]. Boen had become known for his work on the kinetics of peritoneal dialysis in patients with acute renal failure, which was the subject of his PhD thesis and was later published [38]. In January 1962, Boen and his team in Seattle began a program of long-term peritoneal dialysis, one of the first in the world. Around the same time, John Merrill started doing chronic peritoneal dialysis in Boston, at the Peter Bent Brigham Hospital, Harvard Medical School. Both groups presented their 3 months experience in April 1962 at the American Society for Artificial Internal Organs Meeting in Atlantic City, New Jersey [39–41]. At the same meeting, Dr. J. Garrett from the Albany Medical College, New York, mentioned that he had maintained a patient on intermittent dialysis for 9 months [42]. The Seattle group developed the first automatic peritoneal dialysis machine, which was designed with the goal of minimizing the risk of contamination of the dialysis solution at the time of each exchange and also to reduce the need for nursing attendance [40]. They returned to the closed system developed earlier by Frank, Seligman, and Fine and designed a similar but automatic one. The sterile

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History of Peritoneal Dialysis

dialysis solution was contained in 20-L carboys from where it was pumped into an elevated reservoir where the fill volume was preset, usually at 2 L. From there the fill volume would enter in the peritoneal cavity using gravity flow. The inflow, dwell, and outflow times were monitored by the system’s timers, which controlled the opening of the clamps and made the procedure automatic. They used a dwell time of 30 min. The disadvantage of the system was that the 20-L glass bottles were bulky and difficult to handle and, again, required special equipment for preparation and sterilization of the dialysis solution. The advantage was that it eliminated the need for frequent system openings during each exchange by replacing the individual 1-L bottles with large carboys containing the sterile dialysis solution; this way they decreased the risk of peritonitis by contamination. Later, they used a 48-L carboy, which made it possible to use a single container and a completely closed system for each dialysis session. Boen’s group, the same as Merrill’s group in Boston [41], tried to use a permanent, indwelling peritoneal device in order to make frequent access into the peritoneal cavity easier. Their idea was to

Fig. 4 Schematic representation of the Boen’s Button

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create an artificial and permanent conduit or channel through the abdominal wall, which would allow easy passage of a catheter into the peritoneal cavity and eliminate the need for repeated paracentesis. Boen’s access was the modification of a system developed by Garrett [40]. It was initially a Teflon hollow tube, replaced later by a silicon rubber, which was surgically implanted in the abdominal wall with one exit at the skin and the other one in the peritoneal cavity (see Fig. 4). The hollow tube had two perpendicular discs, one located just below the peritoneum in the peritoneal cavity and the other one in the abdominal wall. This tube allowed the repeated introduction of a catheter into the peritoneal cavity. At the end of the treatment, the catheter was withdrawn from the tube, which was then capped. The cap looked like a button at the skin surface and Boen’s device was later called “Boen’s button” or the “silastic button.” Others tried to create a subcutaneous access button, which required cannulation through multiple stab wounds in the skin [43]. The overall performance of these buttons turned out to be poor. Merrill reported the use of such a device in five patients who received 2 to 17 dialysis treatments [41]; one of the patients had acute renal

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failure and did not recover, two patients were dialyzed intermittently for 2 months and the other two for 3 months. One of them was even able to do eight dialysis treatments at home, with the help of her spouse. None of the patients developed clinical peritonitis, but all of them had technical failure of the access device: occlusion of the lumen due to fibrous tissue or omentum, bowel penetration, or disruption of the conduit. Garrett was also not getting good results with his button device, even after further improvements [42]. Kevin Barry and his team from the Walter Reed Army Institute of Research, Washington, D.C., considered the permanent, artificial intraabdominal conduit as a viable access option, and in order to make it easier to insert without the need of a surgical procedure, they developed a flexible, polyvinyl cannula implanted with the help of a trocar [44, 45]. The cannula had a balloon at the intraperitoneal end, which kept the device in place after it was expanded by infusion of saline. This device was able to accommodate the standard, nylon catheter. They recruited 116 investigators from several countries to participate in trials involving these polyvinyl cannulae [45]. Frequent complications were noted, including fluid leaks, separation of the intraperitoneal balloon, massive bleeding, and bowel perforation. This device has never gained popularity. Norman Lasker was one of those who used the Barry pericannula with some success [46, 47], but abandoned this method later in favor of the Roberts and Weston stylet catheter [47]. Other investigators were trying to find ways to use implanted, indwelling catheters without the need for artificial conduits. Gutch, for instance, from the Medical Service and Dialysis Unit of the V.A. Hospital in Lincoln, Nebraska, experimented with long-term catheters of different materials and found that silicon catheters were the least irritating and caused the least protein loss in the dialysis fluid [48, 49]. He reported the use of such silicone catheters for as long as 17 months, which was a significant achievement in survival of peritoneal dialysis patients; of note, this group preferred to dialyze patients daily, rather than two or three times a week, which was the common dialysis schedule during that time. Insertion of the catheter was done as usual, through a 24 French trocar.

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In 1964, Boen and his group became convinced that chronic indwelling conduits or catheters of any material were not practical for longterm peritoneal dialysis because of frequent episodes of peritonitis and adhesion formation causing technical difficulties and poor general condition [50]. Their experience in humans was limited to only two patients, but none of them did well using Boen’s button; their research in rats had demonstrated that polyethylene, Teflon, or silastic indwelling tubes inevitably produced adhesions and infections. As a result, Boen started using the “repeated puncture technique”: a new puncture and a new nylon catheter were used each time the patient was dialyzed. Using this technique in combination with the closed sterile dialysis system and their automatic cycling machine, their second patient had no peritonitis for more than 8 months, compared with the development of peritonitis after 10 weeks when using Boen’s button. The patient was dialyzed once weekly for 14– 22 h and maintained a good quality of life. The trocar used for the repeated puncture was the one described by McDonald [51, 52]. Dr. Harold McDonald was a urologist who became familiar with peritoneal dialysis while training at the Peter Bent Brigham Hospital in Boston, with John Merrill’s group in the early 1960s. There he witnessed an unsuccessful event of catheter insertion for peritoneal dialysis and became interested in developing a tool that could facilitate catheter placement and resolve the pericatheter leakage. He designed a smaller, 14 French trocar, with a triface pointed tip. The common catheters used at that time were 11 French in size and were introduced using a 24 French Duke or Ochner paracentesis trocar. This new trocar made a smaller hole in the abdominal wall for catheter insertion, which helped in diminishing leakage around the catheter.

The Tenckhoff Catheter In 1963, Henry Tenckhoff, a German physician, accepted a fellowship position at the University of Washington in Seattle, where he replaced Charles Mion, who was returning to France [36]. Tenckhoff also developed his interest in

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History of Peritoneal Dialysis

nephrology and dialysis while working in Boston with John Merrill. He could not nurture his interest for dialysis in Germany, and decided to return to the United States to continue working in dialysis. In 1964, Boen’s team started training patients for home intermittent peritoneal dialysis using the repeated puncture technique and the Seattle, automatic closed system [36, 53]. The patients were trained in the hospital and then sent home with the dialysis equipment; the dialysis solution was prepared in the hospital, sterilized in the 40-L glass containers, and delivered to the patient’s home at regular intervals. Dialysis was done weekly, usually on weekends. Tenckhoff had to go to the patient’s home and insert the peritoneal dialysis catheter and start the dialysis treatment, which was carried out for 20–22 h each session. After this time, the patient with the help of the spouse, would terminate the treatment, turn off the machine, and remove the catheter. Initially they used the McDonald trocar to insert the catheter, but afterwards they started using the Weston and Roberts stylet catheter, which helped further in reducing the problems of bleeding and leakage. The procedure was simple and allowed long-term survival without peritonitis. In 1965, the Seattle group had treated one patient at home for 1 year, and another patient was treated using the same technique, but in the hospital, for 2 years. Soon it became clear that more than once weekly treatments were needed for the home peritoneal dialysis patient, and Tenckhoff had to go now twice a week to the patient’s residence to start dialysis. Although the previous experience with permanent, indwelling catheters was not favorable, Tenckhoff recognized that, in order to make home peritoneal dialysis a viable procedure, a safe, permanent access to the peritoneal cavity was crucial [54]. Of the previously designed catheter, he believed that the Palmer–Quinton catheter was most appropriate for chronic use, with some improvements. Russell Palmer, a Canadian physician from Vancouver, was one of the first to do hemodialysis in North America, starting in 1946 [55]. In the early sixties he also became interested in peritoneal dialysis and became familiar with the work done in Seattle, including with the work of Wayne

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Quinton in developing the silicone arteriovenous fistula for hemodialysis. He asked Quinton to help him design a permanent peritoneal dialysis access and, after experimenting with different materials, they decided to use silicon rubber. Their final product was an 84-cm-long catheter, with a lumen of 2 mm [56]. The intraperitoneal portion was coiled and had numerous perforations extending 23 cm from the tip. At the middle of the length of the catheter, there was a triflange step for placing the catheter in the deep fascia and peritoneum. The catheter was introduced surgically in the peritoneal cavity through a midline incision located about 5 cm below the umbilicus. From this level, the extraperitoneal portion was tunneled under the skin and the exit site was in the left upper quadrant. This long, tunneled portion was designed to decrease the risk of infection due to migration of bacteria from the skin. The external portion of the catheter was capped between dialysis treatments. Although this design was innovative and allowed peritoneal dialysis treatments for more than a year, peritonitis continued to occur [57]. Tenckhoff took this catheter a step further and designed the access that is even today most commonly used for peritoneal dialysis [58]. The most important improvement was the addition of two Dacron felt cuffs, obviating the need for the triflange step, which was eliminated from the new design [54]. At that point, it was recognized that Dacron felt attached to the catheters improves tissue fixation, permits tissue ingrowth, and this way creates a barrier that reduces the chances of infection. McDonald also created a permanent silicon peritoneal catheter equipped with a Teflon velour skirt in the subcutaneous tissue and a Dacron sleeve in the intramural portion [59]. After extensive animal studies, Tenckhoff and Schechter decided that they would use a silicon catheter, of 40 or 75 cm length [54]. Two Dacron felt cuffs were attached to the silastic catheter in two places, dividing the catheter into three portions: the intraperitoneal portion was a straight 20-cm tube with 60 perforations in the area 15 cm from the tip. Some of the catheters also had a curled intraperitoneal section, similar to the one described by Palmer. One of the Dacron

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felt cuffs was located in the peritoneal cavity, abutting the parietal peritoneum. The intramural section was also tunneled under the skin, but in an arcuate pattern and varied in length from 45 to 10 cm. They shortened this segment as they felt that the presence of the two cuffs closed the catheter sinus tract at both sides and thus decreased the risk of bacterial invasion. The second cuff was placed in the subcutaneous tissue just beneath the skin. They also recommended the arcuate tunnel so that the external part of the catheter and the sinus were directed caudally. In 1968, Tenckhoff and Schechter presented their 4-year experience in eight patients: one catheter had been used without complication for as long as 14 months in one of the patients [54]. Although the Tenckhoff catheter has not completely eliminated the risk of peritonitis, it was a major breakthrough and became the most important factor in promoting peritoneal dialysis in other centers.

The Growth of and Disappointment with Intermittent/Periodic Peritoneal Dialysis The next limiting steps in the widespread use of home peritoneal dialysis was represented by the difficulties in providing the adequate supply of sterile peritoneal dialysis fluids to the increasing number of patients using this technique and patients’ problems in handling the large and heavy bottles [60]. The Seattle group was still preparing the dialysate in their hospital’s “fluid factory” and was shipping the 40-L containers to the patients’ homes. Charles Mion in France was using smaller, 10-L plastic containers connected in series for closed-circuit peritoneal dialysis [61]. The next proposal was to design a machine that could make sterile dialysate in the home of the patients, obviating the need for shipping large quantities of dialysate. Harold McDonald from the Department of Surgery – Urology, State University of New York, Downstate Medical Center, Brooklyn, New York – created a system that used tap water and dialysate concentrate, which could be integrated in an automatic peritoneal dialysis machine for hospital or home use [62]. Cold tap

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water, after going through a purifying and warming system, was mixed with the dialysate concentrate, and the resulting dialysis solution was further sterilized by passing through a 0.22μ millipore filter before entering the peritoneal cavity. McDonald presented his system at the American Society for Artificial Internal Organs Meeting in 1969 [62]. At the same meeting, Tenckhoff presented the first system of water purification, which was developed by the Seattle group [60]. The latter experimented with different methods of water or dialysate purification, including bacterial filtration, heat sterilization, and UV-light irradiation, and found that heat sterilization using a pressure boiler tank was the only way to achieve perfect sterilization. This system was further improved and allowed production of large quantities of safe, sterile dialysate in the hospital and at home; its disadvantages were the large weight and bulkiness, high cost, and requirement for high pressure and temperatures to operate. As a result of progress made in water treatment technology, Tenckhoff and his team were able to design a new, much smaller and extremely efficient and safe system [63]. This system used the reverse osmosis method to produce large quantities of sterile, pyrogen-free water from tap water and contributed to the increase in the number of home peritoneal dialysis patients, making the Seattle center one of the largest centers for home intermittent peritoneal dialysis in the 1970 s. In 1973, they reported the experience of 12,000 peritoneal dialysis treatments in 69 patients [61]. In 1977, 161 dialysis patients had been on dialysis at this center. The other large peritoneal dialysis center in North America at that time was in Toronto, Canada, [61]. In Europe, Charles Mion, formerly trained in Seattle, was directing the third most important center in the world, which was located in Lyon, France [64]. Dimitrios Oreopoulos accepted a position at the Toronto Western Hospital in 1970, to manage a four-bed intermittent peritoneal dialysis program with approximately 16 ambulatory patients [64]. He acquired knowledge about peritoneal dialysis while training in Belfast, Ireland, where he was using the Deane prosthesis to establish access. At the beginning of his experience in

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History of Peritoneal Dialysis

Toronto, he was able to maintain patients on peritoneal dialysis for up to 20 months, and their chronic peritoneal dialysis patient population increased steadily to close to 40 patients in a few years. At the same time, one of Oreopoulos’ former colleagues from Belfast, Dr., Stanley Fenton, started working at the Toronto General Hospital. Fenton had trained in Seattle with Scribner and Tenckhoff after leaving Belfast and before coming to Toronto. He had a few Tenckhoff catheters, which he showed to Oreopoulos who tried them and was so impressed with the results that he abandoned the Deane prosthesis and converted all patients to Tenckhoff catheters. Having this reliable permanent peritoneal access available, Oreopoulos began sending patients home with reverse osmosis systems. During the early 1970 s. the president of American Medical Products visited Toronto and introduced a simpler cycler machine to Oreopoulos, the one designed by Lasker. Norman Lasker [47, 65] was another pioneer in peritoneal dialysis, who had visited Seattle and studied the automated systems developed by Tenckhoff. He considered they were superior over the manual technique and the wider application of peritoneal dialysis could be facilitated if simpler machines would be available. With the help of Gottscho Packaging Equipment Company, he designed a simpler “peritoneal dialysis cycler.” Ira Gottscho was a business man whose daughter died of kidney disease and he established a foundation in her memory. Lasker’s peritoneal cycler was simple, efficient, and easy to use: it used gravity principles and eliminated pumps, and used commercially available 2-L bottles of dialysis solution and presterilized disposable tubing and bags. By connecting four bottles, an 8-L reservoir was obtained each time [47, 65]. Oreopoulos was the first to see the value of Lasker’s work and had 40–45 patients use his cycler [64]. Another innovation was also available in Canada: in 1973–1974, Baxter provided dialysis solution (Dianeal) in plastic bags and all patients started using this product, which became available in the United States in 1978. The high cost of care of dialysis patients was an additional factor that held back the dissemination

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of peritoneal dialysis. In the United States, new renal care legislation was approved in 1972 and Medicare started to cover medical expenses of end-stage renal disease patients in 1973 [47, 66], making peritoneal dialysis affordable. This modality was available not only in the hospital, but also as a home therapy, being delivered intermittently, usually three to four times a week for about 10 h per session [67]. As more experience started to accumulate, it became evident that real long-term success could not be achieved with intermittent peritoneal dialysis. In a 1979 analysis of the outcomes of chronic peritoneal dialysis therapy at the Seattle center, it was found that the cumulative technical survival rate was 72% for 1 year, 43% for 2 years, and only 27% for 3 years [68]. One of the leading causes of intermittent peritoneal dialysis failure was inadequate dialysis. Different approaches had been investigated in humans and animal models to increase the efficiency of intermittent peritoneal dialysis and summarized by Gutman also in 1979 [69]: increase of dialysate flow rate from the standard of 4 L/h to 12 L/h allowed only modest increase in clearance and was expensive, and increases in the dwell volumes over 3 L were uncomfortable for the patients. Other modalities explored were the use of tris-hydroxymethyl aminomethane (THAM) to increase the permeability of the peritoneal membrane, use of vasodilators to increase the effective surface area of the peritoneum, or the use of hypertonic solutions to increase solute removal by solvent drag [69]. None of these methods found applicability and intermittent peritoneal dialysis remained inferior to hemodialysis in terms of achievable small solute clearance. For this reason, peritoneal dialysis was considered a “second-hand” therapy for chronic renal failure until a new form of peritoneal dialysis was born in Austin, Texas.

Continuous Ambulatory Peritoneal Dialysis (CAPD) In 1975, a young, otherwise healthy patient entered the chronic hemodialysis program directed by Jack Moncrief at the Austin

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Diagnostic Clinic in Austin, Texas [67]. Each arteriovenous fistula that was created in this patient failed, and in the absence of a hemodialysis access, he was advised to move to Dallas, where an intermittent peritoneal dialysis program was available. He refused to relocate and his doctors were in the situation of losing this young father of four children due to the impossibility of providing life-saving dialysis therapy. One of Moncrief’s collaborators was Robert Popovich [67], a young biomedical engineer formerly trained in Seattle under Belding Scribner and Albert Babb. The case of their unfortunate patient was reviewed during a routine weekly meeting and the team decided to try peritoneal dialysis but in a new form, which would allow complete equilibration of plasma urea with peritoneal fluid and thus maximum urea removal with each dwell. They calculated what was the minimum volume of dialysis fluid required to remove the urea generated daily on a 1 g/kg protein diet, knowing that dialysate urea equilibrates with plasma urea in 2 h. In a 70-kg man who eats 1 g of protein per kilogram of body weight, daily urea generation will be 7000 mg per day. They decided that a level of 70 mg/dL for the blood urea nitrogen was desired. If at equilibrium dialysate urea concentration will be 70 mg/dL, then 10 L of dialysate are required daily in order to remove the generated urea and maintain a constant plasma urea concentration. The commercial dialysate solutions were available in 2-L glass bottles. Their prescription was for 2-L fill volumes, dwell time of at least 3 h, and a total of five exchanges per day. This prescription was applied to the patient using a Tenckhoff catheter as access, and improved and controlled the patient’s chemistries, volume, and clinical status [67]. Moncrief and Popovich called this procedure the “portable/ wearable equilibrium peritoneal dialysis technique” and they submitted the results of their first application of the technique as an abstract to the American Society of Artificial Organs in 1976 [67, 70]. This abstract was not accepted for presentation, probably because the name was confusing. In January 1977, Moncrief and Popovich attended the National Institute of Health

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Contractors Meeting, where they met Karl Nolph [71], who was practicing nephrology at the University of Missouri in Columbia, Missouri. Nolph became interested in the new technique and decided to start collaboration with the Austin group. During their initial discussions, they agreed that “continuous ambulatory peritoneal dialysis” (CAPD) might be a more appropriate name for the new modality [71]. They published the experience with nine patients treated for 136 patient weeks in a classical article that established the use of CAPD [72]. The procedure was simple and involved the continuous presence (i.e., all day long, 7 days a week) of dialysis solution in the peritoneal cavity. Manual exchanges were done 4–5 times a day, and the dialysis catheter was capped between the exchanges, allowing participation in daily activities. The dialysis was called “portable” or “internal” and did not require the presence of a machine [72]. Other advantages of CAPD were identified: it allowed continuous, steady state chemistries after a few weeks because there was constant removal of waste products from the body; the procedure could be done by the patient unaccompanied at home or “anywhere” dietary restriction was not necessarily severe (later it has been recognized that sodium restriction is actually very important); CAPD was better tolerated from the cardiovascular perspective; and larger molecule clearance was significantly higher compared with hemodialysis. CAPD did not eliminate one of the most important problems encountered in peritoneal dialysis, namely, peritonitis. On the contrary, the risk of peritonitis was higher because of increased number of connections per day. Their patients had peritonitis, on average, every 10 weeks [72]. Two further modifications of the technique contributed to the decrease of peritonitis rates and facilitated worldwide acceptance of CAPD: the first was the use of dialysate in plastic bags, introduced by Oreopoulos in Canada, and the second was the introduction of the innovative Y-set connector system by Buoncristiani in Italy [64, 71, 73].

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History of Peritoneal Dialysis

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CAPD with Plastic Bags

bag at the other end. After consulting with his Baxter representative, he realized they had the straight tube available from the reverse osmosis machine [64]. They started using this tube and developed the Toronto Western Hospital Technique for CAPD, known also as the “spike technique” [64, 74]. With this technique, their rate of peritonitis was decreased to one episode every 10.5 patient months [74]. As a result of this remarkable improvement and with substantial pressure from the groups in Columbia, Missouri, and Austin, Texas, and also from the National Institutes of Health, the Food and Drug Administration (FDA) finally approved the use of the plastic bags in the United States in October 1978 [64, 71].

In 1976, Jack Rubin [64, 71], one of the fellows trained at Toronto Western Hospital under Dr. Oreopoulos, was accepted by Dr. Nolph to come for further training and research at the University of Missouri in Columbia, Missouri. He became involved in the emerging CAPD program and was impressed with the new technique. A year later, he returned to Toronto and tried to convince Oreopoulos to adopt this new, continuous procedure that seemed to be better than the typical intermittent peritoneal dialysis. Because of the high peritonitis rates, he was hesitant to introduce it, until one of his patients, who had been on intermittent peritoneal dialysis for about 2 years, had to be admitted with complications related to uremia. She was severely underdialyzed, and Oreopoulos decided to give CAPD a try: she was started on CAPD on September 27, 1977 [64]. Her improvement was so dramatic that he decided to convert all his almost 40 home intermittent peritoneal dialysis patients to CAPD and was able to do this in only a few weeks [71, 73]. Patients’ acceptance was excellent and the patient population continued to grow at a fast rate at his center [64]. Because, at the time, dialysis solutions in plastic bags were only available in Canada, they adopted a slightly different technique: after filling the peritoneal cavity with 2 L of dialysis solution, the tubing connecting the bag with the dialysis catheter was clamped and the plastic bag was wrapped around the patient, without disconnecting the bag from the catheter. After 6 h, the empty bag was placed on the floor, the tubing was unclamped, and the dialysate was allowed to drain by gravity. When the drainage was complete, the bag was disconnected from the system and a new bag was connected to the permanent catheter to repeat the cycle. They initially used the standard Y-set for acute peritoneal dialysis. The unused arm of the Y-tube was closed and tightly wrapped with the bag, making the tubing system bulky and uncomfortable. Oreopoulos was trying to improve the tubing by eliminating the redundant part and create a straight tube with a Luer connector for connection with the catheter at one end and a spike for connection with the plastic

The Y-Set and “Flush Before Fill” Technique In the 1980 s, Dr. Umberto Buoncristiani [73] from Perugia, Italy, published incredible results with an innovative Y-set, which resulted in a significant drop in the peritonitis rates to one episode to every 40 patient-months [73]. Buoncristiani was searching for an original technique in part because his patients were refusing to switch from the intermittent modality to the more efficient CAPD, as they found the “wearable bag” distasteful [75]. He was more concerned about the high rate of peritonitis and was also trying to develop a system to decrease the risk of infection. He realized that the “contaminating act” takes place at the time when a connection is made between a new bag and the transfer set, followed by the filling phase, when the infused fluid carries bacteria into the peritoneal cavity [75]. He reintroduced the Y-tubing, connected with one arm to the catheter, and the other two arms of the “Y” to bags, one containing dialysate and the other one empty. With this technique, after the connections are made, before the draining is started, some fresh dialysate is washed out into the drainage bag, flushing with it any bacteria that might have contaminated the tubing at the time of the connection. This is followed by drainage of dialysate into the empty bag and then filling of the

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abdominal cavity with the new solution. After the infusion is finished, the two bags are disconnected and the Y-set is filled with an antiseptic. This technique is known as “flush before fill” or “flush after connect,” and the system is known as “the disconnect system” [73, 75]. The results were impressive, but they were not easily accepted in North America. The Italian group carried out a prospective, randomized controlled study to compare the Y-set with the standard spike system [76]. Their results were published in 1983 and were again remarkable: the peritonitis rate was one episode every 33 patient-months in the Y-set group, compared to one episode every 11.3 patient-months in the standard system [76]. A multicenter, randomized clinical trial was then carried out in Canada [77] and the results confirmed the Italian experience: their Y-connector group had one episode of peritonitis in 21.53 patient-months compared to one episode in 9.93 patient-months in the standard system group [77]. Subsequently, the Y-set technique has been accepted worldwide as standard. With these changes, the use of CAPD increased considerably all over the world, a trend that continued through the early 1990 s.

Automated Peritoneal Dialysis (APD) The use of machines for peritoneal dialysis was left behind for a while, as the CAPD technique proved to be much simpler and efficient than intermittent peritoneal dialysis [78]. After longterm use of CAPD, new problems have been discovered: patients were losing motivation after long periods of time using manual peritoneal dialysis; adequate dialysis was difficult to attain after the residual renal function was lost, especially in large patients, requiring an increase in the total volume of daily dialysis solution; recurrent peritonitis, especially due to touch contamination, continued to remain a problem and one of the main causes of technique failure. Interest in using the machines for peritoneal dialysis was re-established in early 1980 s. Diaz-Buxo and his collaborators [79] introduced an automated cycler to deliver three

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exchanges at night, during sleep. In the morning before disconnection, the machine filled the peritoneal cavity with fresh dialysate to be drained at night, when the patient connected again to the machine. The main goal of this modality was to reduce the number of manually performed connections, and thus decrease the risk of touch contamination and peritonitis. This procedure was also a continuous one, as the fluid was always present in the peritoneal cavity and it was thus called “continuous cyclic peritoneal dialysis” (CCPD). The dwell time was supposed to be for at least 3 h, allowing complete equilibration, and small solute clearance was comparable with CAPD. Basically, the CCPD schedule was a reversal of the CAPD schedule, with the three shorter dwells performed at night and one long dwell during the day. Around the same time, Price and Suki [80] described an “automated modification of prolonged-dwell peritoneal dialysis” (PDPD) [80], which was comparable to CAPD in improving blood chemistries and had lower peritonitis rate than CAPD, similar to results reported by Diaz-Buxo [79]. The continuous development of simpler cyclers and patient preferences has driven an increase in the use of cyclers over the years. This technique became more appealing for physicians after the development of the peritoneal equilibration test (PET) as a tool of defining peritoneal transport characteristics of individual patients [81]. Cycler-based prescription made it easier to deliver increased number of short time dwells for high transporters and maintain them on peritoneal dialysis. Later, the CANUSA study [82] showed a strong, positive correlation of the total small solute clearance with survival. National Kidney Foundation – Dialysis Outcome Quality Initiative (NKF – KDOQI) guidelines were published in 1997 and recommended a target weekly Kt/V of 2.0 for CAPD and 2.1 for CCPD, based on results of the CANUSA study [83]. The need to achieve these high targets drove an increase in APD utilization, because the use of automated machines allowed easier delivery of higher daily dialysate volumes. Subsequent reanalysis of the CANUSA study [84] showed that the decrease in the solute

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History of Peritoneal Dialysis

clearance over time was caused by uncompensated loss of residual renal function, suggesting that lower peritoneal clearance targets might be appropriate. This was confirmed by another 2 landmark studies, the ADEMEX study in 2002 [85] and the “Hong Kong” study in 2003 [86]. Even so, APD use has increased significantly since its reintroduction, probably because it allows positive changes in the lifestyle of dialysis patients. As a result of the ADEMEX [85] and “Hong Kong” study [86], new NKF- KDOQI guidelines were released in 2006 [87] recognizing that minimally acceptable weekly small-solute clearance for all forms of peritoneal dialysis is equal to at least a Kt/V urea of 1.7 and includes both peritoneal and residual kidney clearances. This new target would also allow more patients to stay or get started on peritoneal dialysis.

Peritoneal Dialysis Catheters The Tenckhoff catheter remains the gold standard for peritoneal dialysis access and is the most widely used [58]. Individual dialysis centers’ preferences for dialysis catheters are based on their particular experience and availability of other catheters. Various improvements were tried over the years in many centers, with the purpose of finding the best design with the lowest rates of mechanical and infectious complications. In Toronto, Dr. Oreopoulos, in collaboration with Gabor Zellerman, attached three silicon discs to the intraperitoneal segment in order to prevent obstruction and migration of the catheter [39, 64]. This catheter was further improved and two variations were described a few years later [88]: Toronto Western Hospital – type 1 and 2. The first type was a double cuff straight catheter with two silicone discs attached to the intraperitoneal segment, and the type 2 was further equipped with a Dacron disc and a silicone ring at the base of the intraperitoneal cuff, which was meant to improve the seal at the peritoneal hole and prevent leaks [88]. In 1980, Ash et al. [89] introduced a “column disc catheter,” which was abandoned later in favor

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of the “T-fluted” Ash catheter [90]. In 1983, the Valli catheter was described: the intraperitoneal segment was enclosed and protected from omental obstruction by a silastic balloon with many holes, which also was supposed to help selfpositioning [91]. The permanently bent intramural segment, known as the “swan neck” [92], decreased the risk of external cuff extrusion and it was introduced by Twardowski et al. in 1986. Two somewhat similar designs were introduced later: the Cruz (pail-handle) catheter in 1992 and the “Swan neck with elongated superficial cuff (Moncrief–Popovich)” in 1993 [39]. Twardowski and his collaborators at the University of Missouri, Columbia, Missouri, introduced several more modifications [39]: a Swan neck Missouri catheter has a slanted flange and bead attached below the deep cuff, to improve catheter fixation and decrease leaks; the Swan neck presternal catheter was introduced in 1992 and has a long, tunneled segment with the exit site located in the presternal area. This design was intended to decrease the rate of peritonitis.

Peritoneal Dialysis Solutions Peritoneal dialysis solutions have evolved over the years as well. The most commonly used today, the conventional PD solution is dextrose based, using glucose as an osmotic agent and lactate as a buffer. The pH of the conventional solution is low at 5.5 [93]. Other PD solutions are available, and were developed with the goal of increasing biocompatibility and reduce the risk of peritoneal membrane damage with long-term use [93]. Glucose and low pH have been associated with changes of the peritoneal membrane, when used for many years. Extraneal (Icodextrin) and Nutrineal are glucose-sparing solutions that use icodextrin and respectively amino acids as osmotic agent instead of glucose, same lactate as buffer, and also have a low pH [93]. Balance, BicaVera, Gambrosol, and Physioneal are glucose-based solutions, with a

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more physiologic pH that use lactate, bicarbonate, or a mix of the two as buffers [93]. The most widely nonconventional solution used today is 7%, Icodextrin which has the benefit of sustained ultrafiltration in long dwells thus offering increased net ultrafiltration and solute clearance [94].

Current State of Peritoneal Dialysis According to the 2018 USRDS Annual Data Report, in 2016 there were 124,675 newly reported cases of ESRD in the US and of these, only 9.7% started on PD [95]. In the same year there were 726,331 prevalent ESRD cases and 7% of them were treated with PD [95]. For various reasons, PD has never been the predominant form of renal replacement therapy in the US (Figs. 5 and 6). From 1980 to 1995 there has been a slow uptake and increase in the utilization of peritoneal dialysis, which then stabilized until 2011 (Figs. 5 and 6). This was the year when Medicare introduced a new payment method for dialysis, known as PPS short for Prospective Payment System, which incentivized the

D. Negoi and R. Khanna

use of peritoneal dialysis over hemodialysis [96]. As a result, there has been a slight growth of PD utilization in the following years, with an overwhelming growth in the rural areas of the USA [95–97]. The penetration of PD in other parts of the world has been variable, partly due to the availability of hemodialysis, PD knowledge among nephrologists and differences in reimbursement of hospitals and doctors. Yet, in Europe the survival of patients starting renal replacement therapy with PD is similar if not better than in those starting on hemodialysis [98]. Development of new cyclers and technology allowed a continuous growth of CCPD. Many patients prefer this modality as it allows more freedom during the day. In 1996, 9.1% of the prevalent ESRD patients were on CAPD and 4.7% on CCPD, compared to 1.8% on CAPD and 8.2% on CCPD in 2016 [95]. In regards to cost of dialysis, Medicare costs for ESRD were $35.4 billion between 2015 and 2016, accounting for 7.2% of overall Medicare paid claims, with peritoneal dialysis been less costly than HD on a per-patient basis in 2016 ($76,177) than HD ($90,971) [95].

Fig. 5 Trends in the annual number of ESRD incident cases, by modality, in the US population, 1980–2016 from USRDS ADR 2018

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History of Peritoneal Dialysis

23

Fig. 6 Trends in the number of ESRD prevalent cases, by modality, in the US population, 19,802,016 by ADR 2018

Table 2 Milestones in the development of clinical peritoneal dialysis Investigator Ganter [21, 22] Wear, Sisk, and Trinkle [23, 26] Frank, Seligman, and Fine [7, 25, 27] Grollman [28] Maxwell [31] Doolan [33] Rubin [32, 34] Boen [36, 37, 40] Boen [50] Tenckhoff [54] Popovich and Moncrief [72] Oreopoulos [64] Buoncristiani [73] Diaz-Buxo Price and Suki [79, 80]

Description First human peritoneal dialysis First successful treatment of ARF with PD Seminal studies of PD in ARF in animals and humans Long-dwell PD for uremia in animals and humans IPD for ARF, commercially available dialysis solutions, and nylon catheter IPD for ARF, PVC catheter First long-term IPD for CKD First program of long-term PD first automatic peritoneal dialysis machine Repeated puncture technique Tenckhoff catheter CAPD CAPD with plastic bags “Flush before fill” APD/CCPD

Date 1923 1938 1946– 1948 1951 1959 1959 1959 1962 1964 1968 1978 1977 1980 1981

ARF acute renal failure, PD peritoneal dialysis, IPD intermittent peritoneal dialysis, PVC polyvinyl chloride, CKD chronic kidney disease, CAPD continuous ambulatory peritoneal dialysis, APD automated peritoneal dialysis, CCPD continuous cyclic peritoneal dialysis

24

Conclusion Development of peritoneal dialysis has been a fascinating intellectual, scientific, and medical journey. Table 2 illustrates the most important moments in the history of peritoneal dialysis, and the most important scientists who made the development of this life-saving treatment possible and applicable to patients afflicted with severe kidney disease.

References 1. Maher J. Antecedents of Dialysis: the evolution of knowledge of uremic biochemical toxicity and therapeutic Bloodwashing. Semin Dial. 1991;4(3):185–8. 2. Cameron J. The science of dialysis:‘uraemic toxins’. History of the treatment of renal failure. Oxford: Oxford University Press; 2002. p. 15–23. 3. Maher J. The origins of American nephrology (1800– 1850). J Am Soc Nephrol. 1991;1(10):1128–35. 4. Gottschalk CW, Fellner SK. History of the science of dialysis. Am J Nephrol. 1997;17(3–4):289–98. 5. Cameron J. The science of dialysis: osmosis, diffusion and semipermeable membranes. History of the treatment of renal failure by dialysis. Oxford: Oxford University Press; 2002. 6. Drukker W. Hemodialysis: a historical review. In: JF M, editor. Replacement of renal function by dialysis. Dordrecht/Boston/Lancaster: Kluwer Academic Publishers; 1989. 7. McBride P. The development of the atomic bomb and a treatment for renal failure. Perit Dial Int. 1982;2:146– 8. 8. McBride P. The development of hemodialysis and peritoneal dialysis. In: Maher JF, editor. Clinical dialysis. New York: McGraw Hill Medical Publishing Division; 2005. p. 1–25. 9. Cunningham R. The physiology of the serous membranes. Physiol Rev. 1926;6:242–56. 10. McBride P. Taking the first steps in the development of peritoneal dialysis peritoneal Dialysis. Bulletin. 1982;2:100–2. 11. Recklinghausen F. Die Lymphgefasse und ihre Beziehung zum Bindegewebe. Berlin: Hirschwald; 1862. 12. Recklinghausen F. Zur Fettresorbtion. Virchows Arch. 1863;26:172–208. 13. Wegner G. Chirurgische Bemerkungen uber die Peritonealhohle, mit besonderer Berucksichtigung der Ovariotomie. Arch f Klin Chir. 1877;20:51–145. 14. Nolph K. Peritoneal dialysis. In: Brenner B M RFC, editor. The Kidney. 3rd ed. Philadelphia: Ardmore Medical Books, W.B. Saunders Company; 1986. p. 1847–84.

D. Negoi and R. Khanna 15. Starling EHTA. The influence of mechanical factors on lymph production. J Physiol. 1894;16:140–8. 16. Cunningham R. Studies on absorption from serous cavities. III. The effect of dextrose upon the peritoneal mesothelium. Am J Physiol. 1920;53:548–65. 17. Putnam T. The living peritoneum as a dialyzing membrane. Am J Physiol. 1923;63:548–65. 18. Engel D. Beitrage zum permeabilitats problem: entgiftungsstudien mittels des lebenden Peritoneums als “Dialysator”. Z Ges Exp Med Physiol. 1927;55: 574–601. 19. Abel JJRL, Turner BB. On the removal of diffusible substances from the circulating blood of living animals by dialysis. J Pharmacol Exp Ther. 1914;5:275–316. 20. Cameron J. The search for better dialysis membranes: the peritoneum and the beginnings of peritoneal dialysis. History of the treatment of renal failure by dialysis. Oxford: Oxford University Press; 2002. p. 44–60. 21. Teschner MHA, Klassen A, et al. Georg Ganter – a pioneer of peritoneal dialysis and his tragic academic demise at the hand of the Nazi regime. J Nephrol. 2004;17:457–60. 22. Ganter G. Uber die Beseitigung giftiger Stoffe aus dem Blute durch Dialyse. Munch Med Wochenschr Munch Med Wochenschr. 1923;70:1478–81. 23. Odel HMFD, Power MH. Peritoneal lavage as an effective means of extrarenal excretion. A clinical appraisal. Am J Med. 1950;9:63–77. 24. Seligman AMHA, Fine J. Treatment of experimental uremia by means of peritoneal irrigation. J Clin Invest. 1946;25:211–9. 25. Frank HASA, Fine J. Treatment of uremia after acute renal failure by peritoneal irrigation. JAMA. 1946;130: 703–5. 26. Wear JBSI, Trinkle AJ. Peritoneal lavage in the treatment of uremia; an experimental and clinical study. J Urol. 1938;39:53–62. 27. Frank HASA, Fine J. Further experiences with peritoneal irrigation for acute renal failure. Ann Surg. 1948;128:561–608. 28. Grollman ATL, McLean JA. Intermittent peritoneal lavage in nephrectomized dogs and its application to the human being. Arch Int Med. 1951;1951(87):379– 90. 29. Cameron J. The spread of dialysis technology for acute renal failure (1947–1960). History of the Treatment of Renal Failure by Dialysis. Oxford: Oxford University Press; 2002. p. 121–56. 30. McBride P. Morton Maxwell: he made acute peritoneal dialysis a routine procedure. Perit Dial Int. 1984;4:58– 9. 31. Maxwell MRR, Kleeman CR. Peritoneal dialysis. JAMA. 1959;170(8):917–24. 32. McBride P. Paul Doolan and Richard Rubin: performed the first successful chronic peritoneal dialysis. Perit Dial Int. 1985;5:84–6. 33. Doolan PDMW, Wiggins RA, et al. An evaluation of intermittent peritoneal lavage. Am J Med. 1959;26: 831–44.

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34. Cameron J. New materials and methods II: long-term peritoneal dialysis becomes possible. History of the Treatment of Renal Failure by Dialysis. Oxford: Oxford University Press; 2002. p. 201–8. 35. Boen STCF, Tenckhoff H, et al. Chronic hemodialysis and peritoneal dialysis. Proc Eur Dial Transplant Assoc. 1964;1:221–3. 36. McBride P. Henry Tenckhoff: the father of chronic peritoneal dialysis. Perit Dial Int. 1983;3:47–52. 37. McBride PFT, Boen MD. The man who brought science to the art of peritoneal dialysis. Perit Dial Int. 1982;2:50–3. 38. Boen S. Kinetics of peritoneal Dialysis. Medicine. 1961:243–87. 39. Twardowski Z. History of peritoneal access development. Int J Artif Organs. 2006;29(1):2–40. 40. Boen STMA, Dillard DH, et al. Periodic peritoneal dialysis in the management of chronic uremia. Trans Am Soc Artif Intern Organs. 1962;8:256–62. 41. Merrill JPSE, Henderson L, et al. The use of an inlying plastic conduit for chronic peritoneal irrigation. Trans Am Soc Artif Intern Organs. 1962;8:252–5. 42. Kolff WJWW, Garrett J, et al. Discussion at the eighth annual meeting of the American Society for artificial internal organs, Atlantic City, New Jersey, April 13– 14, 1962. Trans Am Soc Artif Intern Organs. 1962;8: 263–5. 43. Malette WGMJ, Bledsoe F, et al. A clinically successful subcutaneous access for repeated peritoneal dialysis. Trans Am Soc Artif Intern Organs. 1964;10:396–8. 44. Barry KGSG, Goler D. A new flexible cannula and seal to provide prolonged access to the peritoneal cavity for dialysis. Trans Am Soc Artif Intern Organs. 1963;9: 105–7. 45. Barry KGSF, Matthews FE. Further experience with the flexible peritoneal cannula in several hospital centers. Trans Am Soc Artif Intern Organs. 1964;10:400– 5. 46. Friedman EALN, Schreiner GE. Discussion at the tenth annual meeting of the American Society for Artificial Internal organs, Chicago, Illinois, April 12–13, 1964. Trans Am Soc Artif Intern Organs. 1964;10:408. 47. McBride P. Norman Lasker: making the first steps towards automated chronic peritoneal dialysis. Perit Dial Int. 1983;3:168–9. 48. Gutch C. Peritoneal dialysis. Trans Am Soc Artif Intern Organs. 1964;10:406–7. 49. Gutch CFSS. Silastic catheter for peritoneal dialysis. Trans Am Soc Artif Intern Organs. 1966;12:106–7. 50. Boen STMC, Curtis FK, et al. Periodic peritoneal dialysis using the repeated puncture technique and an automatic cycling machine. Trans Am Soc Artif Intern Organs. 1964;10:409–13. 51. McBride P, McDonald H Jr. Developing some of the ABC’s of peritoneal dialysis. Perit Dial Int. 1981;1: 109–12. 52. McDonald H. A peritoneal dialysis trocar. J Urol. 1963;89:946–7. 53. Tenckhoff HSG, Boen ST. One year’s experience with home peritoneal dialysis. Trans Am Soc Artif Intern Organs. 1965;11:11–4.

25 54. Tenckhoff HSH. A bacteriologically safe peritoneal access device. Trans Am Soc Artif Intern Organs. 1968;14:181–6. 55. McBride PRA, Palmer MD. The man behind today’s permanent peritoneal catheter. Perit Dial Int. 1981;1: 156–8. 56. Palmer RAQW, Gray JE. Prolonged peritoneal dialysis for chronic renal failure. Preliminary communication. Lancet. 1964;1(7335):700–2. 57. Palmer RANJ, Gray JE, et al. Treatment of chronic renal failure by prolonged peritoneal dialysis. N Engl J Med. 1966;274(5):248–53. 58. Negoi DPB, Twardowski ZJ. Current trends in the use of peritoneal dialysis catheters. Adv Perit Dial. 2006;22:147–52. 59. McDonald HPGN, Mishra D, et al. A subcutaneous Dacron and Teflon cloth adjuncts for silastic arteriovenous shunts and peritoneal dialysis catheter. Trans Am Soc Artif Intern Organs. 1968;16:176–80. 60. Tenckhoff HSG, Van Paasschen WH, et al. A home peritoneal dialysate delivery system. Trans Am Soc Artif Intern Organs. 1969;15:103–7. 61. Boen S. History of peritoneal dialysis. In: Nolph KD, editor. Peritoneal dialysis. 3rd ed. Dordrecht/ Boston/London: Kluwer Academic Publishers; 1989. p. 1–12. 62. McDonald H. An automatic peritoneal dialysis machine for hospital or home peritoneal dialysis: preliminary report. Trans Am Soc Artif Intern Organs. 1969;15:108–11. 63. Tenckhoff HMB, Shilipetar G. A simplified automatic peritoneal dialysis system. Trans Am Soc Artif Intern Organs. 1972;18:436–9. 64. Nolph KD, Khanna R. Dimitrios Oreopoulos: Fondly remembered and greatly missed. Perit. Dial. Int. 2012;32(4):373–374. 65. Lasker NME, Passarotti CT. Chronic peritoneal dialysis. Trans Am Soc Artif Intern Organs. 1966;12:94–6. 66. Nissesnson A. Restructuring the ESRD payment system in the United States. Kidney Int. 2004;66:466–76. 67. Moncrief JWPR, Nolph KD. The history and current status of continuous ambulatory peritoneal dialysis. Am J Kidney Dis. 1990;16:579–84. 68. Ahmad SGN, Shen F. Intermittent peritoneal dialysis: status re-assessed. Trans Am Soc Artif Intern Organs. 1979;25:86–8. 69. Gutman R. Towards enhancement of peritoneal clearances. Dial Transplant. 1979;8:1072–6. 70. Popovich RPMJ, Decherd JF, et al. The definition of a novel portable/wearable equilibrium dialysis technique. (Abstract). Trans Am Soc Artif Intern Organs. 1976;5:64. 71. Nolph KD. 1975 to 1984 – an important decade for peritoneal dialysis: memories with personal anecdotes. Perit Dial Int. 2002;22:608–13. 72. Popovich RPMJ, Nolph KD, et al. Continuous ambulatory peritoneal dialysis. Ann Intern Med. 1978;88(4): 449–55. 73. Oreopoulos D. A backward look at the first 20 years of CAPD. Perit Dial Int. 1998;18:360–2.

26 74. Oreopoulos DGRM, Izatt S, et al. A simple and safe technique for continuous ambulatory peritoneal dialysis (CAPD). Trans Am Soc Artif Intern Organs. 1978;24:484–7. 75. Buoncristiani U. Birth and evolution of the “Y” set. ASAIO J. 1996;42(1):8–11. 76. Maiorca RCA, Cancarinin GC, et al. Prospective controlled trial of a Y-connector and disinfectant to prevent peritonitis in continuous ambulatory peritoneal dialysis. Lancet. 1983;2:642–4. 77. Chruchill DNTD, Vas SI, et al. Peritonitis in continuous ambulatory peritoneal dialysis (CAPD): a multicenter randomized clinical trial comparing the y-connector disinfectant system to standard systems. Perit Dial Int. 1989;9:159–63. 78. Venkataraman VNK. Utilization of PD modalities: evolution. Semin Dial. 2002;15(6):380–4. 79. Diaz-Buxo JAFC, Walker PJ, et al. Continuous cyclic peritoneal dialysis – a preliminary report. Artif Organs. 1981;5:157–61. 80. Price CGSW. Newer modifications of peritoneal dialysis: options in treatment of patients with renal failure. Am J Nephrol. 1981;1(2):97–104. 81. Twardowski ZJNK, Khanna R, et al. Peritoneal equilibration test. Perit Dial Bull. 1987;7:138–47. 82. Churchill DNTD, Keshaviah PR. 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. 83. Golper TCD, Burkart J, et al. NKF – KDOQI clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis. 1997;30:S67–136. 84. Bargman JMTK, Churchill DN. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol. 2001;12:2158–62. 85. Paniagua RAD, Vonesh E, et al. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol. 2002;13:1307–20.

D. Negoi and R. Khanna 86. Lo WK, Ho YW, Li CS, Wong KS, Chan TM, Yu AW, et al. Effect of Kt/Von survival and clinical outcome in CAPD patients in a randomized prospective study. Kidney Int. 2003;64(2):649–56. 87. Burkart JM, Piraino B et al. Clinical practice guidelines for peritoneal adequacy, update 2006. Am J Kidney Dis. 2006;48:S91–S7. 88. Ponce SPPA, Izattt S, et al. Comparison of the survival and complications of three permanent peritoneal dialysis catheters. Perit Dial Bull. 1982;2:82–6. 89. Ash SRJH, Hartman J, et al. The column disc peritoneal catheter. A peritoneal access device with improved drainage. ASAIO J. 1980;3:109–15. 90. Ash SRJE. T-fluted peritoneal catheter. Adv Perit Dial. 1993;9:223–6. 91. Valli ACU, Midiri O, et al. 18 months experience with a new (Valli) catheter for peritoneal dialysis. Perit Dial Int. 1983;3:22–4. 92. Twardowski ZJKR, Nolph KD, et al. Preliminary experience with the Swan Neck peritoneal dialysis catheters. ASAIO Trans. 1986;32:64–7. 93. McIntyre C. Update on peritoneal dialysis solutions. Kidney Int. 2007;71(6):486–90. 94. Wolfson M OF, Mujais S. Review of clinical experience with icodextrin. Kidney Int. 2002;62:S46–52. 95. United States Renal Data System. https://www. usrds.org 2018. 96. Wang V, Coffman CJ, Sanders LL, Lee S-YD, Hirth RA, Maciejewski ML. Medicare’s new prospective payment system on facility provision of peritoneal Dialysis. Clin J Am Soc Nephrol. 2018;13(12):1833. 97. Lin E, Cheng XS, Chin K-K, Zubair T, Chertow GM, Bendavid E, et al. Home Dialysis in the prospective payment system era. J Am Soc Nephrol. 2017;28(10): 2993. 98. van de Luijtgaarden MWM, Jager KL, Segelmark M, Pascual J, Collart F, Hemke AC, et al. Trends in dialysis modality choice and related survival in the ERA-EDTA registry over a 20-year period. Nephrol Dial Transplant. 2016;31:120–8.

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Current Status and Growth of Peritoneal Dialysis Fahad Aziz and Ramesh Khanna

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Trends in the PD Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trends in Catheter Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trends in Connectology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trends in PD Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trends in Types of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28 28 29 29 30

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Number of Patients on PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth of Automated PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting the Choice of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31 31 31 31

Outcomes of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemodialysis and Peritoneal Dialysis: Survival Comparison . . . . . . . . . . . . . . . . . . . . . . . . . . . Residual Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adequacy of Small Molecule Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutritional Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiovascular Effects of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anemia in Patients on PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infectious Complications of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Encapsulating Peritoneal Sclerosis (EPS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32 32 33 33 34 34 35 35 36 36 36

F. Aziz (*) Division of Nephrology, University of Wisconsin, Madison, WI, USA e-mail: [email protected] R. Khanna School of Medicine Department of Medicine, Division of Nephrology, Health Sciences Center, Columbia, MO, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 R. Khanna, R. T. Krediet (eds.), Nolph and Gokal's Textbook of Peritoneal Dialysis, https://doi.org/10.1007/978-3-030-62087-5_41

27

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F. Aziz and R. Khanna Psychosocial Benefits of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Financial Benefits of PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Abstract

The use of peritoneal dialysis (PD) in end-stage renal disease is a well-known renal replacement modality now. The interest in using PD for ESRD has been increasing over the last three decades. Due to its high cost and infrastructural benefits over hemodialysis (HD), PD is often used in developing countries, where cost and available sources constitute a significant issue. This chapter discusses (a) development of PD, (b) trends in different aspects of PD, and (c) advantages and disadvantages of PD.

Introduction The history of dialysis goes back to 1940. Dutch physician Willem Kolff had first gotten the idea of developing a machine to clean the blood after seeing patients suffering from kidney failure. He developed the first type of dialyzer, and then called it “the artificial kidney,” in 1943 [1]. With a better understanding of the solute and water kinetics over the last six decades, PD has now been successfully used for both acute kidney injury and end-stage renal disease [2–4]. With the improvement in the surgical techniques of PD catheter placement, frequency of PD catheter-related infections and mechanical complications have gone down significantly. With these significant advances, PD has grown worldwide to become the third most common modality for renal replacement. This chapter will review a brief overview of the significant advances and growths in the world of PD.

Trends in the PD Technique The basic PD system consists of a (1) PVC bag, (2) transfer set, and (3) catheter access to the peritoneal cavity. The introduction of

sterile plastic bags for dialysate was a significant advancement in the world of PD [5]. In the last two decades, significant advances occur in the PD system and methods of insertion of the PD catheter.

Trends in Catheter Design Maxwell initially introduced multiple side-hole catheters, which improved the performance of the system, and then by introducing a semirigid nylon design, they prevented catheter kinking. They then introduced a “paired bottle” technique, which used gravity for installation and drainage [6, 7]. In 1965, Henry Tenckhoff began to treat the patients with end-stage renal disease on chronic peritoneal dialysis [8]. He introduced the concept of home peritoneal dialysis by using silicon rubber tubing, which can be used multiple times. His technique was successful in his hands but was overall cumbersome. This initial design underwent multiple revisions until the most successful design was introduced, which consisted of a silicone rubber tube with a coiled intraperitoneal portion and two Dacron cuffs at the peritoneum level, promoting tissue ingrowth which prevents peri-catheter leaks. This catheter was named after Dr. Tenckhoff. The Tenckhoff catheter became the gold standard for peritoneal access. Even after 50 years, the Tenckhoff catheter in its original form has remained the most widely used catheter type [9, 10]. With more use, it has been found that these catheters are associated with (1) exit-site infection, (2) recurrent peritonitis, (3) external cuff extrusion, and (4) obstruction due to change in the position of the catheter and omental wrapping around the catheter. PD catheter designs have been changed over time in multiple ways, which include several cuffs (single

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Current Status and Growth of Peritoneal Dialysis

vs. double), design of subcutaneous pathway (swan-neck vs. straight), and the intra-abdominal portion (straight vs. coiled) [11]. Double-cuff catheters have been shown to be associated with a lower incidence of infections, including peritonitis and exit-site infections [12–14]. In 1976, Stephen et al. introduced a subcutaneous catheter to prevent exit infections [15]. Their catheter had two tubes in the peritoneal cavity with a subcutaneous reservoir. With each dialysis, the reservoir needed to be punctured. However, with recurrent access to the reservoir, peritonitis episodes became a problem. Later, Gotloib et al. introduced a prosthesis, consisting of a Teflon tube [16]. With the head located in the subcutaneous tissue and the tube penetrating through the parietal peritoneum, the prosthesis was implanted surgically. Several catheters have been introduced since then to decrease various complications associated with the standard Tenckhoff catheter. In 1985, Twardowski et al. introduced silicone rubber “swan-neck” catheters [17]. These catheters are permanently bent between two cuffs. Insertion without distorting the shape of the catheter is the most important advantage of these catheters. Later, Twardowski et al. introduced modified “swan-neck” catheters with exit site on the chest instead of the abdomen [18, 19]. By changing the exit site to the chest, peritonitis can significantly be reduced in patients with paraplegia, obesity, hernias, or pediatric patients. With the advancement in the catheter designs and insertion techniques, the 1-year catheter survival is over 80% now [20]. The skills of surgeons or interventional nephrologists involved in the implantation of the catheter and careful monitoring of the PD team involved in catheter care are the most important predictors of catheter survival and complications.

Trends in Connectology The first bag-and-spike system was associated with a high incidence of infections due to touch contamination. Buoncristiani et al. introduced a

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double-bag Y-set device that used a disconnect system with a flush before technique [21]. This technique showed a significant reduction in the incidence of peritonitis [22–25]. With the tremendous success in the technique in Italy, more than 90% of all patients in North America, Europe, Australia, and New Zealand are now using disconnect devices [26].

Trends in PD Solutions Initially, the composition of the PD fluids used to be normal saline to 5% dextrose [27]. Odell et al. found that the dialysis fluid with high-sodium concentrations was associated with hyperchloremic acidosis [28]. Maxwell is primarily responsible for the introduction of glucose-based dialysate solutions [29]. The osmotic agent glucose was buffered with lactate or acetate to produce a low pH of 5.2 to avoid the caramelization during heat sterilization of the PD solutions. The shortcomings of PD-based solution is now wellrecognized [30]. The exposure of the peritoneal membrane to glucose and glucose degradation products leads to ultrafiltration failure in PD patients [31, 32]. To reduce the acidity of the peritoneal fluid and to reduce the glucose degradation products, the multi-bag system is currently available. In these systems, the glucose solution is separated from the buffer. This helps to get the glucose stored at a very low pH and thus decreases the formation of glucose degradation products during heat sterilization. Some studies suggested survival advantage and preservation of the residual renal function with these new systems [33, 34]. Icodextrin is a glucose polymer that has undergone clinical trials since the 1990s [35]. The molecular size of icodextrin is larger than that of glucose and is very slowly removed from the peritoneal cavity via lymphatics. Due to its molecular structure, it allows sustained ultrafiltration during long dwells [36]. The use of 7.5% of icodextrin for an overnight exchange in patients with CAPD can generate 3.5 times greater ultrafiltration at 8 h than the 1.5% dextrose solution

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and similar to the 4.25% dextrose solution [37]. Similarly, as compared to standard glucose solutions, the use of icodextrin in continuous cyclic PD (CCPD) is associated with significantly higher ultrafiltration, increased peritoneal clearance, increased sodium removal, and better preservation of residual renal function [38–41]. In fast transporters, ultrafiltration during the long daytime CCPD dwell with icodextrin is superior to that obtained with 4.25% dextrose [42]. No significant adverse effects were noticed with the use of icodextrin in patients with CAPD and CCPD. However, the use of icodextrin is associated with increased serum maltose and rarely skin rash [43–46]. With a better understanding of the importance of ultrafiltration, icodextrin-based peritoneal solutions are increasingly being used in clinical practice in many countries. Being cheap, safe, and readily available dextrose-based solutions remained the most widely used PD solutions. To date, no other osmotic agent has been shown superior to dextrose [47]. As malnutrition is common in the PD patients, amino acid-containing peritoneal dialysis solutions have been proposed to improve nutritional status in PD patients [48] possibly. With the amino acid absorption from the peritoneal membrane, the nutritional status of the patients can be improved [48]. When used in a 1.1% solution, amino acid-based PD solutions are shown to improve the nutritional status of the patients [49]. Like icodextrin, amino acid-based peritoneal solutions are more compatible with the peritoneal membranes than conventional dextrose-based solutions [50–52]. The common side effects of these solutions include the worsening of acidosis and a rise in blood urea nitrogen (BUN). Xylitol-containing PD solutions have been tried in diabetic patients. An early study found this solution very helpful in avoiding the metabolic complications of diabetes [53]. However, due to its potential side effects like lactic acidosis, hyperuricemia, and worsening liver function, it is not used anymore [47]. PD solutions with neutral pH and reduced glucose degradation products (GDPs) have been approved by the European Drug Registry [54].

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Trends in Types of PD Automated PD (APD) APD defines all forms of peritoneal dialysis using a cycler to perform the dialysis exchanges. APD regimens include (1) CCPD, (2) intermittent PD, (3) nocturnal intermittent peritoneal dialysis (NIPD), and (4) tidal peritoneal dialysis (TPD). Studies looking at the outcomes in patients on APD have generally been small and have conflicting results. Lobbedez et al. reported a more than 80% 1-year survival in patients on APD [55]. However, Povlsen et al. found a survival rate of only 58% in patients on APD with decreased functional status [56]. As patients on APD are a self-selected group, it is difficult to compare the outcomes of this group with others. Early studies also showed a decreased incidence of peritonitis and hospital admissions in patients on APD as compared to the patients on CAPD [57]. However, later studies failed to confirm the lower incidence of peritonitis in APD patients [58]. APD has several advantages over CAPD, like better solute clearance and reduced incidences of hernias [59]. APD, mainly intermittent nocturnal PD, also has been shown to have more psychosocial and physical benefits over CAPD [59]. With frequent rapid exchanges and shorter dwell times, APD is also considered to be more suitable in patients who are fast transporters [59]. The most crucial advantage of APD compared to CAPD is the better quality of life [58, 60]. Assisted PD As per one study, patients undergoing assisted PD appear to have a higher risk of infections than family-assisted patients [61]. Assisted PD is usually offered to the patients who can be trained to perform the manual PD. Many centers have demonstrated the safety of assistance for PD treatment by district or private nurses at the patient’s home for physically dependent or elderly patients [55, 62]. Home nurses are sometimes needed to optimize the care given at home. Boyer et al. conducted a retrospective, multicenter study based on data from the French Language

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Peritoneal Dialysis Registry. They analyzed 11,987 patients who started PD in France from January 1, 2006, to December 31, 2015. 51% of patients were on assisted PF, 82% on nurseassisted PF, and 18% on family-assisted PD during the study period. In the adjusted analysis, the use of nurse-assisted PD increased significantly after 2012, whereas family-assisted PD utilization decreased linearly over time (prevalence ratio ¼ 0.94, 95% CI 0.92–0.97) [63].

Epidemiology Number of Patients on PD The costs of HD and PD vary across the world [64]. As the PD is a cheaper form of dialysis, many countries implemented a public policy that promotes the use of cheaper therapy in patients with end-stage renal disease [64]. During the 1980s, rapid growth occurred in the utilization of PD. The rapid growth continued between 1990 and 1995. During that time, the annual global growth rates of PD reached 15% [26]. By the end of 1997, the number of patients on chronic PD reached 115,000, representing 14% of the world dialysis population [65]. The popularity of PD in that area was due to several reasons, including: 1. 2. 3. 4. 5.

A cheaper form of dialysis. Readily available. Easy to understand by the nephrologists. Its use in emergencies. It can be started in any location.

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ultrafiltration in the last 15 years also led to a decline in the use of PD [69]. Further, the corporation of dialysis care in the United States also led to a significant decline in the use of PD. The utilization of PD is different among countries [70]. The proportion of patients on dialysis treated with PD varies from 20% to 30% in the Scandinavian countries; 5 to 10% in France, Germany, and the United states; and 2 to 4% in some countries like Chile [70]. The utilization of PD even varies inside the United States. In 2004, the prevalence of PD ranged from 5% in New York to 10.8% in Network 16 (Alaska, Idaho, Montana, Oregon, and Washington) [67]. In Italy, the disparity in the use of PD among regions has increased, varying from 0% to 55% [71]. In France, there are significant differences in the use of PD, and the percentage of patients treated with PD can vary from 0% to 22% between different towns in the same region [72]. In Romania, the share of the dialysis pool of incident patients has increased from 10% in 1995 to 29% in 2004 [73].

Growth of Automated PD With the expansion of CAPD programs in the 1980s–1990s, the number of patients on PD increased overall [73, 74]. This growth in PD is driven by patient preference and the development of new and simpler cyclers [10, 75]. With further advancements in the cyclers, it is expected that the CAPD will continue to grow.

Factors Affecting the Choice of PD However, after 2000, there is a slow, gradual decrease in PD use worldwide [66]. At the end of 2004, 149,000 patients were undergoing PD, representing 11% of the world dialysis population [67]. This drop-in PD is multifactorial. Due to barriers to self-care, the utilization of PD declined among elderly patients, and the elderly are the most significant and fastest-growing group of patients with chronic kidney disease [68]. Setting unrealistic goals for the solute clearance and

Multiple factors affect the choice of PD in patients with end-stage renal disease. A few important factors are described below.

Medical Factors For technical reasons, PD is the modality of choice in infants and small children with renal failure [76]. The presence of medical contraindications to PD is more frequent when compared to

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hemodialysis. In one study, previous major abdominal surgery was the most common medical contraindication followed by cystic kidneys, poor lung function, chronic inflammatory bowel disease, and poor cardiac condition [77, 78]. Unfortunately, most patients deemed to have a social contraindication to PD were judged by the nephrologist to be incapable of performing the treatment by themselves. The number of patients with contraindication to PD increases with age. However, studies show that up to 70% of adults have neither medical nor social contraindications to either maintenance HD or chronic PD [79, 80]. Recently Aziz et al. reviewed the PD options in patients with different abdominal complications. They concluded that when appropriately planned, PD can still be an acceptable option for patients with end-stage renal disease and certain abdominal complications [81].

Patient Education Pre-dialysis care is shown to be associated with a great probability of selection of PD [82– 85]. Adequate pre-dialysis education is associated with a far higher probability of choosing home dialysis [86, 87]. APD provides a better quality of life. Many patients, who want to continue work, prefer APD over the in-center dialysis. The patients must be explained all possible modalities available for the renal replacement therapies at the time of their dialysis education. Physician Bias Physician bias plays a vital role in the utilization of PD [88]. As per one study, only 25% of the patients who chose HD reported that PD was discussed with them, whereas 68% of the patients who chose PD reported that HD was discussed with them [67]. One study from the United States confirmed that the majority of patients are not presented with the choice of either chronic PD, home HD, or renal transplantation (66, 88, and 74%, respectively) [80]. An incomplete discussion about the available renal replacement therapies leads to decreased selection of PD and delays the access to transplantation. Reimbursement for pre-dialysis education may ensure timely access to renal replacement therapies.

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Economic Factors The effect of economic factors on the selection of dialysis modality varies by region of the world. In Europe and America, it appears that the higher the involvement of the “public” (as opposed to “private”) facilities in the provision of dialysis care, the larger the proportion of dialysis patients on chronic PD [88–90]. In these areas of the world, the cost of health-care workers in the provision of dialysis therapy is higher than the cost of dialysis supplies. Thus, delivering hemodialysis is much more expensive than PD [90]. However, in many Asian and African countries, the workforce is substantially cheaper than the cost of dialysis supplies, which are often imported from Western countries. This makes hemodialysis more economical than PD in these societies [91]. Manufacture of dialysis solutions in developing countries has gone a long way in making PD affordable in some of these societies. The impact of physician reimbursement on the choice of PD has been thought to be an essential factor in the selection of PD [71, 88]. However, the financial incentives in Germany, Canada, and the United States have not translated into a higher utilization of PD [92, 93].

Outcomes of PD Hemodialysis and Peritoneal Dialysis: Survival Comparison Over the last three decades, multiple studies were done to compare mortality risks in patients on HD and PD [94–104]. Luijtgaaren et al. reviewed data of 196,076 patients from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. They found that although initiating PD was associated with favorable patient survival when compared with starting on HD treatment, PD was often not selected as initial dialysis modality [103]. A higher comorbidity burden diminishes the advantage of PD and may even be associated with an increased risk after 1–2 years [105]. It continues to be unclear, if the difference in the outcomes is from the dialysis modality or from the

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inability of our statistical tools to adjust for the patient characteristics. Considering these factors, the patient choice should take preference in the selection of dialysis modality.

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and nonsteroidal anti-inflammatory drugs should be avoided in patients with any degree of residual renal function.

Technique Failure Residual Renal Function Residual renal function in patients with ESRD plays a vital role in maintaining (1) removal of middle molecules, (2) fluid balance, (3) removal of uremic toxins, and (4) phosphorous [106]. The presence of residual renal function is associated with overall better patient survival. However, it’s still a matter of discussion if the improved mortality is from higher urine production or with other kidney functions like tubular secretions [107, 108]. Some studies have shown inverse relationships with valvular calcifications and cardiac hypertrophy in patients with ESRD with residual renal function [106, 109]. Several studies have shown that residual renal function is better preserved in patients on PD as compared to the patient on HD [110–113]. As per one study, the patients on PD have 30% higher residual renal function as compared to the patients on hemodialysis [113]. The use of nephrotoxic medications and dehydration is usually associated with a rapid decline in residual function in patients on PD. Considering the importance of maintaining residual renal function, special measures should be taken to preserve the renal function on PD [114]. Residual renal function should be monitored regularly. This should be done with a 24-h collection of urine every 1–3 months to measure volume and urea and creatinine clearances. The arithmetic mean of urea and creatinine clearance is the best approximation of residual glomerular ultrafiltration rate [115, 116]. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to play an important role in the preservation of residual renal function [117]. Although the use of loop diuretics increases diuresis and natriuresis and helps in maintaining the fluid balance, they do not affect the preservation of residual renal function [118]. The use of nephrotoxic medications like aminoglycosides

PD outcomes are described by technique failure in patients on PD. It usually implies the transfer of patients from PD to HD. The PD technique survival varies between the different countries and even between the different centers in the same country [119–122]. Almost by definition, technique failure is a soft end point, because it will always be influenced by physician bias. Something perceived by one physician as a reason to transfer a PD patient to HD may be judged differently by another. Multiple factors influence the PD technique survival: (1) Some racial groups may have short-term technique survival than others [120]. (2) Late referral for PD is more likely to be transferred to HD than those who are referred early [11]. (3) In one study, female sex was associated with a decreased rate of technique failure [123]. (4) Uncontrolled systolic blood pressure has also been associated with an increased incidence of technique failure [123]. With the improvement in patient selection, referral timings, appropriate training, and aggressive management of complications, it is possible to obtain 1-year technique survival over 80% [124, 125]. As per one study, 1-, 2-, and 3-year technique survival was 87%, 76%, and 68%, respectively [126]. Infections continue to be the leading cause of PD technique failure [127, 128]. With a better understanding of the infections related to PD, the rate of infections has significantly decreased in the last two decades. Over time, the PD technique may fail in some patients due to structural and functional changes in the peritoneal membrane from the use of conventional bio-incompatible PD solutions, which are hyperosmolar and acidic and contain very high concentrations of glucose and glucose degradation products [129–131]. The peritoneal membrane can be protected from the long-term toxic and metabolic effects of glucose and glucose degradation products by the use of new so-called

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biocompatible PD solutions, which have a normal pH and a reduced content of glucose degradation products, but still contain glucose as an osmotic agent. Retrospective studies have shown that it may be possible to increase peritoneal technique survival by the use of icodextrin-based peritoneal dialysis fluids [38, 132–134]. An extensive discussion on biocompatible PD solutions and icodextrin is given in the chapter on new PD solutions.

Adequacy of Small Molecule Clearance Earlier the attempts to measure the effects of dialysis were focused on the function of the hemodialysis membranes. However, it was commonly accepted that subjective clinical judgment was enough for determining that a patient was well dialyzed on PD [135]. The concept of urea kinetic modeling was first extended to PD in the mid-1980s [136]. However, it was until the 1990s that the kinetic modeling was systematically investigated in PD patients [137– 139]. Based on some of these, especially the CANUSA study [140], KDOQI guidelines recommended a target Kt/V urea of 2.0 per week and a creatinine clearance of 60 L/week/1.72 m2 body surface for CAPD, and somewhat higher levels were recommended for APD [141]. However, a reanalysis of the CANUSA study showed evidence that the effect of solute removal on outcome was entirely attributable to the effect of residual renal function [142]. To overcome the effect of residual renal function, the importance of the dialysis dose on outcome has been evaluated in four different studies in patients with no urine output; these studies suggest a minimum threshold of peritoneal Kt/Vurea of 1.5–1.7 [143– 146]. However, none of these studies was randomized. Two randomized controlled clinical trials were also not able to demonstrate an improvement in survival by increasing the peritoneal small solute clearances [147, 148]. Based on these observations, various expert groups now recommend a minimum total Kt/Vurea of 1.7 [149]. Furthermore, it has been recognized that besides solute removal, the achievement of

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euvolemia should be an essential goal of adequate dialysis [145, 149].

Nutritional Status Multiple studies showed that protein-energy wasting is widely prevalent in PD patients [150, 151]. Protein-energy wasting is a strong predictor of mortality in patients on dialysis [152]. This critical association assesses the nutritional status of the patients on PD, an essential clinical priority. As per one estimate, 40% of the patients on PD have protein-energy malnutrition, with 5–10% of patients demonstrating severe malnutrition. Suboptimal protein intake is an important cause of nutritional decline in PD patients [153].

The Malnutrition-InflammationAtherosclerosis (MIA) Syndrome The combination of malnutrition, inflammation, and atherosclerotic vascular disease is referred to as MIA syndrome [154]. Several studies have shown the interrelation between malnutrition, inflammation, and atherosclerotic vascular disease, and each one of them is associated with increased mortality in the patient on dialysis [155]. Stenvinkel et al. suggested two types of protein-energy wasting in ESRD patients. The first type (type 1) is characterized by a modest reduction in serum albumin due to low dietary intake. It is associated with the uremic syndrome or factors associated with uremia such as physical inactivity, underdialysis, dietary restrictions, and psychosocial factors. On the other hand, type 2 protein-energy wasting, characterized by significant comorbid conditions, severe hypoalbuminemia, and an inflammatory response evidenced by higher levels of CRP and pro-inflammatory cytokines, may be more challenging to treat [154]. Protein Loss in the Dialysate It is a well-known fact that the PD is associated with a significant amount of protein loss in the dialysate [156]. As per the European guidelines on peritoneal dialysis, nutrition in patients on PD should include protein loss in the dialysate

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[157]. Due to a number of nighttime exchanges and the duration of dwell, APD may be associated with somewhat higher-protein losses as compared to CAPD patients [158].

Strategies to Improve Protein-Energy Wasting in PD Patients Multiple interventions have been described to improve the protein-energy wasting in patients on dialysis [153]. Some of the crucial strategies are described below: (a) Residual renal function Residual renal function plays a vital role in maintaining the nutritional status of patients on chronic dialysis [159]. Loss of residual renal function is associated with anorexia, severe malnutrition, and muscle wasting [150]. Hence, preserving renal function is also extremely important to preserve the nutritional status of this important group of patients. (b) Small solute clearances Several cross-sectional studies have shown a relationship between the peritoneal clearances, the dietary protein intake, and the nutritional status of patients [160, 161]. In the CANUSA study, the addition of dialytic clearances resulted in a marked increase in solute clearances during the first 6 months of CAPD. This led to significant improvement in several estimates of nutritional status, and these changes were significantly correlated with the estimates of the dose of dialysis [162]. (c) Correction of metabolic acidosis The adverse effects of chronic metabolic acidosis on nutritional status are well documented [163–165]. Further, the studies have shown improvement in the nutritional status and reduced hospitalization with the correction of metabolic acidosis in patients on PD [166, 167]. (d) Role of intraperitoneal amino acid solutions Two metabolic balance studies have demonstrated that intraperitoneal amino acid solutions induce anabolism, particularly when a surfeit of calories (as with glucose-based

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dialysate) is provided [49, 168]. However, subsequent randomized controlled clinical trials have demonstrated that the nutritional benefits of these solutions may be modest [153].

Obesity Early studies on CAPD focused on weight gain during PD [169]. Many PD patients experience significant weight gain upon initiation of therapy, but weight usually stabilized after that [170]. The weight gain appears to correlate with the daily amount of glucose absorbed from the dialysate and seems to be most prominent in patients who are already obese at the start of treatment [171]. More recently, the impact of obesity on the outcomes of dialysis patients has been questioned. Unlike the observations in the general population, in HD patients, obesity appears to be associated with improved survival [172]. The advantage associated with obesity in PD patients appears, though, to be less pronounced [173, 174]. In a report from the Australian and New Zealand registry, among patients undergoing PD, obesity was associated with worse outcomes and a higher risk for peritonitis [175, 176].

Cardiovascular Effects of PD With the better preservation of the residual renal function, PD is associated with better fluid and blood pressure control than hemodialysis [177, 178]. Multiple cardiac issues have been reported with hemodialysis, including high-output heart failure due to arteriovenous fistula, increased incidence of de novo heart failure, and myocardial stunning [169, 179]. None of these adverse cardiovascular outcomes have been observed in patients on PD. However, the gradual loss of residual renal function and peritoneal membrane over several years leads to increased risk of hypertension and volume overload in patients on PD [180]. It has been shown that the loss of residual renal function is associated with increased mortality and cardiovascular death risk in patients on

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PD [181]. While traditional risk factors like diabetes mellitus, hypertension, smoking, physical inactivity, obesity, and hyperlipidemia contribute substantially to cardiovascular disease in the general population, nontraditional risk factors like inflammation, anemia, and abnormal mineral metabolism are probably also important in dialysis patients [182]. Further, inflammation, indicated by elevated serum concentrations of acute phase proteins or cytokines, is associated with worse outcome in dialysis patients. These inflammatory manifestations interact with many pathophysiologic pathways that lead to vascular damage [183].

Anemia in Patients on PD There is significant evidence that the treatment of anemia in dialysis patients improves the quality of life and objective markers of physical and cognitive performance [184]. Anemia has been shown to contribute to left ventricular hypertrophy [185]. While correction of anemia is recommended in patients on dialysis, complete correction of anemia cannot be recommended due to a lack of evidence that complete correction of anemia can be beneficial [186, 187].

Infectious Complications of PD Infectious complications have been well described in the literature and are considered the primary cause of PD technique failure and loss of catheter [20, 128, 188]. With the advancement in PD technique in the last two decades, the incidence of peritonitis in PD patients has significantly decreased [189, 190]. The first step in preventing catheter-related infections is ensuring that an experienced operator places the PD catheter under sterile conditions. The risk can be further reduced by using exit-site antibiotic prophylaxis by employing either mupirocin or gentamicin [191]. Guidelines for prevention, diagnosis, and treatment of infectious catheter-related complications were first published in 1983, have been revised several times, and are evidence-based when evidence existed [190]. Despite these guidelines, it is highly recommended that each

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center should modify its protocol based on their own experience with the infections in PD patients [192].

Encapsulating Peritoneal Sclerosis (EPS) EPS is a rare but life-threatening complication of peritoneal dialysis [193, 194]. It develops in 0.7 to 3.3% of patients, especially after a PD duration exceeding 3 years [195]. The high mortality of, on average, 40% after 1 year has been documented in many studies [195]. More details are given in the chapter on encapsulating peritoneal sclerosis. Optimal patient management requires a high index of suspicion for the diagnosis of the condition. Appropriate investigations include longitudinal modified peritoneal equilibration tests using 3.86/4.25% glucose dialysate with D/P sodium assessment after 1 h and regular measurement of CA125 or another biomarker in the dialysate. A recent analysis reported that free water transport after 60 min less than 75 mL had a sensitivity of 100% and a specificity of 81% for the clinical diagnosis of EPS within 1 year [196]. Combining free water transport with an effluent biomarker increased the specificity to 94%. These encouraging results require further confirmation. CT scanning of the abdomen for detecting fibrosis, thickening of the peritoneum, and calcifications may be helpful. There is no agreement about the therapy of choice for EPS, although it is generally agreed that total parenteral nutrition, steroids, and, sometimes, surgical enterolysis maybe important components [193]. Treatment of EPS with tamoxifen can be beneficial [197]. The cause of EPS may be multifactorial. Given that only a small proportion of patients develop EPS, it is proposed that genetic factors may set up a predisposition for this lifethreatening complication [198]. To address further research on this rare entity, international collaboration in the form of a global registry and DNA bank has recently been proposed [198]. Fortunately, the incidence of EPS has declined in some countries, like Japan, Germany, and the Netherlands, possibly due to the increased use of biocompatible PD solutions.

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Psychosocial Benefits of PD As compared to HD, PD offers excellent flexibility to the patients in terms of time management. Patients on PD are trained to adapt the PD prescription to their daily life activities. Patients on PD visit PD clinic every 4–12 weeks as compared to the patients on hemodialysis who visit the dialysis unit thrice weekly. Further, the technical simplicity of PD allows the patients to perform PD while traveling without any facility support. This high autonomy in PD patients results in higher employment rates in patients on PD as compared to the patients on HD [199]. One prospective cohort study involving 37 dialysis centers in the United States showed that the patients on PD rated their care higher than the patients on HD [200]. These results were recently confirmed [201]. Assisted PD is an excellent form of dialysis in suitable patients with disabilities, where the caregivers can administer PD at home [200, 202].

Financial Benefits of PD Due to the lower staff-to-patient ratio, PD has a significantly lower actual cost as compared to the HD [203, 204]. As per US data, the annual cost for dialysis care is $24,293 higher for patients on HD as compared to PD [204]. As per one Canadian study, even with PD technique failure and transitioning to HD, there is a significant financial benefit of starting dialysis with PD as compared to HD [205]. Another critical direct cost in dialysis patients is related to the use of erythropoietin-stimulating agents. One study found three to four times higher doses to be used in patients on HD as compared to the patients on PD [206].

Future Directions PD provides an adequate form of renal replacement therapy for patients with end-stage renal disease. The studies suggest at least similar outcomes with PD when compared to other renal replacement therapies. In many aspects, i.e., the

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ease of use and less need of technology and being cost-effective, PD is in several aspects superior to other forms of renal replacement therapies. However, the PD prescription needs to be individualized based on individual patient needs. PD is also an effective renal replacement modality in neonates and children with end-stage renal disease. However, also in this population, the PD prescription needs to be prescribed carefully based on the individual needs of neonates and children. The main challenge for the future is the establishment of PD as a mode of long-term renal replacement therapy that can be performed for many years as second best to kidney transplantation. Better training of nephrologists in all aspects of PD is a prerequisite. Important issues include better regular assessment of peritoneal function with a shift in patient surveillance from the importance of solute transport to that of fluid status, including peritoneal ultrafiltration and its mechanisms. On top, real long-term PD will only be possible with more biocompatible PD solutions than the currently available ones, in which glucose exposure is markedly reduced, for instance, by the use of combinations of osmotic agents, all in a low concentration.

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F. Aziz and R. Khanna management: a randomized controlled trial. Clin J Am Soc Nephrol. 2011;6(6):1337–44. 134. Silver SA, Harel Z, Perl J. Practical considerations when prescribing icodextrin: a narrative review. Am J Nephrol. 2014;39(6):515–27. 135. Twardowski ZJ, Nolph KD. Peritoneal dialysis: how much is enough? Semin Dial. 1988;1:75. 136. Teehan BP, Schleifer CR, Sigler MH, Gilgore GS, et al. A quantitative approach to the CAPD prescription. Perit Dial Bull. 1985;5:152–6. 137. Blake PG, Sombolos K, Abraham G, Weissgarten J, Pemberton R, Chu GL, et al. Lack of correlation between urea kinetic indices and clinical outcomes in CAPD patients. Kidney Int. 1991;39(4):700–6. 138. Lameire NH, Vanholder R, Veyt D, Lambert MC, Ringoir S. A longitudinal, five year survey of urea kinetic parameters in CAPD patients. Kidney Int. 1992;42(2):426–32. 139. Maiorca R, Cancarini GC, Brunori G, Camerini C, Manili L. Morbidity and mortality of CAPD and hemodialysis. Kidney Int Suppl. 1993;40:S4–15. 140. Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. Canada-USA (CANUSA) Peritoneal Dialysis Study Group. J Am Soc Nephrol. 1996;7(2):198–207. 141. Di Giulio S, Meschini L, Triolo G. Dialysis outcome quality initiative (DOQI) guideline for hemodialysis adequacy. Int J Artif Organs. 1998;21(11):757–61. 142. Bargman JM, Thorpe KE, Churchill DN, Group CPDS. 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(10):2158–62. 143. Bhaskaran S, Schaubel DE, Jassal SV, Thodis E, Singhal MK, Bargman JM, et al. The effect of small solute clearances on survival of anuric peritoneal dialysis patients. Perit Dial Int. 2000;20(2):181–7. 144. Szeto CC, Wong TY, Chow KM, Leung CB, Law MC, Wang AY, et al. Impact of dialysis adequacy on the mortality and morbidity of anuric Chinese patients receiving continuous ambulatory peritoneal dialysis. J Am Soc Nephrol. 2001;12(2):355–60. 145. Jansen MA, Termorshuizen F, Korevaar JC, Dekker FW, Boeschoten E, Krediet RT, et al. Predictors of survival in anuric peritoneal dialysis patients. Kidney Int. 2005;68(3):1199–205. 146. Lo WK, Lui SL, Chan TM, Li FK, Lam MF, Tse KC, et al. Minimal and optimal peritoneal Kt/V targets: results of an anuric peritoneal dialysis patient’s survival analysis. Kidney Int. 2005;67(5):2032–8. 147. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, et al. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol. 2002;13(5):1307–20. 148. Lo WK, Ho YW, Li CS, Wong KS, Chan TM, Yu AW, et al. Effect of Kt/V on survival and clinical outcome in CAPD patients in a randomized prospective study. Kidney Int. 2003;64(2):649–56.

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149. Lo WK, Bargman JM, Burkart J, Krediet RT, Pollock C, Kawanishi H, et al. Guideline on targets for solute and fluid removal in adult patients on chronic peritoneal dialysis. Perit Dial Int. 2006;26(5):520–2. 150. Young GA, Kopple JD, Lindholm B, Vonesh EF, De Vecchi A, Scalamogna A, et al. Nutritional assessment of continuous ambulatory peritoneal dialysis patients: an international study. Am J Kidney Dis. 1991;17(4):462–71. 151. Cianciaruso B, Brunori G, Kopple JD, Traverso G, Panarello G, Enia G, et al. Cross-sectional comparison of malnutrition in continuous ambulatory peritoneal dialysis and hemodialysis patients. Am J Kidney Dis. 1995;26(3):475–86. 152. Jadeja YP, Kher V. Protein energy wasting in chronic kidney disease: an update with focus on nutritional interventions to improve outcomes. Indian J Endocrinol Metab. 2012;16(2):246–51. 153. Mehrotra R, Kopple JD. Protein and energy nutrition among adult patients treated with chronic peritoneal dialysis. Adv Ren Replace Ther. 2003;10(3):194–212. 154. Stenvinkel P, Heimburger O, Lindholm B, Kaysen GA, Bergstrom J. 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(7):953–60. 155. Kaysen GA. Association between inflammation and malnutrition as risk factors of cardiovascular disease. Blood Purif. 2006;24(1):51–5. 156. Guedes AM. Peritoneal protein loss, leakage or clearance in peritoneal dialysis, where do we stand? Perit Dial Int. 2019;39(3):201–9. 157. Dombros N, Dratwa M, Feriani M, Gokal R, Heimburger O, Krediet R, et al. European best practice guidelines for peritoneal dialysis. 3 Peritoneal access. Nephrol Dial Transplant. 2005;20(Suppl 9): ix8–ix12. 158. Westra WM, Kopple JD, Krediet RT, Appell M, Mehrotra R. Dietary protein requirements and dialysate protein losses in chronic peritoneal dialysis patients. Perit Dial Int. 2007;27(2):192–5. 159. Wang AY, Sea MM, Ip R, Law MC, Chow KM, Lui SF, et al. Independent effects of residual renal function and dialysis adequacy on actual dietary protein, calorie, and other nutrient intake in patients on continuous ambulatory peritoneal dialysis. J Am Soc Nephrol. 2001;12(11):2450–7. 160. Bergstrom J. Why are dialysis patients malnourished? Am J Kidney Dis. 1995;26(1):229–41. 161. Caravaca F, Arrobas M, Dominguez C. Influence of residual renal function on dietary protein and caloric intake in patients on incremental peritoneal dialysis. Perit Dial Int. 1999;19(4):350–6. 162. McCusker FX, Teehan BP, Thorpe KE, Keshaviah PR, Churchill DN. How much peritoneal dialysis is required for the maintenance of a good nutritional

43 state? Canada-USA (CANUSA) Peritoneal Dialysis Study Group. Kidney Int Suppl. 1996;56:S56–61. 163. Soleymanian T, Ghods A. The deleterious effect of metabolic acidosis on nutritional status of hemodialysis patients. Saudi J Kidney Dis Transpl. 2011;22(6):1149–54. 164. de Oliveira CM, Vidal CL, Cristino EF, Pinheiro FM Jr, Kubrusly M. Metabolic acidosis and its association with nutritional status in hemodialysis. J Bras Nefrol. 2015;37(4):458–66. 165. Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutritioninflammation complex syndrome in chronic renal failure. Semin Dial. 2004;17(6):455–65. 166. Stein A, Moorhouse J, Iles-Smith H, Baker F, Johnstone J, James G, et al. Role of an improvement in acid-base status and nutrition in CAPD patients. Kidney Int. 1997;52(4):1089–95. 167. Szeto CC, Wong TY, Chow KM, Leung CB, Li PK. Oral sodium bicarbonate for the treatment of metabolic acidosis in peritoneal dialysis patients: a randomized placebo-control trial. J Am Soc Nephrol. 2003;14(8):2119–26. 168. Tjiong HL, van den Berg JW, Wattimena JL, Rietveld T, van Dijk LJ, van der Wiel AM, 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(5):1486–93. 169. Brown M, Burrows L, Pruett T, Burrows T. Hemodialysis-induced myocardial stunning: a review. Nephrol Nurs J. 2015;42(1):59–66. quiz 7 170. Faller B, Lameire N. Evolution of clinical parameters and peritoneal function in a cohort of CAPD patients followed over 7 years. Nephrol Dial Transplant. 1994;9(3):280–6. 171. Bouma SF, Dwyer JT. Glucose absorption and weight change in 18 months of continuous ambulatory peritoneal dialysis. J Am Diet Assoc. 1984;84(2):194–7. 172. Tzamaloukas AH, Murata GH. Obesity and patient survival in chronic dialysis. Adv Perit Dial. 2004;20:79–85. 173. Abbott KC, Glanton CW, Trespalacios FC, Oliver DK, Ortiz MI, Agodoa LY, et al. Body mass index, dialysis modality, and survival: analysis of the United States Renal Data System Dialysis Morbidity and Mortality Wave II Study. Kidney Int. 2004;65(2):597–605. 174. Stack AG, Murthy BV, Molony DA. Survival differences between peritoneal dialysis and hemodialysis among "large" ESRD patients in the United States. Kidney Int. 2004;65(6):2398–408. 175. McDonald SP, Collins JF, Johnson DW. Obesity is associated with worse peritoneal dialysis outcomes in the Australia and New Zealand patient populations. J Am Soc Nephrol. 2003;14(11):2894–901. 176. McDonald SP, Collins JF, Rumpsfeld M, Johnson DW. Obesity is a risk factor for peritonitis in the Australian and New Zealand peritoneal

44 dialysis patient populations. Perit Dial Int. 2004;24(4):340–6. 177. Dasgupta I, Burden R. Blood pressure control before and after starting dialysis. Nephron Clin Pract. 2005;99(3):c86–91. 178. Lameire N, Vanholder RC, Van Loo A, Lambert MC, Vijt D, Van Bockstaele L, et al. Cardiovascular diseases in peritoneal dialysis patients: the size of the problem. Kidney Int Suppl. 1996;56:S28–36. 179. Wang IK, Lu CY, Lin CL, Liang CC, Yen TH, Liu YL, et al. Comparison of the risk of de novo cardiovascular disease between hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Int J Cardiol. 2016;218:219–24. 180. Konings CJ, Kooman JP, van der Sande FM, Leunissen KM. Fluid status in peritoneal dialysis: what’s new? Perit Dial Int. 2003;23(3):284–90. 181. Wang AY, Wang M, Woo J, Lam CW, Lui SF, Li PK, et al. Inflammation, residual kidney function, and cardiac hypertrophy are interrelated and combine adversely to enhance mortality and cardiovascular death risk of peritoneal dialysis patients. J Am Soc Nephrol. 2004;15(8):2186–94. 182. Zoccali C, Tripepi G, Mallamaci F. Predictors of cardiovascular death in ESRD. Semin Nephrol. 2005;25(6):358–62. 183. Zoccali C. Traditional and emerging cardiovascular and renal risk factors: an epidemiologic perspective. Kidney Int. 2006;70(1):26–33. 184. Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckardt KU, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2):ii1–47. 185. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28(1):53–61. 186. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339(9):584–90. 187. Volkova N, Arab L. Evidence-based systematic literature review of hemoglobin/hematocrit and all-cause mortality in dialysis patients. Am J Kidney Dis. 2006;47(1):24–36. 188. Weber J, Mettang T, Hubel E, Kiefer T, Kuhlmann U. Survival of 138 surgically placed straight doublecuff Tenckhoff catheters in patients on continuous ambulatory peritoneal dialysis. Perit Dial Int. 1993;13(3):224–7. 189. Piraino B. Peritonitis as a complication of peritoneal dialysis. J Am Soc Nephrol. 1998;9(10):1956–64. 190. Piraino B, Bailie GR, Bernardini J, Boeschoten E, Gupta A, Holmes C, et al. Peritoneal dialysis-related

F. Aziz and R. Khanna infections recommendations: 2005 update. Perit Dial Int. 2005;25(2):107–31. 191. Bernardini J, Bender F, Florio T, Sloand J, Palmmontalbano L, Fried L, et al. Randomized, double-blind trial of antibiotic exit site cream for prevention of exit site infection in peritoneal dialysis patients. J Am Soc Nephrol. 2005;16(2):539–45. 192. Boeschoten EW, Ter Wee PM, Divino J. Peritoneal dialysis-related infections recommendations 2005 – an important tool for quality improvement. Nephrol Dial Transplant. 2006;21(Suppl 2):ii31–3. 193. Cnossen TT, Konings CJ, Kooman JP, Lindholm B. Peritoneal sclerosis – aetiology, diagnosis, treatment and prevention. Nephrol Dial Transplant. 2006;21(Suppl 2):ii38–41. 194. Chin AI, Yeun JY. Encapsulating peritoneal sclerosis: an unpredictable and devastating complication of peritoneal dialysis. Am J Kidney Dis. 2006;47(4):697–712. 195. Korte MR, Sampimon DE, Betjes MG, Krediet RT. Encapsulating peritoneal sclerosis: the state of affairs. Nat Rev Nephrol. 2011;7(9):528–38. 196. Barreto DL, Sampimon DE, Struijk DG, Krediet RT. Early detection of imminent encapsulating peritoneal sclerosis: free water transport, selected effluent proteins, or both? Perit Dial Int. 2019;39(1):83–9. 197. Wong CF. Clinical experience with tamoxifen in encapsulating peritoneal sclerosis. Perit Dial Int. 2006;26(2):183–4. 198. Summers AM, Brenchley PE. An international encapsulating peritoneal sclerosis registry and DNA bank: why we need one now. Perit Dial Int. 2006;26(5):559–63. 199. Julian-Mauro JC, Cuervo J, Rebollo P, Callejo D. Employment status and indirect costs in patients with renal failure: differences between different modalities of renal replacement therapy. Nefrologia. 2013;33(3):333–41. 200. 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(6):697–703. 201. de Fijter CWH, van Diepen ATN, Amiri F, Dekker FW, Krediet RT. Patient-reported outcomes (PROs) argue against the limited use of peritoneal dialysis in end-stage renal disease. Clin Nephrol. 2018;90(2):94–101. 202. Brown EA. Peritoneal dialysis for older people: overcoming the barriers. Kidney Int Suppl. 2008;108: S68–71. 203. Just PM, de Charro FT, Tschosik EA, Noe LL, Bhattacharyya SK, Riella MC. Reimbursement and economic factors influencing dialysis modality choice around the world. Nephrol Dial Transplant. 2008;23(7):2365–73. 204. Lee H, Manns B, Taub K, Ghali WA, Dean S, Johnson D, et al. Cost analysis of ongoing care of patients with end-stage renal disease: the impact of

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45 206. Duong U, Kalantar-Zadeh K, Molnar MZ, Zaritsky JJ, Teitelbaum I, Kovesdy CP, et al. Mortality associated with dose response of erythropoiesis-stimulating agents in hemodialysis versus peritoneal dialysis patients. Am J Nephrol. 2012;35(2):198–208.

3

Patient Survival Comparisons Between Peritoneal Dialysis and Hemodialysis Marlies Noordzij and Peter G. Blake

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Points to Consider When Interpreting Survival Analyses in Dialysis Therapy . . . . The Use of Prevalent Versus Incident Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . As-Treated (AT) Versus Intent-to-Treat Analysis (ITT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . When to Enter Patients in Comparative Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjustment for Baseline Confounders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Statistical Methods for Comparison of Patient Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48 49 49 50 50 51 52

The Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Randomized Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Registry-Based Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prospective Cohort Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53 53 53 57

What Conclusions Can be Made Regarding Patient Survival in PD Compared with HD? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Abstract

The previous edition this work was authored by K.E. Yeates and P.G. Blake. M. Noordzij (*) Clinical Epidemiologist, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands e-mail: [email protected] P. G. Blake Western University, London, OT, Canada London Health Sciences Centre, London, OT, Canada

The choice between hemodialysis (HD) and peritoneal dialysis (PD) has been discussed for decades and outcomes have been compared inevitably between dialysis modalities. Many studies have been performed comparing costs of treatment, quality of life, and hospitalization and results have been variable. Most important and most controversial have been the studies that have attempted to compare patient survival on PD to that on HD. There is, however, still no final consensus on whether HD or PD treatment modality gives the best results. Consequently, both options have to be weighed in individual patients according to their specific

© Springer Nature Switzerland AG 2023 R. Khanna, R. T. Krediet (eds.), Nolph and Gokal's Textbook of Peritoneal Dialysis, https://doi.org/10.1007/978-3-030-62087-5_3

47

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M. Noordzij and P. G. Blake

needs, preferences, and clinical characteristics, with the aim of providing a patient-tailored kidney replacement therapy. Keywords

Peritoneal dialysis · Hemodialysis · Dialysis modality · Patient survival · Mortality · Outcomes · Epidemiology

Introduction Ever since the emergence of peritoneal dialysis (PD) as a widely used, feasible, and successful home-based therapy in the 1980s, there has inevitably been interest in comparing outcomes on this modality with those on hemodialysis (HD). In the past three decades numerous studies comparing costs of treatment, quality of life, and hospitalization have been performed and results have been variable [1–8]. Most important and most controversial, however, have been the studies that have attempted to compare patient survival on PD to that on HD. The background to this controversy is that in most developed countries, PD is less costly for payers and providers than HD [5–8]. Pressure from payers to use PD has therefore been significant and the question that arises is whether survival is equivalent or better and whether the therapy can consequently be deemed to be more cost-effective. Despite the positive attributes of PD, the proportion of patients treated with the modality has fallen in many countries over the last decades. Jain and colleagues gave an overview of the use of PD treatment in 130 countries worldwide between 1997 and 2008 [9]. They showed that there was an enormous variation in the proportion of patients that received PD as opposed to HD; in Hong Kong this proportion was as high as 79.4%, while there were no patients on PD at all in several developing countries and only very few in some developed countries such as Luxembourg (0.7%) and Japan (3.3%). Over 12 years, the number of PD patients increased in developing countries by 24.9 patients per million population and in developed countries by 21.8 per million population.

The proportion of all dialysis patients treated with PD did not change in developing countries but significantly declined in developed countries by 5.3% [9]. This trend towards a more expensive modality mix emphasizes the importance of resolving the relative benefits of the two modalities. As this chapter will show, historically, most comparative survival studies have utilized renal registry data. Head-to-head randomized controlled trials directly comparing PD to HD survival have never been successfully completed [10, 11]. The literature is therefore imperfect and so is a source of ongoing controversy. Another striking feature of the literature comparing survival between PD and HD is that results seem to differ greatly between different countries or when different methods of analysis are used. This confusing situation is partly related to different study designs, and the variety of statistical methods that have been applied to compare overall patient survival [12–15]. In this chapter historical and more contemporary survival outcomes of PD and HD are critically reviewed. In addition, we will review changes in statistical methodology that have been utilized over time to compare survival across treatment modalities and discuss the merits and drawbacks of each study and its design.

Points to Consider When Interpreting Survival Analyses in Dialysis Therapy Two key points need to be remembered when considering the design and methodology of studies comparing mortality on PD and HD. First, modality switches from PD to HD are much more frequent than those in the opposite direction [16–19], as illustrated in Fig. 1. Second, almost all studies indicate that PD compares best with HD in the early months and years after onset of end-stage kidney disease (ESKD) [16–18]. The cause of this is unclear, though it may be related to better retention of residual renal function on PD or to unrecognized baseline case-mix differences between patients on the two modalities. It is often referred to as an

3

Patient Survival Comparisons Between Peritoneal Dialysis and Hemodialysis 1993-1997

1998-2002

Death

49.0%

0.6

HD

0.4

23.8% 3.5%

PD

0.2 0.0

0

1

Transplantation 23.7%

2 3 patient years

4

5

1.0 Death

0.8 0.6

HD

0.4

0.0

52.3%

23.6% 3.0% Transplantation 21.1% PD

0.2 0

1

2 3 patient years

4

5

Death

30.6%

0.4

0.6

HD

30.8%

0.4

Death

29.8%

1

2

Transplantation 30.7% 3

patient years

4

5

0.0

25.9% 3.0% Transplantation 18.0% PD

0.2 0

1

2 3 patient years

4

HD

Death

0.8

8.3%

0.6

32.5%

0.4

PD

0.2

0.2 0

0.4

0.0

53.1%

HD

5

1.0

0.8

7.9%

PD

0.6

0.6

2003-2007

1.0

0.8

Death

0.8

1998-2002

1993-1997 1.0

0.0

2003-2007

1.0

1.0 0.8

49

27.6% 8.6%

PD HD

33.9%

0.2 0

1

2

Transplantation 29.4% 3

patient years

4

5

0.0

0

1

2

Transplantation 29.9% 3

4

5

patient years

Fig. 1 Unadjusted cumulative incidence survival curves for a switch to the other dialysis modality, transplantation, or death for patients who started HD (upper row) and PD

(bottom row) in 1993–1997, 1998–2002, and 2003–2007. (From van de Luijtgaarden et al. [19])

example of disproportionate hazards and it greatly complicates comparative survival analysis [11, 12]. Furthermore, there are several factors that could potentially explain the differences in findings between studies comparing mortality in HD and PD patients. These factors include methodological issues and other, clinical, factors such as practice patterns and patient characteristics. Below, a variety of factors that have to be taken into account in designing and evaluating studies done in this area are discussed.

adverse effect will be missed in a purely prevalent study. Because of the disproportionate hazards phenomenon mentioned above, HD, the modality with the higher early mortality, will look misleadingly good in a purely prevalent study. Studies that use prevalent patients only should therefore be interpreted with caution and for that reason become less and less common [20].

The Use of Prevalent Versus Incident Patients The prevalence of a treatment modality describes the number of existing cases at a certain point in time, whereas the incidence represents the number of cases new on the treatment within a certain time period. Studies that compare survival between PD and HD could use prevalent patients only, incident patients only, or a mix of both. However, it is preferable to include only incident patients who are new on the dialysis modality, because an early

As-Treated (AT) Versus Intent-to-Treat Analysis (ITT) Careful consideration of each of these study design methods is important as the choice can have a significant impact on study outcomes in analyses that compare survival in PD and HD. ITT attributes a patient’s death to the treatment that the patient was originally placed on or “intended” to be receiving. AT attributes a patient’s death to the therapy that the patient was actually receiving at the time of their death. ITT has been used in many of the survival analyses and does not allow the researcher to account for switches in therapy. It attributes a patient’s death to the initial therapy they received without

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accounting for the “actual” therapy, or multiple therapies, the patient may have received during their course of treatment. The different types of analyses aim to answer subtly different research questions. An ITT analysis asks the most clinically relevant question, which is whether initial modality assignment influences patient survival. This is what a physician needs to know when advising patient about modality choice prior to initiation of dialysis. An AT analysis tries to determine which modality is likely to be associated with better survival while a patient is receiving it. In a sense, the AT analysis compares the actual modalities while the ITT compares two strategies: “HD first” versus “PD first.” Often, the comparative studies use a modified ITT approach with censoring of patients either at the time of any modality switch, including transplantation, or at some designated time period after a switch. Most statisticians would suggest that both ITT and AT analyses should be performed when comparing outcomes, as each answers a distinct question and because differences in those answers can indicate that more detailed analyses are required. AT models require more complicated statistical models to deal appropriately with modality switches and are likely to yield the more accurate results when large administrative datasets are being used.

When to Enter Patients in Comparative Studies Most studies assign patients to the modality they are being treated with 90 days after initiation of dialysis and the period prior to that is omitted from the comparison, for example, in [18–20]. Intuitively, it might appear more appropriate to use the true initial modality to assign patients and to include all treatment time in the analysis. However, in most centers, patients presenting acutely or late are all treated with HD and because these patients tend to be sicker and to have a worse prognosis, a survival comparison based on initial modality would be biased against HD. Also, deaths in the first 90 days are likely to be more

M. Noordzij and P. G. Blake

affected by preexisting comorbidity than by dialysis modality per se. The notion is that by 90 days these patients will have stabilized or recovered renal function or died and that some will even have switched to PD and that, overall, the comparison will be fairer. In contrast, others argue that the 90-day approach removes from the analysis part of the time period where PD is most successful and this introduces a bias in favor of HD from Weinhandl et al. [21]. Furthermore, this is a period when HD patients are most likely to be using venous catheters for blood access and these are associated with significant complications so that omitting this period might again leads to a bias against PD. The 90-day rule is probably a fair compromise. However, it is important that the large influence of this issue on the results of the analysis be clearly understood. One US study by Winkelmayer surprisingly reports a bias in the opposite direction, with more deaths on PD in the first 90 days, but the cohort studied was small and comprised only elderly patients and the findings did not quite reach statistical significance and seem out of line with those in other studies [23].

Adjustment for Baseline Confounders None of the comparative survival studies is randomized and so adjustment for baseline population differences is important. In most developed countries, patients treated with PD tend to be younger and healthier than those on HD and so, in countries such as the USA, Canada, Australia, and the largest part of Europe, an unadjusted analysis will show misleadingly better results for PD [24]. Clearly, adjustment of comparisons for age, sex, and baseline comorbidity is crucial. However, comorbidity information is often lacking or incomplete in renal registries, while prospective studies typically have more detail available and attempt to quantify comorbidity by using scoring systems [22, 24, 25]. They may also adjust for functional characteristics, residual renal function, and laboratory measurements [24].

3

Patient Survival Comparisons Between Peritoneal Dialysis and Hemodialysis

A key point about adjustment for comorbidity is that only baseline data be used. It is completely inappropriate to adjust for data points or events occurring after initiation of dialysis as the modality may be influencing these. For example, outcomes should not be adjusted for residual renal function after initiation of dialysis as this may be better preserved on PD than HD and the adjustment may therefore take a key advantage of PD out of the analysis. Similarly, adjustment for serum albumin after initiation is inappropriate because it tends to be systematically lower on PD due to dialysate protein losses and the adjustment would introduce a bias against HD. Adjustments will inevitably be incomplete, even in the most detailed of prospective cohort studies there are always factors that are not measured. Factors such as motivation and family support may be critical but are difficult to measure. Consequently, even after adjustment for potential confounders in the statistical analysis, there is usually at least some amount of residual confounding due to unmeasured variables. This may prevent a fair comparison of outcomes between patient groups, something which is usually feasible from well-conducted randomized controlled trials [15]. Adjustments are complicated and over time awareness has increased about complex interactions between modality and factors such as age, sex, and diabetic status and their effects on survival. As a result, more and more studies nowadays report their findings separately for men and women, younger and older patients, diabetic and nondiabetic patients etc. [16–19]. There is a realization that there is not one simple answer to the question of which modality is best and that the answer varies between the different subpopulations with ESKD.

Statistical Methods for Comparison of Patient Survival An important issue regarding treatment comparisons is the difficulty of making causal inference based on observational studies. The most important weakness of observational studies is that

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selection bias by the clinician – also called confounding by indication – may occur [26]. There are several strategies to reduce the influence of such selection bias. Of these, multivariable adjustment for potential confounders during statistical analysis is most commonly applied. In the last years, more and more research groups started to apply advanced statistical methods in addition to the conventional methods of survival analysis, i.e., Kaplan–Meier and standard Cox proportional-hazards models, to assess the associations between dialysis modality and mortality risk [15]. Such methods include timedependent Cox regression models (for example, in [19, 27]), marginal structural models (for example, in [27–30]), and the use of treatment propensity scores in statistical models by means of adjustment, stratification, or matching (for example, in [19, 21, 27–32]). As already mentioned, the relative mortality risks between patients on HD and PD do not appear to be constant with time on dialysis. Most studies suggest PD is at its best in the initial 2 years after initiation of dialysis and that HD is at its best with longer-term patients. Indiscriminate application of the Cox proportional hazards model to such a “disproportionate” situation is clearly inappropriate. Some studies have therefore done repeated analyses using different start points, i.e., redoing the analysis at 6 months, 12 months, 24 months, etc. [22]. In this case, the adjustments involved must still be based on predialysis baseline characteristics, as explained above. Some other longitudinal studies used adjustment for time-dependent covariates [19, 27]. It is, however, important to keep in mind that this technique is inappropriate in comparative survival studies if adjustment would be made for a timedependent covariate that is affected by the treatment that is being studied, potentially adjusting out the effect that is being measured. Another advanced method that has been applied in some HD versus PD survival comparisons is marginal structural model [27–30]. This method can help to minimize the effects of casemix differences and the potential for confounding in registry-based and observational studies but

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requires substantial statistical expertise. The most popular method (with the same aim) is the use of propensity scores. A propensity score can be calculated based on observed covariates and represents the probability of a patient of being assigned to a particular treatment modality. This score can subsequently be used for standard statistical adjustment, weighting or for matching. An advantage of propensity score matching is that the patients who are being compared are more similar than when using a standard approach for survival analysis. However, a drawback of propensity score matching is that part of the patients cannot be matched and are excluded from the analysis. Another important disadvantage is that both propensity score methods and marginal structural models are only based on those variables that are measured, and cannot take into account any effects of unmeasured variables. Only a randomized trial can do this. So, usually there is at least some amount of residual confounding due to unmeasured variables and this may prevent a fair comparison of treatment outcomes. Applying propensity scores is most useful in dealing with situations where there are complex interactions between covariates that influence treatment assignment and also where there may be significant center effects influencing outcomes. This is clearly relevant in PD versus HD comparisons. To date, propensity scores have been applied relatively often [19, 21, 27–32] and very recently even a systematic review with meta-analysis was published by Elsayed et al. summarizing those studies that used this method for the comparison of PD and HD survival [33]. Their meta-analysis of 17 studies including a total of 113,578 propensity score-matched incident dialysis patients suggests that PD and in-center HD treatment carry equivalent survival benefits [33]. The fact that so many different statistical methods are being applied can partly explain the inconsistency in study results.

Clinical Factors Other issues that deserve consideration when comparing survival outcomes in PD and HD

M. Noordzij and P. G. Blake

include dissimilarities either in quality of the dialysis modality provided or in patient population characteristics across continents or by a combination of both. Firstly, dialysis modality–specific practice patterns may affect dialysis modality– specific outcomes. Factors, such as treatments times and the types of vascular access, peritoneal catheters, and PD or HD fluids used, may contribute to the efficiency and quality of the dialysis provided. It is often not taken into account to which extent PD and HD are provided in a stateof-the-art manner. For example, in many survival comparisons the type of vascular access used for HD is not included in the analyses, whereas Perl et al. showed that type of vascular access plays an important role in the relationship between dialysis modality and mortality [34]. They found in a Canadian cohort that starting HD with a central venous catheter largely explained the higher early-mortality risk of HD [34]. It should be kept in mind, however, that the use of a central venous catheter is tightly correlated with an urgent start of HD, which is associated with acute illnesses and complications and could thus be driving the higher mortality. Another example of a clinical factor that is usually not taken into account is the circumstance in which a patient started dialysis. It has been postulated that patients who start dialysis urgently are at high risk of death and as they are treated predominantly with HD, this could induce selection bias in the comparison of mortality between HD and PD patients. Couchoud et al. showed in 2007 that mortality risk was significantly increased with 50% among elderly patients (75 years or older) with an “unplanned” start of HD when compared to patients with a “planned” start suggesting that a comparison between both dialysis modalities would be more balanced after removing the unplanned HD starts [35]. Two Canadian studies confirmed these findings. In 2011, Quinn et al. showed that PD and HD were associated with similar survival in incident patients starting dialysis electively as outpatients [36]. More recently, Wong et al. reported that HD and PD are associated with similar mortality among incident dialysis patients who are eligible for both modalities [37]. They claim that – to

3

Patient Survival Comparisons Between Peritoneal Dialysis and Hemodialysis

better reflect the outcomes for patients who have the opportunity to choose between HD and PD in clinical practice – future comparisons of dialysis modality should be restricted to patients who are deemed eligible for both modalities [37]. Finally, the experience with a treatment modality within a certain center or even country could play a role. There is significant literature suggesting improved outcomes with increased experience in many areas of medicine including ESKD [38].

The Studies The first study comparing continuous ambulatory PD with HD in incident patients was performed in the UK more than 30 years ago [39]. The investigators used Kaplan-Meier analyses to show that patient survival was not different between the two dialysis modalities during 3 years of follow-up. Since then, several survival comparisons between the dialysis modalities have been published, but their findings were inconsistent [12, 15]. Over the last three decades, the study design has evolved from single-center and multicenter studies in the 1980s and early 1990s, to either prospective cohort studies or those using data from national registries of dialysis patients thereafter. Below, the results of studies with the most important study designs are summarized.

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This has been a recurring problem and underlines the point that there is a limit to the types of therapies that patients will accept on a random basis. Between 1997 and 2000, the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) initiative aimed to enroll in a randomized trial all new dialysis patients who had no contraindication to either HD or PD at 38 dialysis centers in the Netherlands [10]. The primary and secondary outcomes were quality-of-life-adjusted life year (QALY) score and survival, respectively. The study was stopped early due to low enrollment, with only 38 patients (5% of the 773 eligible subjects) agreeing to participate. In the first 2 years, there was only a slight difference in mean QALY score, which favored HD over PD. After 5 years of follow-up there was no persisting difference in quality of life but the hazard ratio for death with HD versus PD was significant at 3.8, suggesting that long-term survival favors PD. However, it could be argued that low study enrollment makes these results difficult to interpret and the small number of patients who agreed to participate in the study may have been “different” from the large number who chose not to be included [10]. Despite these failures, a new attempt for setting up a trial started in China in 2011 (trial registration NCT01413074 at clinicaltrials.gov). However, 5 years later, it also was terminated. Consequently, outcomes in HD and PD patients can only be compared based on the results of observational and registry-based studies.

Randomized Trials Ideally, the decision on which dialysis modality gives the best outcomes should be based on results of randomized controlled trials in which the allocation of the dialysis modality is not influenced by attitudes or preferences of the nephrologist and the patient. In the 1990s, Baxter attempted to enroll patients in a worldwide randomized trial comparing HD and PD. The study was abortive because once interested patients completed the pre-randomization education session, the large majority had developed a preference and were no longer willing to undergo randomization.

Registry-Based Studies Since the mid-1990’s several studies reporting patient outcomes based on data from regional, national, and international renal registries have been published. Most of these studies were based on data from the US Renal Data System (USRDS), Canadian Organ Replacement Register (CORR), Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), and the European Renal Association-European Dialysis Transplant Association (ERA-EDTA) Registry.

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M. Noordzij and P. G. Blake

One of the first large registry-based studies was published in 1995 by Bloembergen et al. [20]. They used Poisson regression to analyze a large sample of prevalent-only patients from the USRDS for the years 1987–1989 with adjustment for demographic characteristics and showed 19% higher all-cause mortality in prevalent PD patients in the USA as compared to HD. The excess risk of death was significant for patients aged over 55 years and was most pronounced in females and those with diabetes. However, the methodology used here was unusual. In addition to the prevalent-based analysis method, the study only started analyzing patients who had completed 90 days of treatment on 1 January of each of the 3 years concerned and so systematically omitted the majority of the first 12 months of treatment in many patients. This introduced a substantial bias against PD. A few years later, Vonesh et al. did a similar analysis with the USRDS dataset, but included both incident and prevalent patients from 1990 to 1993, and for these more contemporary cohorts reported no significant difference between PD and HD mortality although there was still a trend favoring HD in older diabetics and PD in younger diabetics [40]. Comparable US results were reported by Collins et al. in 1999 in a study that comprised incident patients from 1994 to 1996 followed for the first 2 years of dialysis [41]. The authors used Poisson regression to compare death rates and adjusted for age, gender, race, and primary renal

disease. A Cox model was utilized to evaluate cause-specific mortality with the issue of proportionality addressed through a separation of patients with and without diabetes. This study showed a significant survival advantage for PD over the first 2 years compared with HD in younger patients with and without diabetes and in older nondiabetic patients also (Fig. 2). The effect was most apparent, being almost 40%, in the younger nondiabetics. Only in older patients with diabetes did the authors report a survival advantage for HD [41]. The first study on this topic from the Canadian colleagues from CORR was published only somewhat later than that by Bloembergen et al. Fenton and colleagues published results of incident PD and HD patients who initiated therapy between 1990 and 1994, and were followed up for 5 years [42]. After adjustment for baseline differences including age, primary renal disease, center size, and comorbidity at the initiation of dialysis, and using both an ITT and AT approach, the authors showed that, in Canada, there was a significant 27% survival advantage for PD patients compared to HD and that this advantage was greater in the first 2 years of dialysis and for younger patients [42]. Subsequent US studies have, however, been less favorable to PD. In 2003, Ganesh et al. and Stack et al. from the same research group published two US registry-based studies that compared mortality differences among PD and HD patients with ischemic heart disease and

1.4

Male

1.21

Relative Risk

1.2 1.0

Female

1.03

0.86 0.88

0.87

0.87

0.72

0.8

0.61 0.6 0.4 0.2 Diabetic

0.0