Living Donor Transplantation

Living Donor Transplantation

Living Donor Transplantation Edited by

Henkie P. Tan

Thomas E. Starzl Transplantation Institute Pittsburgh, Pennsylvania, USA

Amadeo Marcos

Thomas E. Starzl Transplantation Institute Pittsburgh, Pennsylvania, USA

Ron Shapiro

Thomas E. Starzl Transplantation Institute Pittsburgh, Pennsylvania, USA

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

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

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

2007005324

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

Preface

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

vi

Preface

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

Acknowledgments

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

Contents

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

77

87

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

x

Contents

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

259

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

xi

Contents

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

341

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

405

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

431

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

Contributors

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

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

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

xiv

Contributors

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

Department of Surgery, University of Alberta, Edmonton,

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

xv

Contributors

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

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

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

xvi A. M. James Shapiro

Contributors

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

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

Part I

1

OVERVIEW

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The donor

The recipient

Motives, expectations

Hopes, expectations

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

Survival, quality of life

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

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

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

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

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

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Dew et al.

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

13

Psychosocial Aspects of Living Organ Donation

Percentage

Liver donor candidates

U.S. norm75

Related donor candidate

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

An yp

sy c

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

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

FIGURE 2

0

An yp sy

ch iat ric

Unrelated donor candidate

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

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

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

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

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

14 TABLE 1

Dew et al.

Core Components of Predonation Psychosocial Evaluation of Living Organ Donors

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

Psychosocial history and current status

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

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

Psychosocial Aspects of Living Organ Donation

15

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

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

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

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Dew et al.

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

17

Psychosocial Aspects of Living Organ Donation 100

Percentage of respondents

90 80 70 60 50 40 30 20 10 0

1

4

7

Median percentage 3

95

72

10

8

20

No. of studies

12

10

21

7

9

2

11

23

10

5

7

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

a

13

each datapoint represents an independent empirical investigation

FIGURE 3

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

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

18

Dew et al. 100

Percentage of respondents

90 80 70 60 50 40 30 20 10 0

Median percentage 0 No. of studies

4

100

96

7

12

36

4

29

33

6

3

4

2

2

1

3

3

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

et gr Re

a

each datapoint represents an independent empirical investigation

FIGURE 4

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

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

50

Percentage

45

US Norm (75)

40

Kidney donor (n=65) (98)

35

Kidney donor (n=48) (72)

30

Liver donor (n=31) (98)

25 20 15 10 5 0

M ajor depression

Anxiety disorder

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

19

Psychosocial Aspects of Living Organ Donation 100

Mean

90 80

Kidney donors

70

(7 studies)

60 50 100

Mean

90 80

Liver donors

70

(5 studies)

60 50 Vi

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

la

lity

So

cl

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

le

lth

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

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

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

Factors found to be predictors or correlates of outcome

Factors found to be unrelated to outcome

Regret or would not donate again

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

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

Psychological distress and negative reactions

Recipient lost graft or died (27)

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

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

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

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

Donor was non-first degree relative (93) aSee

text for definition.

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

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

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

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

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

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

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

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

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

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

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

Part II

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LIVING-DONOR KIDNEY TRANSPLANTATION

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

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

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

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

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FIGURE 1

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Flowchart for living donor kidney evalution.

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

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TABLE 1

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

Risk factors Kidney function Hypertension

Proteinuria

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

Hematuria

Urine dipstick; history

Kidney stone

History, CT angiography, renal ultrasound

Diabetes and glucose intolerance

History and fasting plasma glucose (FPG)

Obesity

Body mass index; physical examination Renal ultrasound

Family history of PKD Family history of glomerulonephritis

Urinalysis

Follow up testing

Clinical intervention to continue donor candidacy

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

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

A 75g 2-hour oral glucose tolerance test if: a. impaired FPG (FPG >110mg/dL and less than 126mg/dl), b. first degree relative with history of diabetes, c. second degree relative with history of diabetes in a donor, candidate 9 pound birth weight e. BP >140/90,fasting triglycerides > 250 mg/dl, BMI > 30, or HDL < 35. Evaluation for associated comorbid conditions Genetic screening if 1 g/d. No donor death was reported from renal disease; most deaths were caused by cardiovascular disease. At least 56 prior living donors have been listed for deceased-donor kidney transplantation in the database of the United Network for Organ Sharing (UNOS) (6). The donors’ ages at time of donation ranged from 17 to 61, with an average age of 31, and the time from donation to listing ranged from 2 to 32 years, with a mean and median of 15 years. Based on the number of living donors who have subsequently been listed for deceased-donor kidney transplantation, the estimated incidence of ESRD in living donors since 1987 is 0.04%, similar to the incident rate of ESRD in the general U.S. population of 0.03% (USRDS 2001 Annual Data Report). However, this select group of former living donors listed for transplantation may underrepresent the risk to kidney donors, as it fails to capture those donors who were listed prior to the establishment of the OPTN registry, those who developed ESRD and were not listed, and those who suffered a significant decline in renal function but died before reaching ESRD. Finally, data from individual centers are available, but need to be interpreted with caution because of relatively short follow-up times and the potential lack of sufficient resources to maintain complete records, as well as the disincentive to find poor outcomes. In one series, 464 of 773 individuals who donated a kidney between 1963 and 1979 were assessed for outcomes; 84 patients had died, and three patients were on dialysis therapy at the time of death (7). Of the 380 surviving donors, mean creatinine values were 1.2 ± 0.04 mg/dL (106 ± 3.5 μmol/L) in the 20- to 29-year group and 1.3 ± 0.1 mg/dL (115 ± 8.8 μmol/L) in the >30-year group (7). Proteinuria rates were 11% and 5%, and hypertension was present in 36% and 38%, respectively. Overall, the prevalence of ESRD in the donor population was five of 464 donors, or 1%. Because genetic predisposition is known to play a role in the development of ESRD (8), a better comparison group might be the siblings of kidney donors. Najarian et al., compared the renal function, BP, and presence of proteinuria in 57 donors from 20 to 30 years after nephrectomy with those of 67 siblings (9). There were no differences in mean serum creatinine levels, proteinuria, or hypertension between donors and their siblings. Thus, donor nephrectomy appears to result in maintained renal function over 20 to 30 years if the subject has normal renal function, no hypertension, and no proteinuria at the time of nephrectomy. Although there are crude methods to estimate the risk of kidney donation, these methods are particularly difficult when donors have multiple potential risk factors for kidney disease. As the number of living donors has increased and surpassed the number of deceased donors in the United States, transplant centers have also begun to adjust their definition of the acceptable donor to include those with pre-existing medical conditions such as hypertension. In the remainder of this chapter, we will discuss the long-term risks attendant to specific isolated comorbidities and medical conditions. AGE A steady decline in GFR has generally been considered a part of the general aging process. Following kidney donation, a similar, but not accelerated, rate of decline is seen in kidney donors (5). The percentage of nephrosclerosis in donor biopsies appears to be more in older donors (10–16), and the early experience with living donors suggested a poorer outcome for recipients of kidneys from older donors (17). However, not all individuals demonstrate a decline in GFR with advancing age (18,19). Comparable one-year outcomes in recipients of older living donor kidneys with those in recipients of kidneys from younger donors (80ml/min, corrected to body surface area (BSA) of 1.73/m2 is generally considered to be acceptable for kidney donation. However, Thiel et al., advocate calculating a ‘minimal creatinine clearance required’ for each individual donor (20). The calculation involves a minimal creatinine clearance of 40 ml/ min/1.73/m2 at an age of 80 and then adjusts for an abrupt loss of 25% of the GFR with nephrectomy and a more gradual decline with age (20). Using this calculation, transplantation from older living donors with lower creatinine clearances have been performed, and the donors have had good outcomes with short-term follow-up. Despite the apparent safety of ‘low’ GFR donors, the increased relative risk for recipient graft loss of 2.28 has been reported for kidneys from living donors with a baseline predonation GFR 140 mmHg or diastolic BP values of >90 mmHg, 36.7% of subjects were initially considered hypertensive in the clinic; this decreased to 11% with awake ABPM findings. It is critical to note that a substantial number of subjects with excellent kidney function were misclassified as hypertensive with clinic oscillometric measurements alone. Despite issues with sensitivity, the clinic BP and medical history are used in clinical practice to screen for hypertension. A BP of >140/90 at the visit supports a diagnosis of hypertension, and the patient with a history of hypertension or use of antihypertensives is considered hypertensive. In either case, the candidate subsequently undergoes outpatient BP checks at the primary physicians’ clinic or with ambulatory BP monitoring. It is preferred to have a candidate with borderline clinic hypertension get ABPM, particularly if the candidate is >50 years old, given the improved sensitivity of ambulatory BP monitoring. Candidates who are found to be normotensive after subsequent testing proceed with the donor evaluation. Patients found to be hypertensive or with known and treated hypertension have a modified risk of donation, and these patients should have follow-up counseling from the surgical and nephrology team regarding the risk of donation. Patients with difficult-to-control hypertension or evidence of target organ damage are usually excluded. The data support considering candidates for living donor nephrectomy if the BP is easily controlled and they meet other criteria (>50 year old, GFR > 80 ml/min, urinary albumin 6000 patients with a baseline creatinine clearance of 90ml/min were examined after a mean follow-up of 4.2 years (29). De novo renal impairment, defined as a GFR < 60ml/min, developed in 4.2% of patients. Urinary albumin excretion was an independent risk factor for renal impairment, with an unadjusted odds ratio of 1.63 and adjusted odds ratio of 1.3 (29). The risk of developing renal impairment increased as baseline urine albumin concentration increased, with a steep increase in the incidence of renal impairment to >25% in patients with a baseline urine albumin concentration of >300mg/24h compared to 300 mg is generally considered to be a contraindication to kidney donation, the significance of lesser amounts of urinary albumin has not been clearly established. Microalbuminuria is a sensitive indicator of glomerular pathology in patients with diabetes and may also be the first sign of glomerular pathology both before and after nephrectomy (30). Although the evaluation of microalbuminuria is not consistently recommended as a part of the preoperative assessment of kidney donors, its detection may be important in prognostic and therapeutic recommendations in the long-term follow-up of kidney donors. The Kidney Disease and Outcome Quality Innitiative (KDOQI), American Diabetes Association (ADA), and National Kidney Foundation (NKF) guidelines regarding assessment of proteinuria recommend a first morning urine specimen, but consider random urine specimens acceptable if first morning urine specimens are not available. A first morning urine specimen correlates best with 24-hour protein excretion and is required for the diagnosis of orthostatic proteinuria. Among the over 2500 participants of the PREVEND study, both sensitivity and specificity of first morning urine albumin concentration in predicting microalbuminuria on a 24-hour urine collection were reported as 85%. Sensitivity and specificity for spot urine albumin to creatinine ratios were approximately 87% (31). Therefore, for ease and consistency of collection, a random urine specimen for protein or albumin to creatinine ratio is acceptable if a first-morning urine specimen is not available. Not all proteinuria is the result of glomerular disease. Increased protein excretion can be the result of altered renal hemodynamics in conditions, such as fever, exercise, and extreme cold. Proteinuria related to changes in renal hemodynamics is transient and, if suspected, can be confirmed with repeat testing. The condition of orthostatic proteinuria should also be considered, particularly in young donors. Approximately 2% to 5% of adolescents have orthostatic proteinuria, and this condition accounts for 60% to 75% of proteinuria in adolescents. However, this condition is rare in those >30 years of age (32). Twenty-four hour protein excretion is usually 10 years previously may still be a suitable kidney donor.

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The number of prior events, rather than the metabolic risk profile, is more predictive of future events. However, laboratory studies, including serum electrolytes, uric acid, and calcium, urinalysis to examine the sediment for crystals, urine nitroprusside test for cystine, and 24-hour urine collections for volume, calcium, uric acid, citrate, oxalate, pH, sodium, and creatinine (to assess adequacy of the sample) are helpful in ruling out metabolic stone forming abnormalities, such as primary hyperparathyroidism, hyperuricemia, cystinuria, hyperoxaluria, or metabolic acidosis. Urinary tract infection should be excluded. CT should demonstrate the absence of multiple stones or nephrocalcinosis. Acute transplant renal failure due to donor nephrolithiasis has been reported. Because the grafted kidney is denervated, the classic symptoms of renal colic may be absent (57–60). However, ex vivo ureteroscopy to remove stones from donor kidneys at the same time preserving graft integrity and function has been successfully accomplished (61). Therefore, potential donors with a current single stone may be acceptable candidates for kidney donation if they meet the above criteria, and the current stone is either 10 years prior to candidacy is not necessarily a contraindication to donation. Stone formers with cystine or struvite stones, with stone disease related to inherited or systemic disorders (hyperoxaluria, distal renal tubular acidosis, sarcoidosis, inflammatory bowel or short gut disease) or with evidence of nephrocalcinosis should not donate. However, stone disease related to primary hyperparathyroidism that has resolved following parathyroidectomy is not a contraindication to kidney donation. Stone formers with a history of bilateral stones or recurrence on appropriate preventive therapy probably should not donate. Older donors with a history of a single stone between 5 to 10 years in the past, and those found to have an asymptomatic stone, potentially removable or 126 mg/dl was recommended for the diagnosis of diabetes. Normal FPG was defined as 200 mg/dl (11.1 mmol/l) was defined as diabetes and a level of 144 to199 mg/dl (7.8–1.0 mmol/l) was accepted as representing impaired glucose

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

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

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

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Giessing M, Slowinski T, Deger S, et al. 20-year experience with elderly donors in living renal transplantation. Transplant Proc 2003; 35:2855–2857. Ivanovski N, Popov Z, Kolevski P, et al. Use of advanced age donors in living renal transplantation— is it justified? Transplant Proc 2001; 33:1227–1228. Ivanovski N, Popov Z, Kolevski P, et al. Living related renal transplantation—the use of advanced age donors. Clin Nephrol 2001; 55:309–312. Hadjiyannakis EJ, Hadjidimitriou F, Drakopoulos S, et al. Renal transplantation from older living donors. Transplant Proc 2001; 33:906–908. Tanaka K, Kinukawa T, Matsuura O, et al. The effect of donor age on living-related kidney transplantation. Transplant Proc 2000; 32:1583–1584. Kostakis A, Bokos J, Stamatiades D, et al. The 10 years single center experience of using elderly donors for living related kidney transplantation. Geriatr Nephrol Urol 1997; 7:127–130. Darmady EM. Transplantation and the ageing kidney. Lancet 1974; 2:1046–1047. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33:278–285. Lindeman RD. Overview: renal physiology and pathophysiology of aging. Am J Kidney Dis 1990; 16:275–282. Thiel GT, Noldte C, Tsinalis D. Living kidney donors with isolated medical abnormalitites: the SOL-DHR experience. In: Gaston RS, Wadstrom J, eds. Living Donor Kidney Transplantation, London, U.K., and New York, NY: Taylor & Francis, 2005:196. Norden G, Lennerling A, Nyberg G. Low-absolute glomerular filtration rate in the living kidney donor—A risk factor for graft loss. Transplantation 2000; 70:1360–1362. Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: Accuracy in good health and in chronic kidney disease. Ann Intern Med 2004; 141:929–937. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003; 290:199–206. Saran R, Marshall SM, Madsen R, Keavey P, Tapson JS. Long-term follow-up of kidney donors: a longitudinal study. NephrolDial Transplant1997; 12:1615–1621. Kim SH, Cho SW, Kim HD, Chung JW, Park JH, Han MC. Nutcracker syndrome: diagnosis with Doppler US. Radiology 1996; 198:93–97. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560–2572. Delmonico F. A Report of the Amsterdam Forum On the Care of the Live Kidney Donor: Data and Medical Guidelines. Transplantation 2005; 79:S53–66. Mann JF, Yi QL, Gerstein HC. Albuminuria as a predictor of cardiovascular and renal outcomes in people with known atherosclerotic cardiovascular disease. Kidney Int Suppl 2004; S59–62. Verhave JC, Gansevoort RT, Hillege HL, Bakker SJ, De Zeeuw D, de Jong PE. An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population. Kidney Int Suppl 2004; S18–21. Bock HA, Bachofen M, Landmann J, Thiel G. Glomerular hyperfiltration after unilateral nephrectomy in living kidney donors. Transpl Int 1992; 5 (suppl 1):S156–159. Gansevoort RT, Verhave JC, Hillege HL, et al.The validity of screening based on spot morning urine samples to detect subjects with microalbuminuria in the general population. Kidney Int Suppl 2005; S28–35. Springberg PD, Garrett LE Jr, Thompson AL Jr, Collins NF, Lordon RE, Robinson RR. Fixed and reproducible orthostatic proteinuria: results of a 20-year follow-up study. Ann Intern Med 1982; 97:516–519. Rytand DA, Spreiter S. Prognosis in postural (orthostatic) proteinuria: forty to fifty-year follow-up of six patients after diagnosis by Thomas Addis. N Engl J Med 1981; 305:618–621. Ekim M, Bakkaloglu SA, Tumer N, Sanlidilek U, Salih M. Orthostatic proteinuria as a result of venous compression (nutcracker phenomenon)—a hypothesis testable with modern imaging techniques. Nephrol Dial Transplant 1999; 14:826–827. Bia MJ, Ramos EL, Danovitch GM, et al. Evaluation of living renal donors. The current practice of US transplant centers. Transplantation 1995; 60:322–327. Froom P, Ribak J, Benbassat J. Significance of microhaematuria in young adults. Br Med J (Clin Res Ed) 1984; 288:20–22. Mohr DN, Offord KP, Owen RA, Melton LJ III. Asymptomatic microhematuria and urologic disease. A population-based study. JAMA 1986; 256:224–229. Messing EM, Young TB, Hunt VB, Emoto SE, Wehbie JM. The significance of asymptomatic microhematuria in men 50 or more years old: findings of a home screening study using urinary dipsticks. J Urol 1987; 137:919–922. Schroder FH: Microscopic haematuria. BMJ 1994; 309:70–72. Culclasure TF, Bray VJ, Hasbargen JA. The significance of hematuria in the anticoagulated patient. Arch Intern Med 1994; 154:649–652.

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

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

5

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

length. Gill and colleagues (13) have had success in maximizing the right renal vein length at the same time minimizing the operative time and blood loss. In their initial experience of right LLDN at the Johns Hopkins Hospital (9), three (37.5%) of eight renal allografts were lost because of vascular complications. With modifications of the donor and recipient operations below, further graft losses were avoided (9). Three modifications of the donor operation were developed to preserve maximal right renal vein length: (i) passing the GIA stapler through a right lower quadrant port at the lateral border of the rectus abdominis muscle in a plane parallel to the IVC, (ii) relocation of the incision for extracting the kidney to the right subcostal region for open division of the right renal vein, and (iii) lengthening the right renal vein by using a panel graft constructed from the recipient greater saphenous vein (9). The recipient operation was also modified to provide a tension-free venous anastomosis. To do so, the left iliac vein is mobilized completely by dividing all posterior branches and transposed lateral to the left iliac artery. At the University of Pittsburgh Medical Center, of the over 400 LLDNs now performed, the vast majority are performed in about two hours of operating time, with a warm ischemia time less than five minutes, and blood loss 7 hrs) (v) Aborted donor operation (e.g., intended recipient not transplanted) (vi) Donor nephrectomy completed but kidney not used for intended recipient (excluding donor swap program) B. Minimal interventions (i) Minor splenic/liver injury ( 2 uPRBCs) E. Donor kidney injury (i) Perinephric hematoma, capsular tear (ii) Parenchymal laceration (bleeding versus nonbleeding) (iii) Renal vascular injury (vein versus artery, surgical repair) (iv) Delayed graft function, requiring dialysis ≤7 days post-transplant (v) Primary nonfunction II. Minor postoperative complications requiring no/minimal interventions A. NO interventions postoperatively during initial hospitalization (i) Atelactasis, postoperative fever ≤48 hrs with no evidence of infection (ii) Pneumothorax (no surgical intervention) (iii) Scrotal edema and pain B. Minimal interventions postoperatively during initial hospitalization (i) Infections (e.g., UTI, epididymitis, wound, pneumonia, bacteremia), requiring ≤7 days antibiotics (ii) Urinary retention, requiring Foley >3 days (iii) Ileus, >5 days, or requirement of NGT (iv) Nausea/emesis >5 days requiring antiemetics, or dehydration requiring IV fluids C. Prolongation of hospital stay (LLDN >5 days, ODN >8 days) D. Emergency room visits for any reason but no rehospitalization E. Rehospitalization with minimal interventions (e.g., IV hydration) III. Postoperative complications with no residual disability, requiring moderate/major interventions, generally ≤4–6 months duration A. Moderate interventions, rehospitalization for any reason (i) Infections (e.g., intra-abdominal abscess, pneumonia, pyelonephritis), >7 days antibiotics (ii) Chylous ascites, requiring paracentesis or TPN (≤4 months in duration) (iii) Pancreatitis (IV hydration >7 days, TPN) (iv) Deep venous thrombosis, pulmonary emboli B. Additional nonsurgical therapeutic intervention (e.g., drainage of abscess, paracentesis of chylous ascites) C. Re-explorations or additional surgery for any reasons (e.g., bowel obstruction, perforation, retained sponge, incisional hernia repair) D. Neuropathy/paresthesias/pain (brachial, femoral, testicular) < 6 months (Continued )

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Proposed Live Donor Nephrectomy Complication Classification Schemea (Continued )

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

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

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

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

7

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

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

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Nephrectomy

Survival

0.75 Control 0.50

0.25

0 24

36

48

60

72

84

Age

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

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

observed and exopected survival

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

5 10 15 20 time (years) since donation

25

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

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TABLE 1

Over 20 Years After Donation Preoperative (n = 78)

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

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

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

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

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

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

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

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

Total cases

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

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

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

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

TABLE 3

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

Age

White (%)

African American (%)

30–39

0.008

0.04

40–49 50–59 60–69

0.016 0.038 0.067

0.086 0.18 0.28

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

Incidence of ESRD in living donors overall White

African American

50/48760 (assuming donation from 1988) 0.10%

47/9053 (assuming donation from 1988) 0.52%

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

African American

White

P value

1 ± 0.1 1.5 ± 0.3 75% 2

0.8 ± 0.2 1.2 ± 0.2 25% 0

NS NS 180 days from donation is often from an unknown cause (Tables 5 and 6). However, it is also not uncommonly due to suicide, homocide, or accidents especially in the young donor (Table 6). Jordan and colleagues recently reported that 3% of donors had a psychopathological illness related to donation and that younger donors had more characteristics associated with psychosis than older donors (14). Corley and colleagues reported that 20% of donors thought that they had done something prior in their lives that their families disapproved of, 6% had recently done something that their families disapproved of, 25% felt they had given up something by donating without getting TABLE 5 Living-Kidney Donor Deaths (Donors Oct. 25, 1999–Oct. 31, 2004)—Cause of Death Where Death >180 Days After Donation Cause of death

N

%

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

22 4 2 2 1 4 35

62.9 11.4 5.7 5.7 2.9 11.4 100.0

Source: From Ref. 11.

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

N

%

2 3 3 1 1 1 11

18.1 27.3 27.3 9.1 9.1 9.1 100.0

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anything in return, and several donated in order to get societal approval (15). Although donors overall are less likely to have depression, anxiety or somatisation, and have higher self-esteem than the general population, they still do have psychological characteristics and stresses that might put them at risk for accidental or self-determined death. In particular, younger donors need to be evaluated for thought processes that might put them at increased risk for self-destructive behavior following donation (14,15). ASSOCIATED MEDICAL CONCERNS The metabolic syndrome is the current and future plague of living donors. Donors who develop the metabolic syndrome are likely to be at increased risk for future renal disease, the most glaring risk being the development of diabetic nephropathy (16–18). Obesity, a major risk factor for diabetes, is increasing worldwide and will become an increasing impediment to donor safety. The renal injury seen with obesity and the metabolic syndrome is related to abnormal glucose metabolism, hypertension, hyperlipidemia, and increased levels of inflammatory factors (19). Donor teams need to discuss the possible risks of current or future obesity on renal outcome. This is especially true if donors have a family history of diabetes, renal disease, or the metabolic syndrome, even if they are clear at the time of donation. Unfortunately, no specific numerical value can be given to the risk of obesity. Special studies of the obese donor need to be undertaken, given the association of obesity not only with diabetes and the metabolic syndrome but also with nephrolithiasis, renal cell cancer, and focal segmental glomerulosclerosis (16,19–24). Finally, the long-term impact of minor degrees of proteinuria in up to 30% of donors needs to be reviewed. Proteinuria, even small amounts, is a marker for endothelial dysfunction, and is associated with the development of cardiovascular disease (25–27). QUALITY OF LIFE Physical and psychological function in living donors is higher than in the general population (28–30). Donors start the donation process at a higher than average functional state; after surgery, they note declines that remain unchanged or improve again with time (Fig. 4) (14,28,29,31–34). Most studies of donor attitudes and functional status are retrospective, include at most 40% to 75% of the possible donors, include a small total sample size (often 15 yrs) consequences of living with a single kidney. A major concern regarding the use of LDs is whether unilateral nephrectomy predisposes to the development of kidney disease and/or premature death. IMPACT OF NEPHRECTOMY ON LONG-TERM SURVIVAL Survival of Kidney Donors Anderson et al. compared the survival rates of 232 patients who underwent nephrectomy for benign disease with the overall Danish population (15). Follow-up ranged from two months to 26 years. If the remaining kidney was normal, survival was identical to that of the overall population. In Sweden, Fehrman-Ekholm et al. found that kidney LDs live longer than the age-matched general population (16). Although Fehrman-Ekholm’s finding may reflect the selection bias of healthy LDs, both studies offer a contradiction to the idea that LD longevity may be limited. Of concern, however, is the recent finding that mild renal dysfunction or proteinuria correlates with cardiovascular risk. All LDs lose more than 20% renal function, and, as discussed below, proteinuria is common after kidney donation.

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

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

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

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

Predictors of Albuminuria in Kidney Donors Smoking

DBP > 85

Albuminuria in donors (%)

Albuminuria in NHANES (%)

Rate Ratioa

No No Yes Yes No No

No No No No Yes Yes

2 13.6 0 60 6.25 80

0.8 1.77 3.11 3.93 0.92 2.78

2.5 7.71 — 15.27 6.79 28.8

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

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

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

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

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2. 3. 4. 5. 6.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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TABLE 1

Characteristics of 225 Living Donor Renal Transplant Recipients

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

Alemtuzumab preconditioning

Historical control

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

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

were two retransplants in the series.

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

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

Alemtuzumab preconditioning

Historical control

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

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

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

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

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

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

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

TABLE 5

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

Incidence of Acute Cellular Rejection Alemtuzumab preconditioning

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

Historical control

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

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

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

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

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

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

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

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

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

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

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

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

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

Five-year allograft survival

Median waiting time (days)

69.7% 65% 60.7%

857 1620 Unable to calculatea

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

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

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

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

Approach to the Patient Presumed to Have Donor Specific Antibody

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

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

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

Starting titer Cytotoxic + XM

# PP/IVIg Pre Tx

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

3 4 5 5 6 7 8 9 10

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

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

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

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

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

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

11

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

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

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

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

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

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Living Donor

10,000 9,000 # Kidney Transplants

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

1990

1992

1994

1996 Year

1998

2000

2002

2004

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

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

90

# Living Non-Directed Donors

80 70 60 50 40 30 20 10 0 1998

1999

2000

2001 Year

2002

2003

2004

FIGURE 2 Growth of nondirected kidney donation since 1998.

Live-Donor Renal Transplantation Through Paired and Nondirected Donation Donor

(A)

(B)

B

ABO incompatible with intended donor

B

A

ABO incompatible with intended donor

O

ABO incompatible with intended donor

O

A

Positive crossmatch with intended donor

Recipient

A

O

ABO incompatible with intended donor

B

A

ABO incompatible with intended donor

O

B

Positive crossmatch with intended donor

Donor

Recipient

O

A

Crossmatch titer >1024 with intended donor

O

O

Crossmatch titer >1024 with intended donor

O

O

Crossmatch titer >1024 with intended donor

Donor

(D)

Recipient

A

Donor

(C)

Recipient

A

Donor

127

Recipient

O

A

Negative crossmatch with matched donor

O

O

Low titer crossmatch (4) with matched donor

O

O

Negative crossmatch with matched donor

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

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

TABLE 1

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

Type of paired donation

No. of recipients

Age (median)

PRA (mean peak)

12 2 4 6 3

55 49 41 33 41

7 0 54 58 48

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

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TABLE 2

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

Type of paired donation

Cellular rejection

Antibody rejection

Graftsa lost

One week median Cr

Three months median Cr

Six months median Cr

Median follow-up (months)

1 0

0 0

1 0

1.2 1.4

1.2 1.2

1.2 1.2

21 7

0 3 1

0 0 0

0 0 0

1.3 1.3 1.2

1.4 1.2 1.2

1.5 1.3 1.5

37 28 9

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

Graft lost on first postoperative night due to technical reasons.

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

How many incompatible pairs are out there?

Simulated Patients Mother

Father Friend

Sibling

Patient

Sibling

Child Relationship to Donor

Spouse

Child %

Parent

19.7

Child

16.8

Sibling

42.4

Spouse

10.0

Unrelated

11.2

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

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Simulated work-up:

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

Failed

ABO and XM test

Donor Patient Compatible

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

Check other donors For eligibility

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

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

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

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

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

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

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

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

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

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

Donor

Recipient Nondirected (altruistic) donor

A

O

A

O

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

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

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

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

12

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

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

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

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

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

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

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

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

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

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

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

58

45

32

46

1

2

3

4

C

AA

AA

C

Race

5.6

9.2

1.7

1.3

Tacrolimus, prednisone, mycophenolate,

1.5

4.0

1.6

Tacrolimus, mycophenolate, prednisone,

1.3

Cr (most recent)

Cr (lowest)

Maintenance

HTN, Tacrolimus, HIVAN sirolimus, prednisone, PKD Tacrolimus

HTN, DM

PKD

Indication

Lamivudine, zidovudine, efavirenz Nevirapine, lamivudine, stavudine

Lamivudine, zidovudine, abacavir

Lamivudine, stavudine, nevirapine

Anti-retrovirals

CD4 Post Tx 482

172

98

944

CD4 Pre Tx >500

1054

391

411

200 cc/hr). Use of loop diuretics (furosemide) and osmotic diuretics (mannitol) should be considered to help maintain this goal. In addition, mannitol may act as a free radical scavenger, and in theory may help decrease ischemia/preservation injury of the donor kidney. Finally, proper patient positioning is required to prevent nerve and tissue injury. For an open nephrectomy, the patient is often positioned in the lateral decubitus position. A laparoscopic nephrectomy will require the patient to be in a modified supine position, with slight TABLE 1

Specific Risks Associated with Donor Nephrectomy

Minor early complications

Major early complications

Long-term complications

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

Postoperative sepsis Hemorrhage Pulmonary embolism

Persistent wound pain Incisional hernia

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

TABLE 2

Comorbidities Associated with End-Stage Renal Disease

Renal/metabolic

CV

Other

Volume overload Anemia Hyperkalemia Metabolic acidosis

Hypertension CAD Congestive heart failure

Diabetes mellitus Autonomic neuropathy Gastroparesis

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

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

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

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

Factors Associated with Increased Thrombotic Risk

Platelet

Coagulation factors

Humoral factors

Clinical factors

Source: From Ref. 25.

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

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procedure other than a small dose of intravenous narcotics (fentanyl 50–250 μg) with induction of general anesthesia to blunt the patient’s response to laryngoscopy. The local/narcotic epidural infusion is continued postoperatively and may be augmented by the patient self-administering small boluses (3 mL every 20 minutes as needed) of the local/narcotic mixture via a patientcontrolled epidural analgesia (PCEA) pump. In addition to standard monitoring as recommended by the ASA, patients should have central venous pressure and direct arterial pressure monitoring. Two peripheral intravenous catheters (16-gauge each) are also recommended in the rare event of surgical hemorrhage. Induction of general anesthesia may be achieved by routine methods. When a combined general/epidural technique is planned, minimal systemic narcotics are required. This technique should allow for rapid emergence and tracheal extubation in most patients. The patient is then brought to the PACU immediately after tracheal extubation and transferred to the intensive care unit overnight. Use of intraoperative cell salvaging is recommended. If time permits, autologous donation of blood by the donor can be performed. Significant blood loss is rare, and in most cases hemodilution techniques are not necessary. Average blood loss reported for a right hepatic lobectomy for live donor surgery has been reported to be 20 cmH2O.

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

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

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

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7. Anaissie EJ, Costa SF. Nosocomial aspergillosis is waterborne. Clin Infect Dis 2001; 33:1546–1548. 8. Anaissie EJ, Stratton SL, Dignani MC, et al. Pathogenic Aspergillus species recovered from a hospital water system: a three-year prospective study. Clin Infect Dis 2002; 34:780–789. 9. Jereb JA, Burwen DR, Dooley SW, et al. Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates. J Infect Dis 1993; 168:1219–1224. 10. Singh N, Arnow PM, Bonham A, et al. Invasive aspergillosis in liver transplant recipients in the 1990s. Transplantation 1997; 64:716–720. 11. Neuwelt EA, Lawrence MS, Blank NK. Effect of gentamicin and dexamethasone on the natural history of the rat Escherichia coli brain abscess model with histopathological correlation. Neurosurgery 1984; 15:475–483. 12. Limaye AP, Raghu G, Koelle DM, Ferrenberg J, Huang ML, Boeckh M. High incidence of ganciclovirresistant cytomegalovirus infection among lung transplant recipients receiving pre-emptive therapy. J Infect Dis 2002; 185:20–27. 13. Ascher NL, Simmons RL, Marker S, Najarian JS. Listeria infection in transplant patients. Five cases and a review of the literature. Arch Surg 1978; 113:90–94. 14. Niklasson PM, Hambraeus A, Lundgren G, Magnusson G, Sundelin P, Groth CG. Listeria encephalitis in five renal transplant recipients. Acta Med Scand 1978; 203:181–185. 15. Jain AK, Agarwal SK, el-Sadr W. Streptococcus bovis bacteremia and meningitis associated with Strongyloides stercoralis colitis in a patient infected with human immunodeficiency virus. Clin Infect Dis 1994; 18:253–254. 16. Tabacof J, Feher O, Katz A, Simon SD, Gansl RC. Strongyloides hyperinfection in two patients with lymphoma, purulent meningitis, and sepsis. Cancer 1991; 68:1821–1823. 17. Wu G, Vilchez RA, Eidelman B, Fung J, Kormos R, Kusne S. Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant recipients. Transpl Infect Dis 2002; 4:183–188. 18. Levy SA, Schmitt KW, Kaufman L. Systemic zygomycosis diagnosed by fine needle aspiration and confirmed with enzyme immunoassay. Chest 1986; 90:146–148. 19. Castiglioni B, Sutton DA, Rinaldi MG, Fung J, Kusne S. Pseudallescheria boydii (Anamorph Scedosporium apiospermum). Infection in solid-organ transplant recipients in a tertiary medical center and review of the literature. Medicine (Baltimore) 2002; 81:333–348. 20. Bleggi-Torres LF, de Medeiros BC, Neto JZ, CR, et al. Disseminated Fusarium sp. infection affecting the brain of a child after bone marrow transplantation. Bone Marrow Transplant 1996; 18:1013–1015. 21. Vincent AL, Cabrero JE, Greene JN, Sandin RL. Successful voriconazole therapy of disseminated Fusarium solani in the brain of a neutropenic cancer patient. Cancer Control 2003; 10:414–419. 22. Weprin BE, Hall WA, Goodman J, Adams GL. Long-term survival in rhinocerebral mucormycosis. Case report. J Neurosurg 1998; 88:570–575. 23. Gomez E, Melon S, Aguado S, et al. Herpes simplex virus encephalitis in a renal transplant patient: diagnosis by polymerase chain reaction detection of HSV DNA. Am J Kidney Dis 1997; 30:423–427. 24. Singh N. Antifungal prophylaxis for solid-organ transplant recipients: seeking clarity amidst controversy. Clin Infect Dis 2000; 31:545–553. 25. Julin JE, van Burik JH, Krivit W, et al. Ganciclovir-resistant cytomegalovirus encephalitis in a bone marrow transplant recipient. Transpl Infect Dis 2002; 4:201–206. 26. DeSalvo D, Roy-Chaudhury P, Peddi R, et al. West Nile virus encephalitis in organ transplant recipients: another high-risk group for meningoencephalitis and death. Transplantation 2004; 77:466–469. 27. Baden LR, Rubin RH. The sentinel chicken revisited: the impact of West Nile virus infection on transplant patients. Transplantation 2004; 77:356–357. 28. Abbott KC, Hypolite I, Poropatich RK, et al. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001; 3:203–211. 29. Apaydin S, Altiparmak MR, Saribas S, Ozturk R. Prevalence of clostridium difficile toxin in kidney transplant recipients. Scand J Infect Dis 1998; 30:542. 30. Keven K, Basu A, Re L, et al. Clostridium difficile colitis in patients after kidney and pancreas–kidney transplantation. Transpl Infect Dis 2004; 6:10–14. 31. Gerding DN. Clindamycin, cephalosporins, fluoroquinolones, and Clostridium difficile-associated diarrhea: this is an antimicrobial resistance problem. Clin Infect Dis 2004; 38:646–648. 32. Charpentier B, Salmon R, Arvis G, Fries D. Tuberculous acute colitis in kidney-transplant patient. Lancet 1979; 2:308. 33. Delis SG, Tector J, Kato T, et al. Diagnosis and treatment of cryptosporidium infection in intestinal transplant recipients. Transplant Proc 2002; 34:951–952. 34. Chieffi PP Sens YA, Paschoalotti MA, Miorin LA, Silva HG, Jabur P. Infection by Cryptosporidium parvum in renal patients submitted to renal transplant or hemodialysis. Rev Soc Bras Med Trop 1998; 31:333–337. 35. Roncoroni AJ, Gomez MA, Mera J, Cagnoni P, Michel MD. Cryptosporidium infection in renal transplant patients. J Infect Dis 1989; 160:559. 36. Kusne S, Torre-Cisneros J, Manez R, et al. Factors associated with invasive lung aspergillosis and the significance of positive Aspergillus culture after liver transplantation. J Infect Dis 1992; 166: 1379–1383.

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37. Frank D, Raicht RF. Intestinal perforation associated with cytomegalovirus infection in patients with acquired immune deficiency syndrome. Am J Gastroenterol 1984; 79:201–205. 38. Abderrahim E, Bouhamed L, Raies L, et al. Intestinal perforation following renal transplantation: report of two cases related to cytomegalovirus disease. Transplant Proc 2003; 35:2706–2707. 39. Van Schaeybroeck S, Hiele M, Miserez M, Croes R. Ileal perforation caused by cytomegalovirus infection in an immunocompetent adult. Acta Clin Belg 2002; 57:154–157. 40. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999; 115:462–474. 41. Paya CVRR. Cytomegalovirus infection after organ transplantation. 2nd ed. Lippincott, ed: Williams and Wilkins, 2003. 42. Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev 2000; 13:83–121, table of contents. 43. Mazzulli T, Drew LW, Yen-Lieberman B, et al. Multicenter comparison of the digene hybrid capture CMV DNA assay (version 2.0), the pp65 antigenemia assay, and cell culture for detection of cytomegalovirus viremia. J Clin Microbiol 1999; 37:958–963. 44. Limaye AP, Jerome KR, Kuhr CS, et al. Quantitation of BK virus load in serum for the diagnosis of BK virus-associated nephropathy in renal transplant recipients. J Infect Dis 2001; 183:1669–1672. 45. Shah KV, Daniel RW, Warszawski RM. High prevalence of antibodies to BK virus, an SV40-related papovavirus, in residents of Maryland. J Infect Dis 1973; 128:784–787. 46. Flaegstad T, Ronne K, Filipe AR, Traavik T. Prevalence of anti BK virus antibody in Portugal and Norway. Scand J Infect Dis 1989; 21:145–147. 47. Hogan TF, Borden EC, McBain JA, Padgett BL, Walker DL. Human polyomavirus infections with JC virus and BK virus in renal transplant patients. Ann Intern Med 1980; 92:373–378. 48. Coleman DV, Gardner SD, Field AM. Human polyomavirus infection in renal allograft recipients. Br Med J 1973; 3:371–375. 49. Mylonakis E, Goes N, Rubin RH, Cosimi AB, Colvin RB, Fishman JA. BK virus in solid-organ transplant recipients: an emerging syndrome. Transplantation 2001; 72:1587–1592. 50. Andrews CA, Shah KV, Daniel RW, Hirsch MS, Rubin RH. A serological investigation of BK virus and JC virus infections in recipients of renal allografts. J Infect Dis 1988; 158:176–181. 51. Nickeleit V, Klimkait T, Binet IF, et al. Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 2000; 342:1309–1315. 52. Lin PL, Vats AN, Green M. BK virus infection in renal transplant recipients. Pediatr Transplant 2001; 5:398–405. 53. Singh N, Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management. J Heart Lung Transplant 2003; 22:258–266. 54. Cornet M, Fleury L, Maslo C, Bernard JF, Brucker G. Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area. J Hosp Infect 2002; 51:288–296. 55. George MJ, Snydman DR, Werner BG, et al. The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland. Am J Med 1997; 103:106–113. 56. Husain S, Kwak EJ, Obman A, et al. Prospective assessment of Platelia Aspergillus galactomannan antigen for the diagnosis of invasive aspergillosis in lung transplant recipients. Am J Transplant 2004; 4:796–802. 57. Kwak EJ, Husain S, Obman A, et al. Efficacy of galactomannan antigen in the Platelia Aspergillus enzyme immunoassay for diagnosis of invasive aspergillosis in liver transplant recipients. J Clin Microbiol 2004;42:435–438. 58. Fortun J, Martin-Davila P, Alvarez ME, et al. Aspergillus antigenemia sandwich-enzyme immunoassay test as a serodiagnostic method for invasive aspergillosis in liver transplant recipients. Transplantation 2001; 71:145–149. 59. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347:408–415. 60. Vilchez R, Shapiro R, McCurry K, et al. Longitudinal study of cryptococcosis in adult solid-organ transplant recipients. Transpl Int 2003; 16:336–340. 61. Paterson DL, Singh N. Cryptococcus neoformans infection. Liver Transpl 2002; 8:846–847. 62. Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg Infect Dis 2001; 7:375–381. 63. Taelman H, Bogaerts J, Batungwanayo J, Van de Perre P, Lucas S, Allen S. Failure of the cryptococcal serum antigen test to detect primary pulmonary cryptococcosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1994; 18:119–120. 64. Nocardia infections. American Journal of Transplantation 2004; 4(suppl 10):47–50. 65. Wiesmayr S, Stelzmuller I, Tabarelli W, et al. Nocardiosis following solid organ transplantation: a single-centre experience. Transpl Int 2005; 18:1048–1053. 66. Queipo-Zaragoza JA, Broseta-Rico E, Alapont-Alacreu JM, Santos-Durantez M, Sanchez-Plumed J, Jimenez-Cruz JF. Nocardial infection in immunosuppressed kidney transplant recipients. Scand J Urol Nephrol 2004; 38:168–173.

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

32

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

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

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

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

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

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

Animal reproductive data

Pregnancy category

Y Y Y Y N N Y Y Y N Y

B D C C C C C C B C C

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

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

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

Recipients

Pregnancies

Outcomesa

764 126 4 41 1 36 3 15 990

1180 211 6 66 2 60 3 19 1547

1216 215 7 68 2 60 3 21 1592

383 NR 25 0

Tacro-based Tacro-based Neoral based

CsA-based CsA-based

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

21/27 15/21 14/18

17/19 18/23

6/6

c

b

4 5 24

CsA-based

20

25 21

24

f

Pre-eclampsia (%)

35/47

115/154 146/238

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

Immunosuppression

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

a

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

NTPR

189/194

Recipients/ pregnancies

d

50

N/A 87

N/A 76 72

74

69 83

82

Liveborn (%)

e

32.8

35 34.8

36.6 37.4 36.9

37

35.6 36.2

35.7

Mean GA (wks)

2202

2150 2041

e

2638 3069 2565

2543

2407 2684

2360

Mean BW (gms)

67

11 35

11 38 23

20

22 30

a

3

0

0 0

7 0 0

0

0.9 2.4

1.4

33

0 8.7

11 14 6

24

15 6

19

17

b

g

12 h 11

10 b 0 b 6

26

8 b 4

b

13

Graft dysfunction/ Graft loss Neonatal Newborn (%) complications (%) deaths (%) rejection during (%)

Comparison of Pregnancy Data Reports in the Literature with Those from the National Transplantation Pregnancy Registry

Kidney Toma et al.

TABLE 3

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Is it reasonable to expect that a pregnancy can be well-tolerated in the transplant population, considering the multiple comorbid conditions and immunosuppressive exposures? Series in the literature in the 1970s and 1980s have attested to the thousands of successful post-transplant pregnancies (2,32). The crucial issues that need to be considered include: does pregnancy in and of itself adversely affect graft function, is immunosuppression necessary in pregnancy, and what are the requirements during pregnancy to maintain stable graft function? Pregnancy and Long-Term Graft Prognosis Case-controlled studies comparing transplant recipients with pregnancies to recipients who did not become pregnant suggest that pregnancy in and of itself does not cause deterioration in graft function (33–37). There might be a minor deleterious effect, as shown by an update of one of these studies (35). This is supported by NTPR data where graft loss within two years of delivery has been infrequent, except for lung recipients. NTPR data further suggest that there may be minor deleterious effects on kidney function in some recipients, as there is a slightly higher mean post-partum serum creatinine when compared with prepregnancy. Pregnancy may unpredictably have a deleterious affect on graft function. This appears more likely in the setting of prepregnancy graft dysfunction. An NTPR analysis showed that CsA-treated renal recipients with serum creatinine levels prepregnancy ≥2.5 mg/dL were three times more likely to experience graft loss post-partum than recipients with a mean serum creatinine level ≤1.5 mg/dL (38). Similar outcomes were noted among the recipients studied in the U.K. National Register, where it was identified that lower prepregnancy serum creatinine levels were a favorable predictor for pregnancy outcome (39). Another study illustrated the presence of chronic rejection as a prepregnancy risk for pregnancy-related graft deterioration (40). Serum creatinine alone, however, may not be a sufficient predictor. A more recent analysis of outcomes of six Neoral or tacrolimus-based female kidney recipients with biopsy-proven acute rejection episodes during pregnancy noted a range in prepregnancy creatinine from 1.0 mg/dL to 3.0 mg/dL (summarized in Table 4). Each case had biopsy-proven acute rejection, some with nonviable outcomes and with significantly lower birthweights in the liveborn, illustrating the association of rejection with poorer outcomes. Prepregnancy serum creatinine alone did not predict adverse pregnancy events. Assessment of the risk of pregnancy on graft function has largely come from analyses of renal transplant recipient pregnancies, where thousands have been reported. While the numbers of pregnancies in non-renal recipients do not allow the same detailed evaluation, some conclusions can be drawn. In an NTPR study, outcomes of pregnancies in female liver recipients with biopsy-proven rejection were compared with pregnancies with no rejection episodes. From TABLE 4 NTPR Outcomes of Six Neoral® or Tacrolimus-Based Female Kidney Recipients with Biopsy-Proven Acute Rejection Episodes During Pregnancy

Case

Regimen

Pre-pregnancy creatinine (mg/dL)

Rejection treatment

Graft loss < 2 yrs post partum

Outcome

Gestational age (wks)

Birth weight (gms)

1.3

OKT3® and radiation

Y

SA

6

N/A

2 3 4 5

Neoral® switched a to tacro during pregnancy a Tacro Neoral® Neoral® Neoral®

2.8 1.2 3.0 2.6

N N N N

SA L L L

7 32 29 32

N/A 1378 1247 1417

6

Tacro

1.0

OKT3® and MP MP MP Restart immunob suppression Thymoglobulin® and sirolimus

Y

L

32

1531

1

Cases 1 and 6 from deceased-donor kidney; cases 2–5 from living-donor kidney. a Both recipients stopped their medications during pregnancy. b Recipient was being treated for cancer. Abbreviations: L, live birth; MP, methylprednisolone; NTPR, National Transplantation Pregnancy Registry; SA, spontaneous abortion; Tacro, tacrolimus. Source: From Ref.8

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119 pregnancies in 72 female liver recipients with 91 live births, biopsy-proven rejection occurred in 10 recipients with 11 pregnancies; these rejection episodes were treated with methylprednisolone, OKT3, antilymphocyte serum, or an increase in maintenance immunosuppression (41). Birthweights were lower in the newborns in the rejection group compared with the no-rejection group, 1946 g versus 2107 g (p= 0.006). Also of note was the fact that biopsy-proven rejection occurred within the three months post-partum in 11 female recipients, 45% of whom had had a rejection during pregnancy, illustrating both poor newborn outcomes as well as poor maternal outcomes in the setting of rejection. Registry data also appear to support the concept that liver recipients with recurrent hepatitis C appear to be at risk for peripartum graft dysfunction with subsequent pregnancies (42). An analysis from the registry of PK recipients compared those with and without postpartum graft loss (43). Significant differences between the groups were found in mean serum creatinine levels both during pregnancy and post-partum, and with a higher incidence of rejection during pregnancy in those recipients who lost graft function within two years of pregnancy compared with those who did not have graft loss. While the incidence is fortunately low, rejection during pregnancy can occur and is associated with poor outcomes for both the mother and the newborn. This underscores the need for maintenance immunosuppression during pregnancy. It also raises the question of what to do with the newer immunosuppressive agents, where there is less known about reproductive safety. Outcomes of pregnancies with exposure to MMF and sirolimus are summarized in Table 5. Birth defects occurred in four of 18 liveborn. If this trend continues with a larger experience, an entirely different approach to pregnancy in patients on these agents will be needed. SOME LESSONS FROM THE LITERATURE Although there are many publications about pregnancy after transplantation, no study has specifically compared pregnancy outcome by living or deceased donor source. An analysis of the effect of graft gender on gestational renal adaptation in kidney transplant recipients revealed no significant differences (44). End-stage organ failure often leads to infertility in women. Fertility usually returns with successful transplantation. As fertility can return rapidly, female recipients of child-bearing age need to be educated regarding their contraceptive choices. Ideally, the recipient and her healthcare provider need to discuss which contraception is appropriate, impressing upon the recipient the potential for pregnancy if she is sexually active. This counseling should start at the time of the transplant evaluation and continue during the hospitalization for transplant and at follow-up clinic visits (45,46). Pregnancy After Deceased- and Living-Donor Kidney Transplant The concerns of recipients with living-donor grafts, in addition to the issues already discussed, may include loss of the kidney and/or graft dysfunction. Are the potential risks of pregnancy justified when an organ has been received from a living donor? This section summarizes the outcomes of pregnancies from recipients who received a living-donor organ. As national data show that recipients of living-donor kidneys have, on average, longer graft survival and are generally considered to have lower serum creatinine levels and better function than recipients of deceased-donor kidneys, one might expect that female recipients of living-donor kidneys would have better pregnancy outcomes as well. Outcomes of pregnancy after both types of kidney transplantation appear in Table 6. The similarities between the groups are striking. Of note are the smaller number of reported pregnancy outcomes in tacrolimus-treated recipients. While the incidence of drug-treated hypertension varies among the groups, the incidence of pre-eclampsia in these recipients is similar and approximately three times higher than that in the general population (47). The majority of infections reported during pregnancy are urinary tract infections, which are of course generally minor, and routinely responsive to the appropriate antibiotics. Other infections include vaginal yeast infections and upper respiratory infections. There have been rare reports of other more serious infections, including CMV. Interesting differences for

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TABLE 5 NTPR-Reported Pregnancy Outcomes of Female Recipients with MMF Exposure During Pregnancy Reported to the NTPR Organ

Regimen

1 2 3 4 5

Kidney Kidney Kidney Kidney Kidney

MMF, tacro, prednisone MMF, tacro, prednisone MMF, tacro, prednisone MMF, tacro, prednisone MMF, Neoral®, prednisone

6

Kidney

MMF, Neoral®, prednisone

7 8 9

Kidney Kidney Kidney

MMF, tacro, prednisone, sirolimus MMF, Neoral®, prednisone MMF, tacro, prednisone

10 11

Kidney Kidney

MMF, tacro, prednisone MMF, tacro

12 13

Kidney Kidney

MMF, tacro MMF, Gengraf®, prednisone

14 15 16 17 18 1 1 2 3 1 2

Kidney Kidney Kidney Kidney Kidney P/K Liver Liver Liver Heart Heart

MMF, tacro, prednisone MMF, tacro, prednisone MMF, tacro MMF, Neoral®, prednisone MMF, tacro, prednisone MMF MMF, tacro, prednisone MMF, tacro MMF, tacro MMF, tacro MMF, tacro

Outcome a

L SA L L L SA SA L SA L b L L SA L SA SA SA L SA SA SA c L d L L L L SA L L SA SA SA L

Birth weight (gms) 2240 N/A 822 1701 2495 N/A N/A 2977 N/A 2240 1531 3118 N/A 2211 N/A N/A N/A 3118 N/A N/A N/A 2155 2886 3487 2807 2523 N/A 2466 2608 N/A N/A N/A 1758

Gestational age (wks) 34 7 31 35 36 7 6 36 8 35 31 39 4 33 5 4 5 38 9 6 7 36 39 37 37 34 6 39 37 18 3 6 34

a

Hypoplastic nails, shortened fifth fingers. Cleft lip and palate, microtia. Multiple malformations, neonatal death at age one day. d Microtia. Abbreviations: L, livebirth; MMF, mycophenolate mofetil; SA, spontaneous abortion; Tacro, tacrolimus. Source: From Ref. 8. b c

tacro-treated recipients include a higher incidence of diabetes, and live births that were slightly more premature with proportionately lower birthweights. A comparison of outcomes of pregnancy after living-donor kidney versus deceased donor transplant in CsA-treated is shown in Table 7. The incidence of drug-treated hypertension during pregnancy in recipients who have had a kidney from a deceased donor is higher than the incidence of those who received a living-donor kidney, 69% versus 52%, respectively. Otherwise, the two groups had similar maternal factors. The living-donor recipients reported a higher percentage of live births (81% compared with 73%), fewer premature births, and a longer gestational age in the newborn, a higher mean birthweight, and no neonatal deaths. Graft function as assessed by mean serum creatinine was the same before, during, and after the pregnancy between the two groups. As hypertension alone in women without a transplant can be associated with low birthweight and preterm delivery, this could influence the higher rate of preterm and low-birthweight infants among the deceased-donor kidney recipients. Graft loss within two years of pregnancy, although slightly lower among the living-donor recipients when compared with the deceased-donor recipients (8% versus 11% respectively), has been reported. Careful monitoring of recipient graft function is recommended in the postpartum period.

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Pregnancy After Living-Donor Transplantation

TABLE 6

NTPR—All Female Kidney Transplant Recipient Pregnancy Outcomes Reported CsA

Maternal factors Transplant to conception interval (mean) Hypertension during pregnancy Diabetes during pregnancy Infection during pregnancy a Rejection episode during pregnancy Preeclampsia Mean serum creatinine (mg/dL) Before pregnancy During pregnancy After pregnancy Graft loss within 2 years of delivery b Outcomes (n) Therapeutic abortions Spontaneous abortions Ectopic Stillborn Live births Live births (n) Mean gestational age Mean birth weight Premature (