Transplantation of the Pancreas [2 ed.] 3031209982, 9783031209987

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Rainer W.G. Gruessner Angelika C. Gruessner Editors

Transplantation of the Pancreas Second Edition

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Transplantation of the Pancreas

Rainer W.G. Gruessner  •  Angelika C. Gruessner Editors

Transplantation of the Pancreas Second Edition

Editors Rainer W.G. Gruessner Department of Surgery State University of New York (SUNY) Downstate Health Sciences University Brooklyn, NY, USA

Angelika C. Gruessner Department of Medicine SUNY Downstate Health Sciences University Brooklyn, NY, USA

ISBN 978-3-031-20998-7    ISBN 978-3-031-20999-4 (eBook) https://doi.org/10.1007/978-3-031-20999-4 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This Book is dedicated to our Patients for their Vision and Courage and to David E.R. Sutherland who devoted his Life to Beta-Cell-Replacement through Transplantation for the Treatment of Diabetes Mellitus

David Elmer Richard Sutherland (“DERS”) was born on December 25, 1940, in St. Paul, MN. The second of three children of John E. Sutherland, a Lutheran pastor, and Vivian I. Sutherland, a schoolteacher, he grew up in the suburbs of St. Paul and went to North St. Paul High School. In 1958, he was admitted to Augustana College in Rock Island, Illinois, and majored in premedical sciences.

In 1962, he was admitted to the University of Minnesota Medical School. There he met two faculty members who would determine his future career. The first was Dr. Robert Alan Good (1922–2003), who performed the first successful human bone marrow transplant between individuals who were not identical twins; Good is regarded as a founder of modern immunology. The second was Dr. Richard Carlton Lillehei (1927–1981) who performed the world's first successful pancreas transplant in 1966 (with Dr. William D. Kelly) and the first human intestinal transplant in 1967. As a medical student, David Sutherland worked in the immunology laboratory of Dr. Good, then a Professor of Pediatrics, Microbiology and Pathology who later also served as head of the Department of Pathology. David Sutherland’s research work focused on the immunological role of the thymus, Peyer’s patches, and appendix, resulting in his first publications in the journals Nature (in 1963) and Lancet (in 1965). More than 1,000 peer-reviewed articles would follow over the years. While on his surgical rotation, David Sutherland met Dr. Lillehei, then a Professor of Surgery, who inspired him to pursue a career in surgery. In 1967, David Sutherland began his surgery residency at West Virginia University. However, about two years into his residency, he was drafted by the U.S. Army Medical Corps. He served for initially one year at the U.S. Army Hospital in Fort Devens, Massachusetts, and then for another year in Vietnam at the 3rd Surgical Hospital. During that time, he came to the conclusion that he wanted to go back to Minnesota to finish his residency. An era had just ended there: Owen H. Wangensteen (1898–1981), one of the most renowned American surgeons of the first half of the twentieth century, had just retired as the chairman of the Department of Surgery. David Sutherland’s mentor, Robert Good, had been appointed chair of the search committee for the new Surgery Chairman. He introduced David Sutherland to the newly elected Surgery Chair, Dr. John S. Najarian, as a prospective surgery resident. Fortuitously, Najarian agreed and Sutherland, intrigued by the dynamics and energy radiating from the new transplant program at the University of Minnesota, resumed his residency there in 1970. By then, Najarian had realized that early attempts at pancreas transplantation were fraught with technical and immunologic complications. In light of Sutherland’s experience in Good’s immunology laboratory, Najarian decided to send him back into the

laboratory for two years. As Najarian stated, Sutherland should just “fix the problem for good by making islet transplantation work and have diabetic patients forgo a major surgical procedure.” Sutherland’s research on the isolation, processing, and transplantation of islets resulted in his PhD degree in 1976. The professional relationship that developed between Najarian and Sutherland over three decades became one of the most productive and successful in the history of transplantation. After completing his residency and transplantation fellowship, David Sutherland stayed on the faculty of the Department of Surgery, starting in January 1976 until his retirement in 2009. He was promoted to Associate Professor in 1980 and to Professor in 1986. As of 1995, he served as the Chief of the Division of Transplantation; as of 1994, as the Director of the Schulze Diabetes Institute. In 2013, an endowed chair in his name was established at the University of Minnesota.

When Sutherland left Najarian’s laboratory in 1973, he was very proficient in the islet isolation process and quickly put his experience to work. In 1974, he and Najarian performed the world’s first human islet transplant, using a deceased donor, but insulin independence was not achieved. In 1977, he and Najarian performed the first total pancreatectomy with islet autotransplant (TPIAT). As so critical for any surgical “first,” the procedure was successful: the patient became insulin-independent and remained so for many years. Only 7 months later, the first living related islet transplant was done, quickly followed by a second transplant. However, neither of these transplants achieved lasting insulin independence. So, in 1978, the clinical pancreas transplant program that Lillehei had started a decade earlier resumed under Sutherland’s leadership. The first transplant in this new series was a success and the patient remained insulin-independent for 17 years until she fell off a horse and tragically died. At that time, the results of kidney transplantation from living donors were significantly better than from deceased donors. Sutherland, initially with Najarian, embarked on a unique series of about 125 living donor pancreas transplants that would bring many more “firsts” to fruition: basically all types of different duct management techniques, portal vein drainage, transplants between children and parents, transplants from biologically unrelated donors, ABO-incompatible transplants, and eventually the first dual organ transplants (segmental pancreas and kidney) from living donors. The living donor experience was instrumental in developing the now-called “Sutherland” technique of spleen preservation in patients undergoing distal pancreatectomy and in achieving the world’s first successful split-organ transplant (1988) for two adult recipients. Most important, however, was the twin living donor experience: before the advent of advanced laboratory tests, David Sutherland showed in transplants between identical twins that type 1 diabetes mellitus was an autoimmune disease; that it recurred in twin transplant recipients if no immunosuppression was given; and that it did not recur when standard immunosuppression was given.

Although Richard Lillehei had performed the first pancreas transplant, David Sutherland continued to make many seminal contributions to this evolving field. He performed the first open duct drainage (1978); the first pancreas transplant after a total pancreatectomy for chronic pancreatitis (1988); the first pancreas transplant in a child; the first successful 3rd and 4th pancreas retransplants; the first conversion from pancreas to islet transplant due to graft pancreatitis. In addition, he directed, until his retirement in 2009, the world’s oldest and largest pancreas transplant program, which performed about 150 pancreas transplants per year between 2000 and 2002. He also established the International Pancreas and Islet Transplant Registry (IPTIR) in 1980. David Sutherland never considered pancreas and islet transplantation as competing fields, but rather as complementary treatment options in an allinclusive, comprehensive beta-cell replacement strategy. This explains his treatment shifts from solid-organ to cellular transplantation and vice versa, based on the best approach for an individual patient. For his many seminal contributions to beta-cell replacement through transplantation, Sutherland received many honors and awards during his distinguished career. He served as the President of the American Society of Transplant Surgeons (1990); of the Cell Transplantation Society (1994); of the International Pancreas and Islet Transplant Association (1995); and of the Transplantation Society (2002). He received honorary doctorates from the Université Catholique de Louvain in Belgium and the University of Pisa in Italy as well as honorary memberships in the Spanish and Greek Surgical Societies. His many other awards include the ASTS-Roche Pioneer Award (2007); the inaugural Richard C. Lillehei Award (2011); and, in 2012, the (Sir Peter) Medawar Prize, the world's highest dedicated award for the most outstanding contributions in the field of transplantation.

Honorary doctorate from the University of Pisa, Italy, bestowed on David E.R. Sutherland in 2019 for his lifetime achievements in the field of pancreas transplantation. Masters of ceremonies were Dr. U. Boggi (far left), Dr. Raja Kandaswamy (second from right), and Dr. Rainer W.G. Gruessner (far right). Photo courtesy of Dr. Boggi. A summary of the many seminal achievements of his distinguished career does justice to only part of David Sutherland’s personality. Equally important, he is a great human being who cares deeply for his patients, suffers tremendously with them in case of setbacks, and relishes their successes. He performed transplants in thousands of diabetic patients, many of whom became insulin-independent and dialysis-free for the rest of their lives. He trained transplant surgeons and physicians from all over the world and laid the foundation for the field of pancreas transplantation the way it has developed. His own curiosity, ingenuity, and willingness to think outside the box are legendary; as he said, “true scholars don’t practice evidence-

based medicine, they perform evidence-gathering medicine.” He came up with clinical and research solutions for improbable challenges. His laboratory gave a myriad of research scientists the opportunity to explore new frontiers in the field of beta-cell replacement through transplantation and immunology. Many of his trainees moved on to become directors of large pancreas transplant programs, chiefs of transplantation, or department chairs. He earned tremendous respect and admiration from his peers, patients, and students—while remaining a truly humble, modest, empathetic, and gracious human being with a great sense of humor. Despite becoming one of the greatest surgeons of the second half of the twentieth century, he never forgot his Minnesota roots, nor his many interests in nonmedical fields such as American history and literature, classical music, baseball, and horticulture. The pancreas transplant community at large is indebted to David Sutherland. Rainer and Angelika Gruessner

Preface

The first edition of this textbook Pancreas Transplantation was published in 2004, almost 40 years after the first pancreas transplant performed by William Kelly and Richard Lillehei. By 2004, pancreas transplantation had evolved from an experimental procedure that had initially been fraught with a high technical and immunological complication rate to a standardized clinical procedure for insulin-dependent diabetic patients with or without concurrent uremia. Furthermore, favorable long-term results of the impact of pancreas transplantation on the secondary complications of diabetes mellitus had become available which demonstrated that a successful pancreas transplant not only results in insulin independence but also prevents, halts, or even reverses these devastating secondary complications. Since 2004, the field of pancreas transplantation has seen numerous advances. Specifically, a major change has taken place in the surgical technique itself: the more physiologic enteric drainage is now the preferred technique for the management of exocrine secretions in about 90% of all transplants whereas bladder drainage has fallen out of favor due to its unique spectrum of complications. This change from bladder to enteric drainage became possible because of superior immunosuppressive protocols with the advent of tacrolimus and mycophenolate mofetil in the 1990s, better surgical techniques, and improved antimicrobial prophylaxis and treatment, all of which significantly decreased graft loss rates from rejection and infection. Also since 2004, pancreas transplants are increasingly performed in minorities and Type 2 insulin-dependent diabetic patients. A new BANFF rejection classification and new immunosuppressants have been introduced. Finally, in the U.S., the pancreas allocation policies have changed in a favorable way in that the kidney now follows the pancreas which increases the potential for combined pancreas and kidney transplants. Over the past decade, pancreas transplantation has seen 1-year patient survival rates of >95% and graft survival rates of >80% in all recipient categories. Worldwide, at the time of this writing, almost 64,000 pancreas transplants have been performed in total and about 2,400 transplants per year according to the International Pancreas Transplant Registry (IPTR). It has been very gratifying personally to be part of all these positive developments over the past two decades and between the two editions of this textbook. However, on this road of increasing success, there have been a few bumps as well. Despite the increasing survival rates, a temporary decline in the number of pancreas transplants was noted in the U.S. between 2005 and 2015 which, however, was “counterbalanced” by an increase in pancreas transplants primarily in South America and Asia. The number of “uremia-preemptive” solitary pancreas transplants has not increased, despite the fact that it would result in a decrease in the number of concurrent kidney transplants that could be used for patients with other end-stage renal diseases. Unlike the first edition, this second edition comprises 10 different sections and a total of 93 chapters. All previous chapters were updated. New chapter topics include pancreas transplantation for Type 2 diabetes and minorities, organ allocation policies as well as program and physician certification in different parts of the world, economic and insurance issues, various β-cell transplant options, and the endocrinologists’ viewpoint on the future of pancreas transplantation. Individual chapters are now devoted to topics such as DCD transplants, robotic transplant procedures, pregnancy after transplantation, outcome definitions, and a common xiii

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waiting list for pancreas and islet transplantation. Current topics include a summary of the 1st World Consensus Conference on Pancreas Transplantation in Pisa, Italy, in 2019, the worldwide expansion of pancreas transplantation, and the impact of Covid-19 infection on pancreas transplantation. Like the first edition, this expanded second edition is also designed to provide an all-­ inclusive, state-of-the-art overview of pancreas transplantation as a definitive textbook for all health professionals, physicians, surgeons, and researchers that work in the field of (pancreas) transplantation. It features insight on the pathophysiology of diabetes mellitus, highlights the history of the field, compares different surgical techniques, details the broad spectrum of posttransplant complications and their treatments, focuses on immunosuppression, immunology and pathology, and centers on the impact on secondary complications and quality of life. Pretransplant evaluation, psychosocial aspects, and living donor transplantation are covered as are long-term outcomes and shared aspects with islet transplantation. The first edition was primarily authored by current and former colleagues and students of David Sutherland who had built one of the preeminent pancreas transplant programs in the world over a period of four decades until his retirement in 2009. Many chapters of this second edition are still authored by “Sutherland-trained” transplant surgeons and physicians. However, as the field of pancreas transplantation has continued to evolve since the first edition of this textbook, all or most leading international physicians, surgeons, and scientists in the field of pancreas transplantation have contributed their knowledge and experience to this textbook. This book is again dedicated to all diabetic patients who had the vision and the courage to undergo a pancreas transplant to enjoy life-long freedom from insulin. But it is also dedicated to David E.R.  Sutherland who devoted his life to successful beta-cell-replacement through transplantation for the treatment of patients with diabetes mellitus and who pioneered both pancreas and islet transplantation. Finally, we are grateful to Sangeetha Annaswamy, ArulRonika Pathinathan, Richard Hruska, and Kristopher Spring who competently oversaw the production of this textbook by Springer Inc, New York. New York City, NY, USA 

Rainer W.G. Gruessner Angelika C. Gruessner

Contents

Part I General Aspects of Diabetes Mellitus and Pancreas Transplantation 1 Diabetes  Mellitus: Classification and Diagnosis�����������������������������������������������������    3 Piero Marchetti, Walter Baronti, Ugo Boggi, and Lorella Marselli 2 Epidemiology  and Pathogenesis of Type 1 Diabetes ���������������������������������������������   13 Lars C. Stene and Ake Lernmark 3 Epidemiology  and Pathogenesis of Type 2 Diabetes ���������������������������������������������   41 R. Paul Robertson 4 Medical  Management of Diabetes Mellitus: Options and Limitations ���������������   55 R. Paul Robertson 5 History of Pancreas Transplantation����������������������������������������������������������������������   59 David E. R. Sutherland and Rainer W.G. Gruessner 6 Experimental Pancreas Transplantation ���������������������������������������������������������������   93 Alan C. Farney and Mikel Prieto Part II The Donor 7 Pancreas  Allocation in the United States ���������������������������������������������������������������  117 Dixon B. Kaufman 8 Pancreas  Allocation in the Eurotransplant Area���������������������������������������������������  129 Helmut Arbogast 9 Pancreas  Allocation in the United Kingdom����������������������������������������������������������  141 Claire Counter, John Casey, James A. Shaw, and Steven A. White 10 Pancreas Allocation in Australasia �������������������������������������������������������������������������  151 Henry Pleass 11 Donor Risk Indices���������������������������������������������������������������������������������������������������  159 Priyadarshini Manay and David A. Axelrod 12 Donor  Selection and Management �������������������������������������������������������������������������  167 Pierpaolo Di Cocco, Kiara Tulla, Ivo Tzvetanov, and Enrico Benedetti 13 Pancreas Preservation ���������������������������������������������������������������������������������������������  179 Julien Branchereau, James Hunter, Marten Engelse, and Rutger J. Ploeg 14 Donor  Procurement After Brain Death �����������������������������������������������������������������  189 Stephan A. Gruessner and John F. Renz

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15 Donor  Procurement After Circulatory Death �������������������������������������������������������  203 Josue Alvarez-Casas, Maher Sraj, and Joseph R. Scalea 16 Living Donation���������������������������������������������������������������������������������������������������������  215 Rainer W.G. Gruessner 17 Surgical Back-Table Procedures�����������������������������������������������������������������������������  231 Anand Sivaprakash Rathnasamy Muthusamy, Jeevan Prakash Gopal, and Vassilios E. Papalois Part III The Recipient 18 Patient  Selection: Pancreas or Islet Transplantation���������������������������������������������  245 Swati Rao, Meaghan Stumpf, and Kenneth L. Brayman 19 One  Waiting List for Pancreas and Islet Transplantation: The Canadian Experience ���������������������������������������������������������������������������������������  257 Trevor Reichman and Mark S. Cattral 20 One  Waiting List for Pancreas and Islet Transplantation: The United Kingdom Experience �����������������������������������������������������������������������    263 John J. Casey and Nadey Hakim 21 Pancreas Transplant Recipient Categories�������������������������������������������������������������  269 Rainer W.G. Gruessner 22 Simultaneous  Pancreas and Kidney Transplantation�������������������������������������������  271 Wen Xie, Rami Kantar, Laura DiChiacchio, and Joseph R. Scalea 23 Pancreas After Kidney Transplantation�����������������������������������������������������������������  285 Santosh Nagaraju, John A. Powelson, and Jonathan A. Fridell 24 Pancreas Transplantation Alone �����������������������������������������������������������������������������  291 Rainer W.G. Gruessner and Angelika C. Gruessner 25 Psychosocial Aspects�������������������������������������������������������������������������������������������������  307 Sasja D. Huisman and Eelco de Koning 26 Pre-transplant Evaluation���������������������������������������������������������������������������������������  327 Delphine Kervella, Christophe Masset, Julien Branchereau, and Diego Cantarovich 27 Cardiac Risk Assessment�����������������������������������������������������������������������������������������  339 Oleh G. Pankewycz and Mark R. Laftavi 28 Anesthetic Management�������������������������������������������������������������������������������������������  347 Joaquin Cagliani and Geraldine C. Diaz 29 Standard  Open Procedures from Deceased Donors ���������������������������������������������  353 Rainer W.G. Gruessner 30 Gastric  Drainage: The United States Experience �������������������������������������������������  409 Hosein Shokouh-Amiri and Gazi B. Zibari 31 Duodenal  Drainage: The South American Experience (Brazil)���������������������������  419 Marcelo Perosa, Fernanda Danziere, Juan Branez, and Tercio Genzini 32 Duodenal  Drainage: The European Experience (Germany)���������������������������������  429 Peter Schenker and Richard Viebahn

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33 Robotic  Pancreas Transplantation: The European Experience (Italy)���������������  433 Ugo Boggi and Fabio Vistoli 34 Robotic  Pancreas Transplantation: The United States Experience���������������������  451 Pierpaolo Di Cocco, Kiara Tulla, Mario Spaggiari, Ivo Tzvetanov, and Enrico Benedetti 35 Living Donor Pancreas Transplantation�����������������������������������������������������������������  457 Rainer W.G. Gruessner 36 Pancreas-Multivisceral Transplantation�����������������������������������������������������������������  467 Mathias Clarysse, Laurens J. Ceulemans, Diethard Monbaliu, and Jacques Pirenne Part IV Living Donor Pancreas Transplantation 37 Living Donor Work-Up���������������������������������������������������������������������������������������������  481 Rainer W.G. Gruessner and Elizabeth R. Seaquist 38 The  United States Experience ���������������������������������������������������������������������������������  487 Rainer W.G. Gruessner and Angelika C. Gruessner 39 The Asian Experience�����������������������������������������������������������������������������������������������  509 Duck J. Han and Takashi Kenmochi Part V Post-transplant Management 40 Initial Transplant Hospitalization���������������������������������������������������������������������������  531 Steven Paraskevas and Abrar Nawawi 41 Imaging Studies���������������������������������������������������������������������������������������������������������  543 Jonathan A. Fridell, Jordan Swensson, and David M. Agarwal 42 Surgical Complications���������������������������������������������������������������������������������������������  553 David Harriman, Alan C. Farney, Christoph Troppmann, and Robert J. Stratta 43 Medical Complications���������������������������������������������������������������������������������������������  585 Silke V. Niederhaus 44 Post-transplant Infections ���������������������������������������������������������������������������������������  597 Niyati Narsana, David L. Dunn, and Giuseppe Orlando 45 Post-transplant Malignancies����������������������������������������������������������������������������������  605 Steven Paraskevas 46 Post-transplant Lymphoproliferative Disease �������������������������������������������������������  615 Stefano Fratoni, Justine M. Aziz, Carlo Gazia, Giuseppe Orlando, and Andrea Tendas 47 Non-immunological  Endocrine Graft Dysfunction�����������������������������������������������  623 Christoph Troppmann Part VI Immunological Management 48 Induction Therapy ���������������������������������������������������������������������������������������������������  633 Dixon B. Kaufman, Daniel C. Felix, and Christopher Little 49 Maintenance Therapy�����������������������������������������������������������������������������������������������  655 Dominic Amara, Rainer W.G. Gruessner, and Peter G. Stock

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50 Immunobiology,  Diagnosis, and Treatment of Rejection �������������������������������������  675 Fahad Aziz, Didier Mandelbrot, Sandesh Parajuli, Talal Al-Qaoud, and Jon Odorico 51 Pancreas Graft Pathology ���������������������������������������������������������������������������������������  705 Cinthia B. Drachenberg and John C. Papadimitriou 52 Crossmatch  Positivity: The Khalid Khwaja Memorial Chapter �������������������������  727 Khalid Khwaja, Raja Kandaswamy, and Rainer W.G. Gruessner 53 ABO Incompatibility �����������������������������������������������������������������������������������������������  735 Duck J. Han and Takashi Kenmochi 54 Graft-Versus-Host-Disease���������������������������������������������������������������������������������������  755 Christine E. M. Gruessner 55 Donor  Bone Marrow Conditioning, Chimerism, and Tolerance Induction�����    765 Gaetano Ciancio, Giuseppe Orlando, Rodrigo Vianna, and George W. Burke III 56 Recurrence  of Type 1 Diabetes Mellitus�����������������������������������������������������������������  781 George W. Burke III, Gaetano Ciancio, Mahmoud Morsi, Jose Figueiro, Linda Chen, Junichiro Sageshima, Francesco Vendrame, and Alberto Pugliese Part VII Impact on Endocrine Function and Secondary Complications of Diabetes Mellitus 57 Endocrine  Function and Metabolic Outcomes After Pancreas and Islet Transplantation�����������������������������������������������������������������������������������������������������    801 R. Paul Robertson 58 Nephropathy �������������������������������������������������������������������������������������������������������������  817 Subodh Saggi, Paola Fioretto, Michael Mauer, and Rainer W.G. Gruessner 59 Neuropathy ���������������������������������������������������������������������������������������������������������������  831 Xavier Navarro and William R. Kennedy 60 Retinopathy���������������������������������������������������������������������������������������������������������������  845 Yoon Jeon Kim, Arthur W. Walsh, and Rainer W.G. Gruessner 61 Gastropathy���������������������������������������������������������������������������������������������������������������  859 Rainer W.G. Gruessner, A. Osama Gaber, and Hosein Shokouh-Amiri 62 Micro- and Macrovasculopathy�������������������������������������������������������������������������������  875 Henry Pleass 63 Cardio-Cerebro-Vascular Disease���������������������������������������������������������������������������  883 Oswaldo Aguirre and Matthew Cooper 64 Secondary  Complications: Pancreas Versus Islet Transplantation ���������������������  897 Paola Maffi, Davide Catarinella, and Antonio Secchi Part VIII Outcomes 65 Defining Outcomes for β-Cell Replacement Therapy�������������������������������������������  915 Michael R. Rickels 66 The  Current State of Pancreas Transplantation in the World: The International Pancreas Transplant Registry (IPTR) Report �������������������������������  925 Angelika C. Gruessner

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67 Survival  Benefit of Pancreas Transplantation �������������������������������������������������������  961 Rainer W.G. Gruessner and Angelika C. Gruessner 68 Outcome  of Donation After Circulatory Death�����������������������������������������������������  969 Volkert A. L. Huurman and Eelco J. P. de Koning 69 Management  of the Failing Pancreas Graft�����������������������������������������������������������  975 Richard J. Knight, Archana R. Sadhu, and A. Osama Gaber 70 Retransplantation�����������������������������������������������������������������������������������������������������  989 Ty B. Dunn and Robert R. Redfield III 71 Type  2 Diabetes Mellitus, Minorities, the Young and Elderly �����������������������������  999 Robert J. Stratta and Nicole Turgeon 72 Cystic Fibrosis����������������������������������������������������������������������������������������������������������� 1023 Jonathan A. Fridell, Molly A. Bozic, Andrew J. Lutz, and John A. Powelson 73 Long-Term  Pancreas Graft Function��������������������������������������������������������������������� 1029 Angelika C. Gruessner 74 Quality of Life����������������������������������������������������������������������������������������������������������� 1039 Oleh G. Pankewycz, Cynthia R. Gross, Mark R. Laftavi, and Angelika C. Gruessner 75 Pregnancy After Pancreas Transplantation����������������������������������������������������������� 1053 Robert Öllinger and Joseph M. G. V. Gassner Part IX Organizational and Economical Issues 76 Formulas  for Successful Pancreas Transplant Programs������������������������������������� 1063 Jennifer Carpenter and Peter Abrams 77 Accreditation  and Certification in the United States��������������������������������������������� 1069 John F. Renz 78 Accreditation  and Certification in Europe������������������������������������������������������������� 1077 Daniel Casanova and Vassilios Papalois 79 Economic  and Insurance Issues������������������������������������������������������������������������������� 1087 Rainer W.G. Gruessner Part X Other β-Cell Transplant Options 80 Treatment  of Pancreatic Exocrine Disorders by Pancreas and Islet Transplantation��������������������������������������������������������������������������������������������������������� 1101 Mark Reza Laftavi, Oleh Pankewycz, and Rainer W.G. Gruessner 81 Total  Pancreatectomy and Islet Autotransplantation: Surgical Procedures������� 1113 Chirag S. Desai and Rainer W.G. Gruessner 82 Total  Pancreatectomy and Islet Autotransplantation: Islet Isolation������������������� 1133 Siddharth Narayanan, Krishna Kumar Samaga, Ahad Ahmed Kodipad, Sri Prakash L. Mokshagundam, Jaimie D. Nathan, and Appakalai N. Balamurugan 83 Total  Pancreatectomy and Islet Autotransplantation: Outcome and Metabolism ��������������������������������������������������������������������������������������������������������������� 1149 Sadé M. Finn and Melena D. Bellin

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84 Islet Allotransplantation������������������������������������������������������������������������������������������� 1157 Thierry Berney, Axel Andres, Charles-Henri Wassmer, and Ekaterine Berishvili 85 Pancreas After Islet Transplantation���������������������������������������������������������������������� 1205 Rainer W.G. Gruessner and Angelika C. Gruessner Part XI Perspectives 86 First  World Consensus Conference on Pancreas Transplantation����������������������� 1213 Ugo Boggi, Fabio Vistoli, and Piero Marchetti 87 Global  Expansion: Pancreas Transplantation in Africa��������������������������������������� 1241 Jean-Paul Squifflet 88 Global  Expansion: Pancreas Transplantation in China ��������������������������������������� 1247 Z. Shen, Y. Fu, W. Song, Z. Wang, J. Zhao, and W. Zhang 89 Global  Expansion: Pancreas Transplantation in Latin and South America������� 1253 Pablo Daniel Uva 90 Global  Expansion: Pancreas Transplantation in Russia��������������������������������������� 1257 Alexey V. Pinchuk and Ilya V. Dmitriev 91 The  Impact of the COVID-19 Pandemic on Pancreas Transplantation��������������� 1267 Sivesh K. Kamarrajah, Claire Counter, Derek Manas, and Steven A. White 92 The  Endocrinologist’s View: Strengthening Future Pancreas Transplantation Programs in Europe��������������������������������������������������������������������� 1275 Eelco J. P. de Koning 93 The  Endocrinologist’s View: Toward Enhancing Medical-Surgical Synergy for Pancreas Transplantation in the United States of America������������� 1281 R. Paul Robertson Index����������������������������������������������������������������������������������������������������������������������������������� 1285

Contents

Part I General Aspects of Diabetes Mellitus and Pancreas Transplantation

1

Diabetes Mellitus: Classification and Diagnosis Piero Marchetti, Walter Baronti, Ugo Boggi, and Lorella Marselli

Contents Introduction

 3

Diagnosis of Diabetes

 4

Classification of Diabetes

 5

Monogenic Defects of Beta Cell Function

 6

Diseases of the Exocrine Pancreas

 7

Drug or Chemically Induced Diabetes

 7

Infections

 8

Other Genetic Syndromes

 8

Conclusions

 9

References

 9

Introduction Diabetes mellitus is a disorder of the metabolism of carbohydrate, fat, and protein, due to the interplay of genetic and environmental factors (see Chaps. 2 and 3) [1–8]. It is characterized by an absolute or relative shortage of insulin production and secretion as well as varying degrees of insulin resistance [1–8]. Hyperglycemia is the clinical hallmark of this condition, which substantially contributes to the devel-

P. Marchetti (*) · W. Baronti · L. Marselli Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Section of Endocrinology and Metabolism of Organ and Cellular Transplantation, AOUP Cisanello University Hospital, Pisa, Italy e-mail: [email protected]; [email protected] U. Boggi Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy Division of General and Transplant Surgery, AOUP Cisanello University Hospital, Pisa, Italy e-mail: [email protected]

opment of acute (diabetic ketoacidosis, hyperosmolar hyperglycemic state) and chronic (retinopathy, nephropathy, neuropathy, coronary heart disease, peripheral vascular disease) complications of diabetes [9–15]. In addition, erratic use of certain antidiabetic drugs (insulin and insulin secretagogue agents in particular) is associated with the occurrence of hypoglycemia, the most common acute complication of diabetes treatment [16, 17]. There are heterogeneities among groups of diabetic subjects in terms of etiology, pathogenesis, natural history, and response to treatment. Hence, diabetes is considered a syndrome, rather than a single disease. It has been estimated that the global prevalence of diabetes in 2021 was higher than 10% (more than 500 million people), which is expected to increase to around 11% (643 million) by 2030 and 12% (783 million) by 2045 [18, 19]. In addition, about 50% of people with diabetes do not know that they have the disease [18, 19]. A further burden is represented by impaired glucose tolerance, a condition associated with a high risk for the development of the disease [18, 19]. Impaired glucose tolerance was affecting 541 million adult people in 2021 (with a global prevalence of 10.6%) and is estimated to rise to 730 million (11.4%) by 2045 [18, 19].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. W.G. Gruessner, A. C. Gruessner (eds.), Transplantation of the Pancreas, https://doi.org/10.1007/978-3-031-20999-4_1

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Morbidity and mortality in diabetic patients are high [9– 15, 20, 21]. Cardiovascular diseases account for between one-third to half of all diabetes-related deaths, diabetic retinopathy is the leading cause of blindness in the working age population, and diabetic nephropathy (alone or in combination with hypertension) causes >80% of end-stage renal disease globally. Because of all this, in 2021 diabetes has caused 6.7 million deaths and demanded >900 billion USD in health expenditure [20–22]. Clearly, prompt diagnosis of diabetes and appropriate classification are key to better treatment of affected subjects, including possible replenishment of beta cell functional mass as achievable by pancreas transplantation.

Diagnosis of Diabetes The diagnosis of diabetes is based on plasma glucose levels that can be measured in a random plasma sample, in the fasting state, or during a 75-g oral glucose tolerance test (OGTT). Hemoglobin A1c (A1c) is an indirect measure of blood glucose [23, 24] and is used as a further diagnostic criterion. Circulating glucose concentrations also define the presence of “prediabetes” (impaired fasting glucose (IFG), and impaired glucose tolerance (IGT)), a condition associated with a high risk of diabetes development. The respective thresholds for the diagnosis of diabetes, IFG and IGT, are shown in Table 1.1. In patients with classic (although nonspecific) symptoms of diabetes (such as polyuria, polydipsia, weight loss), measurement of a random plasma glucose is sufficient to diagnose diabetes if the value is ≥200  mg/dL (11.1  mmol/L). However, with IFG and IGT, two abnormal tests are necessary for diagnosis by using the same sample or two separate blood specimens (in which case the two assessments should be performed within a short time frame) [25, 26]. The concordance between the tests reported in Table 1.1 is not absolute. The 2 h OGTT PG measurement is able to detect more individuals with diabetes and prediabetes than FPG and A1c [27]. In fact, the A1c criterion detects only ~30% of cases diagnosed by the collective use of FPG, 2 h OGTT PG, and A1c [28]. If two different tests give discrepant results in the Table 1.1  Criteria for the diagnosis of diabetes and “prediabetes” Measure Random PG (in subjects with symptoms) FPG 2 h OGTT PG A1c

Diabetes ≥200 mg/dL (11.1 mmol/L)

“Prediabetes” NA

≥126 mg/dL (7.0 mmol/L) ≥200 mg/dL (11.1 mmol/L) ≥6.5% (48 mmol/ mol)

IFG: 100–125 mg/dL (5.6–6.9 mmol/L) IGT: 140–199 mg/dL (7.8–11.0 mmol/L) 5.7–6.4% (39–47 mmol/ mol)

PG plasma glucose, NA not applicable, FPG fasting plasma glucose, IFG impaired fasting glucose, OGTT oral glucose tolerance test, IGT impaired glucose tolerance, A1c hemoglobin A1c

same patient, the test result above the diagnostic threshold should be repeated, and the diagnosis made on the basis of the confirmed test. In such cases, FPG and 2 h OGTT PG are preferred, since they are more accurate than A1c [26]. If a patient has test results near the diagnostic cut-off values, the measurements should be repeated within 3–6 months. In addition, preanalytical and analytical variabilities inherent to each test must be taken into consideration, which may affect the results. Samples for glucose measurement should not be kept at room temperature and must be promptly centrifugated and separated to avoid reduction of glucose concentration. Certain conditions affect the relationships between A1c and blood glucose levels (including hemoglobinopathies, pregnancy, recent blood loss, recent transfusions, hemodialysis, administration of erythropoietin) [29–31]. Furthermore, A1C concentrations may be affected by ethnicity, and African Americans have higher values than non-Hispanic Whites with comparable levels of blood [27, 32, 33]. However, A1c has several advantages which include the fact that fasting is not required, the preanalytical stability of the samples is greater than that for glucose, and there are less oscillations due to stress, sickness, physical exercise, or changes in the diet. It is recommended that A1c is measured by a method that is certified by the National Glycohemoglobin Standardization Program [34]. The criteria described in Table 1.1 do not apply to the condition of gestational diabetes mellitus (GDM), the type of diabetes with onset during pregnancy and associated with risks for the mother, fetus, and newborn [35, 36]. The debate on how to better diagnose gestational diabetes is still ongoing. The American Diabetes Association indicates that the diagnosis of GDM can be done with the “one-step” 75 g OGTT according to the IADPSG (International Association of Diabetes and Pregnancy Study Groups) strategy [37], or the “two-step” method, according to an updated interpretation by Carpenter and Coustan’s of the previous O’Sullivan criteria [38, 39]. The IADPSG approach consists of the performance of a 75 g OGTT in the fasting state at 24–28 weeks of gestation, in women without previous diagnosis of diabetes. The diagnosis of GDM is made if PG is: • equal to/greater than 92 mg/dL (5.1 mmol/L) in the fasting state, and/or • equal to/greater than 180  mg/dL (10.0  mmol/L) at 1  h, and/or • equal to/greater than 153 mg/dL (8.5 mmol/l) at 2 h. In the “two-step” approach, a 50 g glucose load is administered at the 24–28 gestational week, and PG is measured at 1 h: if ≥120, 135 or 140 mg/dL (7.2, 7.5, or 7.8 mmol/mol) (the most commonly used thresholds), then a 100 g OGTT must be performed. Classically, the diagnosis of GDM is made if at least two of the following criteria are met:

1  Diabetes Mellitus: Classification and Diagnosis

• equal to/greater than 95 mg/dL (5.3 mmol/L) in the fasting state. • equal to/greater than 180 mg/dL (10.0 mmol/L) at 1 h. • equal to/greater than 140 mg/dL (7.8 mmol/L) at 2 h. Currently, the IADPSG criteria are more used than the “two-step” strategy internationally and are considered the preferred approach.

Classification of Diabetes Although the heterogeneity of diabetes mellitus is promoting efforts to classify this condition based on clusters that include varying phenotypic and biochemical features, aiming to better individualize treatment regimens [40, 41], the current and most widely accepted classification of diabetes consists of four major categories (Table 1.2) [1]: 1. Type 1 diabetes, in most patients due to autoimmune destruction of pancreatic beta cells (type 1A) and in some cases of non-autoimmune, unknown origin (type 1B or idiopathic, also associated with permanent insulinopenia) (see Chap. 2); 2. Type 2 diabetes, due to variable degrees of beta cell functional mass loss, often in the background of reduced insulin sensitivity (see Chap. 3); 3. Specific types of diabetes, due to several, different causes; 4. Gestational diabetes. Patients with type 1 in particular and also type 2 diabetes may take advantage from pancreas transplantation. These two forms of diabetes are discussed in detail in Chaps. 2 and 3 of this book and will not be addressed further in this overview. Gestational diabetes never represents an indication for pancreas transplantation and has been briefly described above. Specific types of diabetes constitute a heterogenous group of

Table 1.2  Classification of diabetes mellitus Category Type 1 diabetes

Type 2 diabetes Specific types

Gestational diabetes

Key features Immune-mediated death of pancreatic beta cells (type 1a) Conspicous/absolute insulin deficiency Includes LADA (latent autoimmune diabetes of adulthood) Includes idiopatic type 1 diabetes (type 1b)a Combination of beta cell dysfunction and death Varying degrees of insulin resistance Heterogenous group Mostly associated with beta cell dysfunction/loss Due to genetic or acquired causes Onset during pregnancy

 Abandoned by the World Health Organization

a

5

conditions, due to several, different causes (genetic or environmental) (Table  1.3) and comprising forms that are also of interest to the pancreas transplantation community. Some of these specific types are discussed below in more detail. Table 1.3  Specific types of diabetes Monogenic defects of beta cell function

Maturity onset diabetes of the young Neonatal diabetes Genetic defects in insulin Type A insulin resistance action Leprechaunism Rabson-Mendenhall syndrome Lipoatrophic diabetes Diseases of the exocrine Trauma pancreas Pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy Endocrinopathies Acromegaly Cushing’s syndrome Glucagonoma Pheochromocytoma Hyperthyroidism Somatostatinoma Aldosterononoma Drug or chemical induced Glucocorticoids Steroid hormones Thyroid hormones Statins Nicotinic acid Diazoxide Thiazides Beta-adrenergic agonists Dilantin Anti-PD1, anti-PDL1 monoclonal antibodies Immunosuppressants (NODT, PTDM) Anti-HIV agents Infections Congenital rubella Cytomegalovirus HCV Sars2-CoV Uncommon forms of immune-­ Stiff-man syndrome mediated diabetes Anti-insulin receptor antibodies Down syndrome Other genetic syndromes sometimes associated with Klinefelter syndrome diabetes Turner syndrome Wolfram syndrome Friedreich ataxia Huntington chorea Laurence-moon-Biedl syndrome Myotonic dystrophy Porphyria Prader-willy syndrome PD1 programmed cell death protein-1, PDL1 programmed cell death ligand-1, NODT new-onset diabetes after transplantation, PTDM posttransplant diabetes mellitus

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Monogenic Defects of Beta Cell Function Monogenic defects that cause beta cell dysfunction are responsible for maturity onset diabetes of the young (MODY) and neonatal diabetes [42–46]. These two conditions represent 3–5% of subjects with diabetes. MODY is typically diagnosed before 25 years of age, has autosomal dominant inheritance, is not associated with autoimmunity, and the patients are usually nonobese. At least 17 genes (mostly transcription factors) on different chromosomes have been identified so far (Table 1.4), whose abnormalities cause impaired insulin secretion, with minimal or no effects on insulin sensitivity. With the exception of MODY 1–3 and 5, the majority of MODY forms are rare or very rare. Some of them (MODY 4, 7, 8) are associated with alterations of the whole pancreas, which include an increased risk of malignancy in MODY 7. Of note, MODY 3 and MODY 5 carry the risk of renal insufficiency, and some patients are in need of a kidney transplant. In a few cases, combined kidney and pancreas transplantation has been performed. A

study [47] has reported on the evaluation of 50 patients referred for kidney and pancreas transplantation. The patients were screened for HNF1A (MODY 3) and HNF1B (MODY 5) mutations if one or more of the following criteria was present: an atypical history of diabetes; one affected parent or two affected relatives; negativity of auto-antibodies at diagnosis; maintained secretion of C-peptide; personal or family history of renal cysts or dysplasia. Four MODY3 and eight MODY 5 patients were identified. All MODY3 patients and four MODY 5 had diabetic nephropathy. Four patients underwent a kidney and pancreas transplant and two a kidney transplant alone. After about 4 years of followup, 83% of patients had functioning kidney and 75% functioning pancreas, suggesting that pancreas transplantation can be offered to MODY3 and MODY 5 patients. However, sulphonylurea treatment is an effective approach in MODY 3 and 5 patients without renal failure or in the post-uremic state after kidney transplantation. MODY screening before transplantation is therefore advisable in patients with an atypical diabetes phenotype [48].

Table 1.4  MODY genes and main associated features Gene HNF4A

Full name Hepatocyte nuclear factor-4 alpha

Locus 20q12

Type Main features MODY May be associated with macrosomia and transient neonatal 1 hypoglycemia; sensitive to sulphonylureas; may require insulin GCK Glucokinase 7p15 MODY Nonprogressive elevated blood glucose; pharmacological 2 treatment not required HNF1A Hepatocyte nuclear 12q24.31 MODY May be associated with transient neonatal hypoglycemia; factor-1alpha 3 progressive insulin secretory defects; lowered renal threshold for glycosuria; may develop diabetic nephropathy; sensitive to sulphonylureas PDX1 Pancreatic duodenal homeobox 13q27.92 MODY Pancreatic agenesis; overweight/obesity in some; may require 4 insulin HNFIB Hepatocyte nuclear factor-beta 17q12 MODY Pancreatic hypoplasia; renal anomalies (cysts); kidney failure; 5 urogenital tract anomalies; may require insulin NEUROD1 Neurogenic differentiation 1 2q31.3 MODY Overweight/obesity in some 6 KLFII Krüppel-like factor 11 2p25.1 MODY Associated with pancreatic malignancy; increased oxidative 7 stress CELL Carboxyl ester lipase 9q34 MODY Pancreas atrophy; pancreas fibrosis/lipomatosis; exocrine 8 dysfunction PAX4 Paired box 4 7q32.1 MODY – 9 INS Insulin 11p15.5 MODY Increased ER stress 10 BLK B-lymphocyte kinase 8p23.1 MODY Overweight/obesity in some 11 ABCC8 ATP binding cassette subfamily 11p15.1 MODY Similar to MODY 1 and 3 affects KATP C member 8 12 KCNJ11 Inward-rectifier potassium 11p15.1 MODY Similar to MODY 1 and 3; affects KATP channel, subfamily J, member 11 13 3p14.3 MODY Overweight/obesity in some APPL1 Adaptor protein, 14 phosphotyrosine interacting with PH domain and leucine zipper 1 ISL-1 ISL LIM homeobox 1 5q11 – – RFX6 Regulatory factor X 6q22.1 – – NK6-1 NK6 homeobox 1 4q21.23 – –

Frequency 5–10%

30–50% 30–65%

35 years. Candidates who did not meet SPK qualifying criteria would still be eligible to receive a kidney alone or a pancreas alone transplant. Candidates who did not meet SPK ­qualifying criteria would not be eligible to accrue waiting time for an SPK transplant, although they may still receive waiting time for a pancreas alone transplant. Waiting time for SPK candidates that met qualifying criteria would begin on the date that they meet the kidney portion of the qualifying criteria (i.e., date of start of dialysis or date of GFR or CrCl test that is 20  mL/min or less). Waiting time for PA candidates would begin at the date of listing. If a candidate was listed for both SPK and PA, waiting times for SPK and PA were independent. Once a candidate qualified for an SPK transplant, the candidate would remain qualified regardless of later test results. The insulin status, C-peptide, and BMI values must be the values at the time of listing or more recent values. The Committee conducted an extensive consensus building effort during August 2009 through January 2010. The Committee presented the concept for a new pancreas allocation system to all UNOS regions at the regional meetings. The Committee also solicited feedback from all pancreas transplant programs and from many UNOS Committees (e.g., Kidney, Pediatrics, Ethics, Minority Affairs), several external constituent organizations (ASTS, AST, NATCO, AOPO), and a review through a US public comment period. It was also recognized that such a large-scale change to the pancreas allocation policy would require extensive education and communication about the changes and how to operate under the new policy. The final proposal was approved by the OPTN/UNOS Board on November 8, 2010 and was eventually enacted October 2014 (delayed until the new kidney allocation sys-

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tem received OPTN/UNOS Board approval in 2013, and simultaneously enacted in 2014). The specific details of the new allocation system that evolved into what is currently in place in 2020 are detailed below.

 ancreas, Kidney-Pancreas, Classifications, P and Rankings Kidney-Pancreas Allocation Order If a host OPO has both a kidney and a pancreas to offer for allocation, then the host OPO must offer the kidney and pancreas in the following order: 1. The host OPO must offer the kidney and pancreas according to classifications 1–5  in Table  7.1: Allocation of Kidneys and Pancreas from Deceased Donors 50  Years Old and Less with a BMI less than or equal to 30 kg/m2 and Table 7.2: Allocation of Kidneys and Pancreas from Donors more than 50  Years Old or with a BMI greater than 30 kg/m2. Table 7.1  Allocation of kidneys and pancreas from deceased donors 50 years old and less with a BMI less than or equal to 30 kg/m2 Candidates that Classification are within the And are 1 OPO’s DSA Zero antigen mismatch, CPRA greater than or equal to 80%, and either pancreas or kidney-pancreas candidates 2 OPO-S DSA CPRA greater than or equal to 80% and either pancreas or kidney-­ pancreas candidates 3 OPO’s region Zero antigen mismatch, CPRA greater than or equal to 80%, and are either pancreas or kidney-­ pancreas candidates 4 Nation Zero antigen mismatch, CPRA greater than or equal to 80%, and either pancreas or kidney-pancreas candidates 5 OPO’s DSA Pancreas or kidney-pancreas candidates 6 OPO’s region CPRA greater than or equal to 80% and either pancreas or kidney-­ pancreas candidates 7 OPO’s region Pancreas or kidney-pancreas candidates 8 Nation CPRA greater than or equal to 80% and either pancreas or kidney-­ pancreas candidates 9 Nation Pancreas or kidney-pancreas candidates 10 OPO’s DSA Islet candidates 11 OPO’s region Islet candidates 12 Nation Islet candidates

124 Table 7.2  Allocation of kidneys and pancreas from deceased donors more than 50 years old or with a BMI greater than 30 kg/m2 Candidates that Classification are within the And are 1 OPO’s DSA Zero antigen mismatch, CPRA greater than or equal to 80%, and either pancreas or kidney-pancreas candidates 2 OPO-S DSA CPRA greater than or equal to 80% and either pancreas or kidney-­ pancreas candidates 3 OPO’s region Zero antigen mismatch, CPRA greater than or equal to 80%, and are either pancreas or kidney-­ pancreas candidates 4 Nation Zero antigen mismatch, CPRA greater than or equal to 80%, and either pancreas or kidney-pancreas candidates 5 OPO’s DSA Pancreas or kidney-pancreas candidates 6 OPO’s DSA Islet candidates 7 OPO’s region Islet candidates 8 Nation Islet candidates 9 OPO’s region CPRA greater than or equal to 80% and either pancreas or kidney-­ pancreas candidates 10 OPO’s region Pancreas of kidney-pancreas candidates 11 Nation CPRA greater than or equal to 80% and either pancreas or kidney-­ pancreas candidates 12 Nation Pancreas of kidney-pancreas candidates

D. B. Kaufman

a BMI less than or equal to 30 kg/m2 and 2: Allocation of Kidneys and Pancreas from Deceased Donors more than 50 Years Old or with a BMI Greater than 30 kg/m2. 11.4.E Sorting Within Each Classification. Within each allocation classification, pancreas, kidney-­ pancreas, and islet candidates are sorted based on waiting time (longest to shortest).

 eceased Donors 50 Years Old and Less D with a BMI Less than or Equal to 30 kg/m2 Pancreas, kidney-pancreas, and islets from donors 50 years old or less and who have a BMI less than or equal to 30 kg/ m2will be allocated to candidates according to Table  7.1 based on waiting time.

 eceased Donors More than 50 Years Old or D with a BMI Greater than 30 kg/m2 Pancreas, kidney-pancreas, and islets from deceased donors more than 50 years old or from deceased donors who have a BMI greater than 30  kg/m2 are allocated to candidates according to Table 7.2 based on waiting time.

Facilitated Pancreas Allocation

OPOs and the Organ Center are permitted to make facilitated pancreas offers if no pancreas offer has been accepted 3  h prior to the scheduled donor organ recovery. The OPO or Organ Center must offer the pancreas only to potential transplant recipients registered at a transplant program that participates in facilitated pancreas allocation. Facilitated pancreas offers must be made in the order of the match run, and OPOs will only have access to facilitated allocation after all local pancreas and kidney-pancreas offers have been Within each allocation classification, pancreas, kidney-­ declined. pancreas, and islet candidates are sorted based on waiting time (longest to shortest) 2. Then, the host opo may do either: (1). continue to offer the kidney and pancreas according to the remaining classifications in Tables 7.1, or 7.2) offer the pancreas to pancreas and islet candidates, but not kidney-pancreas candidates, according to the remaining classifications Table  7.1 and offer the kidney to kidney candidates according to the kidney allocation policy.

 ancreas Allocation When a Kidney Is P Unavailable If a host OPO only has a pancreas, but not a kidney to offer for allocation, then the host OPO must offer the pancreas to pancreas and islet candidates but not kidney-pancreas candidates according to Table  7.1: Allocation of Kidneys and Pancreas from Deceased Donors 50 Years Old and Less with

 esults of Revised UNOS Pancreas Allocation R Policy

Following adoption and implementation of the revised UNOS pancreas allocation policy in 2014, there was a reversal in the slow decline in the annual number of pancreas transplants performed in the US. A nadir occurred in 2015 (n  =  943), with a subsequent 7–8% increase in pancreas transplants steadily occurring through 2019 (n  =  1014) (Fig. 7.4). Interestingly, all of the gains were in the category

7  Pancreas Allocation in the United States

125

Fig. 7.4  Annual number of pancreas transplants performed in the US (1966–2019) as reported by the International Pancreas Transplant Registry (IPTR)

Fig. 7.5  Annual number of pancreas transplants performed in the US (2005–2019) according to transplant type (SPK, PAK, and PTA) as reported by the International Pancreas Transplant Registry (IPTR)

of spk transplants with a continued small decline in solitary pancreas transplants (Fig.  7.5). importantly, the number of pancreas transplants received by underrepresented minority pancreas transplant candidates increased over the 2016–2020

time period (Fig. 7.6). In addition, the number of pancreas transplant candidates with type 2 diabetes in the spk and pak transplant categories both nearly doubled during the same time period (data not shown).

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D. B. Kaufman

Fig. 7.6  Sequential four-year interval cumulative numbers of pancreas transplants performed in the US (1996–2020) in underrepresented minority pancreas transplant candidates according to transplant type

(SPK, PAK, and PTA) as reported by the International Pancreas Transplant Registry (IPTR)

A New Era of Pancreas Allocation

This proposal developed as a result of the OPTN Board of Directors’ 2018 directive and interpretation that to better align with the OPTN Final Rule (NOTA), the organ-specific committees should redevelop organ allocation policies (kidney and pancreas) and remove current DSA and regional geographic boundaries from allocation policies. The new system replaced the local/regional/national three-tiered approach. Thus, with the new policy, the DSA and region were replaced by a 250 nautical mile fixed circle around the donor hospital. The initial pancreas offers as defined by the individual match run are made first to candidates listed at transplant hospitals within that geographic area. Offers not accepted for any of those candidates will then be offered to a wider geographic area beyond 250 nautical miles from the donor hospital.

The elimination of local donation service areas (DSA) and regions as geographical units of organ allocation in OPTN/ UNOS pancreas (and kidney) policy heralded the next iteration of allocation change. The geographic determinant of the DSA served the allocation system well but has been controversial. DSAs are fixed, irregularly shaped geographic boundaries, and in some instances not contiguous, meaning that some “local” donor matches may travel through service areas belonging to other OPOs. In December 2019, the OPTN/UNOS Board approved an allocation system that modified the definition of the geographical relationship between transplant centers within a donor service area and replaced it with a stronger association between the donor hospital and recipient transplant center.

7  Pancreas Allocation in the United States

127

Additional Allocation Components • The new policy also adds points to a waitlist candidate’s total allocation score reflecting the distance between the transplant hospital where the candidate is listed and the donor hospital. These are referred to as, “Proximity Points”, and are intended to improve the efficiency of organ placement by adding priority for candidates closer to the donor hospital. Candidates within the initial 250 nautical mile radius will receive a maximum of two Proximity Points. The point assignment will be highest for those closest to the donor hospital and will decrease as the distance increases. • The new allocation system considers the age and BMI of the deceased donor when considering the geographic sequence of priority with respect to pancreas or islet allocation.

 eceased Donors More than 50 Years Old or D with a BMI Greater than 30 kg/m2 Pancreas, kidney-pancreas, and islets from deceased donors more than 50 years old or from deceased donors who have a BMI greater than 30  kg/m2 are allocated to candidates according to Table 7.4. The new Pancreas Allocation System went into effect on March 15, 2021. The UNOS Pancreas Transplantation Committee will monitor the effect of this policy as data accumulate and become available. Future iterations of the US organ allocation system will continue to evolve to meet the goals of improving fairness and efficiency of access to donor organs.

Table 7.4  Allocation of kidneys and pancreas from deceased donors more than 50 years old or with a BMI greater than 30 kg/m2

 eceased Donors 50 Years Old and Less D with a BMI Less than or Equal to 30 kg/m2 Pancreas, kidney-pancreas, and islets from donors 50 years old or less and who have a BMI less than or equal to 30 kg/ m2 are allocated to candidates according to Table 7.3. Table 7.3  Allocation of kidney and pancreas from deceased donors 50 years old and less with a BMI less than or equal to 30 kg/m2

Classification Candidates that are 1 0-ADBR mismatch, CPRA greater than or equal to 80% and either pancreas or kidney-pancreas candidates 2 CPRA greater than or equal to 80% and either pancreas or kidney-pancreas candidates 3 OPO’s region0-ABDR mismatch, CPRA greater than or equal to 80%, and either pancreas or kidney-­ pancreas candidates 4 Pancreas or kidney-pancreas candidate 5 CPRA greater than or equal to 80% and either pancreas or kidney-pancreas candidates 6 Pancreas or kidney-pancreas candidates 7 Islet candidates 8 Islet candidates

And registered at a transplant program that is within the distance from the donor hospital 500 NM

500 NM

Nation

500 NM Nation

Nation 500 NM Nation

Classification Candidates that are 1 0-ADBR mismatch, CPRA greater than or equal to 80% and either pancreas or kidney-pancreas candidates 2 CPRA greater than or equal to 80% and either pancreas or kidney-pancreas candidates 3 0-ABDR mismatch, CPRA greater than or equal to 80%, and either pancreas or kidney-pancreas candidates 4 Pancreas or kidney-­ pancreas candidate 5 Islet candidates 6 Islet candidates 7 CPRA greater than or equal to 80% and either pancreas or kidney-pancreas candidates 8 Pancreas or kidney-­ pancreas candidates

And registered at a transplant program that is within the distance from the donor hospital 500 NM

500 NM

Nation

500 NM 500 NM Nation Nation

Nation

128

References 1. National Organ Transplant Act of 1984. 42 U.S.C, §201, §273, §2339, §1395, §274 §32, 1984. 2. Task Force on Organ Transplantation. Organ transplantation: issues and recommendations. Washington, DC: DHHS Publication, Office of Organ Transplantation; 1986. 3. Omnibus Budget Reconciliation Act of 1986. 42 U.S.C, §3206, §1395–1396, §273–274, 1986.

D. B. Kaufman 4. Starzl E, Hakala TR, Tzakis A, et  al. A multifactorial system for equitable selection of cadaver kidney recipients. JAMA. 1987;12(257):3073–5. PMCID: PMC2949292. 5. UNOS, Pancreas Transplant Committee. 2008. Dixon B. Kaufman, Rainer W.G.  Gruessner, David Axelrod, David Harlan, Albert Hwa, Sandip Kapur, Chris Kuhr, Marlon Levy, Jim Markmann, Christopher Marsh, Peter Stock; UNOS Staff, Elizabeth F. Sleeman, Jennifer L. Wainright.

8

Pancreas Allocation in the Eurotransplant Area Helmut Arbogast

Contents Historical Background

 129

Pancreas Transplant Activity by the Eurotransplant Member Countries

 130

Pancreas Transplant Waiting List

 132

Pancreas Allocation in the Eurotransplant Area: General Contemplations

 133

General Allocation Rules and Allocation Procedure

 133

Allocation of the Pancreas: Special Regulations

 134

The Interdisciplinary Transplant Conference

 134

 isting Criteria for Pancreas Transplantation (PTA or PAK) and Simultaneous Pancreas-­Kidney L Transplantation (SPK)  134 Immunological Criteria for Allocation

 135

Urgency Codes

 135

Waiting Time Return

 136

Special Rules for Pancreas Retrieval

 136

Ischemia Time

 136

Determination of Allocation Sequence

 136

Extended Donor Criteria

 137

Differences in Member Countries: Islet Transplantation

 137

P-PASS

 138

References

 138

Historical Background The history of Eurotransplant (ET) is dating back to the year 1967. Jon J. van Rood from the Leiden University founded the Eurotransplant international foundation, following the evidence that HLA matching plays a role in the outcome after H. Arbogast (*) Department of General, Visceral and Transplant Surgery, University of Munich—Campus Grosshadern, Munich, Germany e-mail: [email protected]

renal transplantation. Starting as a scientific experiment, 12 transplant centers from three countries decided to report their recipients‘data as well as every donor to Eurotransplant and increase the donor pool in order to facilitate the allocation of better matched organs to the recipients. The idea grew rapidly, and already 3 years later, 68 transplant centers from six member countries provided their data to ET [1]. Today, ET is involved in the allocation of postmortal donor organs within the Netherlands, Belgium, Luxembourg, Germany, Austria, Slovenia, Croatia, and Hungary (Fig. 8.1).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. W.G. Gruessner, A. C. Gruessner (eds.), Transplantation of the Pancreas, https://doi.org/10.1007/978-3-031-20999-4_8

129

130

H. Arbogast H HR

L NL SLO Non-ET

Eurotransplant Member States D

A

B

A - Austria B - Belgium D - Germany H - Hungary HR - Croatia L - Luxembourg NL - Netherlands SLO - Slovenia

Fig. 8.1  Eurotransplant Member States, as of 12-01-2020 [2]

The allocation rules, however, follow the different legislation procedures in each of the member states. This allows an appropriate and matching allocation within a community of about 145  Mio. inhabitants. With a population of roughly 82  Mio., Germany is the biggest contributor to ET and accounts for close to 60% of all transplant wait list recipients as well as funding of the foundation. On August 12, 1979, the first Pancreas within the Eurotransplant area was transplanted in Munich, Germany, only shortly before Raimund Margreiter transplanted a pancreas in Innsbruck, Austria. Performed as a simultaneous pancreas and kidney transplant (SPK) by Walter Land, who used the technique of duct occlusion in a segmental pancreas, this technique formed an era until about 1982, when Hans Sollinger introduced the bladder drainage technique using a whole organ with a small duodenal segment. This latter technique had the advantage of being able to measure

pancreas function by its exocrine secretion in the so-called “pancurine” as a marker for rejection. With the improvement of immunosuppression, in the mid-90s, also this era came to an end and enteric drainage became the predominant technique of pancreas transplantation. Other modifications of the technique (e.g., portal venous drainage or duodenoduodenostomy) were introduced and are performed in several centers of the area, but never replaced systemic drainage and duodenojejunostomy as the main transplant technique.

 ancreas Transplant Activity by P the Eurotransplant Member Countries Since 1979 until December-7, 2020, within the Eurotransplant community, a total of 6851 pancreata (Fig.  8.2) have been transplanted. By now, 37 pancreas

8  Pancreas Allocation in the Eurotransplant Area

131

350

300

250

200

150

100

0

1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

50

Germany

Belgium

Austria

Netherlands

Croatia

Hungary

Slovenia

Fig. 8.2  Pancreas transplant activity in the Eurotransplant area [3]

transplant programs are active within the foundation (22 in Germany, 6 in Belgium, 3 in Austria, 2 in the Netherlands, 2  in Hungary, 1  in Croatia, and 1  in Slovenia). Pancreas transplant activities were registered in the seven of eight member countries with active pancreas transplant programs: German centers contributed 4230 pancreas transplants; in Belgium, 861 and in Austria 822, pancreata have been transplanted, followed by the Netherlands, with 763 pancreas transplants. Croatia joined ET in 2007 (97 pancreas transplants), Hungary in 2013 (64 pancreas transplants), and Slovenia started pancreas transplantation in 2009 (24 transplants) (Table 8.1). With the decreasing frequency of pancreas transplantation, it is remarkable that among the 22

German pancreas transplant centers, in 2017, only 6 programs performed more than 3 (!) pancreas transplantations. Seven programs could be considered “functionally inactive”. Over the years, SPK transplantation evolved as the predominant procedure and accounts for more than 90% of all pancreas transplantations, within Eurotransplant. Solitary pancreas transplants (pancreas after kidney [PAK] transplants or pancreas transplants alone [PTA]) and islet transplants represent less than 10% of all transplants. Since the turn of the millennium, however, pancreas transplantation in general has suffered a steady decline, now stabilizing at around 200 pancreas transplants per year (Fig. 8.2).

132

H. Arbogast

Table 8.1  Pancreas transplant activity by member country and year [3] Year 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020* total

Germany 1 2 3 2 15 18 13 23 41 46 41 42 45 32 50 54 75 113 163 189 221 248 221 173 197 192 169 141 140 139 117 166 173 163 129 120 105 97 72 95 94 90 4230

Belgium

3 2 4 4 4 6 14 10 10 8 15 12 21 13 20 20 38 40 38 61 65 42 38 31 32 31 24 29 33 31 17 18 20 23 22 28 21 13 861

Austria 1 1 1 5 7 8 11 24 8 7 11 8 14 16 12 9 8 25 31 30 30 28 51 40 41 34 39 26 34 33 31 16 14 19 21 27 26 20 20 15 20 822

Netherlands

Croatia

1 2 10 9 7 17 9 11 13 19 17 11 17 18 16 19 20 24 17 17 22 21 23 29 18 19 24 30 34 29 34 33 28 33 45 29 28 753

3 14 13 6 12 8 7 5 8 7 5 3 5 1 97

Pancreas Transplant Waiting List Consequently, the active waiting list has increased to well above 400 patients with the consequence of prolonged waiting time. With an increased effectivity of diabetes therapies, the incidence of the late diabetic syndrome, especially with respect to the diabetic nephropathy, is significantly postponed.

Hungary

Slovenia

2 1 1 9 14 13 6 6 5 5 6 64

4 5 5 3 1 2 24

ET total 2 3 3 3 23 28 27 48 78 67 79 72 74 67 100 95 116 151 226 256 308 338 311 302 319 297 262 234 230 236 208 257 265 250 214 212 211 192 158 199 170 160 6851

Patients thus might miss the window of opportunity for a combined SPK transplant, when terminal renal insufficiency only occurs when macrovascular alterations are too proceeded to grant a benefit by SPK transplantation. Whereas in the 1990s, with an average waiting time for a pancreas transplant of less than 2 years, this time span nowadays has increased to more than 3 years on average (Fig. 8.3). Therefore, preemptive listing of pancreas transplant candidates is crucial.

8  Pancreas Allocation in the Eurotransplant Area

133

500 450 400 350 Active WL

300

Pancrea-Kidney transplants

250 200

Pancreas (whole) transplants

150

Pancreas (islet) transplants

100 50

2019

2018

2017

2016

2015

2014

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

1996

0

Fig. 8.3  Active pancreas waiting list and transplants in Eurotransplant [4]

 ancreas Allocation in the Eurotransplant P Area: General Contemplations

 eneral Allocation Rules and Allocation G Procedure

Organ allocation within the Eurotransplant community follows respective national rules and regulations that have to be implemented in the allocation procedure at the ET offices in Leiden, the Netherlands. At the ET office in Leiden, the Eurotransplant Pancreas Advisory Committee (EPAC), consisting of international specialists in pancreas (and islet) transplantation from the member states, recommendations are elaborated. Rules and guidelines for organ allocation, however, are of legal character; they are implemented by the respective national competent authorities, since legislation affairs remain a responsibility of national governments. The rules and guidelines are worked out by respective national working groups, following the principle of implementing the current state of medical science. These drafts are finally passed by the competent authorities of the different member states. The different national rules and regulations for the implementation and specification of national legislation and national guidelines for waiting list management, organ procurement, and allocation, are contained in the so-called “Eurotransplant Manual” [5]. Legally binding provisions concerning allocation of organs, however, are only the national provisions issued by the competent authorities. The ET Manual is only of informative character [5, 6].

All centers within the Eurotransplant area report their donors electronically to ET; these data are entered directly into the allocation program (in 2020, still being ENIS), thus allowing an immediate start of the allocation procedure. Only donors from outside the Eurotransplant area are reported by fax, their data being entered by a duty officer [5]. Mandatory donor data to start a matching procedure at Eurotransplant are: Donor center/region; blood group; Rhesus factor; date of birth; sex; weight; height; identity; cause of death; type of death: donation after circulatory death (DCD) vs. donation after brain death (DBD); (brain) death date; country of citizenship; donor hospital; contact telephone number [5]. Since having an influence on the outcome of the ranking of the recipients on the match lists, the following data are also reported as soon as possible: Virology (HIV, HBV, HCV); past history of drug abuse or malignancies; sepsis or meningitis; marginal liver donor parameters (only applicable for liver allocation); HLA (only mandatory for kidney allocation). After entering of these data, an ET number and the organ-specific matching procedure and match lists are generated [5]. The offering of the organs follows a specific order: Heart + lung/heart—lung—liver—intestine—pancreas—kidney

134

and is recipient-specific. Whenever a combined organ transplant is necessary, the waiting lists are first screened according to the above order, before a first offer is made. For logistic reasons, the time for acceptance or rejection of an offer is limited to 30 min for the recipient center [5]. In case an organ is not accepted via regular allocation, ET can switch to an “extended allocation” procedure and—in case of again unsuccessful allocation—“rescue allocation” (competitive center offer). A high risk of direct loss of the organ can—in rare cases—initiate the immediate application of a competitive rescue allocation [5, 6]. In case of HIV positive donors, special rules apply. In case of the pancreas, it will not be offered, until matching on HIV profile is present [6]. With the worldwide SARS-CoV-2 pandemic, new precautions have been introduced. All donors have to undergo PCR testing. Active COVID-19 patients are not considered for organ donation. After receiving the offer, the recipient center will be granted access to all available donor information online. All further arrangements after acceptance of an organ, like transport arrangements, are within the responsibility of the recipient center. In Germany, the largest country in the ET area, this responsibility is carried out by the “Deutsche Stiftung Organtransplantation” (DSO), the organ procurement organization (OPO) of Germany. If, upon arrival, an organ is not transplantable (for the selective recipient), the ET office has to be informed immediately. Also the transplantation has to be documented in the ENIS system; then the allocation procedure is finally closed, the recipient taken from the waiting list and transferred to the “FU“(follow-up) status [6].

 llocation of the Pancreas: Special A Regulations In numerous cases, diabetes mellitus can lead to a diabetic late syndrome, with a number of severe micro- and macrovascular complications. In patients with insulin deficiency in the foreground of their metabolic disease, pancreas transplantation can be life-saving, as well as a measure for significant improvement of quality of life [7] (see Chap. 74). Allocation, however, has to follow the principle of weighing both: chance of success and urgency. Therefore, the best time slot for pancreas transplantation is the beginning of the diabetic late syndrome. If this syndrome is too far advanced, the chances for a successful pancreas trans-

H. Arbogast

plantation decrease and risks for severe complications increase.

The Interdisciplinary Transplant Conference According to the specific regulations of each member country, within most centers of the Eurotransplant community, an interdisciplinary transplant conference decides if a patient is accrued to the waiting list. Members of this conference (depicted for Germany) are: –– Transplant surgeon. –– Diabetologist/Endocrinologist. –– Representative of the Medical Director. Additionally, other medical subspecialties can be represented [7]: –– –– –– –– –– –– –– –– ––

Anesthesiologist. Immunologist. Laboratory physician. Neurologist. Pathologist. Pharmacologist. Psychiatrist/Psychotherapist/Psychosomaticist. Radiologist. Nursing representative.

 isting Criteria for Pancreas Transplantation L (PTA or PAK) and Simultaneous Pancreas-­ Kidney Transplantation (SPK) Reason for listing a recipient for pancreas transplantation is (most commonly) the diagnosis of diabetes mellitus with confirmed autoantibodies against –– –– –– –– ––

Glutamatdecarboxylase (GAD) and/or. Islet cells (ICA) and/or. Tyrosinphosphatase 2 (IA-2) and/or. Zinc transporter protein 8 (ZnT8) and/or. Insulin (IAA).

Autoantibody-positive patients can principally be listed for pancreas transplantation. The positive test may originate

8  Pancreas Allocation in the Eurotransplant Area

at the time of listing or before. IAA are only acceptable, if the positive test dates before insulin therapy. Therefore, the time of onset (and eventually end) of insulin therapy has to be submitted, as well as all results of autoantibody testing [8–10]. If no autoantibodies are present, also patients with β-cell deficiency can be listed [6, 7]. β-cell deficiency is defined as: –– C-peptide than 90% of all primary pancreas transplants) in the ET area, patients with (pre-)terminal renal insufficiency may be accrued to the waiting list [13–22]. This can be accomplished if renal damage is considered irreversible and the glomerular filtration rate (GFR) is 30 kg/m2 [32] or a waist circumference of >88 cm (female) or 102 (male) [33] or not being accepted within 2 h. In addition to the criteria mentioned above, pancreata from donors after cardiopulmonary reanimation (>5  min) or an ICU stay of more than 7 days or with a serum sodium level of >160 mmol/L can be defined as extended criteria donor organs [32] and can be considered for allocation. The internationally well-received EXPAND study demonstrated that by careful donor selection, age  >50 y or BMI >30 kg/m2 are no strict contraindications for successful pancreas transplantation. Good outcomes can be obtained with organs from donors well above 50 years of age or higher BMI values [34]. However, the number of criteria outside the limits mentioned above should eventually not exceed 1.

 ifferences in Member Countries: Islet D Transplantation In 2004, the European Union issued a new “European tissue guideline” with the intention to harmonize the differing legal standards in the EU member countries. But what had initially been intended as an effort of harmonization within Europe turned out to create severe disharmony due to different interpretations of this tissue guideline. Pancreas islets were not listed specifically in that guideline, so there was room for interpretation. Whereas in Great Britain, the Netherlands, and Belgium, a pancreas is still considered an organ as long as it is not separated or digested into islets, in Germany, the 15th novel of the “Arzneimittelgesetz” (§4, Abs. 9 of the Pharmaceutical Product Act) defines islet preparation as tissue. The German authorities, however, even went a step further: just the intention to transfer a vascularized pancreas to an islet center for possible islet transplantation defines the organ as tissue, with all consequences: The German DSO (OPO) was no more allowed to coordinate pancreas retrievals nor shipping and ET had to terminate allocation for pancreata intended for islet transplants. This legal construction finally terminated all postmortal islet transplant activities in Germany, whereas Belgium and the Netherlands (and Great Britain) continue with islet transplantation as they did before. This inhomogeneity clearly requires a reopening of the legal discussion within the responsible authorities, especially in Germany, where the overly strict interpretation of the European tissue guideline has severely harmed a clinical reasonable therapeutic alternative (i.e., islet transplantation).

1 2

Immunized1 International SU vascularized

ABO identical before ABO compatible; waiting time in SU

International SU vascularized

ABO identical before ABO compatible; waiting time in SU

Immunized1 National SU islet

ABO identical before ABO compatible; waiting time in SU

National SU islet

ABO identical before ABO compatible; waiting time in SU

National T Islet

ABO identical before ABO compatible then WT, CIP2

International SU/T Islet

ABO identical before ABO compatible then WT, CIP2

Immunized program for pancreas recipient Center offer according to the highest ranked recipient

Fig. 8.5  Allocation of extended criteria donors [6]

Therefore, the flow diagram depicted in Fig. 8.5, in terms of islet transplantation, is only applicable for ET countries with active islet transplant programs (e.g., Belgium and the

138

H. Arbogast

Netherlands). In addition, in Belgium, SU status can be granted to islet recipients who need a (islet) re-transplant within the shortest time possible because of an insufficient primary graft yield or participation in a clinical islet transplant study aiming at efficacy as primary endpoint. The latter SU indications are well under discussion in the EPAC community. DCD transplantation is allowed in the Netherlands and Belgium. Both countries have a pancreas (NL) or islet (B) transplantation program. The other ET countries—due to legal reasons—do not perform DCD vascularized pancreas or islet transplants. In discordance with other member countries, the age limit of a Dutch DBD vascularized pancreas donor is 60 years, therefore all Dutch donors ≤60 years are primarily allocated as vascularized pancreas donors [6].

P-PASS In 2009, the P-PASS (Preprocurement Pancreas Allocation Suitability Score) has been implemented to facilitate the recognition of a suitable pancreas donor. A total of 9 parameters considered crucial for the outcome of a pancreas transplant and available at the time of allocation are calculated (Table 8.3). The P-PASS ranges from a minimum of 9 to a maximum of 27 points. In case of a donor with a P-PASS of 90% of all rejection episodes affect either the kidney alone or the kidney and the pancreas simultaneously; isolated pancreas rejection episodes are rare [10, 17].

R. W.G. Gruessner

Despite its monitoring advantages, bladder drainage is associated with unique metabolic and urologic complications. In contrast to whole-organ pancreaticoduodenal transplants, complications of bladder drainage are usually less serious in recipients of segmental pancreas grafts from LDs, because of the absence of the donor duodenum. Still, even in bladder-drained LD recipients, the loss of exocrine pancreatic secretions in the urine can lead to bicarbonate deficiency and electrolyte derangements, causing chronic (hyperchloremic) metabolic acidosis and dehydration; such recipients can be saddled with permanent bicarbonate supplementation and the need for increased fluid intake. Urologic complications include (recurrent) bacterial urinary tract infections, hematuria, chemical cystitis, urethritis, bladder stones, and graft pancreatitis (secondary to reflux of urine into the pancreatic ducts) [18]. These complications, thought to be the consequences of altered urothelial integrity and a change to an alkaline pH of the urine, can usually be managed nonoperatively (e.g., with the placement of Foley catheter, antibiotics, and urinary tract analgesics). In contrast to deceased donor transplants, serious, albeit rare, complications (such as perineal excoriation, ureteral disruption and strictures, or autodigestion of the glans penis, major labia, and urethra) have not been described after LD pancreas transplants [19, 20]. The operative therapy of choice for persistent or refractory bladder drainage-related complications after LD pancreas transplants is conversion to enteric drainage. Because a segmental pancreas graft has a smaller immunologic reserve than a whole-organ graft, conversion from bladder to enteric drainage in the AZA and CSA eras was performed only if the recipient had been rejection-free for at least 6 months posttransplant [21, 22]. Portal vein drainage via the inferior mesenteric vein (along with enteric drainage) has also successfully been used in at least one LD pancreas transplant (PTA) [23]. Since portal vein drainage of LD pancreas transplants would frequently require the use of a vascular extension graft with drainage into the low-flow recipient portal circulation the major concern with this technique is an increased risk of graft thrombosis. However, as with whole-organ grafts, portal-enteric drainage is theoretically possible by using the recipient’s superior mesenteric vein, portal vein, and splenic vein; for the arterial anastomosis, the recipient (right) common iliac artery (with an interposition graft) or the infrarenal aorta can also be used. Systemic drainage has been the technique of choice for LD segmental grafts. No convincing evidence exists today that systemic vein drainage places pancreas recipients at a higher risk for developing atherosclerosis due to peripheral hyperinsulinemia [24, 25]. Furthermore, comparable metabolic control is achieved with portal and systemic vein drainage [26–28].

35  Living Donor Pancreas Transplantation

459

LD segmental pancreas grafts have been placed both intraperitoneally and retroperitoneally. However, there is widespread consensus among pancreas transplant surgeons that the preferred placement for both whole-organ and segmental grafts is intraabdominal (see Chap. 29) [23, 29].

 tandard Operative Procedures: Segmental S Transplants from Living Donors The dissection of the recipient iliac vessels is as extensive for LD transplants as for DD whole-organ transplants, because of the importance of creating tension-free anastomoses. In contrast to whole-organ transplants, the external iliac vein is positioned medially to the external iliac artery (Fig.  35.1): doing so reflects the natural position of the donor splenic artery and vein if the graft is placed in the caudad position. In general, in order to decrease the risk of thrombosis, extension grafts should not be used. The following is a detailed description of the operative procedure and the surgical variants [1]. The recipient is placed on the operating table in the supine position. After general endotracheal anesthesia is induced, Foley catheter bladder drainage begins, an arterial line is placed for constant blood pressure monitoring, a central venous catheter is placed for volume substitution and central venous pressure monitoring, nasal gastric suction is instituted, prophylactic antibiotics are given (repeated every 4 h during the course of the procedure), and sequential compression devices are used. The recipient is prepped and draped in standard fashion for a lower midline incision. As mentioned above, the pancreas is placed intraabdominally, preferably on the right side of the pelvis, because the iliac vessels are more superficial there than on the left side. The recipient is then placed in a slight Trendelenburg position. The abdomen is entered through the midline incision extending from a point slightly above the umbilicus down to the pubic bone. The abdomen is first explored for any pathologic findings. If the abdominal contents appear normal, the dissection is started by mobilizing the cecum and distal portion of the ascending colon medially. Doing so creates a comfortable retroperitoneal bed for the graft and also allows exposure to the proximal common iliac artery and vein. As part of this initial dissection, the right native ureter is identified, isolated, and fully mobilized to a point mid-way between the iliac vessels and the bladder. The right common, external, and internal iliac arteries are dissected free, all the way from the aortic bifurcation until just proximal to the inguinal ligament (Fig.  35.1). Care is taken not to injure any nerve structures at the aortic bifurcation. Next, the right common, external, and internal iliac veins are mobilized. Major lymphatic vessels and lymph

Fig. 35.1  Dissection of the recipient’s right iliac vessels: The internal iliac veins are ligated and divided. The internal iliac artery is also ligated and divided. The external iliac artery is placed lateral to the external iliac vein. The arteriotomy is made proximal to the venotomy. The ureter is looped and retracted medially and cranially to the common iliac artery

nodes overlying the iliac vessels are ligated; the gonadal or ovarian vein may also be ligated, in order to prevent possible impingement on the venous graft anastomosis. To create tension-free anastomoses, all internal iliac (hypogastric) veins (including the first right lumbar vein) are ligated, stick-­ tied, and divided; for optimal alignment, it may also be necessary to ligate and divide the internal iliac artery. This extensive dissection facilitates the venous graft anastomosis technically, makes unnecessary the use of extension grafts, and decreases the risk of creating a venous anastomosis under tension. Only if bladder drainage is performed the lower abdominal dissection is completed by mobilizing the bladder. Its lateral attachments are divided. In women, the round ligament is divided; in men, care is taken to preserve the spermatic cord. Dissection of the bladder can be limited to its right anterolateral portion: the bladder’s close proximity to the right iliac vessels allows the creation of a pancreaticocystostomy with little mobilization. Once the dissection in the recipient is completed, along with the benchwork preparation (i.e., flushing of the LD’s splenic artery, identification of the pancreatic duct, ligation of vessels and ducts on the cut surface), heparin is given

460

intravenously (50  U/kg for nonuremic, 40  U/kg for posturemic, and 30 U/kg for uremic recipients). In our experience, intraoperative heparinization—even in uremic recipients—helps decrease the rate of thrombosis. The proximal common iliac artery and vein and the distal external iliac artery and vein are clamped with atraumatic vascular clamps. The internal iliac artery (if not ligated and divided earlier; see above) is separately clamped with a short atraumatic vessel clamp (e.g., bulldog clamp) (Fig.  35.1). Only on occasion is the hypogastric artery used for arterial inflow. Because of the varying degree of atherosclerotic disease in recipients, clamps on the proximal and distal iliac arteries should be placed at plaque-free locations. When clamping the iliac vessels, it is important to position the external iliac vein medially to the artery (in contrast to whole-organ transplants, where the iliac vein is positioned laterally to the iliac artery). The venotomy is usually made first and irrigated with a heparin-containing solution. Four double-armed 6–0 nonabsorbable sutures are placed at the corners and sides of the venotomy. The segmental pancreas from the donor is brought into the operative field. The 6–0 nonabsorbable venotomy stitches are taken to their respective points on the LD’s splenic vein. They are tied as the pancreas is lowered into the operative field. The end-to-side venous anastomosis is completed by running the 6–0 nonabsorbable corner sutures continuously from one end to the other and tying them at the corners. Likewise, the arteriotomy is made in the external iliac artery lateral and proximal to the venotomy (Figs.  35.2 and 35.3). The arteriotomy is irrigated with a heparin-containing solution. Four double-­ armed 6–0 or 7–0 nonabsorbable sutures are placed at the corners and sides of the arteriotomy. Any intimal dissections or plaques are tagged at this time, usually with interrupted 7–0 nonabsorbable sutures. The end-to-side arterial anastomosis is completed by running the 6–0 or 7–0 nonabsorbable corner sutures continuously from one end to the other and tying them at the corners. If the diameter of the splenic artery is small, the anastomosis should be accomplished with interrupted 6–0 or 7–0 nonabsorbable sutures. If the external iliac artery cannot be used because of severe atherosclerotic disease, the LD’s splenic artery can also be anastomosed end-to-end to the internal iliac artery which usually requires enteric drainage given the short length of the donor splenic artery (Fig. 35.4). At the beginning of the arterial anastomosis, mannitol (0.5–1.0 g/kg body weight) and octreotide (300 μg) are given intravenously to the recipient to diminish the inflammatory response which usually manifests itself as graft edema and graft pancreatitis. After the vascular anastomoses are completed, all vascular clamps on the iliac artery and vein are removed. Any bleeding sites, particularly on the cut surface of the pancreas, are identified and carefully controlled with fine suture-ligation techniques.

R. W.G. Gruessner

A

B

Fig. 35.2  Living donor (LD) segmental pancreas transplant with systemic vein and bladder exocrine drainage: The donor’s splenic artery and vein are anastomosed end-to-side to the recipient’s external iliac artery and vein. The splenic artery anastomosis is lateral and proximal to the splenic vein anastomosis. A two-layer ductocystostomy (inset B) is constructed. The pancreatic duct is sutured to the urothelial layer (inner layer) using interrupted 7–0 sutures over a stent. Alternatively, a two-layer pancreaticocystostomy can be constructed (inset A): the cut surface of the pancreas is invaginated into the bladder (telescope anastomosis). The ureter of the simultaneously transplanted kidney is implanted into the bladder, using the extravesical ureteroneocystostomy (Lich) technique

If bladder drainage is chosen, a tension-free bladder anastomosis can easily be constructed given the proximity of the external iliac vessels to the bladder. Two techniques for bladder drainage are used: pancreaticocystostomy and ductocystostomy [1]. If a pancreaticocystostomy (Fig. 35.2, Inset A) is created, the cut surface of the pancreas is anastomosed to the bladder by using the invagination (“telescope”) technique, as described for the Whipple procedure. First, an outer layer is begun with interrupted nonabsorbable 4–0 sutures between the posterior surface of the pancreas and the bladder wall. The stitches are anchored in the pancreas about 1–2 cm distal to the cut surface. The bladder is then transversely incised, over a length of 2–4 cm, and opened. An inner layer of running 4–0 absorbable sutures is run around the entire circumference of the pancreas and the cystostomy, anchored in the cut surface line on the pancreas side, thus invaginating the cut surface of the pancreas into the bladder. Before the inner running suture line is completed, a stent is passed into the pancreatic duct and tagged with interrupted 7–0 absorbable sutures to the tip of the pancreatic duct. The anterior outer layer is finished with interrupted 4–0 nonabsorbable sutures, anchored 1–2 cm distal to the cut surface on the pancreatic side. If a ductocystostomy (Fig. 35.2, Inset B) is created, a direct anastomosis is constructed between the pancreatic duct and the bladder urothelium. The seromuscular layer of the bladder is transversely incised down to the urothelium (2–4  cm in

35  Living Donor Pancreas Transplantation

a

461

b

Fig. 35.3  Living donor (LD) segmental pancreas transplant with systemic vein and bowel exocrine drainage via a Roux-en-Y loop: The donor’s splenic artery and vein are anastomosed end-to-side to the recipient’s external iliac artery and vein. The splenic artery anastomosis is lateral and proximal to the splenic vein anastomosis. A two-layer ductojejunostomy or pancreaticojejunostomy (telescope or invagina-

length). An outer layer is begun with running or interrupted nonabsorbable sutures between the posterior surface of the pancreas and the bladder wall. A small incision, about the size of the lumen of the pancreatic duct, is made in the bladder urothelium (0.5  cm), and the bladder is opened (Fig.  35.2). The posterior row of the inner anastomosis is done between the pancreatic duct and the bladder urothelium with interrupted 7–0 absorbable sutures. Before the posterior inner layer is completed, a stent is passed through the duct-­to-­urothelium anastomosis. The stent is tagged at the tip of the pancreatic duct with interrupted 7–0 absorbable sutures. The inner anterior layer of the anastomosis is completed with interrupted 7–0 absorbable sutures over the stent. The outer anterior layer between the seromuscular bladder wall and the anterior surface of the pancreas is done with 4–0 nonabsorbable sutures in running or interrupted fashion. A variant of the outer layer is the creation of an anterior and posterior muscular flap (each 2 cm wide) after the bladder is incised (and while the urothelium is intact). This dissection results in a collar of bladder muscular tissue surrounding a broader area of the proximal and middle portion of the segmental graft [30]. Irrespective of whether a pancreatico- or ductocystostomy is created, the stent is either spontaneously excreted through the urether or cystoscopally removed 4 weeks posttransplant. For enteric drainage (Figs.  35.3, 35.4, and 35.5) of LD segmental grafts, a Roux-en-Y loop is usually used. In prep-

tion technique) is constructed end-to-side (as shown) or end-to-end; about 40 cm distal to that anastomosis, a jejunojejunostomy is created in side-to-side or end-to-side fashion. The ureter of the simultaneously transplanted kidney is implanted into the bladder, using the extravesical ureteroneocystostomy (Lich) technique

Proximal Jejunum

Roux-en-Y

Internal lliac- Splenic a. Anastomosis

External lliacSplenic v. Anastomosis

Pancreatico-jejunostomy

Fig. 35.4  The right internal (rather than the external) iliac artery is used for inflow due to severe atherosclerotic disease of the external iliac artery. The use of the internal iliac artery makes enteric drainage preferable unless an interposition graft is used which makes bladder drainage technically feasible but at a higher thrombosis risk

aration for the pancreaticoenterostomy, the recipient’s proximal small bowel is drawn to the level of the cut surface of the pancreas, to ensure that the mesentery of the jejunum is long enough to reach the graft. The pancreatico- or ductojejunos-

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tomy should be made as proximally as possible (ideally, 40–80 cm distal to the ligament of Treitz; Fig. 35.5) to establish near-normal physiology and to prevent the development of diarrhea (which has been noted if the anastomosis is created more distally in the small bowel). Once the appropriate loop of jejunum is identified, the jejunum is divided with the gastrointestinal anastomosis (GIA) stapler. The stapled distal end of the divided jejunum is oversewn with 4–0 absorbable sutures. The proximal end is anastomosed side-to-side (Fig. 35.3a) or end-to-side (Fig. 35.3b) about 40 cm distal to the distal end of the divided jejunum. Doing so provides an adequate defunctionalized limb for exocrine drainage of the

distal pancreas. The jejunojejunostomy is a two-layer anastomosis, either handsewn or stapled. If a pancreaticojejunostomy is created, the Roux-en-Y loop is anastomosed to the whole cut surface of the pancreas by using the invagination (“telescope”) technique. The anastomosis can be created end-to-side (Figs. 35.3 and 35.4) (by using the antimesenteric side just distal to the jejunal stump end) or, less frequently, end-to-end (Fig. 35.5) (by using the jejunal stump itself after resection of the staple line). The two-layer anastomosis is begun with an outer posterior layer with interrupted 4–0 non-absorbable sutures. If the side, and not the distal stump itself, is used, the jejunum is incised

Fig. 35.5  Living donor (LD) segmental pancreas transplant on the left side in cephalad position with systemic vein and enteric exocrine drainage via a Roux-en-Y loop: The donor’s splenic artery and vein are anastomosed end-to-side to the recipient’s left common iliac artery and vein. The splenic artery anastomosis is lateral to the splenic vein anastomo-

sis. A two-layer pancreaticojejunostomy (telescope or invagination technique) is constructed end-to-end; about 40 cm distal to that anastomosis, a jejunojejunostomy is created in standard fashion. The previously transplanted kidney is on the right side

35  Living Donor Pancreas Transplantation

transversely on the antimesenteric side over the length of 3–4 cm. An inner layer between the cut surface of the pancreas and the jejunal wall (full-thickness bites) is constructed circumferentially with running 4–0 absorbable sutures. Doing so allows the whole cut surface of the distal pancreas to invaginate into the Roux-en-Y limb. An outer posterior layer of interrupted 4–0 non-absorbable sutures completes the anastomosis. If a ductojejunostomy is created, interrupted 4–0 non-­ absorbable sutures are placed on the posterior surface of the pancreas (1–2 cm distal to the cut surface) and the jejunum, to construct the posterior outer layer of the anastomosis. A stab wound (0.5  mm) is made through all layers of the antimesenteric wall of the jejunum, approximately equaling the diameter of the pancreatic duct. The pancreatic duct is then anastomosed to the full thickness of the jejunal wall with interrupted 6–0 or 7–0 non-absorbable sutures. The anterior outer layer is completed between the anterior surface of the pancreas (1–2 cm distal to the cut surface) and the jejunum with 4–0 non-absorbable sutures. Irrespective of whether a pancreatico- or ductojejunostomy is created, a stent is placed in the pancreatic duct and tagged with absorbable 6–0 sutures. The stent extends into the jejunal lumen and usually passes with the enteric contents within a few weeks.

Variations in Operative Procedures LD SPK Transplants In LD (as in DD) SPK transplants, the pancreas is preferentially implanted on the right side and the kidney on the left side of the pelvis. Since the kidney is usually procured first from the donor (see Chap. 16), the kidney is also transplanted first and anastomosed to the recipient’s left external iliac artery and vein; for ureteral implantation, usually, an extravesical anterolateral approach (standard Lich or modified one-stitch Lich technique) is used, sparing the recipient a long anterior cystotomy required for the transvesical or posterolateral approach (Politano-Leadbetter technique) [31–34]. For both renal vascular anastomoses, 6–0 nonabsorbable sutures are used. For the ureteral implantation techniques, absorbable sutures are used (6–0 or 5–0 absorbable sutures for standard Lich or Politano-Leadbetter techniques, 4–0 double-armed absorbable sutures for the modified one-stitch Lich technique). For the construction of a submucosal ureteral tunnel with the extravesical or anterolateral technique, the seromuscular layer is closed on top of

463

the ureter with interrupted or running 5–0 absorbable sutures (tunnel length, 2–3  cm) (see Chap. 29: Figs. 29.9, 29.10, and 29.11).

Positional Variations If a previous kidney (or pancreas) graft was placed on the right side, the LD pancreas segment can be engrafted to the left iliac vessels. Intraperitoneal placement via a midline incision is also preferred on the left side. The dissection of the common, external, and internal iliac vessels is done laterally to the sigmoid colon. If bladder drainage is chosen, the external iliac vessels are used for anastomosis, as on the right side, because their relatively distal position allows the creation of a tension-free bladder anastomosis. Because the external iliac vessels are deeper on the left side than on the right side, it is advisable to ligate and divide the internal iliac artery as well as all hypogastric veins, in order to maximize mobilization and to create a tension-free venous anastomosis. The technique for vascular engraftment of the segmental pancreas on the left side does not differ from the technique on the right side. The arterial anastomosis is lateral and proximal to the venous anastomosis. Likewise, the technique of the pancreaticocystostomy or ductocystostomy is identical to the technique on the right side. If enteric drainage is chosen, the LD segmental pancreas does not have to be placed in a caudad position as described above, but can also be placed in a cephalad position (Figs. 35.4 and 35.5), thus making the enteric anastomosis technically easier. In this case, the proximal common iliac vessels are used for revascularization. The splenic vein is anastomosed end-to-side to the common iliac vein or to the distal inferior vena cava, using 6–0 or 7–0 non-absorbable sutures in running fashion. Likewise, the arterial anastomosis is between the splenic artery and the proximal common iliac artery. On the right side in the cephalad position, the arterial anastomosis is medial and distal to the venous anastomosis. In the cephalad position, the segmental pancreas graft is anastomosed to the proximal jejunum about 40–80 cm distal to the ligament of Treitz, either side-to-side or with a Roux-­ en-­Y loop. The enteric anastomotic technique is basically the same as described above for the caudad position. On the left side in the cephalad position, the common iliac artery and vein are also used for anastomoses (Fig.  35.5). The dissection of the common iliac vessels can be done either laterally or medially to the sigmoid colon. The lateral dissection is as described for the caudad position. If the pancreas graft is placed in the medial position, the dissection has

464

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to be carried out through an avascular window between the vessel-bearing arcades of the mesocolon. According to the natural position of the common iliac artery and vein on the left side, the venous anastomosis is made medially and proximally to the arterial anastomosis.

Management of Exocrine Secretions Enteric drainage and bladder drainage are by far the most common techniques. Two other techniques have been used occasionally in LD segmental pancreas transplants: ureteral drainage and duct injection. Ureteral drainage was originally described in 1973 by Gliedman et al. [35] who anastomosed the pancreatic duct of a DD, segmental, systemic-drained graft to the ipsilateral ureter of the recipient. The native ureter can be used if the recipient is uremic, is on dialysis, and produces no or only very little urine. The ductoureterostomy is a one-layer anastomosis, with 6–0 or 7–0 absorbable sutures over a stent that extends into the bladder. The stent is tagged with a 6–0 absorbable suture so that it can be removed cystoscopically if it does not pass spontaneously. Ureteral drainage is not widely used because of its relatively high anastomotic complication rate (leaks, strictures). Of note, leaks can occur not only at the anastomotic site itself but also at the cut surface of the pancreas. Nonetheless, ureteral drainage is an option if the pancreatic duct and the ipsilateral native ureter are a good size match and if bladder or enteric drainage cannot be used (because of a short pancreatic neck and concern about injuring the LD’s splenic vessels when constructing an outer, second anastomotic layer). Duct injection was first described by Dubernard et al. in 1978 for DD segmental grafts [36]. After revascularization, 3–5 mL of a synthetic polymer (neoprene, prolamine, polyisoprene or silicon) is injected into the main pancreatic duct [37–39]. Duct injection can also be performed on the bench. The pancreatic duct is cannulated with a small blunt-­tipped catheter (Fig.  35.6). Spillage of the polymer should be avoided. After injection of the polymer, the pancreatic duct is oversewn with a single 5–0 absorbable suture. The cut surface can also be oversewn with a single 4–0 absorbable suture. Duct injection is rarely been used, because of its

Fig. 35.6  Living donor (LD) segmental pancreas transplant with systemic vein drainage and duct injection: The donor’s duct is injected with a synthetic polymer that causes fibrosis of the exocrine tissue. Note the meticulous ligation of the vascular and exocrine structures on the cut surface of the pancreas. The ureter of the simultaneously transplanted kidney is implanted into the bladder, using the extra vesical ureteroneocystostomy (Lich) technique

higher complication rate (as compared with enteric or bladder drainage). In particular, duct-injected recipients develop graft pancreatitis obligatorily; pancreatic fistulas with infections are not uncommon. However, duct injection can be used as a rescue conversion technique for recipients with surgical complications after enteric- or bladder-drained pancreas transplants (see Chap. 29).

Portal Vein Drainage As mentioned above, portal vein drainage via the inferior mesenteric vein has also successfully been used in at least one LD pancreas transplant [23]. This LD PTA was placed in a cephalad position with enteric drainage (Fig.  35.7).

35  Living Donor Pancreas Transplantation

465

a

b

Portal v. Spelnic v.

Spelnic v. Inferior Mesenteric V.

Proximal Jejunum Portal v.

Roux-en-Y

Inferior MesentericSplenic v. Anastomosis

Inferior MesentericSplenic a. Anastomosis

Inferior Mesenteric V.

Pancreatico-jejunostomy

Inferior MesentericSplenic v. Anastomosis

Proximal Jejunum Roux-en-Y Inferior MesentericSplenic a. Anastomosis Pancreatico-jejunostomy

c

Injection of Polymer into Pancreatic Duct

Inferior MesentericSplenic Artery Anastomosis

Inferior MesentericSplenic Vein Anastomosis

Fig. 35.7  Use of the inferior mesenteric vessels (artery and vein) with (a, b) enteric drainage or (c) duct injection in cephalad graft position. Alignment of the mesenteric and donor vessels can vary (a, b)

Alignment with the arterial anastomosis to the common iliac artery was more favorable with an anastomosis of the donor splenic vein to the recipient inferior mesenteric vein than to the common iliac vein or vena cava. While portal vein drainage has rarely been used for LD segmental transplants, it is not quite as uncommon for DD segmental transplants for which both the superior and the inferior mesenteric vessels have been used for anastomoses (Fig. 35.7) (see Chap. 29) [40, 41].

References 1. Gruessner RWG.  Surgical procedures. In: Gruessner RWG, Benedetti E, editors. Living donor organ transplantation. New York, NY: McGraw-Hill Companies; 2008. p. 403–8, Chapter 20.2. 2. Gruessner RWG, Sutherland DER. Simultaneous kidney and segmental pancreas transplants from living related donors  – the first two successful cases. Transplantation. 1996;61:1265–8. 3. Gruessner RWG, Kendall DM, Drangstveit MB, et al. Simultaneous pancreas-kidney transplantation from live donors. Ann Surg. 1997;226:471–82. 4. Gruessner RW, Sutherland DE, Drangstveit MB, Bland BJ, Gruessner AC. Pancreas transplants from living donors: short- and long- term outcome. Transpl Proc. 2001;33:819–20.

466 5. Reynoso JF, Gruessner CE, Sutherland DE, Gruessner RW. Shortand long-term outcome for living pancreas donors. J Hepatobil Pancreat Sci. 2010;17(2):92–6. 6. Sutherland DER, Gruessner R, Dunn D, Moudry-Munns K, Gruessner A, Najarian JS. Pancreas transplants from living-related donors. Transpl Proc. 1994;26:443–5. 7. Gruessner AC. International Pancreas Transplant Registry (IPTR) data. Personal communication; 2020. 8. Sutherland DER, Goetz FC, Najarian JS. Pancreas transplants from living related donors. Transplantation. 1984;38:625–33. 9. Gruessner RWG, Najarian JS, Gruessner AC, Sutherland DER. Pancreas transplants from living related donors. In: Touraine JL, Traeger J, Bétuel H, et al., editors. Organ shortage—the solutions. Dordrecht: Kluwer Academic; 1995. p. 77–83. 10. Gruessner RWG, Sutherland DER. Clinical diagnosis in pancreas allograft rejection. In: Solez K, Racusen LC, Billingham ME, editors. Solid organ transplant rejection: mechanisms, pathology and diagnosis. New York, NY: Marcel Dekker, Inc.; 1996. p. 455–99. 11. Gruessner RWG, Sutherland DER, Drangstveit MB, West M, Gruessner A. Mycophenolate mofetil and tacrolimus for induction and maintenance therapy after pancreas transplantation. Transpl Proc. 1998;30:518–20. 12. Gruessner RWG, Nakhleh R, Tzardis P, et al. Differences in rejection grading after simultaneous pancreas and kidney transplantation in pigs. Transplantation. 1994;57:1021–8. 13. Benedetti E, Najarian JS, Sutherland DER, et  al. Correlation between cystoscopic biopsy results and hypoamylasuria in bladder-­ drained pancreas transplants. Surgery. 1995;118:864–72. 14. Sollinger HW, Cook K, Kamps D, et al. Clinical and experimental experience with pancreaticocystostomy for exocrine pancreatic drainage in pancreas transplantation. Transpl Proc. 1984;16:749–51. 15. Prieto M, Sutherland DE, Goetz FC, et  al. Pancreas transplant results according to the technique of duct management: bladder versus enteric drainage. Surgery. 1987;102:680–91. 16. Gruessner RW, Sutherland DE, Troppmann C, et  al. The surgical risk of pancreas transplantation in the cyclosporine era: an overview. J Am Coll Surg. 1997;185:128–44. 17. Gruessner RWG, Dunn DL, Tzardis PJ, et  al. Simultaneous pancreas and kidney transplants versus single kidney transplants and previous kidney transplants in uremic patients and single pancreas transplants in nonuremic diabetic patients: comparison of rejection, morbidity, and long-term outcome. Transpl Proc. 1990;22:622–3. 18. Troppmann C.  Surgical complications. In: Gruessner RWG, Sutherland DER, editors. Transplantation of the pancreas. 1st ed. New York, NY: Springer; 2004. p. 206–37, Chapter 9.2.2. 19. Tom WW, Munda R, First MR, et  al. Autodigestion of the glans penis and urethra by activated transplant pancreatic exocrine enzymes. Surgery. 1987;102:99–101. 20. Mullaney JM, DeMeo JH, Ham JM.  Enzymatic digestion of the urethra after pancreas transplantation: a case report. Abdom Imag. 1995;20:563–5. 21. West M, Gruessner AC, Sutherland DE, et al. Surgical complications after conversion from bladder to enteric drainage in pancreaticoduodenal transplantation. Transpl Proc. 1998;30:438–9. 22. Gruessner RWG, Stephanian E, Dunn DL, et  al. Cystoentericconversion after whole pancreaticoduodenal transplantation. Transpl Proc. 1993;25:1179–81. 23. Sutherland DERS, Najarian JS, Gruessner RWG. History and rationale for pancreas transplantation. In: Gruessner RWG, Benedetti

R. W.G. Gruessner E, editors. Living donor organ transplantation. New  York, NY: McGraw-Hill Companies; 2008. p. 368–83, Chapter 18.1. 24. Diem P, Abid M, Redmon JB, et al. Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients. Diabetes. 1990;39:534–40. 25. Hughes TA, Gaber AO, Amiri HS, et  al. Kidney-pancreas transplantation. The effect of portal versus systemic venous drainage of the pancreas on the lipoprotein composition. Transplantation. 1995;60:1406–12. 26. Cattral MS, Bigam DL, Hemming AW, et  al. Portal venous and enteric exocrine drainage versus systemic venous and bladder exocrine drainage of pancreas grafts: clinical outcome of 40 consecutive transplant recipients. Ann Surg. 2000;232:688–95. 27. Stratta RJ, Shokouh-Amiri MH, Egidi MF, et  al. A prospective comparison of simultaneous kidney-pancreas transplantation with systemicenteric versus portal-enteric drainage. Ann Surg. 2001;233:740–51. 28. Petruzzo P, Laville M, Badet L, et al. Effect of venous drainage site on insulin action after simultaneous pancreas-kidney transplantation. Transplantation. 2004;77:1875–9. 29. Zielinski A, Nazarewski S, Bogetti D, et al. Simultaneous pancreas-­ kidney transplant from living related donor: a single-center experience. Transplantation. 2003;76:547–52. 30. Frisk B, Hedman L, Brynger H. Pancreaticocystostomy with a two-­ layer anastomosis technique in human segmental pancreas transplantation. Transplantation. 1987;44:836–8. 31. Lich R, Howerton LW, David LA. Recurrent urosepsis in children. J Urol. 1961;86:554. 32. Politano VA, Leadbetter WF. An operative technique for the correction of vesicoureteral reflux. J Urol. 1958;79:932. 33. Matas AI, Tellis VA, Karwa GL, et  al. Comparison of posttransplant urologic complications following extravesical ureteroneocystostomy by a single-stitch or mucosal anastomosis. Clin Transpl. 1987;1:159–63. 34. Simmons RL, Najarian JS.  Kidney transplantation. In: Simmons RL, Finch ME, Ascher NL, Najarian JS, editors. Manual of vascular access, organ donation, and transplantation. New York, NY: Springer; 1984. p. 292–328. 35. Gliedman ML, Gold M, Whittaker J, et al. Pancreatic duct to ureter anastomosis for exocrine drainage in pancreatic transplantation. Am J Surg. 1973;125:245–52. 36. Dubernard JM, Traeger J, Neyra P, et al. A new method of preparation of segmental pancreatic grafts for transplantation: trials in dogs and in man. Surgery. 1978;84:633–9. 37. Land W, Gebhardt C, Gall FP, et  al. Pancreatic duct obstruction with prolamine solution. Transpl Proc. 1980;12:72–5. 38. McMaster P, Gibby OM, Evans DM, et  al. Human pancreatic trans- plantation with polyisoprene and cyclosporine A immunosuppression. Proc. 1980 EASD satellite symposium on islet-­ pancreas transplantation and artificial pancreas. Horm Metab Res. 1981;22:151–6. 39. Sutherland DE, Goetz FC, Elick BA, et al. Experience with 49 segmental pancreas transplants in 45 diabetic patients. Transplantation. 1982;34:330–8. 40. Tyden G, Lundgren G, Ostman J, et al. Grafted pancreas with portal venous drainage. Lancet. 1984;1:964–5. 41. Sutherland DE, Goetz FC, Moudry KC, et  al. Use of recipient mesenteric vessels for revascularization of segmental pancreas grafts: technical and metabolic considerations. Transpl Proc. 1987;19:2300–4.

Pancreas-Multivisceral Transplantation

36

Mathias Clarysse , Laurens J. Ceulemans , Diethard Monbaliu, and Jacques Pirenne

Contents Introduction 

 467

Combined Liver-Pancreas Transplantation  Indications  Global Experience  Procurement  Recipient Procedure 

 000  468  000  469  000

Combined Liver–Pancreas–Intestinal Transplantation  Indications  Global Experience  Procurement  Recipient Procedure 

 000  470  000  470  000

Multivisceral Transplantation  Indications  Global Experience  Procurement  Recipient Procedure 

 000  471  000  472  000

Combined Pancreas-Intestinal Transplantation  Indications  Global Experience  Procurement  Recipient Procedure 

 000  474  000  474  000

Pancreas Graft-Related Complications 

 475

References 

 475

Introduction

M. Clarysse · D. Monbaliu · J. Pirenne (*) Department of Abdominal Transplant Surgery and Coordination, Leuven Intestinal Failure and Transplant Center (LIFT), University Hospitals Leuven, Leuven, Belgium e-mail: [email protected]; [email protected]; [email protected] L. J. Ceulemans Department of Thoracic Surgery, Leuven Intestinal Failure and Transplant Center (LIFT), University Hospitals Leuven, Leuven, Belgium e-mail: [email protected]

With the introduction of cyclosporin A in the late 1970s and early 1980s, solid organ transplantation became applied at a large scale in patients with organ failure [1]. Intestinal transplantation (ITx), however, was still challenged by a high risk for rejection and technical complications [2]. With the introduction of FK506 (Tacrolimus®) in 1989, results of ITx clearly improved and hence transplant rates picked up [3, 4]. Due to more experience and improvements in immunosuppression protocols, clinical management, and surgical technique, long-term graft and patient survivals after ITx have improved further during the last two decades [3]. Meanwhile,

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. W.G. Gruessner, A. C. Gruessner (eds.), Transplantation of the Pancreas, https://doi.org/10.1007/978-3-031-20999-4_36

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pancreas transplantation had become the treatment of choice in kidney transplant recipients with diabetes mellitus and in non-uremic recipients with unstable diabetes and hypoglycemia unawareness. With excellent results of single organ transplants, multiple organ transplants (liver, pancreas, intestine, and other grafts) became increasingly performed in patients suffering from the disease of multiple organs. The rationale for the concomitant transplantation of the pancreas in a liver transplant (LTx) recipient with diabetes was the observation that diabetes negatively influences outcome after LTx alone [5, 6]. As these recipients must undergo major surgery and receive immunosuppression, there is no reason not to try to make them insulin-free as well. An identical reasoning supports kidney-pancreas versus kidney transplantation alone in diabetic recipients. In this chapter, we will discuss all subtypes of multiple abdominal organ transplants including the pancreas: combined liver-pancreas (see also Chap. 29); combined liver-pancreas-intestine; standard (and modified) multivisceral; and combined pancreas-intestinal transplantation. For each subtype, we will describe indications, global experience, as well as procurement and transplantation techniques.

Combined Liver-Pancreas Transplantation (cLPTx)

M. Clarysse et al. Table 36.1  Data of the published global experience with the different subtypes of multiple abdominal organ transplants, including a pancreas allograft (adapted from [17, 18, 37]) Organ procurement and transplant network (1988—August 2020) U.S.A.

cLPTx cLPTx + kidney cLITx cLITx + kidney MvTx mMvTx cPITx

Intestinal transplant registry (1985—May 2019) International

97 12

Eurotransplant (2010—August 2020) Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, The Netherlands, Slovenia 52 5

1093 114

30 3

1251 NA

NA NA NA

NA NA NA

810 200 NA

NA NA

cLITx combined liver–pancreas–intestinal transplantation, cLPTx combined liver–pancreas transplantation, cPITx combined pancreas–intestinal transplantation, mMvTx modified multivisceral transplantation, MvTx multivisceral transplantation

ing to the United Network Organ Sharing (UNOS) study by Usatin et al., cLPTx is rarely performed in CF [12] (see Chap. 72, Table 72.1). Of 303 CF patients, who received their first The first reported case of cLPTx was performed on third LTx between 1987–2014 in the USA, 20% had CF-related diaOctober 1979 by Calne et al. [1]. A segmental pancreas was betes but only 3% underwent a cLPTx [12]. In the late 1980s transplanted separately from the liver in a patient with end-­ and early 1990s, en-bloc cLPTx has also been performed for stage liver disease and insulin-dependent diabetes. The recipi- advanced upper gastrointestinal cancers deemed irresectable ent remained 1-year insulin free and survived for 6 years. The by standard techniques, such as sarcoma, hepatocellular carcisecond case was done in 1988, in a 40-year-old man with noma, cholangiocarcinoma, adenocarcinoma or neuroendochronic active hepatitis and insulin-dependent diabetes. He crine neoplasms [13, 14]. It was hoped that wide resection and successfully received an en-bloc liver and full pancreas graft tumor clearance would prevent tumor relapse. However, this and became the longest-surviving cLPTx recipient in 2007 has been abandoned, due to the high cancer recurrence and [7]. Cystic fibrosis (CF) affects not only the lungs, but also the low survival rate, except for selected neuroendocrine tumors liver and the pancreas and represents another potential indica- [14]. Finally, when an intraductal papillary mucinous neotion for cLPTx (see Chaps. 1, 72 and 80). According to the plasm has been diagnosed during evaluation for LTx, total IPTR, a total of 19 combined pancreas-liver transplants have pancreatectomy followed by separate orthotopical liver and been performed with (n = 5) or without (n = 14) other solid heterotopic pancreas Tx has been reported [15]. organs in the U.S. between 1/1/1988 and 12/31/2020 (see Chap. 72, Table 72.1). The first case was described by Stern et al. in 1994. A 21-year-old patient received an en-bloc liver- Global Experience (Table 36.1) pancreas-kidney Tx for endo- and exocrine pancreatic insufficiency, liver cirrhosis, and renal failure [8]. With improved As mentioned above, cLPTx is a rarely performed procetherapy and prolonged survival, an increasing number of dure [16]. According to the Organ Procurement and patients with CF present with liver cirrhosis and diabetes [9]. Transplantation Network (OPTN) registry, 97 cLPTx and Only 5% of children with CF suffer from diabetes, but this 12 cLP/kidney Tx were performed between 1988 and percentage increases up to 80% in young adults [10]. Biliary August 2020 in the USA [17]. Within Eurotransplant (ET), cirrhosis with portal hypertension is seen in 8% of CF patients 52 cLPTx and 5 cLP/kidney Tx have been done between and the incidence increases with age [11]. Despite this, accord- 2010 and August 2020 [18].

Indications

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Procurement If liver and pancreas are to be implanted separately, the donor procedure will not differ from a standard liver and pancreas procurement. In case the liver and pancreas will be implanted en-bloc, both organs should be procured en-bloc, including the celiac axis and the superior mesenteric artery [19]. Minimal dissection is needed, and the liver hilum is left untouched. A long segment of the inferior mesenteric vein will facilitate the flushing of the bloc prior to reperfusion. The duodenum is procured along with the bloc, by stapling the pyloric junction proximally and the duodenojejunal flexure distally. Both duodenal stumps are oversewn to decrease the risk of leakage at the staple line.

Recipient Procedure (Figs. 36.1 and 36.2) There are two ways to describe to perform cLPTx (see Chap. 29). The first option, more frequently used in the late 1980s and 1990s, is a standard orthotopic LTx, followed by a separate standard heterotopic pancreas Tx, usually in the right iliac fossa. In this technique, vascular supply for the pancreas is generally provided by the iliac vessels [20]. Exocrine drainage of the pancreas can be performed via a duodenocystostomy, which provides the possibility to measure amylases in the urine, a potential surrogate of pancreas rejection [21].

Fig. 36.1  Combined liver-pancreas transplantation: suprahepatic cava anastomosis (SHCA), infrahepatic cava anastomosis (IHCA), arterial anastomosis (AA) through an interposition aortic conduit, and portal vein anastomosis (PVA) of the recipient native portal vein end-to-side on the posterior aspect of the donor portal vein. (Figure adapted from [19] with permission)

Fig. 36.2  Combined liver-pancreas transplantation en-bloc, with duodenojejunostomy (1  =  Transplant Liver; 2  =  Transplant Duodenum; 3  =  Transplant Pancreas; 4  =  Recipient Jejunum) (photo from own experience)

However, the latter technique has been progressively abandoned in favor of enteric drainage. The advantage of the separate technique is that, in case of transplant-pancreatitis, thrombosis, or infection, the liver graft will not be affected. The downside is a longer operative time, a longer cold ischemia time, multiple vascular, biliary, and pancreatic anastomoses, their associated morbidity, and larger operative wounds. The second option is the en-bloc liver and full pancreas transplant, as described by the Pittsburgh team at the end of the 1980s in patients with upper gastrointestinal neoplasms [13, 14]. In 2004, we applied this en-bloc technique in selected LTx candidates with diabetes with the rationale that correction of diabetes via concomitant pancreas Tx would improve outcome versus isolated LTx [5, 19]. In this en-bloc technique, the arterial inflow is usually created by anastomosing a carrel patch of the celiac trunk and superior mesenteric artery onto the supra celiac or the infrarenal aorta, either directly end-to-side or preferably with a donor aortic conduit in between. LTx can be performed by either the classical caval replacement technique or by the caval preserving technique (piggyback). In the caval replacement

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technique, the native portal vein is anastomosed end-to-side to the donor portal vein, at the posterior side of the liver hilum. In the caval preserving technique (piggyback), the native portal vein can be anastomosed either to the donor portal vein (end-­to-­side) or to the infrahepatic caval vein (end-to-end). So far, we have given preference to draining the native portal vein (foregut) into the donor portal vein, in order to avoid a potentially low flow into the liver, if the portal flow would originate from the transplanted pancreas only. Biliary and exocrine pancreatic drainage is performed through a duodenoduodenostomy or a duodenojejunostomy with no additional need for a separate biliary anastomosis [19, 22]. This en-bloc technique is easier than the separate implantation of both organs since it requires only one subcostal incision, three or four vascular anastomoses, one intestinal anastomosis, and no separate biliary or pancreatic anastomosis. Operative time is reduced and hence ischemia time of the pancreas is shorter. A potential advantage is the better metabolic control of a physiologically drained pancreas and the drainage of hepatotrophic factors from the pancreas into the liver [23–25]. One should be aware that infrarenal aortic conduits convey their own morbidity, e.g. gastric outlet syndrome (when the aortic tube compresses the gastroduodenal junction as we have seen in one case [26]), as well as bleeding and infection [27].

Combined Liver–Pancreas–Intestinal Transplantation (cLITx) Indications One of the first successful ITx, reported by Grant et  al. in 1988, was a cLITx, without pancreas, in a patient with short bowel syndrome and antithrombin-III deficiency [2]. The most common indication for cLITx now is intestinal failure (IF) with IF-associated liver disease (IFALD). cLITx represented more than 50% of the ITx performed in the 1990s. This percentage has substantially decreased in more recent eras, due to the progress in the management of these complex patients and particularly the development of liver-­sparing parenteral nutrition [28–30]. Intestinal re-transplantation (reITx) is a growing indication, accounting for up to 10% of the current ITx activity [28, 30]. When a first ITx has failed for immunological reasons, it is increasingly advised to perform cLITx instead of an isolated re-ITx, given the protection that a simultaneously transplanted liver offers against rejection [31–33]. To improve the outcome of primary ITx, it has also been proposed to perform cLITx, even in patients with (near to) normal liver function. In that case, the native liver could be used in another recipient (domino-LTx) to avoid losing a liver graft from the donor pool [28, 34].

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Global Experience (Table 36.1) Historically, cLITx was the most frequently performed ITx procedure. However, it declined from 68% in 2007 to 39% of all ITx done in 2011, secondary to improvements in the management of these patients as mentioned above [35]. According to the OPTN registry, 1093 cLITx and 114 cLI/kidney Tx were performed between 1988 and August 2020 in the USA [17]. Within ET, 30 cLITx and 3 cLI/kidney Tx have been reported between 2010 and August 2020 [18]. According to the International Intestinal Transplant Registry (ITR), 1251 cLITx were done between 1985 and May 2019, accounting for 30% of all ITx [36].

Procurement The liver–pancreas–intestine is procured as one single bloc with minimal manipulation of the intestine and the pancreas. Similar to pancreas procurement, the spleen can be used as a handle for gentle traction. The liver hilum is left untouched. The gastrocolic ligament and the mesocolon are transected [37]. The stomach is separated by stapling the duodenogastric junction immediately distally from the pylorus. The ileum is stapled proximally to the ileocecal valve, if only the small intestine is to be transplanted. The colon can be stapled at any given level (with respect to its vasculature), if it is to be co-transplanted. The bloc is procured with an aortic patch including the superior mesenteric artery and the celiac trunk. The advantage of co-procuring and cotransplanting the pancreas in cLITx is that no hilar dissection is needed and there are fewer risks of donor-related vascular complications (torsion) and biliary complications since there is no need for a separate biliary anastomosis [38]. Inclusion of the pancreas into the liver-intestine cluster is often referred to as the “Omaha” technique. In this original technique, the tail of the pancreas was removed from the body and neck during the backtable procedure [38]. The Miami team proposed to simplify the procedure even further by transplanting the full pancreas, a technique now used by most teams [39, 40]. The spleen is usually removed during the backtable work.

Recipient Procedure (Fig. 36.3) The native liver is resected, like in a classical LTx, and the healthy extremities of the gastrointestinal tract are dissected free. An aortic conduit from the donor is anastomosed end-­ to-­side onto the infrarenal or supra celiac aorta. The liver-­ pancreas-­ intestine bloc is implanted by using either the standard caval replacement or the caval preserving (piggyback) technique. The native portal vein, still draining the

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Sudan et al., in the mid-1990s, in which hilar dissection was eliminated. At the backtable, the splenic artery and vein are identified, ligated, and cut near their origin. The pancreas is divided laterally from the portal vein and the remnant parenchyma is oversewn. The bile duct is left intact [38]. However, since the removal of the body and tail of the pancreas is still time-­consuming and conveys a risk of pancreatitis and pancreatic leakage or vascular injury, the team of Tzakis et al. proposed simply the technique by including the entire pancreas in cLITx [40, 42, 43]. With this technique, only the spleen needs to be removed at the backtable, unless it is to be transplanted which remains a point of controversy. Using this technique, it should be noted that recipients have two pancreata, the transplanted one and the native one. In our experience, the presence of a “second” pancreas provides these patients with additional β-cell mass and hence better protection against posttransplant diabetes, a frequent complication after ITx because of highdose steroids and Tacrolimus® that are generally used. For gastrointestinal reconstruction, a proximal duodenoduodenostomy or duodenojejunostomy is performed. In addition, a gastrojejunostomy can also be created to facilitate gastric emptying. Distally, depending upon the length and the quality of the residual intestine, an ileoileostomy, ileocolostomy, terminal ileostomy, and/or terminal colostomy can be created. Although a loop- or Bishop-Koop ileostomy is frequently used, recent evidence suggests the feasibility of ITx without ostomy [44]. Fig. 36.3  Combined liver-pancreas-intestinal transplantation (figure adapted from [45] with permission)

Multivisceral Transplantation (MvTx) Indications

foregut, is anastomosed end-to-side to the donor portal vein at the posterior side of the liver hilum. A simpler and increasingly used alternative is to anastomose the native portal vein end-to-end to the donor infrahepatic caval vein. This technique requires caval preserving implantation of the bloc. The latter portocaval anastomosis is easier to perform and avoids dissection in the liver hilum of the bloc, but late stenosis of this anastomosis and secondary sectorial portal hypertension of the native foregut have been described [41]. In the technique originally described by Grant et  al., the duodenum and pancreas were removed from the liver-­intestine bloc, to avoid the theoretical risk of donor pancreatitis, rejection, or pancreatic duct fistulas [2]. The portal vein was hence skeletonized and was, along with the hepatic artery, the only structure connecting the liver and the intestine, rendering the graft vulnerable to torsion around the arterioportal axis. The pancreaticoduodenal resection done either in situ or during the bench was very tedious and time-­consuming and made all vascular structures at risk of injury. In addition, a separate hepaticojejunostomy had to be performed and had its own morbidity [38]. Therefore, the technique was adapted by the team of

Multivisceral Transplantation (MvTx) involves a complete abdominal exenteration, followed by transplantation of the liver, stomach, duodenum, pancreas, small bowel, and possibly colon. Modified MvTx (mMvTx) is similar but the liver is not replaced. The first human MvTx was performed in 1983 in a child who had developed short bowel syndrome and IFALD.  The recipient died perioperatively due to uncontrollable hemorrhage [46]. The second MvTx was done for a similar indication in 1987 and this child survived 6 months before succumbing to post-transplant lymphoproliferative disease [46]. Around the same period, two other children received an MvTx with a similar outcome [47]. Complete splanchnic mesenteric thrombosis has now become a more frequent indication for MvTx [48]. Other indications are desmoid tumors, familial adenomatous polyposis (Gardner’s syndrome), intestinal failure associated with IFALD, necrotizing pancreatitis, frozen abdomen, and other diffuse abdominal diseases not treatable by any other means [49].

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Patients with intestinal pseudo-obstruction and severe gastroparesis or with other diffuse gastrointestinal diseases but preserved liver function are potential candidates for mMvTx [50, 51]. Albeit the primary indication for these procedures is not diabetes, the inclusion of the entire pancreas in an (m)MvTx re-establishes normal glucose metabolism in those with various degrees of diabetes pretransplant [52].

Global Experience (Table 36.1) (m)MvTx is a relatively rare procedure [39]. According to the ITR, 810 MvTx and 200 mMvTx were done between 1985 and May 2019, accounting for 20% and 5% of all ITx, respectively [36].

Procurement Procurement is largely similar to the one described above for cLITx. The only difference is that there is even less ­dissection, the stomach being preserved, and the gastrointestinal tract transected at the esophagogastric junction.

Recipient Procedure (Figs. 36.4, 36.5, 36.6 and 36.7) MvTx is conducted in two steps: splanchnic exenteration first and transplantation per se next. Splanchnic exenteration consists of the removal of all affected intraperitoneal organs.

Fig. 36.5  Multivisceral transplantation: status after total exenteration (left) and reperfusion of the multivisceral graft (right) (a: cranial; b: caudal; 1  =  suprahepatic caval vein cuff; 2  =  infrahepatic caval vein

Fig. 36.4 Multivisceral transplantation (adapted from [45] with permission)

cuff; * = distal native sigmoid; # = aortic tube anastomosed to infrarenal aorta) (photo from own experience)

36  Pancreas-Multivisceral Transplantation

Fig. 36.6  Modified multivisceral transplantation without preservation of the native pancreaticoduodenal complex (adapted from [45] with permission)

In MvTx for extensive splanchnic thrombosis, we and others have shown that preoperative embolization of the native celiac trunk and the superior mesenteric artery substantially decreases blood loss during the exenteration [53–55]. After the exenteration, the implantation of the bloc takes place in a similar manner to that described for cLITx, with caval replacement or caval preserving technique and arterial inflow by an aortic conduit [39]. Unlike in cLITx, there is no native portal vein left to be anastomosed to the graft portal vein. Only two (caval preserving) or three (caval replacement) vascular anastomoses are required. In case of mMvTx, the native liver is preserved, with or without the pancreaticoduodenal complex [50, 51]. The hepatic artery, including possible aberrant right and left variants, is carefully preserved. If the pancreaticoduodenal complex has to

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Fig. 36.7  Modified multivisceral transplantation with preservation of the native pancreaticoduodenal complex (adapted from [45] with permission)

be removed, the common bile duct is ligated, as well as the gastroduodenal artery, the pancreaticoduodenal arteries, and eventually the splenic artery. The portal vein is identified and cut at its confluence. The vascular reconstruction of a mMvTx is with an aortic conduit and a porto-portal anastomosis [39, 56]. A hepaticojejunostomy needs to be created in this setting. In both MvTx and mMvTx, the gastrointestinal continuity is restored as follows. Proximally, an esophagogastrostomy is performed, followed by a Nissen-fundoplication to prevent reflux and protect the anastomosis. A gastrogastrostomy with preservation of the native esophagogastric junction is another possibility, if the native gastric cuff is kept well vascularized [39]. A pyloroplasty is necessary since interruption of the vagal innervation would otherwise cause poor gastric emptying. The distal intestinal anastomosis is constructed in a manner similar to cLITx.

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Combined Pancreas-Intestinal Transplantation (cPITx) Indications ITx is indicated in patients with irreversible IF, who are parenteral nutrition-dependent and who fulfill at least one of the following criteria: impending vascular access loss, ≥ 2 episodes/year of central line-associated systemic sepsis, or impending/overt liver failure [3]. In the latter circumstances, a cLITx is required. When candidates for isolated ITx simultaneously suffer from endocrine/exocrine pancreatic insufficiency, or recurrent/chronic pancreatitis, a pancreas could be simultaneously transplanted with the intestine. Additionally, and for technical reasons, we advocate adding the pancreas to isolated intestinal grafts. The procurement and the implantation of the pancreas–intestinal bloc are greatly facilitated. No separate resection of the pancreas is necessary and hence, cold ischemia time is decreased [33]. There is also less risk of vascular complications compared with an isolated intestinal graft with a short and sometimes fragile vascular pedicle. In addition, and as discussed above for cLITx, an additional transplanted pancreas graft provides supplementary β-cell mass that can protect the recipient against posttransplant diabetes which is frequent in this patient population. Given the relatively short waitlist for pancreas transplantation, and even more for ITx, we believe that using both the intestine and the pancreas in ITx recipients alone is justified.

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consists of the portal vein and an aortic patch encompassing the celiac trunk and the superior mesenteric artery [33].

Recipient Procedure (Fig. 36.8) During the recipient procedure, the affected bowel is removed first, as well as the pancreas in recurrent/chronic pancreatitis patients. The infrarenal aorta and the inferior caval vein are freed. The bloc is implanted with anastomoses of the aortic patch to the recipient aorta and the graft portal vein to the vena cava, possibly using an extension donor iliac vein graft. With this technique, the bloc is solidly anchored and the risk of vascular complications (thrombosis, torsion, or kinking of the intestinal pedicle) is reduced. This -compared to isolated ITx- offers a real

Global Experience (Table 36.1) cPITx is not registered as a separate subtype in data charts. Therefore, the exact frequency of this transplant subtype is unknown. At our center, cPITx was performed twice and surgery was uneventful. The first patient had a multiresistant CMV-enteritis following rejection and the pancreas-intestine bloc had to be removed 11 months posttransplant. The second patient lost her graft due to intractable severe acute rejection 6 weeks posttransplant.

Procurement Procurement of the pancreas–intestinal bloc is straightforward and in fact identical to that of a pancreas alone, the only difference being that the intestine and its mesentery are left attached to the pancreas. The vascular pedicle of the bloc

Fig. 36.8 Combined pancreas–intestinal transplantation (adapted from [45] with permission)

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advantage, particularly in surgical high-risk recipients. Gastrointestinal anastomoses proceed as for other types of ITx.

Pancreas Graft-Related Complications Inclusion of the pancreas in a multivisceral graft has historically been avoided in fear of graft pancreatitis, fistulas, and rejection [49]. We and others have reported graft pancreatitis, when only the head and body of the pancreas were transplanted, and this has led to total pancreas graft inclusion, as proposed by the Miami team [43]. With the latter technique, isolated pancreatic complications have been rarely observed [49, 52, 57]. To our knowledge, isolated acute or chronic rejection of the pancreas component of a multivisceral graft has not been reported to date [39, 40, 49, 58]. In our own experience with two cases of cPITx, the pancreas had no signs of rejection whereas acute rejection was present in the intestinal component only. Chronic rejection of the pancreas in a multivisceral graft has been reported, but it was concomitant with chronic rejection of the other transplanted organs [59]. There might be immunological protection against rejection by transplanting the liver with the pancreas, since the liver is known to protect other simultaneously transplanted organs [60]. This protection might be favored when the pancreas is transplanted en-bloc with the liver, allowing transplant antigens to pass through the liver [60, 61]. Pancreas graft survival is actually superior when simultaneously transplanted with another organ (usually the kidney), that acts as surrogates for rejection [49, 62–65]. Acknowledgments  We are grateful to the contributors of the databases of the Organ Procurement and Transplantation Network, the International Intestinal Transplant Registry and Eurotransplant. L.J.C. holds a named chair at the KU Leuven of Medtronic. J.P. holds a named chair at the KU Leuven of the Centrale Afdeling Voor Fractionering (CAF) and a named chair at the KU Leuven of the Institute Georges Lopez (IGL).

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475 4. Gruessner AC, Sutherland DER. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant. 2005;19(4):433–55. 5. Shields PL, Tang H, Neuberger JM, Gunson BK, McMaster P, Pirenne J. Poor outcome in patients with diabetes mellitus undergoing liver transplantation. Transplantation. 1999;68(4):530–5. 6. Yoo HY, Thuluvath PJ.  The effect of insulin-dependent diabetes mellitus on outcome of liver transplantation. Transplantation. 2002;74(7):1007–12. 7. Harary AM, Abu-Elmagd K, Thai N, Shapiro R, Todo S, Fung JJ, et al. World’s longest surviving liver-pancreas recipient. Liver Transpl. 2007;13(7):957–60. 8. Stern R, Mayes J, Weber F, Blades E, Schulak J. Restoration of exocrine pancreatic function following pancreas-liver-kidney transplantation in a cystic fibrosis patient. Clin Transplant. 1994;8(1):1–4. 9. Fridell JA, Vianna R, Kwo PY, Howenstine M, Sannuti A, Molleston JP, et al. Simultaneous liver and pancreas transplantation in patients with cystic fibrosis. Transplant Proc. 2005;37(8):3567–9. 10. Mekeel KL, Langham MR, Gonzalez-Perralta R, Reed A, Hemming AW. Combined en bloc liver pancreas transplantation for children with CF. Liver Transpl. 2007;13(3):406–9. 11. Henn C, Kapellen T, Prenzel F, Siekmeyer M, Hau H-M, Kiess W, et al. Combined heterotopic liver-pancreas transplantation as a curative treatment for liver cirrhosis and diabetes mellitus in cystic fibrosis. Pediatr Transplant. 2014;18(1):E6–9. 12. Usatin DJ, Perito ER, Posselt AM, Rosenthal P. Under utilization of pancreas transplants in cystic fibrosis recipients in the United Network Organ Sharing (UNOS) data 1987-2014. Am J Transplant. 2016;16(5):1620–5. 13. Starzl TE, Todo S, Tzakis A, Podesta L, Mieles L, Demetris A, et al. Abdominal organ cluster transplantation for the treatment of upper abdominal malignancies. Ann Surg. 1989;210(3):374–86. 14. Alessiani M, Tzakis A, Todo S, Demetris AJ, Fung JJ, Starzl TE. Assessment of five-year experience with abdominal organ cluster transplantation. J Am Coll Surg. 1995;180(1):1–9. 15. Fridell JA, Vianna R, Mangus RS, Kazimi M, Hollinger E, Joseph TA.  Addition of a total pancreatectomy and pancreas transplantation in a liver transplant recipient with intraductal papillary mucinous neoplasm of the pancreas. Clin Transplant. 2008;22(5):681–4. 16. Johnston TD, Ranjan D. Transplantation of the liver combined with other organs. Hepatogastroenterology. 1998;45(23):1387–90. 17. Health Resources and Services Administration—U.S. Department of Health & Human Services. Organ procurement and transplantation network: data reports. 2020. [cited 2020 Aug 1]. https://optn. transplant.hrsa.gov/data/view-­data-­reports/build-­advanced/. 18. Eurotransplant International Foundation. Eurotransplant statistics report library. 2020. [cited 2020 Aug 1]. https:// statistics.eurotransplant.org/index.php?search_type=&search_ organ=pancreas&search_region=All+ET&search_ period=&search_characteristic=&search_text=&search_collection=. 19. Pirenne J, Deloose K, Coosemans W, Aerts R, Van Gelder F, Kuypers D, et al. Combined “en bloc” liver and pancreas transplantation in patients with liver disease and type 1 diabetes mellitus. Am J Transplant. 2004;4(11):1921–7. 20. Trotter JF, Bak TE, Wachs ME, Everson GT, Kam I. Combined liver-­ pancreas transplantation in a patient with primary sclerosing cholangitis and insulin-dependent diabetes mellitus. Transplantation. 2000;70(10):1469–71.

476 21. Sollinger HW, Odorico JS, Knechtle SJ, D’Alessandro AM, Kalayoglu M, Pirsch JD.  Experience with 500 simultaneous pancreas-­kidney transplants. Ann Surg. 1998;228(3):284–96. 22. Kornberg A, Küpper B, Bärthel E, Tannapfel A, Müller UA, Thrum K, et al. Combined en-bloc liver-pancreas transplantation in patients with liver cirrhosis and insulin-dependent type 2 diabetes mellitus. Transplantation. 2009;87(4):542–5. 23. Starzl TE, Francavilla A, Halgrimson CG, Francavilla FR, Porter KA, Brown TH, et al. The origin, hormonal nature, and action of hepatotrophic substances in portal venous blood. Surg Gynecol Obstet. 1973;137(2):179–99. 24. Starzl TE, Porter KA, Kashiwagi N. Portal hepatotrophic factors, diabetes mellitus and acute liver atrophy, hypertrophy and regeneration. Surg Gynecol Obstet. 1975;141(6):843–58. 25. Starzl T, Porter K, Watanabe K, Putnam C.  Effects of insulin, glucagon and insulin/glucagon infusions on liver morphology and cell division after complete portacaval shunt in dogs. Lancet. 1976;307(7964):821–5. 26. Deylgat B, Topal H, Meurisse N, Jochmans I, Aerts R, Vanbeckevoort D, et al. Gastric outlet obstruction by a donor aortic tube after en bloc liver pancreas transplantation: a case report. Transplant Proc. 2012;44(9):2888–92. 27. Amesur NB, Zajko AB, Costa G, Abu-Elmagd KM.  Combined surgical and interventional radiologic management strategies in patients with arterial pseudo-aneurysms after multivisceral transplantation. Transplantation. 2014;97(2):235–44. 28. Grant D, Abu-Elmagd K, Mazariegos G, Vianna R, Langnas A, Mangus R, et al. Intestinal transplant registry report: global activity and trends. Am J Transplant. 2015;15(1):210–9. 29. Smith JM, Weaver T, Skeans MA, Horslen SP, Noreen SM, Snyder JJ, et  al. OPTN/SRTR 2017 annual data report: intestine. Am J Transplant. 2019;19(S2):284–322. 30. Kaufman SS, Avitzur Y, Beath SV, Ceulemans LJ, Gondolesi GE, Mazariegos GV, et al. New insights into the indications for intestinal transplantation: consensus in the year 2019. Transplantation. 2020;104(5):937–46. 31. Lauro A, Oltean M, Marino IR.  Chronic rejection after intestinal transplant: where are we in order to avert it? Dig Dis Sci. 2018;63(3):551–62. 32. Lauro A, Marino IR.  Update on chronic rejection after intestinal transplant: an overview from experimental settings to clinical outcomes. Exp Clin Transplant. 2019;17(Suppl 1):18–30. 33. Clarysse M, Canovai E, Vanuytsel T, Pirenne J.  Current state of adult intestinal transplantation in Europe. Curr Opin Organ Transplant. 2020;25(2):176–82. 34. Tzakis AG, Nery JR, Raskin JB, Weppler D, Khan MF, Fragulidis GP, et al. “Domino” liver transplantation combined with multivisceral transplantation. Arch Surg. 1997;132(10):1145–7. 35. Sudan D.  The current state of intestine transplantation: indications, techniques, outcomes and challenges. Am J Transplant. 2014;14(9):1976–84. 36. Terasaki. Overall ITR report. 2019. http://graphics.tts.org/ ITR_2019_ReportSlides.pdf. 37. Braun F, Broering D, Faendrich F. Small intestine transplantation today. Langenbecks Arch Surg. 2007;392(3):227–38. 38. Sudan DL, Iyer KR, Deroover A, Chinnakotla S, Fox IJ, Shaw BW, et al. A new technique for combined liver/small intestinal transplantation. Transplantation. 2001;72(11):1846–8. 39. Tzakis AG, Kato T, Levi DM, Defaria W, Selvaggi G, Weppler D, et  al. 100 multivisceral transplants at a single center. Ann Surg. 2005;242(4):480–90. 40. Kato T, Romero R, Verzaro R, Misiakos E, Khan FA, Pinna AD, et al. Inclusion of entire pancreas in the composite liver and intestinal graft in pediatric intestinal transplantation. Pediatr Transplant. 1999;3(3):210–4.

M. Clarysse et al. 41. Monbaliu D, Vandersmissen J, De Hertogh G, Van Assche G, Hoffman I, Knops N, et al. Portal hypertension after combined liver and intestinal transplantation, a diagnostic and therapeutic challenge? Pediatr Transplant. 2012;16(7):E301–5. 42. Troppmann C, Pirenne J, Perez RV, Gruessner RWG.  The unrecognized posterior gastric artery: a potential cause of surgical complications in pancreas transplantation. Clin Transplant. 2004;18(2):214–8. 43. Pirenne J, Coosemans W, Aerts R, Monbaliu D, Van Steenbergen W, Koshiba T. Transplant pancreatitis after liver plus bowel transplantation. Transplant Proc. 2002;34(3):885–6. 44. Moon JI, Zhang H, Waldron L, Iyer KR. “Stoma or no stoma”: first report of intestinal transplantation without stoma. Am J Transplant. 2020;00:1–8. 45. Morsi M, Ciancio G, Gonzalez J, Farag A, Vianna R. Pancreas transplantation in the setting of multivisceral transplantation. In: Orlando G, Piemonti L, Ricordi C, Stratta RJ, Gruessner Bioengineering, Regeneration of the Endocrine Pancreas RWGBT-T, editors. Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas. 1st ed. London: Elsevier; 2020. p. 179–93. 46. Starzl TE, Rowe MI, Todo S, Jaffe R, Tzakis A, Hoffman AL, et  al. Transplantation of multiple abdominal viscera. JAMA. 1989;261(10):1449–57. 47. Williams JW, Sankary HN, Foster PF, Lowe J, Goldman GM. Splanchnic transplantation. JAMA. 1989;261(10):1458–62. 48. Vianna RM, Mangus RS, Kubal C, Fridell JA, Beduschi T, Tector AJ.  Multivisceral transplantation for diffuse portomesenteric thrombosis. Ann Surg. 2012;255(6):1144–50. 49. Vianna R, Fridell JA, Mangus R, Hollinger EF, Matiosky A, Tector AJ.  Safe inclusion of the entire pancreas as a component of the multivisceral graft. Transplantation. 2008;86(1):114–6. 50. Cruz RJ, Costa G, Bond G, Soltys K, Stein WC, Wu G, et  al. Modified “liver-sparing” multivisceral transplant with preserved native spleen, pancreas, and duodenum: technique and long-term outcome. J Gastrointest Surg. 2010;14(11):1709–21. 51. Cruz RJ, Costa G, Bond GJ, Soltys K, Rubin E, Humar A, et  al. Modified multivisceral transplantation with spleen-preserving pancreaticoduodenectomy for patients with familial adenomatous polyposis “gardnerʼs syndrome”. Transplantation. 2011;91(12):1417–23. 52. Beduschi T, Farag A, Gaynor JJ, Selvaggi G, Tekin A, Garcia J, et al. Inclusion of the pancreas as a part of the multivisceral allografts: a single center experience. Transplantation. 2019;103(7):S124. 53. Ceulemans L, Jochmans I, Monbaliu D, Verhaegen M, Laleman W, Nevens F, et  al. Preoperative arterial embolization facilitates multivisceral transplantation for portomesenteric thrombosis. Am J Transplant. 2015;15(11):2963–9. 54. Butler A, Russell N, Amin I, Cee T. Use of arterial embolisation to facilitate exenteration during multivisceral and small bowel transplantation. Transplantation. 2017;101(6S2):S25. 55. Nicolau-Raducu R, Livingstone J, Salsamendi J, Beduschi T, Vianna R, Tekin A, et  al. Visceral arterial embolization prior to multivisceral transplantation in recipient with cirrhosis, extensive portomesenteric thrombosis, and hostile abdomen: performance and outcome analysis. Clin Transplant. 2019;33(8):e13645. 56. Hashimoto K, Costa G, Khanna A, Fujiki M, Quintini C, Abu-­ Elmagd K.  Recent advances in intestinal and multivisceral transplantation. Adv Surg. 2015;49(1):31–63. 57. Nawaz H, Slivka A, Papachristou GI.  Recurrent acute pancreatitis secondary to graft pancreas divisum in a patient with modified multi-visceral transplant. ACG Case Rep J. 2014;1(2):103–5. 58. Takahashi H, Selvaggi G, Nishida S, Weppler D, Levi D, Kato T, et  al. Organ-specific differences in acute rejection intensity in a multivisceral transplant. Transplantation. 2006;81(2):297–9.

36  Pancreas-Multivisceral Transplantation 59. Takahashi H, Delacruz V, Sarwar S, Selvaggi G, Moon J, Nishida S, et al. Contemporaneous chronic rejection of multiple allografts with principal pancreatic involvement in modified multivisceral transplantation. Pediatr Transplant. 2007;11(4):448–52. 60. Wang C, Sun J, Wang L, Li L, Horvat M, Sheil R. Combined liver and pancreas transplantation induces pancreas allograft tolerance. Transplant Proc. 1997;29(1–2):1145–6. 61. Wang C, Sun J, Li L, Wang L, Dolan P, Sheil AG. Conversion of pancreas allograft rejection to acceptance by liver transplantation. Transplantation. 1998;65(2):188–92. 62. Weiss AS, Smits G, Wiseman AC.  Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation. Clin J Am Soc Nephrol. 2009;4(5):988–95.

477 63. Öllinger R, Margreiter C, Bösmüller C, Weissenbacher A, Frank F, Schneeberger S, et al. Evolution of pancreas transplantation. Ann Surg. 2012;256(5):780–7. 64. Montiel-Casado MC, Pérez-Daga JA, Aranda-Narváez JM, Fernández-Burgos I, Sánchez-Pérez B, León-Díaz FJ, et  al. Pancreas graft survival in simultaneous pancreas-kidney versus pancreas-after-kidney and pancreas alone transplantations: a single institution experience. Transplant Proc. 2013;45(10):3609–11. 65. Barlow AD, Saeb-Parsy K, Watson CJE.  An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: a UK transplant registry study. Transpl Int. 2017;30(9):884–92.

Part IV Living Donor Pancreas Transplantation

Living Donor Work-Up

37

Rainer W.G. Gruessner and Elizabeth R. Seaquist

Contents Introduction 

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Metabolic Testing of Potential Donors 

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Metabolic Selection Criteria for Donors 

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Outcome Studies 

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Revised Metabolic Criteria 

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Other Donor Work-Up Considerations 

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References 

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Introduction The principles for evaluating and accepting a potential pancreas donor are not different than for other solid-organ transplants. The potential donor must understand the nature of the procedure and the risks to his or her health, must not be coerced, must provide voluntary consent, must be mentally competent, and must be of legal age (see also Chap. 38). All potential donors must undergo a thorough medical and psychosocial evaluation. Initial screening usually rules out volunteers with major health problems, e.g., current or previous disorders of the pancreas, active infections or malignancies, major personality disorders, and drug or alcohol dependence. Single parents of minor children are also not considered donor candidates. The social and psychological evaluations assess the donor’s voluntarism and altruism as well as the dynamics of the donor-recipient relationship.

R. W.G. Gruessner (*) Department of Surgery, State University of New York (SUNY), Downstate Health Sciences University, Brooklyn, NY, USA e-mail: [email protected] E. R. Seaquist Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota Medical School, Minneapolis, MN, USA e-mail: [email protected]

The medical evaluation of potential pancreas donors includes both pancreas-nonspecific and -specific tests. The former is the same as for kidney donation. They include the following: ABO blood typing and tissue typing; leukocyte crossmatch and PRA tests; electrocardiogram and chest radiograph; biochemistry profile (e.g., electrolytes, serum creatinine and clearance, blood urea nitrogen, uric acid, serum protein, and albumin); liver function tests as well as serum amylase and lipase; lipid profile (fasting cholesterol, triglyceride, and high-density lipoprotein [HDL] levels); complete blood count; coagulation profile international normalized ratio (INR), partial thromboplastin time (PTT); hepatitis A, B, and C tests; cytomegalovirus (CMV), human immunodeficiency virus (HIV), Covid-19, and rapid plasma reagin (RPR) testing; urine analysis and urine culture; in women ≤55  years old, serum pregnancy test; in women ≥40 years old, mammogram and Pap smear; in all women, pelvic and breast examination; and, in men >50  years old, prostate-specific antigen (PSA) test. In addition, all potential donors must undergo a history and physical examination; SPK donors must also undergo serial blood pressure measurements [1]. Additional testing for blood-incompatible pancreas transplants from living donors is detailed in Chaps. 39 and 53. Apart from the general medical work-up, potential pancreas donors must also fulfill certain criteria and undergo

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. W.G. Gruessner, A. C. Gruessner (eds.), Transplantation of the Pancreas, https://doi.org/10.1007/978-3-031-20999-4_37

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initial evaluation specific to their pancreatic endocrine function as it may relate to post-donation development of diabetes mellitus. Related donors must be at least 10 years older than the age at which the intended recipient was diagnosed with diabetes mellitus: It has been shown that if diabetes is going to develop in a sibling or any other family member who is HLA-identical or matched at the HLA-DR3 or DR4 locus with the recipient, it does so within 10  years of the onset of diabetes in the recipient [2]. Yet, the “10-year rule” does not provide absolute donor safety. A study in 156 multiple-­ case families (identified from the Children’s Hospital of Pittsburgh IDDM Registry for 1950 through 1981) found that 11% of siblings did develop diabetes more than 10 years after the onset of diabetes in the index case [3]. Another requirement for sibling donors is that no siblings or family members other than the recipient can be diabetic. Potential donors with a history of gestational diabetes are also excluded. To minimize the risk of selecting individuals at risk for type 2 diabetes, those with historical evidence of insulin resistance are also excluded. Such individuals include those with hypertension and symptoms compatible with polycystic ovarian syndrome. When these criteria are met, donors have not been at greater risk to develop type 1 diabetes mellitus than the general population [4, 5].

R. W.G. Gruessner and E. R. Seaquist

The crucial part of the donor evaluation is the metabolic assessment. From the outset, it must be emphasized that even with sophisticated metabolic testing, it is impossible to determine with absolute certainty whether or not a potential donor will retain normal glucose tolerance after surgery.

Metabolic Testing of Potential Donors The metabolic testing (Table 37.1) performed in the evaluation process of potential pancreas donors includes a standard oral glucose tolerance test, hemoglobin A1c, and measurement of antibodies associated with type 1 diabetes [6]. In addition, a comprehensive insulin secretory test is done in the fasting state. In this test, both arginine- and glucose-­ induced insulin secretion are measured under basal conditions. Functional beta cell reserve is then measured by the glucose potentiation of arginine-induced insulin secretion test (GPAIS) in which the arginine stimulation test is repeated after glucose has been administered intravenously at a rate of 900 mg/min for 60 min. A normal response should be greater than 300% of the basal. Donor candidates with a secretory response less than 300% of basal are informed that their risk of developing diabetes after hemipancreatectomy is too high.

Table 37.1  Metabolic testing for living donor pancreas candidates [6] 1. Fasting glucose level (post 10- to 16-h fast) 2. Hemoglobin A1c level 3. Oral glucose tolerance test (OGTT): A >150 g carbohydrate diet is given for 3 days prior to the test and usual physical activity. After a 10- to 16-h fast (water is permitted, smoking is not), a 75-g oral glucose load in 250–300 mL of water is given over 10 min. The end of the drinking time is time 0. Measurement of glucose and insulin is performed at the following intervals: −10, −5, 0, 15, 30, 60, 90, 120, 150, 180, 240, and 300 min. 4. Arginine stimulation test (AST): A >150 g carbohydrate diet is given for 3 days prior to the test and usual physical activity. After a 10- to 16-h fasting period (water is permitted, smoking is not), the test is commenced between 0730 and 1000 h, 5 g of arginine (arginine HC1 10%) via IV push is given over 30 s. Time 0 is at the end of the bolus. Measurement of glucose, insulin, glucagon, and C-peptide is performed at the following intervals: −10, −5, 0, 2, 3, 4, 5, 7, 10, 25, and 30 min. AIR to arginine is defined as the mean of the peak three insulin values between 2 and 5 min following the arginine injection with the basal value subtracted. 5. Intravenous glucose tolerance test (IVGTT): 35 min after the arginine injection, 0.3–0.5 mg/kg glucose is given IV over 30 s. The end of the infusion is time 0. Glucose, insulin, glucagon, and C-peptide are measured at the following intervals: −5, 0, 1, 3, 4, 5, 10, 15, 20, 25, and 30 min. Acute insulin response (AIR) to glucose is defined as the mean of the 3-, 4-, and 5-min insulin values following the glucose injection with the basal value subtracted. Glucose disposal rate (kg) is defined as the slope of the natural log of glucose values between 10 and 30 min after injection. First-phase insulin release (FPIR) is defined as the sum of insulin levels at 1 and 3 min. 6. Glucose potentiation of arginine-induced insulin secretion (GPAIS): 145 min after the last blood draw in the above test, a glucose infusion (D20W) at 900 mg/min is started through an IV pump. The infusion is maintained for 70 min. At minute 60, 5 g of arginine (10% arginine HCL) IV is given over 30 s. The end of the bolus is time 0. Measurement of glucose, insulin, glucagon, and C-peptide is performed at the following intervals: −10, 0, 2, 3, 4, 5, 7, and 10 min. Acute insulin response at 900 mg/min glucose potentiation (AIR-900) is defined as the mean of the three peak insulin values between 2 and 5 min with the basal value subtracted. 7. Insulin autoantibodies (IAAS): Measured by fluid-phase radioassay incorporating competition with cold insulin and precipitation with polyethylene glycol. 8. GAD 65 autoantibodies (GAAS): Measured in triplicate by radio-assay, using in vitro transcribed and translated recombinant human GAD (65-kDa isoform) and precipitation with protein A-sepharose. 9. Islet cell antigen 512 autoantibodies (IC512): ICA512 is measured by radio immunoassay in duplicate using a 96-well plate format with a recombinant ICA512 protein.

37  Living Donor Work-Up

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Table 37.2  1996 Exclusion criteria for living donors at the University of Minnesota [6] Historical and clinical criteria 1. History of type 2 diabetes in any first-degree relative (parent, sibling, child) 2. Personal history of gestational diabetes 3. Additional first-degree relative with type 1 diabetes (other than the proposed recipient) 4. Body mass index greater than 27 kg/m2 5. Age greater than 50 years 6. Age of the donor within 10 years of the age at which type 1 diabetes was diagnosed in the proposed recipient 7. Clinical evidence of diseases associated with insulin resistance (e.g., polycystic ovarian syndrome, hypertension) 8. Personal history of an autoimmune endocrine disorder involving the thyroid, adrenal, pituitary, gonads 9. History of or active diseases of the exocrine pancreas (e.g., active or chronic pancreatitis) 10. Active or uncontrolled psychiatric disorders 11. Heavy smoking, alcoholism, or excessive alcohol use 12. Hypertension, cardiac disease 13. Active infections or malignant disorders Metabolic criteria 1. Any glucose value above 150 mg/dL during standard oral glucose tolerance tests 2. Hemoglobin A1c greater than 6% 3. Glucose disposal rate calculated from data collected during intravenous glucose tolerance tests less than 1.0% 4. Presence of elevated titer of islet cell autoantibodies or anti-GAD antibodies 5. Acute insulin response to intravenous glucose or intravenous arginine of less than 300% of basal 6. Glucose potentiation of arginine-induced insulin secretion of less than 300% of basal

Metabolic Selection Criteria for Donors Based on comprehensive metabolic testing of donor candidates, strict endocrinological criteria were developed in 1996 at the University of Minnesota for the selection of living donors in an effort to reduce the rate of post-donation ­diabetes (Table 37.2). These criteria recognized the importance of both personal and family history of endocrine disease in establishing risk and the role of obesity and other conditions associated with insulin resistance in unmasking beta cell dysfunction after donation. After these criteria were established, it was recommended that potential donors with any of the exclusion criteria be excluded from donating because of the increased risk of developing diabetes after donation. In addition, potential donors with metabolic abnormalities uncovered during preoperative testing were excluded because of uncertainty over whether their hemipancreas would provide an adequate function for the recipient. These exclusion criteria were initially helpful as early outcome studies showed.

Table 37.3  Metabolic effects of hemipancreas donationa [6] Fasting glucose

Before donation One year after donation

Fasting insulin

Blood glucose 2

(mg/dL) 88 ± 7

(μU/mL) 6.4 ± 4

Hours after oral glucose load 117 ± 18

Percentage with Abnormal response on oral glucose tolerance test 0

97 ± 16*

5.5 ± 4**

156 ± 53***

25%

 [4] *p 15% (= [postdonation BMI  −  predonation BMI]/predonation BMI × 100) over the observation period was a significant RF for the development of diabetes post-donation. The relative risk for the development of diabetes post-­ donation associated with predonation FPG of 100 mg/dL or greater, basal insulin of 9 μU/mL or greater, OGTT 2 h of 120 mg/dL or greater, and postdonation ΔBMI greater than 15%, ranged between 4.6 and 6 with a high specificity (0.82– 1), but a low sensitivity. Using these risk factors, the authors created a risk stratification model (RSM) to predict the risk for the development of postdonation diabetes among potential donors as well as for predonation counseling on postdonation risk modification (Table 37.4).

37  Living Donor Work-Up

485

Table 37.4  RSM for prediction of postdonation diabetes [12] Risk factors FPG ≥100 mg/dL (n = 4) FPG 6% 10. Glucose disposal rate 20 years [60, 61]. On 22 January 1991, the first pancreas transplant from a living donor (brother) with portal drainage via the inferior mesenteric vein and enteric drainage was performed in a PTA recipient [59, 61, 62]. On 7 July 1992, the first living donor pancreas with exocrine drainage via the native ureter was done [59, 61, 62]. The latter was also the first genetically unrelated living donor (wife) pancreas transplant which was followed by the first non-spouse genetically unrelated (friend) living donor pancreas transplant on 16 October 1998 (which also happened to be the first ABO-incompatible living donor pancreas transplant (AB to B) (see Chap. 53) [20, 59, 61, 62]. The first pancreas transplant (PTA with enteric drainage) from a living donor outside of the US and Europe was from Asia at Hallym University Medical Center in Seoul, Korea, on 12 May 1987. The first pancreas transplant (duct-injected, same donor PAK) from the Middle East was performed at the University of Kuwait on 15 October 1989 [63]. Some additional pancreas transplants from living donors, such as a large series from Russia including 13 PTAs-and 2 SPKs (see

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R. W.G. Gruessner and A. C. Gruessner

Fig. 38.5  Title page of first report on simultaneous pancreas and kidney transplants from living donors (from reference [57] by permission of author)

Chap. 91) may have gone unnoticed because they were neither reported to the IPTR nor published in the accessible literature. By early 1994, only one unsuccessful attempt at an SPK transplant from a living donor had been made because of concern of the magnitude of the procedure and the associated donor risk. Almost 25  years after the first solitary living donor transplant pancreas transplant and much preparation, the first combined pancreas and kidney (SPK) transplant from a living donor (mother) was successfully performed at the University of Minnesota on March 10, 1994 (Fig. 38.5); both pancreas and kidney functioned >10  years [57, 59]. This transplant was also the first dual solid organ transplant

of any type from a living donor. The successful outcome of this case provided the basis for other firsts in short sequence: the first SPK from a living donor (mother) to a pediatric (14-­ years old) recipient (15 August 1995); and the first offspring (daughter)-to-parent (mother) SPK transplant from a living donor [20, 59, 64]. After gaining technical experience in open pancreas and kidney procurements from living donors, meticulous arrangements for the first laparoscopic living donor procurement were made at the University of Minnesota. The first successful living donor nephrectomy had been reported by Ratner et al. in 1995 and was widely embraced by the the transplant community in the late 1990s [65].

38  The United States Experience

On 22 November 2000, the first laparoscopic (hand-­ assisted) combined distal pancreatectomy and nephrectomy for a bladder-drained SPK transplant was performed at the University of Minnesota; both grafts are still functioning >19 years (Chap. 16; Fig. 16.3) [66]. The distal pancreas was the first extra-renal solid organ that was successfully procured using the minimally invasive technique [66, 67]. It took almost another 2 years until the first successful laparoscopic removal of the lateral segments for liver transplantation in children was reported [68]. The largest series of living pancreas transplants in the United States outside of the University of Minnesota is the University of Illinois experience. Horgan et  al. and Oberholzer et al. from that group reported the first combined distal pancreatectomy and nephrectomy from 1 donor using the robotic technique in 2010; a successful transplant between identical twins; and a successful living donor ABO-­ incompatible SPK transplant by antibody reduction protocols [69, 70]. Until the beginning of the new millennium, pancreas transplants from living donors had been done predominantly at the University of Minnesota. However, over the past 2 decades, the proportion of living donor pancreas transplants at the University of Minnesota has markedly decreased primarily because the results with deceased donor pancreas transplants have significantly improved and changes in the US organ allocation system have proven favourable to diabetic transplant candidates with increased access to deceased donor pancreas grafts.

 ationale for Living Donor Pancreas R Transplants The rationale for pancreas transplants using living donors has shifted over time. Initially, in the azathioprine (AZA) and early cyclosporin A (CSA) eras, living donors were used because of better graft survival (as compared with deceased donors). In the University of Minnesota series, the 5-year graft survival rate for technically successful pancreas after kidney (PAK) transplants between 1 January 1979, and 31 March 1994 (AZA and CSA eras), was 67% with living donors vs 26% with deceased donors; for technically successful pancreas transplants alone (PTA), 47% with living donors vs. 27% with deceased donors. Better graft outcome with living donors was mainly due to the significantly lower rate of graft loss from rejection: At 5 years, 49% of PAK and PTA recipients with living donors lost their graft from rejection vs. 67% of PAK and PTA recipients with deceased donors [71, 72]. But, the immunologic advantage was offset, in part, by a higher technical failure rate. In contrast to kidney transplants, the technical failure rate and the arterial or

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venous thrombosis rates were initially higher for pancreas transplants using living (vs deceased) donors. The reason is that only a segment of the pancreas is transplanted, and the vessels used for engraftment (splenic artery and vein) are small in diameter and short. Yet, the technical failure rate in the AZA and CSA eras was lower for transplants using living donors than the immunologic failure rate (i.e., graft loss from rejection) for transplants using deceased donors [71, 72]. Therefore, for technically successful pancreas transplants, the probability of long-term function in the AZA and CSA eras was significantly higher with living (vs deceased) donors. With the introduction of tacrolimus (TAC) and mycophenolate mofetil (MMF) and their combined use starting in the mid 1990s [73, 74], graft survival improved markedly for deceased donor pancreas recipients, because of a significantly lower graft loss rate from rejection: The immunologic advantage of living donor pancreas transplants in the TAC era was no longer as distinct as it had been in the AZA and CSA eras. For that reason, even though living donor pancreas transplants in the TAC era have a lower graft loss rate from vascular thrombosis (because of vigorous anticoagulation protocols), the incentive for using living donors has waned. Further, in contrast to kidney and liver transplants, a shortage of deceased donors for solitary pancreas transplants does not exist. Thus, in the TAC era, living donors for solitary pancreas transplants are now used only if the recipient (1) is highly sensitized (panel-reactive antibody [PRA] >80%) and has a low probability of receiving a deceased donor graft; (2) must avoid high-dose immunosuppression; or (3) has a nondiabetic identical twin or a 6-antigen-matched sibling. In contrast to solitary pancreas transplants (for which, there is no shortage of deceased donor organs), the demand for deceased donor kidneys is ever increasing. This created an increasingly difficult situation in the United States for uremic, diabetic (SPK) transplant candidates since UNOS allocation policies until a few years ago had given priority to the kidney (“the pancreas follows the kidney”). Therefore, waiting times for kidney transplant alone (KTA) and simultaneous pancreas-kidney (SPK) transplants using a deceased donor had markedly increased before the new pancreas and kidney allocation rules were enacted in the United States (see below). Given this high, unmet demand at the time for deceased SPK donors, several strategies (aside from being on the waiting list for deceased donor organs) were proposed for SPK candidates. The first option is a living donor for the kidney transplant, followed later by a deceased donor pancreas transplant (thus shifting emphasis from the SPK to the PAK category); that way, however, the recipient must undergo two operations, including receiving anesthesia twice. The second option is an SPK from a deceased pancreas and living kidney

494

R. W.G. Gruessner and A. C. Gruessner

donor that would achieve the one-operation goal; however, a fixed date does not guarantee that a deceased pancreas donor will be available, and an open date means the kidney donor has to be on call until a deceased donor pancreas becomes available [75, 76]. And, even though long-term kidney graft outcome is better with a living (vs. deceased) donor, long-­ term pancreas graft outcome with a deceased donor in the PAK category is still slightly less favorable than in the SPK category [77, 78]. For those two reasons—the shortage of deceased kidney donors and the less favorable long-term pancreas outcome in the PAK (vs. SPK) category—the use of living donors for SPK recipients had been advocated (third option) [57, 79]. The living donor SPK option allows the donor and recipient to undergo only one procedure each, and the recipient has the great (immunologic) benefit of receiving two living donor organs and preempt dialysis. When United Network for Organ Sharing (UNOS) allocation policies changed a few years ago (see Chap. 7), chances for SPK candidates to receive deceased organs increased (“the kidney [now] follows the pancreas”). This important change in US organ allocation policies further diminished the need for pancreas transplants from living donors.

Donor Evaluation

Donor: General Remarks

Donor Operation

There are two major objectives for living donors undergoing distal pancreatectomy: (1) avoidance of surgical complications and (2) selection of volunteers who have sufficient beta cell mass to stay non-diabetic post-donation. As shown below, no donor death has been reported so far in contrast to kidney (mortality rate: 0.03%) and liver (mortality rate: 0.3%) donation. The overall surgical complication rate has been low, and the laparoscopic approach allows rapid recovery [66, 67]. However, the metabolic effect of hemipancreatectomy is less predictable than originally anticipated [38–40, 59], but 5–15% of donors may eventually require oral hypoglycemics or insulin long-term (see Chap. 37) [80, 81]. These long-term findings are of concern despite the fact that in non-diabetic patients before undergoing distal pancreatectomy for pancreatic diseases, the post-operative rates of newly-diagnosed diabetes have been reported to be as high as 22–36% [82, 83]. One might argue that the development of diabetes in living donors after distal pancreatectomy is the result of weight gain and obesity later in life and primarily due to insulin resistance, as it is typical in type 2 diabetes. Interestingly, some of the pancreas recipients remained insulin-­independent, whereas their living donors became insulin-dependent. For that reason, Robertson et al. suggested that obesity should be a contraindication to the donation of the distal pancreas and that donors should assiduously avoid becoming obese [84].

Procurement of the distal pancreas from a living donor using open, laparoscopic or robotic techniques are described in detail in Chap. 16. The introduction of laparoscopic (hand-­ assisted) distal pancreatectomy has shortened hospitalization and recovery time, making living pancreas donation more attractive. The median duration of donor hospitalization in the United States after open distal pancreatectomy is 8 days (range, 6–24 days); after laparoscopic distal pancreatectomy, 4–6 days [66, 67, 71, 89].

The donor work-up is provided in detail in Chap. 37. Suffice it to say that the principles for accepting a potential pancreas donor are not different than for other solid-organ transplants and that potential pancreas donors, in addition, must undergo comprehensive testing specific to their pancreatic endocrine function [80, 85, 86]. If several medically and equally suitable pancreas donors are available, the final selection is based on the histocompatibility result: an HLA-identical sibling is the ideal choice (provided all other criteria for pancreas donation are met). If serologic and endocrinologie evaluation identifies several equally suitable donors, the volunteer with the least reactive mixed lymphocyte reaction (MLR) result is usually chosen. But, selection may also be determined by other factors, such as age and the donor-recipient relationship. Only a few pancreas transplants have been performed using living-unrelated donors, all between spouses. Altruistic donors have not yet been used in pancreas transplantation. ABO-incompatible and cross-match positive living donors have been successfully used [59, 61, 87, 88].

Postoperative Care The postoperative care of living pancreas donors is described in detail in Chap. 16.

Donor Outcome In contrast to living kidney or living liver donors, the mortality rate of living pancreas donors, according to the IPTR, has been 0% [29]. Pancreas donor morbidity includes both surgical and medical complications as well as adverse metabolic changes which are described in detail in Chap. 37.

38  The United States Experience

495

Surgical Complications In general, surgical complications are rare; relaparotomies are required in  30 kg/m2  4. >56 years old  5. Age of donor 1 autoimmune endocrine disorder (thyroid, adrenal, pituitary,gonads)  9. HgbA1C > 6%  10. Glucose disposal rate 120 mg/dl for 75 g OGTT  13. Basal, fasting insulin >9 U/ml (marker of insulin resistance)  14. Acute insulin response to glucose or arginine 20%) were constipation, urinary tract infection, pain, nausea, peripheral edema, hypertension, anemia, headache, and hyperkalemia. No increase in the incidence of lymphoma or cytomegalovirus was seen.

Rabbit Antithymocyte Globulin (ATG) Rabbit ATG (Thymoglobulin, Sanofi Pharmaceutical Company, Paris, France) is a purified, pasteurized, gamma immunoglobulin obtained by immunization of rabbits with human thymocytes [19]. It has potent immunosuppressive properties elicited by cytotoxic antibodies directed against antigens expressed on human T lymphocytes. Rabbit ATG is supplied as a sterile, freeze-dried product for IV administration after reconstitution with sterile water. The manufacturing of rabbit ATG involves many complicated processes, including quality assurance and control checks to ensure batch-to-batch consistency. The consistency of IgG protein is ensured by the use of standardized manufacturing and production processes. Each vial of rabbit ATG must contain 25 mg ± 20% of product. Tests are performed to assure elimination of the following undesirable antibodies: antiplatelet activity, anti-RBC activity, and antiglomerular basement membrane activity. Rabbit ATG was approved by the FDA on December 30, 1998, for the treatment of acute rejection in kidney recipients, and on April 24, 2017, for use in conjunction with concomitant immunosuppression in the prophylaxis, or prevention, of acute rejection in patients receiving a kidney transplant. Mechanism of Action. The immunosuppressive effects of rabbit ATG are induced through multiple mechanisms of action. Several possible mechanisms leading to T-cell depletion by rabbit ATG have been characterized: • • • •

Complement-dependent lysis. Opsonization and phagocytosis by macrophages. Antibody-dependent cell-mediated cytotoxicity. Modulation of T-cell surface antigens, that is, anergy and activation-induced cell death (apoptosis).

48  Induction Therapy

Lymphocyte depletion is most likely the main mechanism of immunosuppression. This depletion may be achieved either by complement-dependent lysis or by opsonization and subsequent phagocytosis by macrophages. Evidence indicates that rabbit ATG recognizes most of the molecules involved in the T-cell activation cascade during graft rejection, such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR, and HLA class I [20–23]. Antibodies against β2-microglobulin and CD45 can also be detected. Antibody-dependent cell-mediated cytotoxicity is dependent on antibody density of the cell. Rabbit antibodies bind with high affinity to the human Fc receptor. Antibody-­ dependent cell-mediated cytotoxicity may be an important mechanism of action of rabbit ATG. Rabbit ATG induces Fas (CD95) and Fas-ligand expression, resulting in Fas/Fas-L-­ mediated apoptosis of activated T cells. In vitro, rabbit ATG does not activate B cells [24–26]. Antithymocyte globulin treatment may lead to T-cell anergy and to the downmodulation of T-cell functional molecules [27]. However, clinically, the main documented effect of ATG is a massive T-cell depletion in the blood. That depletion is long-lasting in solid-­ organ transplant recipients; a relative decrease in CD4-­ positive and increase in CD8-positive and CD57-positive cells can be observed several years after ATG treatment [28]. Activated B cells are highly susceptible to ATG-induced cytotoxicity. In addition to T and B cells, rabbit ATG binds to monocytes and macrophages and only minimally to neutrophils, platelets, and erythrocytes. Because of the potential of ATG cross-reaction with nonlymphoid cells, lots released for clinical use undergo extensive testing to minimize binding to neutrophils, platelets, and erythrocytes. Pharmacokinetic Properties. After an IV dose of 1.25– 1.5 mg/kg/day 4–8 h postinfusion, rabbit ATG levels average 21.5  μg/mL (range, 10–40  μg/mL) after the first dose and 87 μg/mL (range, 23–170 μg/mL) after the last dose. Half-­ life is 2–3 days [29]. The volume of distribution of rabbit ATG is 0.12 L/kg or about twice the plasma volume. Thus, dosing should be based on the recipient’s ideal body weight [30]. The elimination of rabbit IgG has been described with a one-compartment model. During treatment of acute kidney graft rejection, plasma concentrations of rabbit IgG peak at 20–101 μg/mL and gradually decline to zero within 12 weeks [31]. The elimination half-life of rabbit IgG is 29.8 days during the first course of treatment. If recipients are retreated with rabbit ATG, the rate of elimination is slower, with a half-life of 37.7 days. Pregnancy. The mutagenic potential of rabbit ATG and its potential to impair fertility have not been studied. Animal reproductive studies have not been conducted with rabbit ATG. It is unknown whether rabbit ATG can cause fetal harm or affect reproductive capacity. Rabbit ATG should be given to a pregnant woman only if clearly needed. Women of reproductive potential should use effective contraceptive

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methods during treatment and for a minimum of 3 months after ATG therapy ends. Drug Interactions. Because rabbit ATG is administered to recipients who are on a standard immunosuppressive regimen, it may predispose to over immunosuppression. Rabbit ATG can stimulate the production of antibodies that cross-­ react with rabbit immune globulins. Antirabbit antibodies have been reported to develop in recipients treated with rabbit ATG [32]. No controlled studies have been conducted to study the effect of antirabbit antibodies after repeated use of rabbit ATG.  However, the recipient’s lymphocyte count should be monitored to ensure that T-cell depletion is achieved on retreatment with rabbit ATG. Dosage and Administration [33]. The recommended dose of rabbit ATG is 1.5 mg/kg administered daily for 4–7 days for prophylaxis of acute rejection. Rabbit ATG should be infused over at least 6 h for the first infusion and over 4 h on subsequent days of therapy. The recipient’s lymphocyte count should be reduced by >85% after the first dose, with reductions sustained throughout a course of treatment. T-cell depletion in peripheral blood persists for several days to several weeks after treatment ends. Recovery from treatment-­ induced lymphocyte depletion is gradual. Total lymphocyte counts usually return to normal within 2 months after therapy begins but may take 3–6 months or more in some recipients. Antiviral prophylactic therapy is recommended. Infusion solutions are stable for 4 h at room temperature and for 24 h if refrigerated. Rabbit ATG is stable in both dextrose and saline. The recommended volume for infusion is one vial of rabbit ATG per 50 mL of infusion solution (total volume, usually 50–500 mL). Rabbit ATG should be administered through a 0.22-μm filter into a high-flow vein via a central line catheter such as a peripheral in-dwelling central catheter line. In particular during the first infusion, the recipient may experience a transient inflammatory reaction characterized by fever and sometimes chills. Premedication with corticosteroids, acetaminophen, and/or an antihistamine may reduce the incidence and intensity of side effects during an infusion. Anaphylactic hypersensitivity reactions are rare, but delayed allergic responses in the form of serum sickness have been reported. Skin testing is not recommended in solid-organ transplant recipients: A test dose presents the same risks as the treatment and does not offer any therapeutic or safety advantages. Recipients should be monitored for adverse events during and after infusion. Peripheral Administration. The administration of rabbit ATG both via the peripheral route and via arterial-venous fistulas have been described in kidney recipients [34, 35]. Rabbit ATG was diluted in 500–1000 mL of normal saline, with heparin (1000 U) and hydrocortisone (20  mg) and administered over 12  h. Overall, no significant differences were observed in adverse events, other than phlebitis, between two different groups: one whose rabbit ATG was

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infused via a central IV line and the other via a peripheral IV line. The incidence of thrombophlebitis was 5% in the central line group and 33% in the peripheral line group (P  =  0.003). The overall incidence of other adverse events was similar to the findings of other studies, including fever (30%), thrombocytopenia (23%), leukopenia (12%), and serum sickness (4%). Adverse Events. The most frequent, most severe adverse reactions typically occurred after the first infusion. By far the most common event (55%) associated with the use of rabbit ATG was fever (defined as 38.5  °C). Fever was sometimes accompanied by chills or a rash. If a fever and rash occurred during the first infusion, the cause was probably release of cytokines, a reaction known as cytokine release syndrome or first-dose effect. This reaction can include systemic effects such as vomiting, diarrhea, nausea, dizziness, hypotension, hypertension, dyspnea, and wheezing; such effects with rabbit ATG are usually mild and only rarely severe or life-­threatening. Another cause of an early fever or rash is an allergic reaction, which can be clinically similar to a first-­dose effect. Severe adverse reactions such as life-threatening anaphylactic shock are rare. An anaphylactic reaction is an absolute contraindication to continue administration of rabbit ATG.  Premedication with antipyretics, corticosteroids, and antihistamines may decrease both the incidence and severity of cytokine release syndrome. Reducing the infusion rate or using a larger volume of diluent (isotonic 0.9% sodium chloride or 5% dextrose solution) may also reduce some of these adverse reactions. On occasion, delayed allergic reactions may occur such as serum sickness (fever, pruritus, and rash associated with arthralgia, myalgia, lymphadenopathy, or a drop in serum complement). Serum sickness is due to host immunization against rabbit protein and tends to occur 7–15 days after onset of treatment. The clinical outcome is favorable: It usually resolves spontaneously or with initiation of or increased-dose corticosteroid therapy. Hematologic Events. Thrombocytopenia and neutropenia are typical during the first couple of days of treatment or after it ends. They are reversible. One possible mechanism is the presence of antibodies cross-reacting with neutrophils and platelets. Monitoring for white blood cell (WBC) and platelet counts can minimize the severity of hematologic events. The incidence of neutropenia is about 44% and thrombocytopenia ~14%. The recipient’s lymphocyte count (e.g., total lymphocyte and/or T-cell subset) should be monitored to assess the degree of T-cell depletion. Overdosage of rabbit ATG may result in leukopenia and/ or thrombocytopenia. In such cases, the rabbit ATG dose should be reduced by one half if the WBC count is between 2000 and 3000 cells/mm3 or if the platelet count is between 50,000 and 75,000 cells/mm3. Rabbit ATG treatment should ideally be stopped if the WBC count falls below 2000 cells/ mm3 or if the platelet count falls below 50,000  cells/mm3.

D. B. Kaufman et al.

Alternatively, the dose may be withheld until the WBC or platelet count recovers. Rabbit ATG-induced leukopenia or thrombocytopenia is reversible by stopping treatment. Anaphylaxis. Rabbit ATG is contraindicated in recipients with a history of allergy or anaphylaxis to rabbit proteins or who have an acute viral illness. In rare instances, anaphylaxis has been reported with rabbit ATG use. In such cases, infusion must be stopped immediately and never restarted. Emergency treatment should be provided as clinically indicated, e.g., 0.3–0.5  mL aqueous epinephrine (1:1000 dilution) subcutaneously and other resuscitative measures including oxygen, IV fluids, antihistamines, corticosteroids, and airway management.

Alemtuzumab Alemtuzumab (Campath, Sanofi Pharmaceutical Company, Paris, France) is a humanized monoclonal antibody against the CD52 antigen. It has undergone several iterations, including Campath-1M (rat IgM) and Campath-1G (an IgG2b subclass). The current structure of Campath 1H is a genetically engineered human IgG1 kappa monoclonal antibody into which have been grafted the six complementarity-­ determining regions from the murine monoclonal antibody, specific for the 21- to 28-kDa lymphocyte cell surface glycoprotein, CD52. In humans, CD52 is predominantly expressed on peripheral blood lymphocytes, monocytes, and macrophages [36]. The precise biologic function of this antigen is unknown, although it may play a role in cell adhesion, protection of the host environment, and cell proliferation. The CD52 antigen is comprised of a glycosylphosphatidylinositol (GPI)anchored glycopeptide [37]. The CD52 gene product is abundantly expressed at about 5 × 105 molecules/cell, making it a good target for a complement-mediated attack on lymphocytes [38]. The structural features (e.g., small size, lateral mobility due to its GPI anchorage) of the CD52 antigen increase the efficiency of the anti-CD52 antibody to induce lympholysis from complement-mediated lysis or other effector mechanisms [39, 40]. Alemtuzumab was developed for the treatment of lymphoid malignancies, including non-Hodgkin’s lymphoma, chronic lymphocytic lymphoma, prolymphocytic leukemia, and cutaneous T-cell lymphoma (mycosis fungoides). It preferentially affects blood and bone marrow components, as opposed to spleen or lymph node cells, and is associated with profound T-lymphocyte depletion. Alemtuzumab has also been investigated for the treatment of other autoimmune disorders (e.g., rheumatoid arthritis, secondary progressive multiple sclerosis), preparative regimens for stem cell ­transplants, and the prevention of graft rejection in solidorgan transplant recipients.

48  Induction Therapy

Historical Development [41]. The initial Campath-1 series of murine monoclonal antibodies was generated in the early 1980s by Herman Waldmann’s research team at the Department of Pathology, Cambridge University, United Kingdom. The name derives from Cambridge Pathology. Waldmann’s interest in monoclonal antibody development began during a study period in César Milstein’s laboratory, at the Medical Research Council Laboratory of Molecular Biology in Cambridge in the late 1970s. Waldmann’s group made monoclonal antibodies for the purpose of removing T cells from human bone marrow to treat the problems of GVHD.  The first monoclonal antibody developed was Campath-1M (rat IgM), which lysed human lymphocytes. It was successfully used for the in vitro depletion of lymphocytes for the prevention of GVHD. Campath-1M also demonstrated promise as a prophylactic immunosuppressant in kidney recipients as reported by Calne et  al. from the Cambridge University transplant unit [42]. Subsequently, a rat IgG2a subclass was developed and used to generate the rat IgG2b antibody, called Campath-1G. Early clinical studies in lymphoma and leukemia patients showed that it was highly effective at destroying lymphocytes in  vivo, contrary to the rat IgG2a and rat IgM Campath antibodies. Campath-1G induced persistent depletion of lymphocytes from the blood, marrow, and spleen of patients with lymphoid malignancies. Its clinical usefulness, however, was limited: Repeated use ran the risk of a human antirodent antibody response that would block the activity of the antibody or cause an allergic (anaphylactic) response. To eliminate the possibility of a human antirodent antibody response, as well as to optimize the effector function, Campath-1G was humanized by introducing the six hypervariable regions from the heavy and light chain variable domains of the rodent antibody into a human IgGl framework. Initially, the humanized antibody had significantly reduced binding affinity, as compared with its parental antibody, but the binding affinity was fully restored by changing a single amino acid in the first framework region of the heavy chain variable domain. Campath-1H thus retains the affinity and biologic activity of the parental rodent IgG2b antibody. Given the perceived benefits of a humanized monoclonal antibody, Campath was chosen for clinical use in oncology and autoimmune disease. The humanization of Campath-1G to give Campath-1H successfully minimized the human antirodent antibody response. Campath-1H became the first fully humanized antibody against a cell surface molecule to have therapeutic potential. The commercialization of Campath and the circuitous route by which Sanofi came to acquire both the depletional induction agents is quite a journey. Cambridge University and the Medical Research Council assigned the humanized antibody Campath-1H to the organization British Technology Group (BTG). BTG was responsible for filing patents on

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these antibodies and their clinical uses and for sublicensing to the pharmaceutical industry. Initially, it licensed the antibody to the pharmaceutical company Wellcome (which later merged with Glaxo Pharmaceuticals to form Glaxo-­ Wellcome). The clinical development of Campath began in 1991 and included phase I and II studies for the treatment of non-Hodgkin’ s lymphoma, B-cell chronic lymphocytic leukemia (B-CLL) and related disease, rheumatoid arthritis, and acute kidney graft rejection. Despite encouraging early results in treating some forms of lymphocytic leukemia and lymphoma, Glaxo-Wellcome abandoned the Campath project so BTG relicensed Campath-1H to LeukoSite Inc (Cambridge, MA). LeukoSite and ILEX Oncology Inc then entered into a 50−50 Campath joint venture (LeukoSite and ILEX Partners LP). ILEX was founded in 1994 as an oncology drug development company based in San Antonio, Texas. In 1999, Schering AG entered into a distribution and development agreement for exclusive marketing and distribution rights to Campath in the United States, Europe, and the rest of the world except Japan and East Asia, where LeukoSite and ILEX retained rights. LeukoSite and ILEX submitted a biologics license application for Campath to the FDA in December 1999. In October 1999, Millennium Pharmaceuticals (founded in early 1993 and headquartered in Cambridge, MA) purchased LeukoSite for $635 million in stock. The Investigational New Drug application (IND) for Campath was transferred to Millennium and ILEX Partners LP.  In December 2000, the Oncologic Drugs Advisory Committee to the FDA recommended accelerated approval for patients with CLL who have been treated with alkylating agents for whom fludarabine therapy had failed. On May 8, 2001, the FDA approved Campath for use in patients with refractory CLL.  Campath was then marketed and distributed in the United States by Berlex Laboratories Oncology Inc (Richmond, CA), a subsidiary of Schering AG, Germany (founded in 1871). On December 31, 2001, ILEX Oncology Inc completed acquisition of the equity interests held by Millennium Pharmaceuticals Inc in the companies’ 50−50 Campath joint venture. Berlex Oncology Laboratories Inc and ILEX then shared in the profits from the sale of Campath in the U.S. market. Genzyme acquired ILEX in 2004. This transaction was completed a year following its acquisition of SangStat, Medical Corporation, and its principal organ anti-­ rejection agent, Thymoglobulin. On June 2, 2009, Genzyme Corp (Cambridge, MA) acquired worldwide rights to Campath/MabCampath from Bayer HealthCare (Bayer acquired Schering AG, Berlin in March 2006), for future development for treatment of relapsing-remitting multiple sclerosis. Genzyme was acquired by Sanofi (Paris, France), for $20Bn in 2011, which, at the time, was one of the biggest Biotech deals in history. Sanofi then held both Thymoglobulin and Campath agents.

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Mechanism of Action. Campath is a recombinant DNA-­ derived humanized monoclonal antibody that is directed against CD52. CD52 is a nonmodulating cell-surface antigen expressed on essentially all T and B lymphocytes; on most monocytes, macrophages, and natural killer (NK) cells; and on a subpopulation of granulocytes. The Campath antibody has an approximate molecular weight of 150 kDa. Its exact mechanism of action is unknown. The proposed mechanism is antibody-dependent lysis of leukemic cells after cell-surface binding. As an unconjugated monoclonal antibody, Campath relies on the ability of the monoclonal antibody itself to kill the cell directly (e.g., induce an apoptotic signal) or activate effector mechanisms (e.g., activate complement or T cells to attack the targeted cells). Only certain cell-surface antigens allow cell lysis via complement or cellular cytotoxicity mechanisms (i.e., NK cells or cytotoxic T cells); CD52 allows cell lysis via both cellular cytotoxicity and complement-mediated cytotoxicity. However, monocytes and monocytic leukemias are resistant to Campath in vivo, even though they express similar amounts of antigen [43]. In addition, Campath may deliver a surrogate signal to the cell, a property shared by many antibodies against glycosylphosphatidylinositol (GPI)-anchored antigens. It has demonstrated this property in  vitro [44, 45]. The consequences of this signaling depend on the cell type. T lymphocytes respond by release of cytokines, including interferon-γ and tumor necrosis factor-α. This cytokine release is implicated in the flu-like syndrome characteristic after the first dose of Campath. Some cells respond to an antibody-­ mediated signal by apoptosis; such a response can happen when a B-cell line is treated with Campath in  vitro [46]. Thus, several physiological mechanisms may explain how Campath causes the destruction of T and B cells in vivo. It is not possible to tell with certainty which mechanism is the most important. But, evidence from clinical trials with Campath-1 antibodies of different isotypes suggests that Fc-receptor binding is critical, thereby implicating an ADCC mechanism. Campath binds to essentially all B and T lymphocytes, as well as to monocytes, thymocytes, and macrophages via antibody-binding fragment (Fab) interactions. A small percentage ( 30 days Infection Other

Induction (n = 87) 96.6

Noninduction (n = 87) 94.3

0 1

2 0

0 1 1 96.6 3 3 0 0 0 84.0 14 3 1 2 2 3 1 2

1 2 0 92.0 7 3 2 1 1 84.0 14 3 3 5 1 0 1 1

creatinine; however, there was a trend toward lower serum creatinine over time in the induction group (P = 0.063). With respect to infectious complications—the rate of CMV viremia/syndrome—there was a trend toward a greater proportion of patients in the induction group who developed CMV viremia/syndrome (14%) as compared to the noninduction group (6%) (P = 0.074). In summary, patient and graft survival rates were similar in both treatment arms with no kidney graft losses (for reasons other than death) in the induction arm. Induction therapy was associated with a notable decrease in number and severity of biopsy-confirmed and treated acute kidney rejection episodes. Induction recipients also benefited from fewer elevations in serum creatinine levels. At 6 months posttransplant, there was a trend toward more CMV syndrome/viremia in the induction arm. In analysis of outcomes in the induction arm, trends seemed to point toward differences in efficacy and safety. The second multicenter study was administered by the University of Tennessee-Memphis and funded by Roche Laboratories [53]. This is of historical interest since the induction agent studied is no longer available. A prospective, open-label, randomized (1:1:2) study compared two dosing regimens of daclizumab (1 mg/kg for five doses and 2 mg/kg for two doses) vs. no antibody induction therapy in SPK recipients on TAC, MMF, and prednisone. In all, 240 SPK recipients enrolled at 24 centers. The primary endpoint was a composite of the incidence of rejection (kidney or pancreas), graft loss, or death within the first 6 months posttransplant. With respect to patient and graft survival rates, there were no significant differences among the three study groups. The incidence of acute kidney rejection (presumptive or biopsy proven) in recipients receiving the standard five-dose course of induction was 18%, for recipients receiving the short course two-dose therapy rejection was 8%, and in the noninduction treatment arm 36%. The triple endpoint of rejection, graft loss, or death was reached by 34% of the patients receiving the standard dosing course, 20% of the patients receiving the short-course two-­ dose schedule, and 50% in the noninduction treatment arm. The incidence of major bacterial, fungal, or viral infections requiring hospitalization was 6–9% in all three groups. No serious adverse drug events associated with daclizumab were reported [53, 54].

Single-Center Studies Given the paucity of large, multicenter randomized control trials, pancreas transplant induction protocols have largely been influenced by a multitude of single-center trials. The single-center studies are not always as rigorously designed as the formal prospective, multicenter, randomized studies,

48  Induction Therapy

but fill an important need for nimble exploration that may produce leaps of therapeutic improvement above the convention and in a shorter time frame. These selected single-center studies demonstrate how certain induction therapeutic strategies reduced early rejection and permitted maintenance immunosuppression minimization across various maintenance regimens, surgical techniques of venous and enteric drainage, and in the context of opportunistic infectious risk.

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acute and recurrent rejection in pancreas transplantation justified the standardized use of induction therapy by the majority of transplant centers [58]. At this point TAC, MMF, and steroid-based maintenance immunosuppression had been adopted by the vast majority of pancreas transplant programs. Several studies focused on determining the optimal induction agent according to the two classes—IL-2 receptor antagonists or deletional agents. ATG was compared to basiliximab at several centers. Bazerbachi et  al. [5] described retrospective review of 128 SPK recipients, who either Simultaneous Pancreas-Kidney Induction received basiliximab (n = 49) or ATG (n = 79) for induction Therapy therapy. Triple maintenance therapy with TAC, MMF, and steroids was utilized in all recipients. The rate of early acute Conventional maintenance immunosuppressive therapy for rejection by 3 months was 21% among basiliximab recipiSPK transplantation consistently includes calcineurin inhibi- ents and 6% among ATG recipients. This gap closed but tion (tacrolimus [Tac], cyclosporine [CSA]), mycophenolate remained significant by 1-year with a cumulative acute rejecmofetil (MMF), and long-term corticosteroid treatment. tion rate of 27% and 14% in the basiliximab and ATG The first question to be addressed in the era of advanced cohorts, respectively. It was noted that among these acute modern maintenance immunosuppression for SPK, is the rejection episodes, basiliximab was associated with a higher necessity of induction therapy. Indeed, in 1998, Cory et al. rate of steroid-resistance. Furthermore, univariate regression [55] reported on 123 consecutive pancreas transplants, analysis revealed basiliximab as an independent risk factor including 104 performed as SPK.  No recipients received for rejection with a hazard ratio of 7.1. Despite these dispainduction therapy, while maintenance immunosuppression rate early immunologic outcomes, long-term comparisons consisted of TAC, either AZA or MMF, and corticosteroids. between basiliximab and ATG demonstrated no difference in The 1-year patient, kidney, and pancreas survival rates were 1-year (93% vs. 90%), 3-year (89% vs. 87%), and 5-year 98%, 95%, and 83%, respectively. However, the incidence of (83% vs. 78%) pancreas graft survivals. Similarly, there was rejection was enormously high by today’s standards at 64%! no difference in long-term kidney graft survival. Bazerbachi Jordan et al. [56], extended these studies reporting a mean et  al. [59] concluded that basiliximab resulted in a higher follow-up of nearly 3 years, the patient, kidney, and pancreas incidence of early acute rejection compared to ATG therapy; survival rates were similar to the 1-year outcomes at 96.5%, however, long-term outcomes were unaffected by induction 91%, and 80%, respectively. However, there was an 80% agent. incidence of acute rejection within the first 6 months of These findings were supported by single-center analysis transplant, 87% of which were steroid responsive. They chal- performed by Fernandez-Burgos et  al. [60]. Basiliximab lenged the convention of chronic corticosteroid use describ- induction (n = 38) was compared to ATG (n = 59) in 97 SPK ing 48 selective recipients with functioning pancreas grafts recipients. Maintenance immunosuppression consisted of at 3 years, 65% (31) achieving complete steroid withdrawal. TAC, MMF, and corticosteroids. Here, no difference was Reddy et al. [57] reported on a retrospective analysis of detected in pancreas allograft survival after basiliximab vs. SPK recipients who received TAC-based immunosuppres- ATG induction at 1 year (85% vs. 84%), 3 years (80% vs. sion without induction therapy. Of the 30 recipients included, 84%), or 5 years (77% vs. 81%). Similarly, there was no dif18 received portal-enteric drainage, while 12 had systemic-­ ference in patient survivals between the two groups. The bladder drainage. Maintenance immunosuppression con- incidence of cellular rejection was higher among basiliximab sisted of TAC, MMF, and long-term steroids. The 1-year recipients (30%) compared to ATG recipients (14%). Early patient, kidney, and pancreas survival rates were 93%, 93%, acute rejection occurred among 21% of the basiliximab and 90%, respectively. The incidence of acute rejection was group and 6% of the ATG group. However, there was no sta30%, most of which were treated with antilymphocyte ther- tistical difference in the incidence of acute rejection by 1 apy. Approximately 10% of recipients had recurrent rejec- year or 5 years posttransplant. Multivariable analysis found tion episodes. The rate of CMV infection was 13%; however, basiliximab to have a fourfold and fivefold increase in relanone developed tissue invasive disease. They concluded that tive risk for cellular and early rejection, respectively. The TAC, MMF, and steroid immunosuppression without induc- rate of postoperative infection was 73% in basiliximab reciption therapy is a safe and effective regimen for SPK ients compared to 31% in those who received ATG. A similar trend was seen in the 1-year infection rate (80% vs. 58%). recipients. Although these studies demonstrated acceptable long-­ The median length of initial hospital stay was 21 days after term outcomes without induction therapy, the higher rates of basiliximab induction and 16 after ATG therapy. The rate of

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readmission by 3 months posttransplant was 68% and 36% in the basiliximab and ATG groups, respectively. Consistent with prior reports, Fernandez-Burgos et al. identified a higher risk of acute rejection after basiliximab induction, although long-term graft survivals were comparable. Despite acceptable patient and graft survivals, the high rates of early rejection episodes prompted continued evaluation of the utility of induction protocols in SPK transplantation according to pancreas graft exocrine drainage options. Kaufman et al. [61] performed a single-center retrospective analysis of a 100 consecutive SPK recipients maintained on an immunosuppressive regimen consisting of TAC, MMF, and corticosteroids. Fifty recipients received bladder-drained pancreas allografts, all of whom received equine ATG-based induction therapy. This cohort was compared to 50 subsequent recipients of enteric-drained pancreas grafts, who were randomized to receive equine ATG (n = 33) or no (n = 17) induction therapy. All transplants were performed with systemic venous drainage. The 1-year patient, kidney, and pancreas survival rates were similar in all groups. However, the 1-month rate of acute rejection was 18% in the bladder drained cohort and 23.5% in the enteric drained group without induction therapy. This is contrasted to a low rate of 6.1% occurring in recipients of an enteric drained pancreas with induction therapy. Kaufman et al. concluded that with enteric drainage, the addition of induction therapy to a TAC, MMF, and steroid-based maintenance regimen, could significantly reduce the early rate of rejection to 6 months

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posttransplant was accompanied by a 17% reduction in total serum cholesterol levels. But they also noted a parallel reduction in high-density lipoprotein levels, although the ratio of total to high-density lipoprotein cholesterol was unchanged after steroid withdrawal [85]. Except for these few studies, steroid have remained a constant part of CSA-based maintenance therapy in pancreas recipients. Significant reductions in the incidence of acute rejection episodes and graft lost from rejection with TAC-MMF (vs CSA-AZA) maintenance therapy rekindled enthusiasm for steroid withdrawal. In a prospective, randomized, open-label study, the University of Minnesota group investigated the impact of steroid withdrawal at 6–36 months posttransplant on pancreas graft and patient survival, on the incidence of rejection, and on lipid metabolism. A total of 50 recipients (25 SPK, 25 PAK) were randomized to either standard immunosuppression or steroid withdrawal. At 1 year, no significant differences were noted in graft and patient survival, in graft loss from rejection, or in the incidence of rejection between the two groups. But a significant improvement in serum cholesterol and triglyceride levels was observed in the withdrawal group; in the steroid withdrawal group, recipients also reported an overall improvement in the quality of life [79, 86]. The 1-year results confirmed a previous retrospective study, in 14 pancreas recipients, that showed that steroid withdrawal was safe and effective [87]. In a retrospective study, Jordan et al. reported on 58 pancreas recipients who underwent steroid withdrawal at a mean of 15 (range, 4–40) months posttransplant [88]. At last follow-­up, the accumulated risk of rejection was 76% for recipients on versus 74% for those off steroids. Of note, seven recipients whose steroids were withdrawn were treated for subsequent rejection episodes, all of which were steroid sensitive; in two of seven recipients, steroids were subsequently withdrawn again. Of 13 recipients who were treated with anti-T-cell therapy for steroid resistant rejection, 5 remained off steroids [88]. The authors acknowledged that only 47% of all pancreas recipients were enrolled in this nonrandomized study, selected as the most likely to be successfully weaned because they were considered to be at low risk for rejection [89]. The Berlin group also showed that steroid withdrawal >12 months posttransplant could be done without immunologic penalty, provided withdrawal was limited to recipients with no rejection within the previous 6 months prior to withdrawal [90]. Unlike previous studies that showed successful steroid withdrawal as early as 6 months posttransplant, a study by Kaufman et al. investigated the effect of rapid steroid withdrawal during induction therapy  – as early as 6  days posttransplant. Recipients were maintained on TAC-MMF or TAC-SIR.  Compared with a historical control of 87 SPK recipients (on a standard steroid taper with TAC and MMF for maintenance therapy), the rapid steroid withdrawal

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groups showed no increased incidence of rejection episodes or graft loss from rejection. None of them had to go back on prednisone [91]. These early studies in steroid avoidance and steroid withdrawal prompted many investigators to eliminate steroids from immunosuppressive regimens [92–103]. These studies have confirmed that steroid elimination does not result in inferior immunologic outcomes. Interestingly, the use of steroids remains prevalent in maintenance regimens following pancreas transplantation [6]. The ultimate interpretation of the efficacy of steroids in immunosuppressive regimens is challenged by the heterogeneity of immunosuppressive regimens used in the different studies. Some have utilized more potent induction regimens prior to steroid withdrawal, whereas others have replaced steroids with TOR inhibitors (see below). What is evident, however, is that successful elimination of steroids has been associated with improved metabolic profiles [86, 88, 102, 104, 105]. Ultimately, many centers reserve steroid elimination for low immunologic risk patients, but opt to maintain steroids in recipients that are deemed a higher risk for rejection.

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dent differentiation into antibody producing cells, thereby decreasing the synthesis of IgM, IgG, and IgA immunoglobulins [116]. Thus, its inhibiting effects on natural killer, cytokine-­activated killer, and antibody dependent cell cytotoxicity contribute to SIR’s potent immunoregulatory properties. The drug has also been shown to inhibit proliferation of vascular endothelial and smooth muscles [117–119]. Because of this action, SIR may play a key role in prophylaxis against chronic rejection [120]. As discussed below, based on its antiproliferative qualities, the mTOR inhibitors are being used with increased frequency for transplant recipients who have a history of malignancy (i.e., liver transplant recipients with HCC) or transplant recipients with newly acquired malignancies. Interestingly, its inhibition of proliferation of vascular endothelial cells and downregulation of VEGF has prompted the use of sirolimus as a treatment for the highly vascular malignant lesions associated with Kaposi’s sarcoma (KS). In fact, conversion to everolimus has successfully controlled de novo KS following kidney and liver transplantation in the HIV-positive recipient. SIR has limited effect on cytokine expression itself, but clearly inhibits cytokine-activated signal transduction. The idea of inhibiting both cytokine transcription and cytokine-­ Sirolimus and the Evolving Role of TOR mediated signal transduction has given rise to the immunoInhibitors in Pancreas Transplantation suppressive concept of using TOR inhibitors and calcineurin inhibitors in combination. CNI inhibits the transcription of Sirolimus (previously known as rapamycin or RAPA) is a IL2, whereas the TOR inhibitors inhibit the effect of IL2 on macrocyclic triene antibiotic produced by Streptomyces the growth cycle. Their differences in mechanism of action hygroscopicus, an actinomycete that was originally isolated complement each other, and an increasing number of studies from a soil sample on Easter Island [106, 107]. Although SIR have been conducted using this combination in various sethas antitumor and antifungal properties [108, 109], it is also tings in solid-organ recipients. A newer mTOR inhibitor that a potent immunosuppressive agent. In contrast to calcineurin blocks both TOR1 and TOR2 pathways is everolimus. inhibitors (TAC,CSA) or antimetabolites (MMF, AZA), SIR Without going into detailed mechanistic differences, suffice represents a different class of immunosuppressant agents it to say that everolimus shares the efficacy as well as adverse known as the TOR inhibitors. attributes of SIR. However, everolimus has higher bioavailLike TAC, SIR binds to the intracellular cystosolic immu- ability and a shorter terminal half-life, prompting several clinophilin FK-binding protein 12(FKBP-12). But, unlike the nicians to favor its utilization in immunosuppressive TAC-FKBP-12 complex, the SIR-FKBP-12 complex has no regimens [121]. effect on calcineurin phosphatase, but rather binds to and Before discussing the limited experience using mTOR inhibits one or more proteins known as a TOR. The effector inhibitors in pancreas transplantation, it is important to menprotein is now most commonly called “mammalian TOR” tion that the original hope that mTORs did not have beta cell (mTOR), a key regulatory kinase [110, 111], because a mam- toxicity or nephrotoxicity has unfortunately not held out. malian homolog (to the previously described TOR 1 and Numerous publications have confirmed rapamycin toxicity TOR2 proteins isolated from yeast) was identified. The SIR-­ to pancreatic beta cells, as well as an increased incidence of FKBP-­12 complex binds to mTOR and inhibits protein syn- new-onset diabetes in recipients treated with mTOR inhibithesis by arresting the progression of the cell cycle from the tors. This literature is summarized in a comprehensive literalate G1 to the S phase [112, 113]. The cellular effect of SIR ture review [122], as well as a meta-analysis of metabolic is inhibition of lymphocyte activity. It block T-cell prolifera- complications in kidney transplantation after conversion to tion by inhibiting calcium dependent or independent path- mTOR inhibitors [123]. The main adverse events are hemaways that mediate transduction signals induced by a number tologic toxicity and hyperlipidemia, as outlined in Table 49.1.. of cytokines, such as IL-2, IL-3, IL-4, IL-6, IL-12, and IL-15 These adverse events can usually be medically managed [114]. SIR also inhibits antigen- and cytokine-driven B-cell without difficulty. Similarly, the hopes that mTOR inhibitors proliferation [115]. Moreover, it prevents IL-2 or IL-6 depen- lacked nephrotoxicity also has not held, and can result in de

49  Maintenance Therapy

novo nephrotoxicity as well as exacerbation of known proteinuria. That being said, proteinuria 6 months and had discontinued CNI did not require reinitiation of the CNI.  The Nankivell glomerular filtration rate improved significantly within 3 months and remained stable during follow-up (mean, 345  ±  274  days) [131]. SIR was successfully used in three of five SPK recipients with steroid- or OKT3-resistant rejection episodes. In these cases, SIR was added and MMF withdrawn from TAC or CSA-­ based immunosuppressive maintenance therapy [132]. The transplant group from Ohio state incorporated rapamycin into immunosuppressive regimens following SPK in order to withdraw steroids and minimize CNI. A total of 97 pancreas transplant recipients received steroid-free maintenance immunosuppression, consisting of induction with thymoglobulin and prednisone for the first 5 days. Patients were maintained on sirolimus adjusted to a target rapamycin trough level and reduced dose cyclosporine adjusted to target C2 levels. All pancreas transplants (n  =  124) performed in the previous 3 years and maintained on a steroid-based immunosuppressive protocol with MMF and cyclosporine were used for comparison. One-year patient and death censored pancreas graft survival were 93.8% and 94.8% for the steroid-free group versus 95.2% and 87.9% for the comparator group, respectively. The incidence of acute rejection was 9.3% in the steroid-free group versus 28.3% in the comparator group (p 90%) remain dependent on a combination of long-term use of tacrolimus and mycophenolate mofetil. Based on the significant side effects attributed to steroids (Table  49.4), as well as their known toxicity to beta cells, many transplant centers have opted to withdraw steroids in SPK recipients at a lower immunologic risk for rejection. Several strategies use rapid withdrawal of prednisone without any modification to the standard backbone of immunosuppressive regimens. However, some centers have used the strategy of adding sirolimus to the standard backbone of tacrolimus/MMF in order to provide a protective immunosuppressive cushion for the first 6  months following transplantation to facilitate rapid withdrawal of prednisone. The necessity for this use of the mTORi remains in question, although this strategy continues to be used by select transplant centers, including the use of mTORi in steroid withdrawal regimens in low-risk SPK recipients. The UCSF protocols for SPK are listed in Table 49.5, and have evolved based on the series of trials described in this chapter. Steroid withdrawal is reserved for low immunologic SPK recipients. The mTOR inhibitors are added to the regimens at 1 month in recipients withdrawn from prednisone, and continued for 6 months. At that point in time, either the mTOR inhibitor or MMF is discontinued, and recipients are maintained on TAC and MMF alone. Most of the SPK recipients are maintained on triple immunosuppression for long-­ term maintenance. For the higher immunologic risk groups of PAK and PTA, recipients are maintained on quadruple therapy, with lower doses of MMF, mTORi, and CNI to avoid toxicities while capitalizing on synergy. Table  49.3 lists the drug adjustments that are necessary to avoid significant CNI toxicities, most related to inhibition of the cytochrome p450 system. Despite the well-described drug-drug interactions leading to CNI toxicity, this is a frequent problem when patients are treated by outside providers without communication to the transplant center. The historic “tool chest” of immunosuppressive agents are occasionally recycled to replace tacrolimus or MMF in several different scenarios. For example, for recipients suffering from the problematic neurologic sides effects of tacrolimus (tremors/neuropathy), CSA is a reasonable substitute. Similarly, for recipients with potential beta cell toxicity associated with tacrolimus and manifested by evidence of increasing insulin resistance, CSA can be introduced as a better CNI to be used in this circumstance. For pancreas transplant recipients with CNI-induced HUS, CSA can be introduced as a safer CNI – although there is also a risk for HUS attributed to CSA. For transplant recipients who want to become pregnant, MMF must be discontinued due to teratogenicity of this antiproliferative agent. In these cases,

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Table 49.5.  Steroid avoidance and use protocols Steroid avoidance protocol (only considered for low-risk SPK) For: Unsensitized SPK transplants

Steroid use protocol (For PTA, PAK, non-low-risk SPK) For: High-risk patients (second transplant, cPRA >20%) PTA PAK Surgery plan: Systemic portal venous drainage Surgery plan: Systemic portal venous drainage Enteric exocrine drainage Enteric exocrine drainage For PTA—Enteric drainage To monitor rejection, PTA/PAK recipients will have protocol biopsies at 3 months Induction Induction Solumedrol Solumedrol In OR: 500 mg immediately following initial abdominal exploration In OR: 500 mg immediately following initial abdominal POD#1: 250 mg exploration POD#2: 2 mg/kg POD#1: 250 mg POD#3: And until thymo done: 0.5 mg/kg POD#2: 2 mg/kg POD#7: Decrease by 10 mg/week until 20 mg then taper weekly – 15 mg, POD#3–4: 0.5 mg/kg POD#5: No further solumedrol unless patient is in ATN, is 12.5 mg, 10 mg, 7.5 mg, stop at 5 mg still receiving Thymo, or has inadequate levels of tacrolimus. Dose is 0.5 mg/kg Maintenance Maintenance Tacrolimus (Prograf) Tacrolimus (Prograf)  •  Start when evidence of good renal function  •  Start when evidence of good renal function  • Give NG or PO: Very few indications for IV  •  Give NG or PO: Very few indications for IV administration administration  • If patient already on tacrolimus and has poor oral intake, IV dose should not  • If patient already on tacrolimus and has poor oral exceed 1 mg over 24 h as a continuous infusion. (Total dose of 1 mg over 24 h.) intake, IV dose should not exceed 1 mg over 24 h as a continuous infusion. (Total dose of 1 mg over  •  Start levels after two doses given. Run QD except sun. 24 h.)  • Adjust doses keeping in mind renal function and drugs metabolized by  • Start levels after two doses given. Run QD except cytochrome P450, such as fluconazole (see Table 49.3.) sun.  •  Target levels:  • Adjust doses keeping in mind renal function and    – 0–3 months: 10–12 ng/mL drugs metabolized by cytochrome P450, such as    – 3–6 months: 8–10 ng/mL fluconazole.    – >6 months: 5–7 ng/mL  •  Target levels:    – 0–3 months: 10–12 ng/mL    – 3–6 months: 8–10 ng/mL    – >6 months: 5–7 ng/mL Myfortic Myfortic Starting POD#1: MMF 500 IV BID, change to 720 mg Starting POD#1 and while on thymo: 360 mg PO BID or MMF 500 IV BID Myfortic after Thymo ends and until Rapamune starts, then When thymo done: Increase Myfortic to 720 mg PO BID drop to 360 mg BID Reduce Myfortic to 540 mg BID at 6 months  •  Taper for leukopenia or GI irritation  •  Taper for leukopenia or GI irritation  • DC MM fat 6 months (or DC Rapamune and continue MMF) depending on tolerance) Sirolimus Sirolimus/Everolimus (only for PAK, PTA)  •  Start at 4 weeks  •  Start at 4 weeks, no loading dose  •  Target level: 3–5 ng/mL  •  Target level: 3–5 ng/mL  •  Adjust dose for leukopenia or thrombocytopenia  •  Adjust dose for leukopenia or thrombocytopenia  • Additionally, reduce Myfortic to 540 PO BID at 1–6 months and again down to 360 PO BID at 6 months  •  Prednisone maintained at 5 mg/day

Imuran (AZA) is a safer alternative and MMF is discontinued before and during pregnancy. Similarly, AZA is an acceptable choice in the GI toxicities attributed to MMF cannot be abrogated with Myfortic. The use of mTOR inhibitors in pancreas transplantation continues to evolve. Although less than 10% of regimens incorporate the mTOR inhibitors into the immunosuppressive regimens of pancreas transplant recipients, they are

proving to be a very useful tool in the setting of malignancy, as they have known antitumor qualities. This is true not only for pancreas transplant recipients, but also in all solid-organ transplant settings. The mTOR inhibitors are frequently added to immunosuppressive regimens following a moderate to severe rejection episode. If there is a moderate to severe rejection episode in the setting of adequate levels of CNI, the addition of the mTOR inhibitor following treat-

49  Maintenance Therapy

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Reasons for Deviation from Steroid Use Maintenance Regimen QUADRUPLE MAINTENANCE REGIMEN

Steroid withdrawal (see Table 5)

mTORi (low dose) CNI (low dose) Myfortic/MMF (low dose) Prednisone

Low Immunologic risk

Add mTORi after rejection treatment and continuue on quadruple regimen

If PTA/PAK (high immunologic risk): At 1 month, add mTORi

CNI Toxicity (Neurotoxicity, Nephrotoxicity, Beta cell toxicity)

Rejection with appropriate CNI levels

STANDARD BACCKBONE TAC Myfortic/MMF Prednisone

Malignancy 3 Options: 1) Miinimize TAC, switch MMF/Myfortic witth mTORi 2) Minimize TAC, maximize MMF/Myfortic 3) Change CNI (TAC to CSA)

CNI minimization (3-5ng/mL) Add mTORi (5-7mg/mL) Discontinue MMF/Myfortic

Rejection with low CNI levels

Increase CNI dosing after rejection treatment Continue TAC/MMF as per protocol

Pregnancy

Continue CNI (8-10 ng/mL) Discontinue MMF Start Imuran (100mg/d) After pregnancy, resume MMF/Myfortic

Fig. 49.1  Reasons for deviation from steroid use maintenance region

ment with a lymphodepleting agent is an important adjunct to the immunosuppressive regimens. In this setting, lower doses of CNI, MMF, and sirolimus can work synergistically to prevent progression to chronic rejection. Interestingly, quadruple therapy using this approach has been highly effective in preventing rejection solitary pancreas transplants, even in the highly immunogenic setting of pancreas transplantation in the preuremic sensitized recipient with type 1 diabetes. Finally, the ability to taper CNI inhibitors remains an important goal for all solid-organ recipients, and of particular importance in the pancreas transplant recipient. There is no question the long-term use of higher doses of CNI results in significant toxicity for the kidney allograft, and likely is the culprit in gradual loss of function. The beta cell toxicity associated in the CNIs likely impacts the ultimate longevity of the pancreas allograft as well. Nonetheless, all categories of pancreas transplants seem to be dependent on CNIs, perhaps as a result of the efficacy in blocking immunologic memory. Along these lines, perhaps the best chance of using low-dose CNI is in combination with higher doses of the non-nephrotoxic, non-beta cell toxic antiproliferative agents (MMF/Myfortic) if they are tolerated. A more recent strategy suggests the potential used of low-dose CNI/MMF in combination with costimulation blockade. Nonetheless, the combination of belatacept and low-dose CNI/MMF resulted in a higher rates of opportunistic infection, highlighting the trade-off of more potent immunosuppression with a higher incidence of infection. Based on immunologic synergy, the combination of mTOR inhibitors with costimulation blockade may provide the best opportunity for a “tolerizing” immunosuppressive regimen. Figure 49.1

depicts clinical scenarios that require deviation from the traditional backbone of maintenance immunosuppression with MMF, TAC, with or without prednisone. Despite the potential for less toxic, long-term immunosuppressive maintenance regimens, CNI and MMF remain the standard of care and the backbone of immunosuppressive regimens in 2021.

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Immunobiology, Diagnosis, and Treatment of Rejection

50

Fahad Aziz, Didier Mandelbrot, Sandesh Parajuli, Talal Al-Qaoud, and Jon Odorico

Contents Introduction 

 675

Immunobiology of Pancreas Rejection   uman Leukocyte Antigen and Its Role in Pancreas Allograft Rejection  H Minor Histocompatibility Complex and Its Role in Pancreas Allograft Rejection  Mechanism of Pancreas Rejection 

 676  676  677  677

Diagnosis of Pancreas Rejection (Fig. 50.1)   linical Features of Rejection  C Laboratory Markers of Rejection  Tissues Diagnosis of Pancreas Rejection  Imaging for Rejection Investigations 

 678  678  680  685  690

Rejection: Based on Recipient Category   PK Vs. PTA and PAK  S SPK Vs. KTA in Diabetic Recipients  Pre-emptive SPK Vs. SPK in Recipients on Pretransplant Dialysis 

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Impact of Induction and Maintenance Immunosuppression on Rejection 

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Risk Factors for Rejection 

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Treatment of Pancreas Rejection   he Decision When to Treat Vs. Not to Treat Rejection  T Rejection Types and Treatment (Table 50.4)  Novel Agents in the Treatment of Pancreas Rejection  Monitoring of Pancreas Graft Function and Immunological Status After Rejection Treatment 

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Pancreas Allograft Rejection and Long-Term Outcome   ejections Are Associated with Poor Pancreas Allograft Outcomes  R Potential Indications for Pancreas Allograft Pancreatectomy 

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Conclusions 

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References 

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F. Aziz · D. Mandelbrot · S. Parajuli Division of Nephrology, Department of Medicine, School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, University of Wisconsin–Madison, Madison, WI, USA e-mail: [email protected]; [email protected]; [email protected] T. Al-Qaoud · J. Odorico (*) Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, University of Wisconsin–Madison, Madison, WI, USA e-mail: [email protected]

Introduction Prolonged insulin-dependent diabetes is associated with multiple complications, including retinopathy, nephropathy, neuropathy, and increased cardiovascular disease [1–3]. Delaying the progression of diabetic complications and

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. W.G. Gruessner, A. C. Gruessner (eds.), Transplantation of the Pancreas, https://doi.org/10.1007/978-3-031-20999-4_50

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improving mortality in people with diabetes is the ultimate goal for the treatment of diabetes. Currently, the only reliable means of durably restoring glycemic control in diabetic patients is a pancreas transplant. A successful pancreas transplant is associated with reduced long-term complications of diabetes and improved quality of life [4–7] (see Chaps. 58– 64). It also reduces mortality in the diabetic population [8–11]. Over the last few decades, improved surgical techniques, advances in immunosuppression, and a better understanding of pancreas graft rejection have led to improved pancreas transplant outcomes [12–14]. As per the OPTN 2018 report, pancreas allograft survival and rejection rates have steadily improved over the past several years [15]. Currently, the half-life of the pancreas in simultaneous pancreas and kidney (SPK) allografts is close to 15 years, and that of a pancreas transplant alone (PTA) is 13 years [16] (see Chap. 66). Even with the significant improvements in overall pancreas allograft outcomes, acute and chronic pancreas allograft rejection continues to be a significant negative prognostic factor for long-term graft survival [17–20]. The primary immune mechanisms responsible for allograft rejection continue to be a central area of transplant immunology research. A pancreas transplant routinely exposes recipients to multiple human leukocyte antigen (HLA) mismatches, which may lead to the development of anti-HLA antibodies specific to the donor in some recipients; these antibodies are also known as donor-specific antibodies (DSA) [21, 22]. Both pre-transplant DSA and post-transplant de novo DSA (dnDSA) increase the risk of antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR) of the pancreas allograft, which are associated with inferior long-term pancreas allograft outcomes [23–27]. Other than antibodies directed against HLA, antibodies directed against non-major histocompatibility antigens such as angiotensin 1-receptors may also be responsible for initiating a direct and indirect immune response to the pancreas allograft [28–30]. For example, Hankey et al. identified a role of major histocompatibility complex (MHC) class I chain-related antigen A (MICA) and MHC class I chain-related antigen B (MICB) in kidney and pancreas allograft rejection. They found that the MICA and MICB were expressed in epithelial cells in kidney and pancreas grafts that showed histological evidence of rejection and/or acute cellular injury. They concluded that expression of these gene products may participate in allograft rejection [31]. Many advances have been made to better understand pancreas allograft injury due to HLA and non-HLA antibodies to improve long-term pancreas allograft outcomes [32]. This chapter will focus on the immune mechanisms leading to pancreas allograft rejection, the diagnosis of pancreas allograft rejection, and the treatment strategies for different types of pancreas rejection.

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Immunobiology of Pancreas Rejection The initial principles of graft rejection were established by Sir Peter Medawar in the 1940s while performing rabbit skin transplants [33, 34]. Afterward, extensive research was done to understand the complexity of the rejection process to improve overall graft outcomes. Multiple studies showed that the immunobiology of pancreas allograft rejection is similar to that of other types of solid-organ transplants [23, 32]. As pancreas and liver originate from adjacent regions of the definitive endoderm, the histology of the two organs matches with each other [35–37]. At the end of organogenesis, both pancreas and liver develop a tissue organization that allows them to function as amphicrine glands [37]. Due to the similarity in their basic histology, the rejection pattern of both organs also matches with each other. With the variations in MHC expression type and sensitivity to ischemia, different rejection patterns are seen for the exocrine and endocrine components of the pancreas [38–40]. The blood vessels, ducts, and acini are the targets of cell-­ mediated rejection, while islets of Langerhans are usually not affected to a significant degree in the early stages of rejection [41–43].

 uman Leukocyte Antigen and Its Role H in Pancreas Allograft Rejection In humans, the MHC, responsible for vigorous allograft rejection, is called the HLA system and is located on the short arm of chromosome 6. The HLA complex encodes polymorphic cell-surface glycoproteins and has two classes: Class I molecules (HLA-A, B, C) and Class II molecules (HLA-DP, DQ, DR) [44]. Both class I and II glycoproteins determine the recognition of foreign or viral antigens by lymphocytes. Class I molecules are expressed by most cells and tissues, while Class II molecules are expressed only by B lymphocytes, macrophages, monocytes, and dendritic cells [45]. Antigenic peptides from within cells are presented by the Class I molecules (e.g., antigens from intracellular viruses, tumor antigens, and self-antigens) to CD8+ T cells, whereas Class II molecules present extracellular antigens such as extracellular bacteria to CD4+ T cells. In their rat model, Steiniger et al. noted profound changes in MHC antigen expression in the pancreas graft during early phases of acute rejection. Though cells of the normal pancreas are largely MHC Class I antigen-negative, exocrine acinar cells began to strongly express these antigens during rejection. MHC Class II antigens, typically not found in pancreatic endothelium or parenchymal cells, appeared in duct epithelial, acinar cells, and in the endothelial cells of large vessels. However, endocrine islet cells remained MHC Class II antigen-negative throughout the rejection process [39].

50  Immunobiology, Diagnosis, and Treatment of Rejection

Thus, it is now known that both MHC Class I and Class II antigens are expressed on acinar cells. The β-cells express MHC Class I antigens, and duct epithelial and endothelial cells express MHC Class II antigens during the rejection process. As MHC Class II antigens are not expressed on β-cells, the depletion of Class II positive endothelial or passenger leukocytes remains a potential target to avert rejection [46–48].

 inor Histocompatibility Complex and Its Role M in Pancreas Allograft Rejection Minor histocompatibility antigens are T-cell epitopes derived from polymorphic proteins [49]. They are presented by MHC Class I and Class II molecules. They can act as a transplantation barrier in allogeneic HLA-matched solid organ transplantation [50]. Minor antigens are recognized by cytotoxic CD8+ T cells and can cause tissue destruction. The current literature on the influence of minor histocompatibility antigens in pancreas transplant is scarce. Most of the literature on the role of minor histocompatibility antigens in solid organ transplant is derived from the kidney transplantation literature.

Mechanism of Pancreas Rejection Like any other transplanted organ, the pancreas allograft’s immune response consists of cellular and humoral mechanisms. The rejection reaction consists of: (A) sensitization stage and (B) effector stage.

Sensitization Stage The critical step in evoking an immune response is antigen presentation. The antigen can be presented either directly or indirectly. Direct Allorecognition In direct allorecognition, intact allo-MHC antigens on the surface of circulating graft-derived antigen-presenting cell (APC) directly stimulate host T cells in lymphoid tissues. T-cell receptors (TCR) on T cells recognize allogenic MHC molecules and the particular peptides in the allo-MHC groove [51]. Direct presentation can involve allorecognition of Class I and Class II MHC antigens by CD8+ T cells and CD4+ T cells, respectively. Early graft rejection is caused primarily by the direct allorecognition pathway. Indirect Allorecognition In indirect allorecognition, allogeneic MHC antigens are processed and presented by self-MHC molecules on self (host)-APCs. The APCs include dendritic cells, monocytes,

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macrophages, and un-activated B cells. The APCs can degrade internalized antigens by proteolysis; the antigens are then processed into peptide fragments and presented in the groove of host-MHC molecules on the surface of host APCs and recognized by host T cells. Dendritic cells have the most potent antigen presentation. The indirect pathway is weaker than the direct pathway but plays a critical role in developing chronic rejection due to persistent antigenic stimulus. Although both CD4+ and CD8+ T cells can recognize processed alloantigens via the indirect pathway, indirect pathway CD8+ T-cell responses are not believed to contribute strongly to rejection of vascularized allografts. Semi-Direct Allorecognition and Cross-Dressing In semi-direct allorecognition, MHC alloantigens are acquired by recipient dendritic cells by uptake of extracellular vesicles, or membrane fragments, from donor graft cells. However, unlike indirect presentation which occurs through processed allopeptides, semi-direct alloantigen presentation occurs by re-presentation of conformationally intact protein.

Effector Stage T-Cell Activation The activation of host T cells through the TCR (with costimulatory signals) is an essential step in the alloimmune response. The first signal is provided when the TCR recognizes the peptide–MHC complex. This signaling pathway is the primary target of immunosuppressants. Once the TCR signal is received, a second or costimulatory signal is required for further activation. The absence of a second signal can lead to T-cell anergy or T-cell apoptosis. The costimulatory signal involves a series of proteins on the T-cell surface-like CD28, or CTLA4. The costimulatory signal via the CD28 protein is crucial for the activation of T cells. The signal via the CD40 protein is critical for activating B-cells, monocytes, and dendritic cells. In a mouse model, blockade of both signals resulted in permanent skin graft survival [52]. In a monkey model of kidney transplantation, antibodies to CD40 prevented rejection [53]. Belatacept is a selective T-cell co-stimulation blocker. By binding to CD80 and CD86 on APCs, belatacept inhibits CD-28-mediated T-cell co-stimulation. By blocking co-­ stimulatory molecules, belatacept also inhibits the clonal proliferation of cytotoxic T cells, which play a main role in graft rejection [54, 55]. The clinical trials showed that belatacept was associated with superior renal function and similar patient and graft survival vs. cyclosporine at 1-year post-­ kidney transplant, despite a higher risk of early acute rejection [56]. This difference was maintained even at 7-year post-kidney transplant [57]. However, the utility of belata-

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cept as maintenance immunosuppression in pancreas allograft recipients is not known. In a recent study, Stock et al. randomized SPK recipients into a calcineurin inhibitor (CNI)-based immunosuppressive regimen or investigational arm using low-dose CNI plus belatacept with the intent to withdraw the CNI.  Both arms had induction with anti-­ thymocyte globulin and were maintained on mycophenolate sodium or mycophenolate mofetil with rapid steroid withdrawal. The rate of biopsy-proven rejection of the pancreas allograft was low in both groups until CNI was withdrawn. Four out of five pancreas allograft rejections occurred during or after CNI withdrawal. Interestingly, the rate of biopsy-­ proven acute rejection in the kidney allografts was low in both arms. Pancreas allograft survival at 52 weeks was 100% in the control arm and 86% in the investigational arm [58]. Further studies are needed to understand the use of belatacept in the pancreas allograft recipients. Generation of Immunity After activation, CD4+ (T helper) cells differentiate into effector T cells. CD4+ T cells play a dominant role in directing graft rejection. Activated CD4+ T cells can be categorized into two distinct subsets based on cytokine secretion: T helper 1 (Th1) and T helper 2 (Th2) cells. Th1 cytokine production leads to cell-mediated immunity with the generation of specific cytotoxic T lymphocytes (CTLs) and activated macrophages. Th2 cytokine production leads to humoral immunity [59]. Apart from the different immune responses generated by Th1 or Th2 cells, the immune outcome may differ. A Th1-dominant response results in rejection, whereas a Th2-dominant reaction may be associated with induction of tolerance to the graft [60, 61]. Graft Infiltration The migration of activated leukocytes into the graft, across the blood vessel barrier and to the site of injury are crucial sequential steps in the rejection cascade. Activation of endothelial cells increases the expression of adhesion molecules and facilitates neutrophil and lymphocyte diapedesis and transmigration across the vessel wall. The establishment of chemoattractant gradients of chemokines facilitates homing of inflammatory cells to graft areas of inflammation/injury. Once inside the graft, the host lymphocytes become activated on exposure to a foreign antigen. They then either produce additional chemokines, which enhance the inflammatory response (CD4+ T cells) or directly kill the foreign cells (CD8+ T cells). Graft Destruction Migration of T lymphocytes and monocytes across the graft endothelium launches the last step of the rejection cascade and causes the graft’s morphologic destruction. The various effector mechanisms can cause (1) hyperacute rejection, (2) acute rejection, or (3) chronic rejection (see Chap. 51).

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Hyperacute Rejection

Hyperacute rejection is antibody and complement-mediated. The major effector cell type involved is the B lymphocyte. Precursor B cells mature into plasma cells and release large amounts of soluble antibody specific for HLA antigens. Antibodies can cause direct damage to the graft via complement binding or via NK cells in antibody-dependent cell-­ mediated cytotoxicity [62]. Antibody (humoral) responses occur rapidly, within seconds, and lead to diffuse vascular injury. Fibrinoid necrosis, thrombosis, and necrosis of the graft occur within minutes to hours. Historical risk factors for hyperacute rejection via preformed antibodies include previous transplants, blood transfusions, or pregnancy. With modern virtual crossmatching techniques using single antigen bead assays, very high serum anti-donor HLA antibody titers are the principal risk factor for hyperacute rejection. Routine pretransplant crossmatching has virtually eliminated hyperacute rejection after a pancreas transplant. It is usually a difficult rejection to reverse. Acute Rejection

Acute rejection is a cell-mediated response. The major effector cell types are T lymphocytes (NK cells, CTLs), monocytes, and granulocytes. NK cells are capable of lysing target cells without antigen interaction. In contrast to NK cells, CTLs are activated to kill foreign graft cells on specific antigen recognition but require CD4+ T cell help to be activated [63]. Chronic Rejection

Chronic rejection is mediated by both cellular and humoral mechanisms. After an initial period of graft damage invoked by an antibody-mediated immune response, cell-mediated damage (first by T cells and later by macrophages) may follow. In contrast to acute rejection, chronic rejection thus far has been resistant to current immunosuppressive therapies. Chronic rejection remains the leading cause of pancreas graft loss after the first year posttransplant. Unique to the pancreas allograft is the observation that chronic rejection may destroy the exocrine, but not the endocrine portion.

Diagnosis of Pancreas Rejection (Fig. 50.1) Clinical Features of Rejection Earlier studies showed that only 5–20% of the patients have clinical symptoms of pancreas graft rejection [64, 65], and as for other organs in modern transplantation practice, most patients have no symptoms or at most mild discomfort in the region of the allograft. In the early post-transplant period, it is clinically difficult to distinguish pancreas rejection from other intra-abdominal processes [66]. In the azathioprine era,

50  Immunobiology, Diagnosis, and Treatment of Rejection

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Fig. 50.1  Algorithm for diagnosis of pancreas rejection

Clinical signs of rejection (elevated lipase and/or amylase, fever of unknown origin, tenderness over allograft)

CT scan or MRI fasting C-peptide/HbA1c/DSA/dd-cfDNA*

Negative intrabdominal findings on imaging, functional pancreas, de novo DSA, elevated dd-cfDNA*

Hyperglycemia Exogenous insulin requirment Atrophic pancreas

Proceed with pursuing tissue diagnosis of pancreas allograft rejection

No biopsy

Pancreas allogtaft biopsy via US or CT guidance or laparoscopically

If the above techniques fail, consider treating emperically. If the tissue diagnosis is still needed, open biopsy can be considered after weighing risk vs benefit.

fever was an important sign of solid transplant organ ­rejection. However, with the widespread use of CNI, this relationship has become less clear. While fever of unknown origin (FUO), or fever with no obvious other infectious cause identified, was considered possible rejection until proven otherwise in earlier eras, in the modern era of pancreas transplant practice, FUO alone is a rare indication for biopsy and is rarely associated with rejection. In their series of 94 pancreas transplant biopsies, Niederhaus et al. performed 3.3% the pancreas biopsies for

FUO [67]. In a recent series, Klasek et al. evaluated the cause of unknown fevers in pancreas transplant recipients. They found that 25% of pancreas transplant recipients experienced an FUO within 31 ± 17-day post-transplant. No particular etiology of the fever was identified in these patients. The fever was not associated with an increased risk of biopsy-­ proven rejections, graft-loss, death, or documented persistent fever [68]. Due to a lack of sensitivity of these clinical features, the diagnosis of pancreas rejection relies heavily on laboratory markers. Even with clinical symptoms, the diagnosis of

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rejection is usually a composite decision based on clinical and laboratory criteria if a biopsy is not obtained.

Laboratory Markers of Rejection Multiple markers of rejection have been studied in pancreas transplantation. These markers can be divided into two classes: (1) exocrine rejection markers and (2) endocrine rejection markers. Depending on the surgical technique for managing exocrine pancreatic secretions, rejection markers can be determined in the serum (all drainage techniques) or urine (bladder drainage only). In the current era of enterically drained pancreas grafts, recent studies have demonstrated that serum lipase is the most sensitive marker of acute rejection [23, 69]. Other exocrine markers studied over the years are either less sensitive or not widely available as a routine lab test and are, therefore, largely of historical interest. Endocrine markers are very late indicators of rejection as the exocrine compartment comprises >95% of the gland by weight/volume and acinar/ductal cells are the major target histologically.

Exocrine Rejection Markers Serum Exocrine Markers of Rejection Serum markers of exocrine rejection can be monitored in all types of pancreas transplants, irrespective of the technique used to manage pancreas exocrine secretions. Serum Amylase and Lipase

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operative period (1 year after transplant), the underlying etiology of elevated pancreas enzymes may be acute rejection, chronic rejection, small bowel obstruction, native pancreatitis, or CMV pancreatitis (Table 50.1) [23]. Cheng et  al. evaluated 41-pancreas transplant patients with biopsy-proven pancreas allograft rejection. The comparison of serum amylase vs. serum lipase revealed sensitivities for rejection of 71% for lipase vs. 50% for amylase. Interestingly, in SPK recipients, serum creatinine sensitivity was higher than the serum lipase [73]. Papadimitriou et al. evaluated 151 pancreas transplant biopsy samples. They found a correlation between the mean levels of pancreatic enzymes and the grade of rejection (r = 0.24, p = 0.012). In Table 50.1  Causes of elevated amylase and lipasea Causes of elevated amylase and Time after pancreas transplant lipase 1-year post-pancreas Acute rejection transplant Chronic rejection Small bowel obstruction Native pancreas pancreatitis CMV pancreatitis Constipation IPMN/Adenocarcinoma Incarcerated hernia Pancreatic transplant duct stricture

Though many studies have shown the non-specificity of the elevated amylase and lipase in pancreas allograft recipients [70–73], elevated pancreatic enzymes remain the most common presentation of pancreas allograft rejection [23]. In otherwise asymptomatic patients, elevated pancreatic enzymes are frequently due to rejection of the pancreas allograft, although constipation, bowel obstruction, pancreatic pseudocyst, pancreatic graft adenocarcinoma or CMV pancreatitis can also elevate the enzymes. However, especially in symptomatic patients, one must consider native gland sources (since the native gland is still innervated) or more sinister surgical complications of the transplanted graft. Of course, it is always important to consider the possibility that the elevation in pancreatic enzymes may be due to inflammation in the native gland [23]. In their systematic review, Hameed et  al. found that reduced clearance of lipase caused by renal impairment, hepatobiliary or gastroduodenal issues, neoplasms, and critical illness can cause a threefold rise in the serum lipase [74]. It is recommended to consider a complete differential diagnosis, including the presence of symptoms and timing of presentation, when evaluating pancreas transplant recipients with a Not including the expected day 1–2 rise in pancreatic enzymes immeelevated serum enzyme levels. For example, in the peri-­ diately post-operatively which represents ischemia reperfusion injury

50  Immunobiology, Diagnosis, and Treatment of Rejection

this study, amylase and lipase correlated very well (r = 0.84, p = 0.0001). However, no correlation was found between the mean serum glucose and the severity of rejection [75]. Similar findings were reported by Sugitani et al. who found the sensitivity of serum lipase to be 71% for detecting pancreas allograft rejection. They also found that a rise in serum creatinine in simultaneous pancreas and kidney transplants with biopsy-proven rejection was a better marker than serum lipase with a sensitivity of 86% [72], though it is well-known that SPK recipients can present with elevated pancreatic enzymes with normal creatinine and have bona fide pancreatic graft rejection detected on biopsy. Niederhaus et al. confirmed that compared to amylase and glucose, serum lipase is a more sensitive marker of rejection. In their series of acute cellular, antibody and mixed rejections, the majority of patients presenting with elevated lipases at the time of biopsy proven rejection had no or minimal elevations in amylase and normal glucoses [67]. In addition, lipase levels are expected to have greater specificity, as serum amylase may also be derived from other tissues, such as salivary glands. Eckfedt et al. recommended that the analyses of serum amylase isoenzymes may help diagnose pancreas allograft rejection [76]. In a recent study, Parajuli et al. analyzed pancreatic enzymes in pancreas transplant recipients within 5-days of the transplant. The study had 287 SPK recipients and 156 solitary pancreas recipients. The study showed higher amylase and lipase were associated with an increase in early complications, primarily fluid collections [77]. Serum Anodal Trypsinogen (SAT)

In 1986, Borgstrom et al. described serum anodal trypsinogen (SAT) as a possible marker to detect pancreas allograft rejection [78]. The concept of human SAT is based on the idea that extensive damage to pancreatic exocrine tissue during an episode of rejection or pancreatic inflammation releases anodal trypsinogen in the blood, and SAT measurement can be used as a marker of pancreas rejection [79]. Perkal et al. reviewed the SAT levels in nine SPK and two PAK recipients with a presumptive kidney allograft rejection diagnosis. The biopsy results correlated with SAT levels in all cases of kidney allograft rejection [80]. Ploeg et al. also found a significant relationship between the kidney and pancreas allograft rejection and the rise in SAT [71]. Similar results were also reported by the other studies, which showed elevated SAT levels in SPK patients with rejection [81]. Despite these small studies, the specificity of the SAT is limited. The levels of SAT are frequently elevated in the early post-transplant period, reflecting preservation injury. SAT levels are also elevated in patients with reduced kidney function, as the kidneys are the primary route for degradation of trypsin [72, 73]. Though early reports suggest that SAT can be a valuable marker for detecting rejection in SPK recipients, its usefulness has yet to be determined in PTA recipients.

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Plasma Pancreatic Secretory Trypsin Inhibitor

Plasma pancreatic secretory trypsin inhibitor (PSTI) has been used as a marker of acute pancreatitis [82, 83]. Kuroda et al. first reported increases in PTSI levels in a dog model of pancreas transplant rejection [84]. Suzuki et al. studied PSTI in 17 SPK and 7 kidney alone transplants. PTSI levels increased significantly in SPK recipients, 1 day before the clinical diagnosis of rejection. However, the PSTI elevation was less valuable in patients with kidney allograft rejection [85]. Later, Suzuki et  al. found that the specificity of increased PSTI levels was not sufficient to diagnose pancreas allograft rejection [86]. Pancreas-Specific Protein

Pancreas-specific protein (PSP) is elevated in both acute pancreatitis and pancreas rejection [87]. Small clinical studies showed that PSP is elevated in pancreas allograft rejection and pancreatic graft thrombosis and pancreatitis [88–91]. Taken together, these findings suggest that PSP monitoring has low sensitivity and is not specific for pancreas allograft rejection [91]. Pancreatitis-Associated Protein

Pancreatitis-associated protein (PAP) is absent from normal pancreatic secretions but is present in the pancreatic juice 6–24-h post-pancreas transplant. PAP is expressed on acinar cells when activated by injury to the pancreas, including in the setting of acute and chronic pancreatitis, hypoxia, toxins, lipopolysaccharides, and diabetes [92–97]. Van der Pijl et al. found that the PAP values in SPK recipients were significantly higher in patients with histological rejection than in patients with no rejection (median: 925 ng/ ml vs. 322 ng/ml, p = 0.006). Furthermore, in patients with pancreas rejection, there was significant PAP staining on acinar cell membranes. They also found a substantial relationship between immunostaining and serum PAP levels (p = 0.0008). Importantly, positive PAP staining was not observed in concurrently collected biopsies of kidney grafts undergoing rejection. Serum PAP levels had a positive predictive value of 78% and the negative predictive value was 60% [98]. Cytokines

Animal studies suggest that disease-specific serological cytokine profiles can distinguish between allograft rejection and infections [99]. Georgi et  al. observed eight SPK and two PAK recipients and found that elevated serum or urinary interleukin-2 (IL-2) levels correlated well with the clinical and histological diagnosis of rejection. Interestingly, most IL-2 levels were elevated 1–3 days before the diagnosis of rejection, and with the successful treatment of rejection, the levels returned to baseline. Unfortunately, septic complications also led to elevated IL-2 levels comparable to those

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with rejection [100] severely reducing specificity. Several other studies also found that an elevation of IL-2 serum levels was associated with rejection, benign pancreatitis, and a variety of viral infections [101, 102]. Small cohort studies evaluated the potential relationship of interleukin-6 (IL-6), interleukin-10 (IL-10), and tissue necrosis factor levels with pancreas allograft rejection. Due to smaller sample sizes, these studies failed to show significant predictive value in diagnosing the pancreas rejection [103, 104]. Others

A few studies evaluated pancreatic elastase as a potential biomarker of pancreas allograft rejection. It was not found to be a useful marker for detecting pancreas allograft rejection [105, 106]. A marker of T-lymphocyte activation, neopterin, was evaluated by Brattstrom et  al. as a potential marker for detecting pancreas allograft rejection. They looked at 18 pancreatic rejection episodes and evaluated neopterin in the serum and the pancreatic juice. They found neopterin in the pancreatic juice correlated well with the pancreas rejection episode and was positive even before cytology turned positive. Unfortunately, in this same study, serum neopterin was not found to correlate with pancreas allograft rejection [107]. Königsrainer et al. also found that pancreatic juice neopterin is a sensitive and specific marker of pancreas rejection in SPK recipients [108]. However, more extensive trials are needed to find neopterin’s utility as a potential marker for detecting pancreas allograft rejection, as it not common to have routine, non-invasive, serial access to pancreatic juice in modern clinical practice. Small studies have also evaluated phospholipase A2 (PLA2) and amyloid A, but are inconclusive and larger cohort studies are needed [87, 109]. Urine Exocrine Markers of Rejection With a bladder drained pancreas allograft, urinary markers have been used to detect pancreas allograft rejection. However, in the recent era with more enteric-drained pancreas allografts, the use of these markers has become much less common. In addition, they are not specific for rejection. Urinary Amylase and Lipase

Early animal studies suggested that the urinary amylase declines significantly before the onset of hyperglycemia and with pancreas allograft rejection [110]. Reductions in urinary amylase levels correlate with loss of acinar mass and exocrine gland atrophy/fibrosis. Thus, decreased urinary amylase levels may be a late indicator of rejection based on modern concepts of rejection pathology studied by direct parenchymal biopsies and codified by the Banff Pathology groups [111] (see Chap. 51).

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Another limitation of urine monitoring is that hypoamylasuria is not specific for pancreas allograft rejection. Hypoamylasuria may be caused by preservation injury, graft thrombosis, chronic pancreatitis, ductal obstruction, extremely acidic urine (urine pH < 6), extremely alkaline urine (urine pH > 9), and faulty collection and processing, including repeated freezing and thawing of the sample[112–114]. In addition, it is a very cumbersome process for patients to collect and transport large volumes of urine for repetitive analysis. Benedetti et  al. evaluated hypoamylasuria and pancreas graft biopsy results in all three pancreas recipient categories. In assessing the urine amylase test quality, they found a sensitivity of 100% (stable urinary amylase levels indicated no rejection), but a specificity of only 30%; the predictive value of a positive test was 53% and of a negative test was 100% [115]. Munn et al. reported 18 episodes of hypoamylasuria in 30 SPK patients. Histological examination of 14 specimens showed rejection in 64% only, fibrosis in 14%, enzymatic necrosis in 7%, CMV pancreatitis in 7%, and no abnormal features in 7% [116]. Thus, stable urinary amylase levels can rule out pancreas allograft rejection. However, with a decline in urinary amylase levels, other possibilities should also be ruled out along with pancreas allograft rejection, and a pancreatic biopsy is indicated in this setting. The measurement of urinary lipase in pancreas transplant recipients has not gained widespread application. The utility of measuring urine lipase is still not well-described. Urine pH

Nghiem et  al. tested the urine pH of pancreas transplant recipients. They found that patients with bladder-drained pancreas grafts had higher urine pH than did patients with an enteric-drained pancreas (7.8 ± 0.1 vs. 6.1 ± 0.3), which is not surprising given the sodium bicarbonate-rich pancreatic juices secreted by the graft. They also found that with rejection episodes, the pH of urine in bladder-drained pancreas transplant patients dropped to 7.1 ± 0.1 [116]. Though being the most straightforward test, the urine pH is the least specific test for detecting rejection.

Endocrine Rejection Markers Plasma Glucose As early acute pancreas allograft rejection usually affects the exocrine tissues first, i.e., ducts, acinar cells, and vasculature, before it affects the islet cells, the presence of fasting hyperglycemia is a late but important finding [70]. Papadimitriou et al. found that an increased serum lipase correlates with the grade of acute rejection of the pancreas allograft, but glucose levels were not sensitive markers for acute rejection [75]. Niederhaus et  al. observed similar findings in their large series of pancreas graft rejections [67].

50  Immunobiology, Diagnosis, and Treatment of Rejection

Hyperglycemia with elevated pancreas enzymes is more specific for acute rejection, although this can represent a late and ominous finding with poor reversibility. On the other hand, hyperglycemia without elevated pancreas enzymes may present complete graft thrombosis, or if mild and gradual, this could represent infection, CNI toxicity, increased insulin resistance due to weight gain, post-transplant diabetes or more rarely recurrence of autoimmune type 1 diabetes [70, 117–120]. Gill et al. found that hyperglycemia has high specificity for pancreas allograft rejection (90–95%) representing a late rejection phenomenon; however, its sensitivity to diagnose rejection is low (20%), as there are numerous other causes as noted above[70]. C-peptide C-peptide is a 31-amino acid polypeptide that is cleaved from proinsulin during the process of insulin production and storage. Its half-life is 3–4 times greater than the half-life of insulin. Basal and stimulated C-peptide determinations in plasma are a common method of assessing endocrine pancreatic function in diabetic recipients with or without kidney failure, and with and without a kidney transplant. Singh et al. found that higher C-peptide levels were associated with poor patient survival in SPK recipients [121]. Xie et al. assessed whether an acute rise in C-peptide could predict pancreas allograft rejection. C-peptide levels drawn prior to the documented rejections were significantly more elevated in patients with acute rejection than patients with borderline or no rejection (P = 0.006) [122]. Serum C-peptide levels are affected by fasted/fed status and kidney function. Baseline fasting serum C-peptide levels in T1D recipients are generally very low, 2–8 ng/mL), and high (>8 ng/mL). In the multivariate analysis, higher levels of pretransplant C-peptide was associated with the inferior graft dysfunction [125].

 re-transplant and De Novo Donor-Specific P Antibodies Multiple studies showed that the presence of pretransplant DSA and the development of dnDSA are associated with poor kidney allograft outcomes [126–128]. Betjes et al. evaluated

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patients with kidney transplants between 1995 and 2005. Pretransplant DSA were determined retrospectively. Pretransplant DSAs were found in 21.8% of the patients. The presence of pre-transplant DSA was associated with increased risk of graft failure within 3 months after transplantation due to rejection (p < 0.01). One year after transplant, the pretransplant positive DSA group continued to have increased risk of ABMR through 10-year post-­transplant [129]. Parajuli et al. reviewed kidney allograft biopsies of 45 kidney transplant alone (KTA) patients who had positive dnDSA. 64% of these patients had stable graft function at time of biopsy. Even with stable graft function, they found a high rate of rejection (53%). With a high rate of subclinical rejections, they recommended protocol biopsies in patients with dnDSA [130]. In another study, Kauke et al. retrospectively investigated the clinical relevance of de novo C1q-binding HLA–DSA antibodies on graft outcomes in 611 kidney transplant recipients. Patients who developed dnDSA had a significantly increased risk of acute rejection. dnDSA was also associated with reduced 5-year graft survival [131]. Standard monitoring of DSA in kidney transplant recipients reduces the risk of kidney allograft loss [132]. The emergence of dnDNA in heart and liver transplant is also associated with an increased incidence of allograft loss [133–137]. Despite these significant findings in other solid organ transplants, the importance of dnDSA monitoring in pancreas transplant recipients is less well-understood. Cantarovich et  al. followed 167 consecutive patients (152 SPK) for 9 years to detect dnDSA. 24% of these patients developed dnDSA.  Rejection episodes were significantly higher in patients with dnDSA (42.5% vs. 11%, p = 0.001). The patients with dnDSA had more severe rejection based on rescue therapy (p < 0.001). Furthermore, non-technical pancreas allograft loss and kidney allograft loss were higher in patients with dnDSA (32.5% vs. 11%, p < 0.01) [25]. Mittal et  al. reported similar findings. They monitored anti-HLA–DSA in four hundred and thirty-three pancreas transplants (317 SPK and 116 isolated pancreas transplants) at 0-, 6- and 12-month post-transplant, annually thereafter and during any clinical event. Approximately 40% of the patients in this cohort developed dnDSA. The emergence of dnDSA was significantly associated with poorer 1- and 3-year pancreas graft survival in SPK recipients (85.2% vs. 93.5%; 71.8% vs. 90.3%, respectively; log-rank p value = 0.002) and isolated pancreas transplants, including PTA and PAK recipients (50% vs. 82.9%; 16.7% vs. 79.4%, respectively; log-rank p value = 0.001). In the multivariate analysis, the development of dnDSA was retained as a strong independent predictor of pancreas graft failure (HR = 4.66, 95%Cl 2.40–9.05, p < 0.001) [138]. Malheiro et  al. also observed that the emergence of dnDSA was associated with significantly increased risk of both kidney and pancreas allograft loss in SPK recipients [139].

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Parajuli et al. published the University of Wisconsin experience with dnDSA in pancreas transplant recipients. The study comprised 541 pancreas transplant recipients. One hundred twenty-one patients developed dnDSA (22.4%). 32% of those that developed dnDSA exhibited dnDSA to HLA Class I, 56% had dnDSA to Class II, and 12% had dnDSA to both Classes I and II. Pancreas allograft rejection was found in 42% of patients with dnDSA and 20% of the patients without DSA (P < 0.001). In most cases, detection of dnDSA was observed either at the time of or after a rejection episode. The multivariate analysis retained dnDSA as a significant predictor of death-censored pancreas allograft failure (HR = 2.01, 95%Cl 1.26–3.20, p = 0.003) [140]. These studies highlight the potential benefit of monitoring post-transplant dnDSA and doing biopsies for dnDSA. Redfield et al. reviewed the management of pancreas transplant recipients with pre- and post-transplant DSA at the University of Wisconsin. They recommended using a depleting agent for induction therapy in patients with pre-­transplant DSA. Furthermore, the presence of pre-transplant DSA merits more frequent post-transplant DSA monitoring. Elevated pancreatic enzymes in the setting of pre-transplant or dnDSA are an indication for performing pancreas allograft biopsy to rule out rejection. However, it is unclear what to do in the setting of dnDSA with normal pancreatic enzymes (i.e., subclinical dnDSA) [23]. Parajuli et al. examined pancreas transplant recipients in their center from 2005–2020. The patients were divided into 4 groups based on index biopsy and DSA status as rejection-/DSA-, rejection+/DSA-, rejection-/DSA+ and rejection+/DSA+. At 5 year post-biopsy, the rate of death censored graft failure for rejection-/DSA- was 18%, 24% in rejection+/DSA-; 17% in rejection-/DSA+ and 36% in rejection+/DSA+ (P = 0.14). In multivariable analysis, compared with rejection-/DSA-, Rej+/DSA+ was significantly associated with death-censored graft failure (HR = 2.32; 95% CI 1.03–5.20; P = 0.04); however, Rej+/DSA- was not (HR = 1.06; 95% CI 0.32–3.56; P = 0.92). Thus, showing that pancreas allograft rejection in setting of positive DSA has increased risk of allograft failure [141].

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Gielis et  al. evaluated 107 kidney transplant recipients. They collected dd-cfDNA at 10 points over the first 3-month post-transplant. They found that elevations in dd-cfDNA levels were associated with acute rejection, acute tubular necrosis, and acute pyelonephritis [147]. In another study, Jordan et  al. also found that patients with positive dd-cfDNA and positive DSA had a high probability of active ABMR. Furthermore, dd-cfDNA > 2.9% was highly specific for ABMR, with an 89% positive predictive value [148]. Snyder et al. found significantly elevated dd-cfDNA levels in heart transplant recipients with biopsy-proven rejection[149]. Several other studies also demonstrated elevated dd-cfDNA levels in heart transplant recipients with acute rejection in both pediatric and adult patient populations [150, 151]. In their systematic review of 95 articles from 47 studies, Knight et al. found that dd-cfDNA is a promising marker for monitoring the health of solid organ transplants. Their review included 18 kidney, 7 liver, 11 heart, 1 SPK, 5 lung, and 5 multi organ studies [152]. The utility of dd-cfDNA is not yet defined in the setting of pancreas transplantation. Olaitan et al. performed an analysis to establish clinical reference ranges for dd-cfDNA in SPK recipients compared to kidney transplants, including both solitary (SKTR) and repeat (RKTR) kidney transplant recipients. 26 SPK transplant recipients were compared to 202 SKTR, and 12 RKTR. 21 SPK patients had no clinical symptoms/signs of rejection and were deemed stable. Five patients were classified as having an event based on clinical parameters. These events included acute pancreatitis, acute rise in lipase, and kidney biopsy confirmed rejection, and de novo or rising DSA. Stable SPK had median dd-cfDNA = 0.19% (IQR 0.19–0.19 95% CI 0.14–0.42), SKTR had median dd-­ cfDNA = 0.33% (IQR 0.2–0.55, 95%CI 0.39–0.55), with RKTR dd-cfDNA median = 0.51% (IQR 0.24–0.73 95% CI 0.31–0.70); Kruskal–Wallis comparison between groups (p = 0.002) but it is not clear if this is clinically meaningful. Acute event SPK median dd-cfDNA = 0.59% (IQR 0.46–2.2, 95% CI 0.02–2.34), which was significantly elevated compared to stable patients (p = 0.004) [153]. Ventura-Aguiar et al. reported on 41 SPK recipients who underwent pancreas Donor-Derived Cell-Free DNA allograft biopsies, both for cause and surveillance and had Pathologically injured cells release cell-free DNA (cfDNA). ddcf-DNA samples drawn simultaneously. They found that The emergence of commercial assays to measure donor-­ the sensitivity and specificity of ddcf-DNA (cut off 70 cp/ml) derived cfDNA (dd-cfDNA) provides a useful non-invasive for allograft rejection was 85.7% and 93.7%, respectively. marker of allograft injury [142–146], which has been exten- Beyond 45 days post-transplant an increased ddcf-DNA sively studied in kidney and heart transplant recipients. level was better at distinguishing rejection vs. no rejection Bloom et al. evaluated 102 kidney transplant recipients. [154]. In another recent study, Williams et al. prospectively They measured plasma levels of dd-cfDNA and correlated collected dd-cfDNA in 46 SPK recipients. In this cohort, the levels with allograft rejection based on biopsy samples. there were 10 rejection events, 5 of which were confirmed The dd-cfDNA levels were significantly higher in patients with biopsy. The other 5 were treated based on the value of with any type of rejection than they were in patients without ddcfDNA. 97% of the patients had dd-cfDNA < 0.5 in the rejection (95% Cl 0.61–0.86, p < 0.001). Positive and nega- patients who did not have rejection. Interestingly, they tive predictive values for active rejection at a cutoff of 1% claimed ddcf_DNA also helped to distinguish rejection from dd-cfDNA were 61% and 84%, respectively [143]. the graft injury with median values in rejection 2.25%, injury

50  Immunobiology, Diagnosis, and Treatment of Rejection

0.36% and quiescence 0.18% (p = 0.0006). This study showed promising role of dd cf-DNA for rejection surveillance in SPK recipients [155]. The use of dd-cfDNA as a non-invasive monitoring tool in pancreas transplant recipients is conceptually enticing given the significant risk of performing pancreas allograft biopsies. However, more extensive studies are needed to: (1) identify reference cutoff values of dd-cfDNA in SPK, PTA, and PAK transplants, (2) understand assay sensitivity, specificity, ­negative, and positive predictive value, and (3) determine the clinical response of dd-cfDNA to anti-rejection treatments.

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tion in the setting of elevated pancreas enzymes and normal serum creatinine. Routine performance of pancreas allograft biopsies and standardized histological grading is associated with significantly improved 1-year graft survival [159].

Pancreas Allograft Biopsy Methodology

Percutaneous Needle Core Pancreas Allograft Biopsy Allen et al. were first to describe the percutaneous needle core biopsy of the pancreas allograft. They compared percutaneous needle core biopsy with fine-needle aspiration cytology to diagnose rejection in 18 SPK transplants and one pancreas Eosinophil-to-Monocyte Ratio alone transplant recipient. Percutaneous real-time US-guided Recently, Ryu et al. evaluated the utility of serum eosinophil-­ needle core biopsy was successful in 37 of 40 attempts (93%), to-­monocyte ratio as a potential biomarker of acute rejection while fine-needle aspiration was successful in 33 of 47 in 32 pancreas allograft recipients. They found that the attempts (70%). Transient elevation in amylase occurred in eosinophil-to-monocyte ratio was a reasonable predictor of 29% of the patients, which returned to baseline in 3 days. One acute pancreatic allograft rejection (sensitivity 100%, speci- patient with a bladder-drained graft developed transient macficity 76.2%, p < 0.001) at a cutoff ratio of 0.80. Combining roscopic hematuria. Both percutaneous needle core biopsy the eosinophil-to-monocyte ratio and the lipase level was and fine-needle aspiration showed rejection on six occasions even more specific and had 100% sensitivity and 90.5% and the absence of rejection in 16. Their pilot study showed specificity to detect the pancreas allograft rejection. They that a pancreas allograft percutaneous needle core biopsy was concluded that the eosinophil-to-monocyte ratio could be an a practicable and valuable investigation without significant excellent and straightforward predictor of acute rejection in complications [112]. Martinenghi et al. reported similar findpancreas allograft recipients [156]. Larger clinical trials are ings. Using a 21-gauge needle under real-time US guidance needed to validate this potentially valuable finding and to and local anesthesia, they performed biopsies on 14 pancreas determine if the eosinophil to monocyte ratio remains spe- transplant recipients. The sample was adequate in 93% of the cific in the broader setting of other surgical and infectious procedures. Percutaneous biopsies were found to be a reliable causes of pancreatic inflammation and increased enzymes. marker for rejection [160]. A large study from the University of Maryland showed that US-guided percutaneous biopsies provided adequate samples in 88% of cases. Only two cases Tissues Diagnosis of Pancreas Rejection in their series had intra-­abdominal bleeding (only one patient needed surgical intervention). To avoid hemorrhagic compliAs described above, the clinical symptoms and different cations, they recommended that the pancreas should be markers of pancreas allograft rejection generally lack speci- located under US guidance, and the main blood vessels ficity. For example, CMV pancreatitis, though rare, presents should be distinguished and then determine an approach free in an indistinguishable manner compared to allograft rejec- from major blood vessels and overlying bowel [161]. tion, yet the treatments are diametrically opposed. As a Atwell et  al. performed 232 US-guided pancreas transresult, a pancreas allograft biopsy currently represents the plant biopsies in 88 patients. All biopsies were performed gold standard for diagnosing rejection. In the past, pancreas on an outpatient basis using local anesthesia. Seventy-eight allograft biopsies were done reluctantly, given the potential biopsies were performed for clinically indicated reasons, complications, including intra-abdominal bleeding, pancre- and 154 were for surveillance purposes. Two-needle passes atitis, and pancreatic fistulas. However, with the introduction were performed in 84.5% of the biopsy procedures. Almost of better imaging techniques, including ultrasound (US), CT, all biopsies were performed using an 18-gauge biopsy and MRI, and with the availability of special biopsy needles, device. Adequate pancreatic tissue was obtained in 223 the complication rate from pancreas allograft biopsy is sig- (96.1%) of the procedures. 72% of the biopsies were comnificantly reduced [157, 158]. pleted, while the patients were receiving therapeutic aspirin. An accurate diagnosis of pancreas allograft rejection, Clinically significant complications happened in six biopincluding the grade and type, is essential to avoid exposure to sies (2.6%). These complications included three cases of unnecessary rejection treatments and over-­ intra-abdominal bleeding, one case of gross hematuria, one immunosuppression while targeting therapeutic drugs appro- case of allograft pancreatitis, and one case of severe abdompriate to the pathology. Moreover, even in SPK recipients, inal pain requiring overnight observation. Two out of four isolated pancreas allograft rejection can occur, so a pancreas bleeding complications occurred in patients who were on allograft biopsy is required for the timely diagnosis of rejec- aspirin [162].

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Niederhaus et al reported their successful experience with percutaneous real-time US-guided biopsies performed in 49 pancreas allografts for various indications [67]. Later, Redfield et al. described their experience with percutaneous real time US-guided pancreas biopsies at University of Wisconsin. They used 18-guage automatic biopsy devices with the trajectory of the needle toward the tail, avoiding the splenic artery and vein. They reported a very low complication rate with this approach [23]. Percutaneous real-time US-guided biopsy is currently the most commonly used approach at most centers. Percutaneous biopsies can also be performed under CT guidance. Aideyan et al. evaluated 63 CT-guided core biopsies of 42 pancreas allografts. Adequate histopathologic diagnosis was made in 90% of the cases. Minor complications included a transient rise in serum amylase levels (6% of these cases) and transient mild hematuria (1% of these cases). 3% of the cases had a significant complication (substantial hemorrhage). They concluded that CT-guided percutaneous needle biopsy is a safe alternative method for obtaining tissue in pancreas transplant recipients with graft dysfunction [163]. The identification of the pancreas allograft in non-enhanced CT before biopsy may be difficult. Oral contrast is usually given 2 h before the biopsy procedure to opacify the adjacent small bowel [164]. Ability to access the graft by CT-guidance may depend on implantation site and placement. The primary choice of imaging technique varies from center to center, generally depending on available expertise. While both US and CT are effective, US-guided biopsies have the advantages of being more readily available, less expensive and are able to visualize vessels and vital structures in real time. The patient’s prothrombin time, international normalized ration, partial thromboplastin time, hemoglobin level, and platelet count should be evaluated before US- and CT-guided percutaneous biopsy. Post-procedure, vital signs and hemoglobin level should be carefully checked up to 6–8 h after the biopsy. Plavix and aspirin may increase the risk of bleeding complications. Fine-Needle Aspiration Biopsy of Pancreas Allograft Fine-needle aspiration biopsy is a useful skill for the diagnosis of pancreatic rejection in the early stage. The aspiration of infiltrated mononuclear cells can detect both cell and humoral rejection [165]. Acute cellular rejection is defined by an accumulation of immature cells (lymphoblasts, plasmablasts, and monoblasts) that can be quantified according to established cytologic criteria. Vascular rejection is, in general, associated with the proliferation of mononuclear phagocytes and tissue macrophages. The procedure is performed under US guidance. The procedure is usually safe without any significant reported com-

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plications [165, 166]. The major disadvantage is that there is a failure rate of approximately 30%, especially in the presence of peripancreatic effusion or graft thrombosis [112]. Furthermore, the sample can be tested only once, tissue architecture is not ascertained and precise information about type and grade of rejection is not obtained [66]. Cystoscopic Pancreas Allograft Biopsy In 1990, Perkins et al. developed the cystoscopic transduodenal pancreas biopsy technique for bladder-drained grafts [167]. They obtained adequate pancreas tissue in only 2 of their first 10 biopsy attempts and later in 91% (21) of 23 biopsy attempts. The introduction of intraoperative US and modified biopsy needles (18-gauge 40-cm needles) resulted in ≥80% yield of pancreas tissue [168, 169]. An advantage of the cystoscopic biopsy technique is that concurrent duodenal biopsies can be obtained. Studies suggest that the rejection of the duodenum positively correlates with the rejection of the pancreas; however, the absence of duodenal rejection does not preclude rejection of the pancreas itself [170–172]. The rate of massive hematuria with cystoscopic pancreas allograft biopsy is less than 10% [115, 168]. If massive hematuria occurs, it requires continuous bladder irrigation with a three-cavity catheter [168, 169]. Casanova et al. compared open vs. cystoscopic pancreas allograft biopsies. The open approach was associated with a higher incidence of graft loss and is less cost-effective [173]. The main disadvantage of cystoscopic biopsies is their invasiveness. Recipients need to be hospitalized for the procedure and regional or general anesthesia is required [168, 169]. The other drawback is that it can only be used in patients with bladder drained pancreas allografts. With the development of percutaneous biopsy technology and the nearly full transition to enteric drainage, transduodenal cystoscopic biopsy procedures are rarely used. Laparoscopic Pancreas Allograft Biopsy Laparoscopic pancreas allograft biopsy may be required when a CT- or US-guided graft biopsy cannot be performed safely, mostly because the allograft is not easily or safely accessible percutaneously. West and Gruessner initially described the technique of laparoscopic pancreas allograft biopsy; large experiences were later reported by other groups [174–176]. Uva et al. performed 160 laparoscopic pancreas biopsies in 95 patients. There were 146 simultaneous kidney–pancreas biopsies and 14 pancreas-only biopsies due to pancreas alone transplants, kidney loss, or extraperitoneal kidney. 56% of the biopsies were performed due to graft dysfunction, and 44% were protocol biopsies. The pancreas diagnostic tissue yield was 91.2%. The pancreas could not be visualized in 5% of patients, and 3.8% had a non-diagnostic

50  Immunobiology, Diagnosis, and Treatment of Rejection

tissue sample. The kidney tissue yield was 98.6%. 2.5% of the patients had complications requiring laparotomy. Half of all these complications were kidney related. There were no episodes of pancreatic enzyme leak, and there were no graft losses related to the procedure [177]. Open Pancreatic Allograft Biopsy An open biopsy may be an option when an adequate specimen cannot be obtained by less invasive procedures. However, it may be associated with a high incidence of complications, even graft loss. The risks of laparotomy vs. (possibly unnecessary) antirejection treatment must be weighed individually, leaving an open biopsy as the final alternative if a tissue diagnosis is essential [178]. Donor Duodenal Biopsies Early animal studies exploring the utility of this technique suggested that concordance of duodenal and pancreas rejection occurs in only 47% of cases. If the duodenal biopsies are positive for rejection, they likely represent the presence of pancreatic pathology; however, if the duodenal biopsy is negative for rejection, it does not rule out rejection of the pancreas itself [170]. Nordheim et  al. evaluated 113 endoscopic US-guided biopsies of the duodenum graft in pancreas allograft recipients. A total of 22 biopsy-proven pancreas rejections were detected, with two matching duodenal biopsies showing rejection, with a sensitivity of only 9% for the detection of a pancreas allograft rejection. They concluded that the donor duodenum biopsy is not a useful marker to detect rejection in the pancreas allograft [179]. Recently, Brockmann et  al. evaluated the role of endoscopic protocol duodenal graft biopsies at regular intervals post-transplant. Protocol duodenal graft biopsies were performed in 27 consecutive pancreas allograft recipients (10 SPK and 17 PAK) at days 14, 30, 90, 180, 360, and 430. One hundred sixty-seven endoscopic biopsy procedures were performed in 27 grafts. Biopsies showed rejection in 30% of SPK recipients and 82% of PAK recipients as early as 14-day post-transplant. They concluded that the protocol graft duodenal biopsies could detect complications after whole-organ pancreas transplantation and help guide therapy with the potential for improving outcomes [180]. Further studies are needed to evaluate the role of donor duodenal biopsies in pancreas allograft recipients. Moreover, the incidence and management of duodenum alone rejection is not well-defined. Biopsy Algorithm Laftavi et al. described a biopsy algorithm for directly assessing the pancreas allograft. According to their recommendations, percutaneous biopsies should be attempted first, on an out-patient basis, irrespective of the drainage technique. If

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the percutaneous biopsy procedures fail to retrieve an adequate sample, the following options exist: (1) in bladder-­ drained pancreas recipients, a cystoscopic biopsy can be attempted, and if that fails, a laparoscopic biopsy can be done and (2) in enteric-drained pancreas recipients, a laparoscopic biopsy should be tried next. If all of the above techniques fail, and a definitive histopathological diagnosis is needed, an open biopsy can be attempted. However, before moving to an open biopsy, the risk and benefits should be carefully evaluated [178].

 ole of Protocol Biopsy for dnDSA R Multiple studies have shown that pre-transplant DSA in kidney transplant recipients is associated with an increased risk of early rejection and graft loss [181–183]. Similarly, it is also well-known that the emergence of dnDSA in kidney transplant recipients is associated with increased risk of late ABMR, chronic ABMR, transplant glomerulopathy and reduced long-term graft survival [182, 184–187]. Based on these studies, consensus guidelines recommend a protocol biopsy in the transplant kidney recipients who have either pre-transplant DSA or dnDSA. Multiple studies have shown that the presence of DSA in pancreas transplant recipients is also associated with a significantly increased risk of rejection and pancreas allograft loss [188]. However, there are no recommendations on using protocol biopsies in response to dnDSA in the setting of normal pancreatic enzymes in a pancreas transplant recipient. Redfield et  al. described their experience at the University of Wisconsin with pancreas allograft biopsies, where they prefer to perform pancreas biopsies in the setting of dnDSA if there are no contraindications, e.g., no anticoagulation, technically not challenging. The emergence of dnDSA signifies under-immunosuppression and warrants consideration for up-titration of baseline immunosuppression in the absence of a biopsy and the presence of normal pancreatic enzymes. Furthermore, the elevation of pancreatic enzymes in the setting of dnDSA warrants a pancreas allograft biopsy [23]. Future randomized controlled trials are needed to determine the role and timing of protocol pancreas allograft biopsies in the setting of dnDSA with normal pancreatic enzymes.  ejection in Pancreas and Kidney Grafts Is not R Concordant in SPK Recipients Initially, immunological dogma falsely alleged that an equal degree and generally the same type of rejection occurs simultaneously in kidney and pancreas grafts in SPK recipients, as both organs are from the same donor [189, 190]. However, it was later shown that this is not the case, and pancreas and kidney allograft pathology on simultaneous biopsies can be discordant [191].

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Troxell et  al. evaluated 56 pancreas allograft biopsies from 27 patients. There were 21 concurrent pancreas and renal biopsies. Thirteen pairs were concordant for rejection and eight pairs were discordant for rejection; six pairs showed pancreas rejection without kidney rejection and two pairs showed kidney rejection without pancreas rejection [192]. Parajuli et al. published an experience with relatively concurrent biopsies of both organs in SPK recipients. Forty patients were included in the study. 25 (62.5%) patients had some concordance in biopsy findings (11 had rejection of both organs, and 14 had no rejection of either organ). The other 15 (37.5%) were discordant for rejection, as 10 had rejection of only the pancreas, and 5 had rejection of only the kidney allograft. Interestingly, 4 of the 11 patients (36%) with concordance for rejection had different types of rejection (ABMR, TCMR, or mixed) in the two organs. This study highlights the importance of performing biopsies on both organs when indicated [193]. In another study, Uva et al. analyzed 101 concurrent biopsies from 70 SPK recipients with graft dysfunction of either one or both organs. 23 of 57 (40%) of the cases had simultaneous rejection; 19 of 57 (33.5%) and 15 of 57 (26.5%) showed kidney or pancreas only rejection, respectively. The degree and type of rejection were different in most cases with concurrent rejection (13 of 23, 56.5%), and the pancreas generally had a higher grade of rejection. Importantly, a positive kidney biopsy in patients with pancreas graft dysfunction correctly predicted pancreas rejection in 86% of instances. However, there was a lack of complete concordance between the two organs, as discrepancies were also observed in the grade and type of rejection in many cases [194]. The prevalence of discordant pancreas and kidney rejection histopathology in SPK transplants underscores the merits of concomitant organ biopsies in this population.

Biopsy Adequacy An adequate core biopsy sample from the pancreas allograft is recommended to have: (1) three lobular areas and (2) associated inter-lobular septae (see Chap. 51). Though arterial structures are sampled with less consistency, the absence of arterial structures in the biopsy core should be noted in the pathology report due to its diagnostic importance [111, 195, 196]. As inflammation affects the exocrine portion of the pancreas before the endocrine portion, the presence of islets in a pancreatic core biopsy is not necessary to determine the presence or absence of rejection or biopsy adequacy [111]. In the setting of hyperglycemia, size and quality of the islet cells, and the presence or absence of islet inflammation should be noted, and consideration made for performing endocrine staining.

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Histological Diagnosis of Rejection (see Chap. 51) Acute Cellular Rejection (ACR) of the Pancreas Allograft (Table 50.2) A histological diagnosis of acute cellular rejection is made by finding inflammatory infiltrates in the pancreatic parenchyma. Interestingly, the features of pancreas graft ACR more closely model that of liver graft ACR than kidney graft ACR.  The inflammatory infiltrate includes lymphocytes, eosinophils, mononuclear cells, and plasma cells [198–200]. These infiltrates first access the septal regions via the venules resulting in endothelialitis and then progressively invade acinar lobules, ductal epithelium (ductitis), and arterioles (arteritis) in more advances cases. Islets of Langerhans are largely spared in routine ACR cases. Acinar and ductal inflammation can also occur in non-rejection-related pancreatitis and can sometimes be difficult to differentiate. However, vascular lesions such as endothelialitis and arteritis are very specific for the diagnosis of rejection. The term “isletitis” or “insulitis” is used when there is a lymphocytic infiltrate of the islets of Langerhans and is an uncommon finding, yet if present in isolation would suggest recurrent autoimmune diabetes [158]. Drachenberg et al. evaluated 26 histological features in 92 biopsies performed to confirm the clinical diagnosis of rejection. They compared those results with 31 protocol biopsies, 12 allograft pancreatectomies with non-rejection pathology, and 30 native pancreas resections with various disease Table 50.2  Grades of T-cell-mediated rejectiona Grade of rejection Grade I/mild acute T-cell-mediated rejection

Histology Active septal inflammation (activated, blastic lymphocytes with or without eosinophils) involving septal structures: Venulitis (subendothelial accumulation of inflammatory cells and endothelial damage in septal veins, ductitis (epithelial inflammation and damage of ducts) and/or Focal acinar inflammation. No more than two inflammatory foci per lobule with absent or minimal acinar cell injury Grade II/moderate Multifocal (but not confluent or diffuse) acinar inflammation (≥3 foci per lobule) with spotty acute T-cell-­ mediated rejection (individual) acinar cell injury and dropout and/or Mild intimal arteritis (with minimal, 25% luminal compromise. and/or Transmural inflammation—necrotizing arteritis  Drachenberg et al. [197]

a

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p­ rocesses. Based on these comparisons, a group of findings relating to vascular, septal, and acinar inflammation was identified indicating a diagnosis of rejection. Graft loss due to pure immunologic causes increased proportionally to the grade of rejection (0, 50, 66, and 100% for grades II, III, IV, and V, respectively) [42].

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ity of patients in this cohort were treated with steroid pulses, with some cases requiring anti-thymocyte globulin (rATG), IVIG, and plasmapheresis. 46% of the patients who suffered ABMR lost their pancreas allograft during a mean follow-up of 269.41 ± 168.25 days [208]. In another study, de Kort et al. reported on 27 pancreas transplants with 28 biopsies analyzed for positive C4d stainAntibody-Mediated Rejection of the Pancreas ing and the presence of DSA. The patients were divided into Allograft (Table 50.3) three groups: group 1, patients with no C4d staining, and no ABMR is a well-recognized entity in the field of heart and DSA (n = 13); group 2, patients with either positive C4d kidney transplantation. The diagnostic criteria and treatment staining or DSA (n = 6); and group 3, patients with both difregimens for ABMR in heart and kidney allografts are well-­ fuse C4d staining and DSA (n = 9). They found that features established [201–206]. ABMR of the pancreas allograft was of active septal inflammation, acinar inflammation, and acidescribed later but is now well-characterized and included in nar cell injury/necrosis were significantly more abundant in the current Banff schema. In 2006, Melcher et al. reported a the patients who had both C4d staining and DSA. The uncencase of ABMR in a pancreas allograft recipient. The patient sored pancreas graft survival rate was significantly worse in presented with elevation in serum amylase and hyperglycemia group 3 (p = 0.04). They concluded that patients with both 1 month after an SPK transplant. The pancreas allograft biopsy positive C4d staining and DSA may have worse graft outshowed no cellular infiltrates but strong immunofluorescent comes than patients with no C4d staining and DSA [209]. staining for C4d in the interacinar capillaries. Donor-­specific In 2013, Niederhaus et al. looked at risk factors for ABMR HLA-DR alloantibodies were also found in the serum. The in pancreas transplant recipients. They analyzed 162 panpatient was successfully treated with rituximab, intravenous creas transplants in 159 patients who underwent 94 “for-­ immunoglobulins (IVIG), and plasmapheresis [207]. cause” pancreas allograft biopsies. Multivariate analysis In 2009, Torrealba et al. published the experience at the identified several risk factors for biopsy proven acute rejecUniversity of Wisconsin with the diagnosis of ABMR in pan- tion including primary solitary pancreas transplant (HR = creas transplant recipients. Twenty-seven pancreas transplant 4.42, 95%Cl 1.84–10.59, p = 0.001), non-primary SPK (HR biopsies from 18 patients were analyzed. 16 biopsies = 4.34, 95%Cl 1.55–12.17, p = 0.005), and race mismatch (59.26%) showed at least 5% C4d staining in inter-acinar (HR = 2.96, 95% Cl 1.27–6.85, p = 0.01). 20% of the pancapillaries (IAC) (range 5–90%). Of those, five biopsies creas allografts failed within 1 year after ABMR despite (18.5%) revealed diffuse staining (>50% C4d staining in treatment. Graft survival after acute cellular rejection, IAC), and 11 biopsies (40.74%) showed focal C4d staining ABMR, and mixed rejection was similar. C4d staining >5% (5–50% C4d staining in IAC). 5% or greater C4d staining in in IAC was strongly associated with increased Class I DSA IAC was significantly associated with DSA for Class I or in this study [67]. Class II (p < 0.018). Whereas IAC C4d staining correlates With an increasing understanding of diagnosis and risk with ABMR, C4d staining of small and medium-size vessels, factors for ABMR in the pancreas allograft, Banff 2011 islets, or parenchymal interstitium was not significantly guidelines now define the diagnosis of ABMR based on the associated with the presence of DSA or ABMR. The major- presence of three components: (1) presence of DSA; (2) C4d positivity in IAC; and (3) morphologic evidence of pancreas tissue injury. The histological grading of pancreatic ABMR a Table 50.3  Grades of antibody-mediated rejections also includes acinar inflammation, inter-acinar capillaritis, Grade of vasculitis, and thrombosis [70]. The grades of ABMR are rejection Histological features given in Table 50.3. Grade I/mild Well-preserved architecture, mild monocytic– acute AMR macrophagic or mixed (monocytic–macrophagic/ Recently, Roufosse et al. hypothesized that a 34-gene set neutrophilic) infiltrates with rare acinar cell damage associated with ABMR in other solid organ transplants could Overall preservation of the architecture with Grade II/ improve the diagnosis of ABMR in pancreas grafts. The inter-acinar monocytic–macrophagic or mixed moderate ABMR 34-gene set, composing of the endothelial, natural acute AMR (monocytic–macrophagic/neutrophilic) infiltrates, killer cell, and inflammatory genes, was quantified in 52 pancapillary dilatation, capillaritis, congestion, multicellular acinar cell dropout and extravasation of creas transplant biopsies from 41 patients. 15 samples had red blood cells ABMR only or mixed rejection, 22 had TCMR, and 15 had Architectural disarray, scattered inflammatory Grade III/ no rejection. The ABMR-34 gene set expression profile was severe acute infiltrates in a background of interstitial hemorrhage, significantly correlated with ABMR and mixed rejection in multifocal and confluent parenchymal necrosis, AMR arterial and venous wall necrosis and thrombosis this study (p = 0.001). Interestingly, the ABMR-34 gene set a was the only biopsy feature which was predictive of allograft  Drachenberg et al. [197]

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failure (p = 0.048). They concluded that assessment transcripts could have the potential to improve the diagnosis and outcomes prediction of pancreas allograft biopsies [210].

Imaging for Rejection Investigations Many pathological conditions, such as graft thrombosis, pseudocyst, and intra-abdominal infections, can be diagnosed using different imaging techniques. As such, imaging is useful for initial interrogations for elevated pancreatic enzymes with and without abdominal symptoms. However, no imaging modality findings are sufficiently sensitive and specific for diagnosing pancreas allograft rejection.

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A few studies have investigated the potential utility of contrast-enhanced US for assessing perfusion and/or rejection after pancreas transplantation [215, 216]. Swensson et  al. compared conventional duplex US and contrast-­ enhanced US for identifying vascular abnormalities in pancreas allografts in the immediate post-transplant setting. They found contrast-enhanced US provided a timely and effective evaluation of pancreas allograft perfusion after surgery [217]. As there may be numerous etiologies of regional perfusion abnormalities, the precise role of contrast enhanced US for non-invasively diagnosing rejection has not been defined.

 omputerized Tomography (CT) Scan C Oral and IV contrast-enhanced abdominal and pelvic CT Doppler Ultrasound scans are the work-horse imaging methodology for panUS, both Doppler and gray-scale interrogation, is the most creas transplant recipients, even though there are no specommon imaging modality performed in pancreas transplant cific findings on CT scan imaging suggestive of rejection. recipients. Most commonly, it is used to assess pancreatic Moulton et  al. retrospectively evaluated 68 CT scans in blood flow (i.e., rule out thrombosis) and to guide percutane- 17-patients with pancreas allografts. Patients with clinical ous biopsy. Various US findings and measurements have complications demonstrated a variable degree of pancreatic been tested for their correlation with rejection; however, inhomogeneity and peri-pancreatic inflammation on CT none have proved useful for definitively, noninvasively diag- scan. Unfortunately, these findings were non-specific and nosing rejection. were seen with pancreas allograft rejection, peripancreatic Wong et  al. evaluated 51 US studies performed on 36 infection, bleeding, and anastomotic leak. They concluded patients. They correlated imaging with the US-guided biop- that neither acute nor chronic pancreas allograft rejection sies performed for clinically suspected acute rejection. Gray-­ could be reliably detected by CT scan [218]. However, CT scale US abnormalities in the pancreas graft were present in studies are useful in detecting significant parenchymal 37 studies (73%). The most common abnormality was pan- abnormalities in pancreas allografts, including thrombosis, creatic enlargement (n = 23) with a sensitivity and specificity edema, hemorrhage, pseudocysts, abdominal fluid collecof 58% and 100%, respectively, for acute rejection. Loss of tions, masses, and ductal dilatation, among other findings marginal definition occurred in nine studies, with a sensitiv- [218, 219]. ity and specificity of 15% and 73%, respectively, for acute rejection. A Doppler resistive index (RI) ≥ 0.7 was found in Magnetic Resonance Imaging (MRI) 11 studies with a sensitivity and specificity of 20% and 73%, MRI is a valuable imaging modality for pancreas transrespectively, for acute rejection [211]. plant recipients. Studies have demonstrated that the Aideyan et al. reviewed arterial RIs in pancreas transplant water content of the graft increases during rejection and recipients and correlated RIs with the presence or absence of decreases significantly with effective treatment [220, biopsy-proven rejection. The nine transplants with no evi- 221]. Krebs et al. evaluated 30 MRI imaging studies perdence of rejection had a mean arterial RI of 0.64 (range, 0.49– formed in 25 patients within 3 days of percutaneous 0.80). The six transplants with acute mild or moderate rejection biopsy. The mean percentage of parenchymal enhancehad a mean RI of 0.67 (range, 0.56–0.73). The two transplants ment (MPPE) at dynamic contrast-­e nhanced MR imagwith severe acute rejection had a mean RI of 0.85 (range, ing was calculated. The MPPE was significantly greater 0.80–0.90). They did not find any statistically significant dif- in the normal group than in the rejection or infarction ference between the arterial RI in pancreas transplants of group (P < 0.05). However, those authors concluded patients with acute mild or acute moderate rejection and those that, given the overlap of cases in the normal and rejecwith no evidence of rejection [212]. Other studies also failed tion groups, graft biopsy remains the gold standard for to find a significant relationship between US-derived arterial diagnosing early acute rejection [222]. Other studies RI measurements and pancreas allograft rejection [211, 213]. also had inconsistent results in diagnosing pancreas Although duodenal edema on US may be present with allograft rejection on MRI [223, 224]. Further studies acute pancreas rejection, duodenal edema can also be seen in are needed to better understand which, if any, MRI findischemic–reperfusion injury or pancreatitis [214] and, there- ings are predictive of a diagnosis of pancreas allograft fore, is a non-specific finding. rejection.

50  Immunobiology, Diagnosis, and Treatment of Rejection

Rejection: Based on Recipient Category SPK Vs. PTA and PAK Comparing various recipient categories of pancreas transplantation, SPK has historically been associated with better pancreas allograft outcomes and lower rates of rejection than solitary pancreas transplants [225]. In the cyclosporine era, Gruessner et al. analyzed the incidence of rejection episodes and pancreas graft outcome in all three categories. The cumulative incidence of pancreas rejection episodes at 1-year post-transplant was 61% for SPK, 75% for PAK, and 96% for PTA recipients. The number of recipients with multiple rejection episodes was also significantly higher for PTA and PAK as compared to SPK recipients. The 1-year pancreas graft loss rate from rejection was 7% for SPK, 17% for PAK, and 42% for PTA recipients [226]. Another study also found a higher rate of rejections 1-year post-transplant in PTA and PAK recipients as compared to SPK recipients [227]. Parajuli et al. compared the outcomes of SPK and PAK recipients transplanted over 17 years between 2000 and 2017. There were a total of 611 SPK and 24 PAK recipients during the study period. There were no significant differences between the two groups in pancreas or kidney allograft rejections at 1 year. Similarly, 1-year graft survival for both organs was not different. At last follow-up, uncensored and death-censored graft survival was not statistically different for pancreas or kidney grafts. Furthermore, in Cox regression analysis, SPK and PAK were associated with similar graft survival [228]. On the other hand, PTA remains a risk factor for rejection even in the modern immunosuppressive era [67]. Fridell et al. compared patient survival in a UNOS registry analysis of patients with IDDM and CKD. Whether a patient received an SPK or a PAK, similar early patient survival rates were observed, with equal benefit compared to remaining on dialysis [229]. They were unable to definitively study pancreas rejection, however, because of inconsistent national practices of diagnosing and reporting of pancreas rejection to the UNOS registry. Weiss et al. showed that in patients surviving with kidney function at 1 year, subsequent 1-year unadjusted kidney graft survival in PAK (living donor kidney) recipients was 83% and in SPK recipients was 83.1%. Patient survival in PAK and SPK recipients was 89.6% and 93.6%, respectively [230]. Fridell et al. in a single-­center study compared the outcomes of 142 SPK and 61 PAK transplants. Immunosuppression included induction with anti-thymocyte globulin, early steroid withdrawal and maintenance with tacrolimus and sirolimus or mycophenolate mofetil. One-year patient, pancreas graft and kidney graft survival were similar between the two groups. Acute cellular rejection was uncommon, with 2% requiring treatment in each group [231]. The Toronto pancreas trans-

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plant group also showed comparable 5-year patient, pancreas and kidney graft survival between SPK and PAK transplants, even though higher rejection rates were observed in the SPK group [232]. Nowadays with use of depletional T-cell induction therapies, the 1-year immunological graft loss rate is expected to be 7%, and low C-peptide indicate severely damaged pancreatic tissue. There are currently no firm guidelines on whether to initiate rejection treatment in the presence of significant hyperglycemia or if the patient is already on insulin. Nakhleh et al. reviewed 53 pancreas allograft biopsies to assess the significance of various histopathological features of pancreatic rejection. They found that more patients who suffered ultimate allograft failure had presented with elevated blood glucose at the time of rejection diagnosis than did patients with normoglycemia and evidence of a functional pancreas allograft (p < 0.0001). Histological features that strongly correlated with a negative outcome included moderate to severe inflammation of acinar tissue (p < 0.0001), acinar tissue loss and fibrosis (p < 0.008), and vascular luminal narrowing due to chronic rejection (p < 0.003) [196]. It may be worth treating a rejection episode aggressively if there is minimal fibrosis on the biopsy with detectable normal-appearing islets and normal fasting C-peptide despite short-term hyperglycemia, using corticosteroid pulse therapy [23]. As immunological injury first damages the pancreas’ exocrine compartment before islet cells, extensive parenchymal fibrosis and hyperglycemia are not an absolute contraindication to treating pancreas allograft rejection, if normal-appearing islet cells can be identified on the biopsy [23, 117]. However, fibrosis and hyperglycemia likely portend a worse overall outcome.

Rejection Types and Treatment (Table 50.4) Pancreas allograft biopsy helps to definitively diagnose the type and grade of rejection. Identifying the type and grade of rejection permits the implementation of targeted therapy [188]. Pancreas grade and type are accurately and harmoniously characterized using the Banff schema which was first published in 2008 and subsequently updated in 2011 (Tables 50.2 and 50.3) [111, 197] (see Chap. 51). Niederhaus et  al. analyzed 162 pancreas transplants. They found that after pancreas rejection, patient survival

694 Table 50.4  General recommendations for pancreas allograft rejection treatment T-cell-mediated rejection (TCMR) Treatment TCMR Grade I Steroid pulse alone TCMR Grade II Steroid pulse + rATG with minimum 4.5 mg/kg; uptitrate maintenance immunosuppression as appropriate TCMR Grade III Steroid pulse + rATG with minimum 6 mg/kg; uptitrate maintenance immunosuppression as appropriate Steroid Pulse + Plasmapheresis + IVIG ± Antibody-­ Rituximab; uptitrate maintenance mediated immunosuppression as appropriate rejection Mixed rejection Steroid pulse + Plasmapheresis + IVIG +rATG; uptitrate maintenance immunosuppression as appropriate

was 100%; however, 20% of pancreas allografts failed within 1 year. Graft survival after acute cellular rejection (TCMR), ABMR, and mixed rejection were similar. Interestingly, they also found that in mixed rejection cases, follow-up pancreas survival mirrored that for TCMR alone, if treated [67].

 cute Cellular Rejection A Nonrandomized controlled trials have evaluated the optimal management of different grades of TCMR in pancreas allografts. However, it is important to note that when present, TCMR should be treated appropriately. Recently, Aziz et  al. analyzed the University of Wisconsin experience with the treatment of biopsy-proven pancreas rejection in 158 pancreas allograft recipients. Cases were retrospectively categorized by Banff grade of TCMR I–III, and the response rates and long-term outcomes with steroids alone vs. steroids plus ATG were compared. Interestingly, the response to treatment and graft survival was not different in grade I pancreas rejection between those treated with steroids alone vs. those treated with corticosteroids plus ATG. However, in grades II and III rejection, the response rates and graft survivals were significantly better in patients treated with corticosteroids plus ATG compared with those treated with steroids alone [254]. This study’s findings suggest that it is reasonable to treat mild pancreatic graft TCMR grade I with corticosteroids alone, especially if there is no ABMR component; maintenance therapy can be up titrated with close followup monitoring for adequate response to therapy (i.e., stable, normal lipase levels).  cute Antibody-Mediated Rejection A Definitive evidence for the best treatment for pancreatic allograft ABMR is lacking. If the DSA is positive with histological findings suggestive of ABMR, even in the absence of C4d staining, ABMR treatment should be initiated. The pri-

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mary goal of ABMR treatment is to: (1) eliminate B cells and plasma cells responsible for the production of DSA; (2) remove circulating DSA; and (3) reduce the inflammatory process. Three-to-five plasmapheresis sessions are usually done to remove circulating DSA, and each session of plasmapheresis is followed by low dose IVIG [23, 253]. In addition to plasmapheresis, anti-B cell therapies such as rituximab are usually added to eliminate the B cells and plasma cells responsible for DSA production. Like TCMR, a high dose of corticosteroids is given to reduce the inflammation in the pancreas allograft. Furthermore, baseline immunosuppression is usually increased [253]. Avoidance of DSA, by choosing donors without positive virtual or flow crossmatches, may be the best way to avoid ABMR.

Mixed Rejection Mixed rejection occurs in 7% of pancreas allograft recipients at 1-year post-transplant [23]. In the presence of mixed TCMR and ABMR, a regimen based on a high dose of steroids, ATG, plasmapheresis, and IVIG is usually initiated [23, 117, 253]. Mixed rejection can be treated by first treating TCMR and then ABMR or vice versa. Even in mixed TCMR grade I and ABMR, ATG should be added to the steroid regimen [188].

 ovel Agents in the Treatment of Pancreas N Rejection Eculizumab Eculizumab is a monoclonal antibody against the C5 fragment of the complement cascade and inhibits the generation of the membrane attack complex. It has been approved by the US Food and Drug Administration (FDA) for the treatment of paroxysmal nocturnal hemoglobinuria, and atypical hemolytic uremic syndrome. The use of eculizumab to treat severe and resistant ABMR in kidney transplant recipients is well-known [255–259]. Although the use of eculizumab in the treatment of ABMR in pancreas recipients is not well-­studied, it may be used in cases of resistant ABMR [253]. Bortezomib Bortezomib is a potent, reversible proteasome inhibitor that has been approved by the FDA as first-line therapy for multiple myeloma since 2008. Due to the high protein synthesis rate in plasma cells, bortezomib effectively eradicates the differentiated plasma cells [260, 261]. Various studies have shown that bortezomib can effectively treat severe and resistant ABMR in kidney transplant recipients [262–265].

50  Immunobiology, Diagnosis, and Treatment of Rejection

The use of bortezomib in the pancreas allograft ABMR is not well-documented in the literature. However, it can be used as a second-line treatment of ABMR in pancreas allograft recipients if conventional therapy fails. Other proteasome inhibitors, such as carfilzomib, are also being investigated for ABMR treatment and prevention in other organ systems. To what extent and what niche proteasome, inhibitors will fill in the management of pancreas rejection is undefined.

Tocilizumab Tocilizumab is a humanized monoclonal antibody against interleukin-6 receptor. It has been used in phase I and II trials for the treatment of ABMR in kidney transplant recipients unresponsive to standard of care therapy [266, 267]. There are no randomized controlled trials showing the benefit of toclizumab for the treatment of ABMR in pancreas allografts. I gG-Degrading Enzyme of Streptococcus Pyogenes (IdeS) IdeS cleaves a specific amino acid sequence in the hinge region of human IgG, and neutralizes all the IgG in the body in 4 h of administration [268, 269]. Further studies are needed to look into the utilization of IdeS in the treatment of ABMR. Montgomery et al. described in detail various novel agents which can be potentially used in the treatment of ABMR [270].

 onitoring of Pancreas Graft Function M and Immunological Status After Rejection Treatment After treatment of rejection, pancreatic enzymes and DSA should be monitored closely. Serum lipase is felt to be a more sensitive marker than serum amylase based on prior studies [67] (see above). Pancreatic enzymes are usually monitored twice weekly until they are normalized. If the descent of pancreatic enzymes stalls or starts rising again, some transplant centers will perform pancreas allograft biopsy again. If the pancreas allograft biopsy shows persistent rejection or the type of rejection has changed, then immunotherapy is up-titrated and/or modified. In case of persistent ABMR, more plasmapheresis and IVIG sessions should be done with the addition of anti-B cell therapies, such as rituximab, bortezomib, and eculizumab. In the case of persistent TCMR, ATG should be added if not given already, or additional doses of ATG can be added to the treatment and lymphocyte levels checked. The decision to add additional maintenance therapy, such as sirolimus or everolimus, should be made on a case-by-case basis [23, 253].

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 ancreas Allograft Rejection and Long-Term P Outcome  ejections Are Associated with Poor Pancreas R Allograft Outcomes Studies have shown that acute rejection of the kidney allograft is associated with chronic graft dysfunction and has a negative impact on long-term kidney graft outcomes [271]. Clayton et al. looked at the long-term effect of acute rejection on long-term kidney graft outcomes. Using the Australia and New Zeeland Dialysis and Transplant Registry, 13,614 kidney alone transplant recipients were analyzed. Acute rejection occurred in 2906 recipients and was associated with not only graft loss (HR = 1.39, 95% Cl 1.23–1.56) but also with recurrent acute rejection beyond month 6 (HR = 1.85, 95% Cl 1.39–2.46). Interestingly, acute rejection was also associated with death with functioning graft (HR = 1.3, 95%Cl 1.08– 1.36), death due to cardiovascular disease (HR = 1.30, 95% Cl 1.11–1.53) and cancers (HR = 1.35, 95%Cl 1.12–1.64) [272]. Similarly, acute rejection in liver allografts is associated with poor long-term allograft outcomes [273–275]. In an early era SPK study, Reddy et al. analyzed 4251 SPK recipients, of which 45% did not experience rejection, 36% experienced kidney only rejection, 3% had pancreas only rejection, and 16% had both kidney and pancreas allograft rejection within the first year after transplant. The relative risk of kidney allograft loss was 1.32 when acute rejection involved the kidney allograft alone, while the relative risk was 1.53 when rejection involved both organs. They concluded that patients who have acute rejection of both kidney and pancreas have the worst long-term allograft survival [276]. Niederhaus et al. described a larger single-center experience with SPK, PAK and PTA pancreas transplants, all of whom experienced biopsy-proven pancreas rejection. They found that after pancreas rejection patient survival was 100%, but 20% of pancreas allografts failed within 1 year after the rejection. Graft survival after TCMR, ABMR, and mixed rejection was similar [67]. Parajuli et  al. evaluated 39 pancreas allograft recipients who enjoyed graft survival of more than 25 years. Only 7.7% of this cohort had pancreas allograft rejection, a rate substantially lower than their institutional average rejection rate. The low pancreas allograft rejection rate in this group undoubtedly contributed to the prolonged allograft survival [277].

 otential Indications for Pancreas Allograft P Pancreatectomy Rarely, pancreas allograft failure after rejection requires graft removal. In an earlier report, Troppmann et  al. analyzed 77 allograft pancreatectomies. Vascular graft throm-

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bosis (31%) was the leading indication for pancreas allograft pancreatectomy, followed by failure from rejection (19%) [278]. In another series of 37 transplant pancreatectomies, 22% of pancreatotomies were performed in patients with pancreas allograft loss from severe rejection [279]. In another study, Nagai et  al. analyzed 47 patients who underwent allograft pancreatectomy. The study found that all the patients who had early graft loss (within 14 days after transplant) eventually required allograft pancreatectomy. 61% of patients with late graft loss underwent allograft pancreatectomy. In late allograft pancreatectomy, 68% had graft failure with clinical symptoms, such as abdominal pain and nausea [280]. Parajuli et  al. looked into the reasons for needing late (>90 days) pancreatectomy in those SPK and PAK recipients with failed pancreas allograft but who retained kidney allograft function and remained on full dose immunosuppression. Despite continued immunosuppression, 15% of patients required late pancreatectomy for symptoms. The most common presentation of the patients who required pancreatectomy was abdominal pain. Pancreas graft thrombosis was the most common histolopathology, with fibrosis, necrosis, and chronic rejection also contributing. In multivariate cox regression analysis, only female gender was associated with a higher risk of allograft pancreatectomty (HR = 3.13, 95%Cl 1.48–6.6, p = 0.003) [281]. Late pancreatic graft thromboses are believed to reflect subclinical immunological phenomena and not technical issues, though this remains poorly defined. Wallace et  al. evaluated 23 patients with early allograft pancreatectomy. Acute pancreatic rejection was identified histologically in 9 of the 15 recipients (60%) who lost their grafts due to duodenal leaks or recurrent peripancreatic collections. Interestingly, no acute pancreatic rejection was identified in any patients, whose grafts were lost due to thrombosis or ischemia. They concluded that unsuspected acute pancreatic rejection appears common in the explanted grafts of recipients who have undergone early allograft pancreatectomy for apparently technical reasons [282]. The main indications for allograft pancreatectomy are given in Table 50.5.

Table 50.5  Potential pancreatectomy

indications

of

pancreas

allograft

 1. Duodenal or anastomotic leak  2. Uncontrolled parenchymal enzyme leak and severe intra-­ abdominal sepsis  3. Graft thrombosis  4. Pancreas allograft necrosis  5. Pseudoaneurysm of the pancreatic vessels  6. Arterio-enteric fistulas  7. Chronic rejection in a PTA and desire to eliminate immunosuppression

Conclusions A refined understanding of alloimmune injury mechanisms in pancreas transplant recipients is crucial to preserve the long-term graft function by providing targeted therapy. Over the last decade, knowledge has advanced in many aspects of pancreas rejection as described in this chapter. Pretransplant DSA and dnDSA are important markers to predict rejection in the pancreas allograft and are associated with worse graft survival. Regular DSA monitoring post-transplant is usually recommended. A pancreas allograft biopsy should be performed in a suspected case of pancreas allograft rejection to identify the type and grade of rejection. Well-documented data suggest that pancreas and kidney allograft rejection in SPK recipients may be discordant; therefore, a biopsy of both grafts should be considered if indicated. Once the diagnosis of rejection is made, TCMR, ABMR, and mixed rejections should be treated accordingly. Recent literature suggests that mild grade I TCMR can be first treated with steroid pulse only, with low relapse rates and good preservation of graft function, whereas moderate and severe rejection show better complete response rates with steroids plus ATG.  Further research is needed to look into the utility of protocol biopsies in all or selected patients and whether dnDSA in the setting of normal enzymes warrants a surveillance pancreas biopsy.

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50  Immunobiology, Diagnosis, and Treatment of Rejection ous pancreas/kidney transplants in uremic diabetic patients. Transplant Proc. 1990;22(4):1581. 228. Parajuli S, Arunachalam A, Swanson KJ, Aziz F, Garg N, Redfield RR, et  al. Outcomes after simultaneous kidney-pancreas versus pancreas after kidney transplantation in the current era. Clin Transpl. 2019;33(12):e13732. 229. Fridell JA, Niederhaus S, Curry M, Urban R, Fox A, Odorico J. The survival advantage of pancreas after kidney transplant. Am J Transplant. 2019;19(3):823–30. 230. Weiss AS, Smits G, Wiseman AC. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation. Clin J Am Soc Nephrol. 2009;4(5):988–95. 231. Fridell JA, Mangus RS, Hollinger EF, Taber TE, Goble ML, Mohler E, et  al. The case for pancreas after kidney transplantation. Clin Transpl. 2009;23(4):447–53. 232. Bazerbachi F, Selzner M, Marquez MA, Norgate A, McGilvray ID, Schiff J, et  al. Pancreas-after-kidney versus synchronous pancreas-­kidney transplantation: comparison of intermediate-term results. Transplantation. 2013;95(3):489–94. 233. Cheung AH, Sutherland DE, Gillingham KJ, McHugh LE, Moudry-Munns KC, Dunn DL, et  al. Simultaneous pancreas-­ kidney transplant versus kidney transplant alone in diabetic patients. Kidney Int. 1992;41(4):924–9. 234. Sollinger HW, Stratta RJ, D’Alessandro AM, Kalayoglu M, Pirsch JD, Belzer FO.  Experience with simultaneous pancreas-kidney transplantation. Ann Surg. 1988;208(4):475–83. 235. Odorico JS, Rayhill SC, Heisey DM, Knechtle SJ, D’Alessandro AM, Pirsch JD, et  al. Immunologic risks of combined kidney-­pancreas transplantation. Transplant Proc. 1998;30(2):249–50. 236. Schulak JA, Mayes JT, Hricik DE. Kidney transplantation in diabetic patients undergoing combined kidney-pancreas or kidney-­ only transplantation. Transplantation. 1992;53(3):685–7. 237. Hiesse C, Paradis V, Benoit G, Kriaa F, Blanchet P, Bellamy J, et  al. Analysis of incidence and pattern of acute rejection episodes after simultaneous pancreas and kidney transplantation. Transplant Proc. 1997;29(1-2):671–2. 238. Rayhill SC, D’Alessandro AM, Odorico JS, Knechtle SJ, Pirsch JD, Heisey DM, et  al. Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: is there a difference in survival? Ann Surg. 2000;231(3):417–23. 239. Gruessner AC, Gruessner RW. Pancreas transplantation of US and Non-US cases from 2005 to 2014 as reported to the united network for organ sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud. 2016;13(1):35–58. 240. Gruessner AC, Gruessner RWG.  Pancreas transplantation for patients with type 1 and type 2 diabetes mellitus in the United States: a registry report. Gastroenterol Clin N Am. 2018;47(2):417–41. 241. Dinckan A, Aliosmanoglu I, Kocak H, Mesci A, Altunbas H, Gurkan A. The impact of method on kidney graft and patient survival in kidney-pancreas transplantations for type I diabetes mellitus. Int Surg. 2015;100(1):137–41. 242. Aufhauser DD Jr, Peng AW, Murken DR, Concors SJ, Abt PL, Sawinski D, et  al. Impact of prolonged dialysis prior to renal transplantation. Clin Transpl. 2018;32(6):e13260. 243. Goldfarb-Rumyantzev A, Hurdle JF, Scandling J, Wang Z, Baird B, Barenbaum L, et  al. Duration of end-stage renal disease and kidney transplant outcome. Nephrol Dial Transplant. 2005;20(1):167–75. 244. Parajuli S, Swanson KJ, Patel R, Astor BC, Aziz F, Garg N, et al. Outcomes of simultaneous pancreas and kidney transplants based on preemptive transplant compared to those who were on

703 dialysis before transplant  - a retrospective study. Transpl Int. 2020;33:1106–15. 245. Stratta RJ, Rogers J, Orlando G, Farooq U, Al-Shraideh Y, Farney AC. 5-year results of a prospective, randomized, single-center study of alemtuzumab compared with rabbit antithymocyte globulin induction in simultaneous kidney-pancreas transplantation. Transplant Proc. 2014;46(6):1928–31. 246. Fernandez-Burgos I, Montiel Casado MC, Perez-Daga JA, Aranda-­ Narvaez JM, Sanchez-Perez B, Leon-Diaz FJ, et  al. Induction therapy in simultaneous pancreas-kidney transplantation: thymoglobulin versus basiliximab. Transplant Proc. 2015;47(1):120–2. 247. Bartlett ST, Schweitzer EJ, Johnson LB, Kuo PC, Papadimitriou JC, Drachenberg CB, et  al. Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression with percutaneous biopsy. Ann Surg. 1996;224(4):440–9; discussion 9–52. 248. Gruessner AC, Sutherland DE.  Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Clin Transpl. 2002;2002:41–77. 249. Odorico JS, Becker YT, Groshek M, Werwinski C, Becker BN, Pirsch JD, et al. Improved solitary pancreas transplant graft survival in the modern immunosuppressive era. Cell Transplant. 2000;9(6):919–27. 250. Odorico JS, Pirsch JD, Knechtle SJ, D’Alessandro AM, Sollinger HW.  A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation. Transplantation. 1998;66(12):1751–9. 251. Merion RM, Henry ML, Melzer JS, Sollinger HW, Sutherland DE, Taylor RJ. Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation. Transplantation. 2000;70(1):105–11. 252. Rudolph EN, Dunn TB, Mauer D, Noreen H, Sutherland DE, Kandaswamy R, et al. HLA-A, -B, -C, -DR, and -DQ matching in pancreas transplantation: effect on graft rejection and survival. Am J Transplant. 2016;16(8):2401–12. 253. Alhamad FKA, Stratta RJ. Pancreas-kidney transplantation in diabetes mellitus: pancreas allograft rejection. Waltham: UpToDate; 2020. 254. Aziz F, Parajuli S, Uddin S, Harrold K, Djamali A, Astor B, et  al. How should pancreas transplant rejection be treated? Transplantation. 2019;103(9):1928–34. 255. Yelken B, Arpali E, Gorcin S, Kocak B, Karatas C, Demiralp E, et  al. Eculizumab for treatment of refractory antibody-mediated rejection in kidney transplant patients: a single-center experience. Transplant Proc. 2015;47(6):1754–9. 256. Tan EK, Bentall A, Dean PG, Shaheen MF, Stegall MD, Schinstock CA.  Use of eculizumab for active antibody-mediated rejection that occurs early post-kidney transplantation: a consecutive series of 15 cases. Transplantation. 2019;103(11):2397–404. 257. Tran D, Boucher A, Collette S, Payette A, Royal V, Senecal L.  Eculizumab for the treatment of severe antibody-mediated rejection: a case report and review of the literature. Case Rep Transpl. 2016;2016:9874261. 258. Marks WH, Mamode N, Montgomery RA, Stegall MD, Ratner LE, Cornell LD, et  al. Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: a randomized trial. Am J Transplant. 2019;19(10):2876–88. 259. Eskandary F, Wahrmann M, Muhlbacher J, Bohmig GA. Complement inhibition as potential new therapy for antibody-­ mediated rejection. Transpl Int. 2016;29(4):392–402.

704 260. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et  al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906–17. 261. Jagannath S, Barlogie B, Berenson JR, Singhal S, Alexanian R, Srkalovic G, et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function. Cancer. 2005;103(6):1195–200. 262. Perry DK, Burns JM, Pollinger HS, Amiot BP, Gloor JM, Gores GJ, et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant. 2009;9(1):201–9. 263. Nigos JG, Arora S, Nath P, Hussain SM, Marcus RJ, Ko TY, et al. Treatment of antibody-mediated rejection in kidney transplant recipients: a single-center experience with a bortezomib-based regimen. Exp Clin Transplant. 2012;10(6):609–13. 264. Walsh RC, Brailey P, Girnita A, Alloway RR, Shields AR, Wall GE, et  al. Early and late acute antibody-mediated rejection differ immunologically and in response to proteasome inhibition. Transplantation. 2011;91(11):1218–26. 265. Walsh RC, Everly JJ, Brailey P, Rike AH, Arend LJ, Mogilishetty G, et  al. Proteasome inhibitor-based primary therapy for antibody-mediated renal allograft rejection. Transplantation. 2010;89(3):277–84. 266. Choi J, Aubert O, Vo A, Loupy A, Haas M, Puliyanda D, et  al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant. 2017;17(9):2381–9. 267. Vo AA, Choi J, Kim I, Louie S, Cisneros K, Kahwaji J, et  al. A phase I/II trial of the interleukin-6 receptor-specific humanized monoclonal (tocilizumab) + intravenous immunoglobulin in difficult to desensitize patients. Transplantation. 2015;99(11):2356–63. 268. Wenig K, Chatwell L, von Pawel-Rammingen U, Bjorck L, Huber R, Sondermann P.  Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG.  Proc Natl Acad Sci U S A. 2004;101(50):17371–6. 269. Jarnum S, Bockermann R, Runstrom A, Winstedt L, Kjellman C. The bacterial enzyme IdeS cleaves the IgG-Type of B cell receptor (BCR), abolishes BCR-mediated cell signaling, and inhibits memory B cell activation. J Immunol. 2015;195(12):5592–601. 270. Montgomery RA, Loupy A, Segev DL.  Antibody-mediated rejection: new approaches in prevention and management. Am J Transplant. 2018;18(Suppl 3):3–17.

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Pancreas Graft Pathology

51

Cinthia B. Drachenberg and John C. Papadimitriou

Contents Introduction 

 706

Histological Evaluation of Pancreas Transplants   ormal Pancreas: Histological Aspects  N Biopsy Types 

 706  706  708

Technical Recommendations  Biopsy Adequacy  Processing and Ancillary Tests  Pathological Evaluation of Allograft Pancreatectomies 

 709  709  709  710

Histological Diagnosis of Acute Allograft Rejection  Acute TCMR  Acute AMR  Mixed TCMR and AMR  Chronic TCMR  Chronic AMR  Banff Guidelines for Diagnosis and Grading of Rejection 

 712  712  714  716  716  717  717

Diagnostic Categories  Normal Pancreas  Indeterminate for Rejection  Acute TCMR  Acute AMR  Chronic Allograft Arteriopathy  Chronic Allograft Rejection/Graft Fibrosis  Islet Pathology  Other Histological Diagnosis 

 717  717  717  717  718  718  718  718  718

Islet Pathology  I mpact of Graft Fibrosis  Recurrence of Auto-Immune Type 1 Diabetes Mellitus  Post Transplant DM After Successful Pancreas Transplantation  Beta Cell Injury in Delayed Graft Function  Islet Amyloid  Islet Cell CNI Drug Toxicity 

 718  718  719  719  719  719  719

References 

 720

C. B. Drachenberg (*) · J. C. Papadimitriou Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. W.G. Gruessner, A. C. Gruessner (eds.), Transplantation of the Pancreas, https://doi.org/10.1007/978-3-031-20999-4_51

705

706

Introduction Overall outcomes in pancreas transplantation continue to improve, but allograft rejection and other non-­immunological complications still affect short- and long-term graft survivals [1–4] (see Chap. 66). Laboratory tests including ­determination of abnormal pancreatic enzymes (amylase, lipase) are not specific, and their correlation with biopsy proven rejection is approximately 80% [5] (see Chap. 50). Allograft biopsies, the gold standard for the diagnosis of pancreas rejection, can also determine rejection type, and provide additional information about overall graft status for prognostic purposes [2, 3, 5–44]. In addition to allograft rejection, tissue evaluation is essential for the diagnosis of other pathological processes, including viral infections, lymphoproliferative disorders, drug toxicity and recurrence of autoimmune Type 1 diabetes mellitus (DM) [29]. Pathological studies were crucial for the advancement of pancreas transplantation since the inception of this procedure [45], and will continue to provide essential information that can help develop strategies to prolong graft survival. Ongoing tissue studies should shed further light on the etiology of complete or partial graft loss and can help in their correct categorization [1, 46].

 istological Evaluation of Pancreas H Transplants Normal Pancreas: Histological Aspects More than 80% of the pancreas parenchyma consists of exocrine glandular tissue; hence, pancreas allograft biopsies are predominantly composed of exocrine glands or

a Fig. 51.1 (a) Normal pancreas transplant biopsy core predominantly composed of exocrine acinar tissue. The exocrine glands (acini) are tightly packed forming lobules separated by connective tissue fibrous septa (S). There are veins (V) and arterial branches (black arrows). Top left insert shows a duct (D) in a septal area. The top right insert shows

C. B. Drachenberg and J. C. Papadimitriou

“acini” tightly clustered forming lobules [47, 48] (Fig.  51.1a, b). The acini are formed by pyramidal cells that converge to form a small glandular lumen that collects exocrine secretions; these drain into the ductal system and eventually reach the main pancreatic ducts. The exocrine cells characterized on electron microscopy by abundant apical zymogen granules that store the digestive enzymes and also have prominent rough endoplasmic reticulum cisternae (Fig. 51.2). The exocrine lobules are separated by connective tissue septa that invaginate from the thin fibrous capsule that surrounds the pancreas (Fig. 51.1b). The endocrine islets of Langerhans, embedded in the exocrine parenchyma, are scattered throughout the pancreas with denser concentration toward the tail [49]. Alpha (α), beta (β), and delta (δ) cells, producing glucagon, insulin, and somatostatin, respectively, are the main components of the islets and are identified histologically with immunostains (Figs. 51.3 and 51.4). The islets vary in size from few to 200 cell aggregates with a predominance of β cells (60–75%) and about 10% of δ cells. Βeta cells tend to form clusters of variable sizes, with the α cells arranging in the periphery of these clusters in a mantle-type arrangement [49–51]. On electron microscopy, α and β cells show distinct features corresponding to the glucagon and insulin secretory granules, respectively. Branches of arteries of various sizes, and thin-walled veins course randomly through the parenchyma and are typically found within the fibrous tissue septa separating exocrine lobules. Branches of the pancreatic duct are also found in the fibrous septa (Fig. 51.1a, b). In addition to the standard arterial and venous vascularization, the pancreatic lobules have a dense network of inter-­ acinar capillaries (IAC) that drain in lobular venules [52]

b two islets embedded in the exocrine tissue (white arrows). (b) Normal pancreas tissue stained with a collagen stain (trichrome stain) that marks the fibrous septa green (arrows) and larger septa with ducts (D). Two islets are also present. Note the lack of fibrosis/collagen between the acini. Compare with Fig. 51.10

51  Pancreas Graft Pathology

Fig. 51.2  Electron microscopy of pancreas exocrine gland (acinus), formed by a cluster of acinar cells with their apical cytoplasm pointing toward the central lumen (L). Near the lumen the apical cytoplasm has abundant secretory granules (zymogen granules), and the basal parts of the cells contain abundant stacks of rough endoplasmic reticulum. Note an interacinar capillary in the connective tissue space to the right of the acinus. The insert is a light microscopic tissue section stained with CD31, a vascular marker that highlights the network of interacinar capillaries. These are the target of antibody-mediated allograft rejection and are marked by the C4d stain when there is endothelial cell injury due to circulating donor-specific antibodies

707

Fig. 51.3  Electron microscopy of islet cells. The islet is separated from the exocrine tissue by the glandular basement membrane (Bm). The alpha cell (A) has the characteristic round, dark secretory granules, whereas the beta cells (B) have more polymorphic granules. The other cell (D) has features compatible with a somatostatin producing delta cell (delta cell)

Fig. 51.4  Hematoxylin and eosin (H&E)_staining of an islet of Langerhans formed by cell clearly distinctive from the surrounding acinar cells. Insulin (β cells), glucagon (α cells) and somatostatin (δ cells) immunostains identify the main populations of endocrine cells forming the islets

708

(Fig. 51.2). The endocrine islets and the exocrine c­ omponents have an integrated microvascular network, functionally working as one organ, rather than two separate tissue components [53, 54].

Biopsy Types Depending on the location of the pancreas transplant, different biopsy approaches may be indicated. Percutaneous needle biopsies are usually done under ultrasound or computer tomographic guidance, with 18 or 20 gauge needles [22, 55, 56]. Adequate tissue is obtained in 88–90% of procedures, with rare complications reported ( 0.1) between the three groups. The only significant predictor of survival was duration of diabetes. On the other hand, comparison of survival curves for TNS1 patients with moderate neuropathy showed an overall significant difference (p < 0.01) with NoPTx and PTxFx groups both doing better than the PTxFld group (p < 0.01) (Fig. 59.4b). A Cox model for the TNS1 patients from the series transplanted after January 1986 showed that, when the pancreas graft functioned at least 3 months, survival was significantly increased (p = 0.02) compared to the NoPTx group, while PTx failure within 3 months did not increase the risk of death significantly (p > 0.3) compared to the NoPTx group. This is in contrast to the pre-1986 period when the survival of PTxFx and No PTx groups was not significantly different (p > 0.3) and graft failure greatly decreased survival chance (p < 0.001). Increased survival expectancy of diabetic patients with a PTx is presumably associated with halt of deterioration and partial improvement of neuropathy, enhanced responses to stressful events, and removal of the metabolic alterations that resulted in secondary complications [37, 108]. In addition, other studies have shown that a simultaneous kidney and pancreas transplant reduced mortality in T1DM patients with end-stage nephropathy compared with diabetic patients with kidney transplants alone or with failed pancreas grafts [105, 125]. The finding that patients with moderate, but not severe, neuropathy transplanted from 1986 had longer survival than non-transplanted patients with a similar degree of neuropathy suggests that patients who elect to have a PTx would benefit more by receiving it early, before the neuropathy progresses to severe. Technic of the transplantation surgery, patient management, and graft failure are all known to affect patient survival [72, 73, 128]. The improved results after 1986 are attributable to several factors, including improved immunosuppressive therapies, earlier detection of graft rejection, availability of antiviral drugs, more frequent simultaneous pancreas and kidney transplants, and better donor–

841

recipient matching, all of which improved graft survival rates. Survival studies performed in the last two decades have reported increased survival rates of diabetic patients after SPK transplants than these previous studies. T1DM patients with renal failure in a waiting list for PTx had about six times higher risk of mortality, even without surgery, than SPK transplanted patients after 1 year [129]. In a registry study in Japan from 2000 to 2018, the survival rates of patients waiting for SPK transplant at 1, 5, and 10 years were 98%, 89%, and 75%, respectively, while those after SPK transplant were significantly improved at 100%, 95%, and 89% [130]. The continuous improvement in management and the early performance of PTx will likely result in amelioration of neuropathy and increased long-term survival of diabetic patients (see Chap. 66).

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842 sive management of insulin-dependent diabetic patients: a two year randomized prospective study. Lancet. 1983;1:204–8. 14. Fedele D, Negrin P, Cardone C, et al. Influence of continuous subcutaneous insulin infusion (CSII) treatment on diabetic somatic and autonomic neuropathy. J Endocrinol Investig. 1984;7:623–8. 15. Service FJ, Rizza RA, Daube JR, et  al. Near normoglycemia improved nerve conduction and vibration sensation in diabetic neuropathy. Diabetologia. 1985;28:722–7. 16. Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, et  al. Effect of near normoglycaemia on progression of early diabetic retinopathy, nephropathy, and neuropathy: the Oslo study. Br Med J. 1986;293:1195–9. 17. Ehle AL, Raskin P. Increased nerve conduction in diabetics after a year of improved glucoregulation. J Neurol Sci. 1986;74:191–7. 18. Krönert K, Hülser J, Luft D, et al. Effects of continuous subcutaneous insulin infusion and intensified conventional therapy on peripheral and autonomic nerve dysfunction. J Clin Endocrinol Metab. 1987;64:1219–23. 19. Judzewitsch RG, Jaspan JB, Polonsky KS, et al. Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N Engl J Med. 1983;308:119–25. 20. Pfeifer MA.  Effects of glycemic control and aldose reductase inhibition on nerve conduction velocity. Am J Med. 1985;79(5):18–23. 21. Sima AAF, Bril V, Nathaniel V, et al. Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J Med. 1988;319:548–55. 22. Sorbinil Retinopathy Trial Research Group. The Sorbinil retinopathy trial: neuropathy results. Neurology. 1993;43:1141–9. 23. Greene DA, Arezzo JC, Brown MB, et al. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Neurology. 1999;53:580–91. 24. Reichard P, Nilsson B-Y, Rosenqvist U.  The effect of long-­ term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329:304–9. 25. Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-­ dependent diabetes mellitus. N Engl J Med. 1993;329:977–86. 26. Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38:869–80. 27. Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122:561–8. 28. Linn T, Ortac K, Laube H, Federlin K. Intensive therapy in adult insulin-dependent diabetes mellitus is associated with improved insulin sensitivity and reserve: a randomized, controlled, prospective study over 5 years in newly diagnosed patients. Metabolism. 1996;45:1508–13. 29. Callaghan BC, Little AA, Feldman EL, Hughes RA.  Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;6:CD007543. 30. Fullerton B, Jeitler K, Seitz M, et  al. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2014;2014:CD009122. 31. Committee on Health Care Issues. Does improved control of glycaemia prevent or ameliorate diabetic polyneuropathy? Ann Neurol. 1986;19:288–90. 32. Ziegler D, Dannehl K, Wiefels K, et  al. Differential effects of near-normoglycaemia for 4 years on somatic nerve dysfunction and heart rate variation in type 1 diabetic patients. Diabet Med. 1992;9:622–9.

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59 Neuropathy 54. LeQuesne PM, Fowler CF, Parkhouse N.  Peripheral neuropathy profile in various groups of diabetics. J Neurol Neurosurg Psychiatry. 1990;53:558–63. 55. Mulder DW, Lambert EH, Bastrom JA, et  al. The neuropathies associated with diabetes mellitus. A clinical and electromyographic study of 103 unselected diabetic patients. Neurology. 1961;11:275–84. 56. Daube JR. Electrophysiologic testing in diabetic neuropathy. In: Dyck PJ, Thomas PK, editors. Diabetic neuropathy. Philadelphia: Saunders; 1999. p. 222–38. 57. Neil HAW, Thopson AV, John S, et al. Diabetic autonomic neuropathy: the prevalence of impaired heart rate variability in a geographically defined population. Diabet Med. 1988;6:20–4. 58. Kennedy WR, Navarro X, Sutherland DER.  Neuropathy profile of diabetic patients in a pancreas transplantation program. Neurology. 1995;45:773–80. 59. Edmonds ME, Watkins PJ.  Clinical presentations of diabetic autonomic failure. In: Bannister R, Mathias CJ, editors. Autonomic failure. 3rd ed. Oxford: Oxford University Press; 1993. p. 698–720. 60. Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Quart J Med. 1980;93:95–108. 61. Page MB, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet. 1978;1:14–6. 62. Niakan E, Harati Y, Rolak R, et  al. Silent myocardial infarction and diabetic cardiovascular autonomic neuropathy. Arch Intern Med. 1986;46:2229–30. 63. Zola B, Khan JK, Juni JE, et  al. Abnormal cardiac function in diabetic patients with autonomic neuropathy in the absence of ischemic heart disease. J Clin Endocrinol Metab. 1986;63:208–14. 64. Malcolm A, Camilleri M.  Assessment of gastrointestinal function. In: Dyck PJ, Thomas PK, editors. Diabetic neuropathy. Philadelphia: Saunders; 1999. p. 211–21. 65. McCulloch DK, Young RJ, Prescott RJ, et al. The natural history of impotence in diabetic men. Diabetologia. 1984;26:437–40. 66. Kennedy WR, Navarro X. Sympathetic sudomotor function in diabetic neuropathy. Arch Neurol. 1989;46:1182–6. 67. Landgraf R.  Impact of pancreas transplantation on diabetic secondary complications and quality of life. Diabetologia. 1996;39:1415–24. 68. Navarro X, Sutherland DER, Kennedy WR. Long term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol. 1997;42:727–36. 69. Greene DA, Brown MJ, Braunstein SN, et al. Comparison of clinical course and sequential electrophysiological tests in diabetics with symptomatic polyneuropathy and its implications for clinical trials. Diabetes. 1981;30:139–47. 70. Pfeifer MA, Schumer MP. Clinical trials of diabetic neuropathy: past, present, and future. Diabetes. 1995;44:1355–61. 71. Gibbons CH, Freeman R, Tecilazich F, et  al. The evolving natural history of neurophysiologic function in patients with well-­ controlled diabetes. J Peripher Nerv Syst. 2013;18(2):153–61. 72. Sutherland DER, Dunn DL, Goetz FC, et al. A 10-year experience with 290 pancreas transplants at a single institution. Ann Surg. 1989;210:274–88. 73. Sutherland DER, Gruessner RWG, Gores PF, et al. Pancreas transplantation: an update. Diabetes Metab Rev. 1995;11:337–63. 74. Kennedy WR, Navarro X, Sakuta M, et al. Physiological and clinical correlates of cardiorespiratory reflexes in diabetes mellitus. Diabetes Care. 1989;12:399–408. 75. Kennedy WR, Navarro X, Goetz FC, et  al. Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med. 1990;322:1031–7. 76. Navarro X, Kennedy WR. Evaluation of thermal and pain sensitivity in type I diabetic patients. J Neurol Neurosurg Psychiatry. 1991;54:60–4.

843 77. Consensus Statement. Report and recommendations of the San Antonio Conference on diabetic neuropathy. Diabetes. 1988;37:1000–4. 78. Kahn R.  Proceedings of a consensus development conference on standardized measures in diabetic neuropathy. Diabetes Care. 1992;15:1080–107. 79. Solders G, Anderson T, Borin Y, et al. Electroneurography index: a standardized neurophysiological method to assess peripheral nerve function in patients with polyneuropathy. Muscle Nerve. 1993;16:941–6. 80. Dyck PJ. Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle Nerve. 1988;11:21–32. 81. Behse F, Buchthal F, Carlsen F.  Nerve biopsy and conduction studies in diabetic neuropathy. J Neurol Neurosurg Psychiatry. 1977;40:1072–82. 82. Dyck PJ, Karnes JL, Daube J, et al. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain. 1985;108:861–80. 83. Claus D, Mustafa C, Vogel W, et al. Assessment of diabetic neuropathy: definition of norm and discrimination of abnormal nerve function. Muscle Nerve. 1993;16:757–68. 84. Ewing DJ, Martyn CN, Young RJ, et al. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985;8:491–8. 85. Sampson MJ, Wilson S, Karagiannis P, et al. Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics. Quart J Med. 1990;75:635–46. 86. Van der Vliet JA, Navarro X, Kennedy WR, et al. Long term follow-­up of polyneuropathy in diabetic kidney transplant recipients. Diabetes. 1988;37:1247–52. 87. Albers JW, Herman WH, Pop-Busui R, et  al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care. 2010;33:1090–6. 88. Martin CL, Albers JW, Pop-Busui R, DCCT/EDIC Research Group. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:31–8. 89. Dholakia S, Sharples EJ, Friend PJ. Impact of pancreas transplant on diabetic complications: retinopathy, gastroparesis and automatic dysregulation. Curr Transpl Rep. 2016;3:167–73. 90. Van der Vliet JA, Navarro X, Kennedy WR, et al. The effect of pancreas transplantation on diabetic polyneuropathy. Transplantation. 1988;45:368–70. 91. Navarro X, Kennedy WR, Sutherland DER. Autonomic neuropathy and mortality in diabetic patients. Effects of a pancreas transplantation. Diabetologia. 1991;34:S108–12. 92. Vial C, Martin X, Lefrancois N, et al. Sequential electrodiagnostic evaluation of diabetic neuropathy after combined pancreatic and renal transplantation. Diabetologia. 1991;34:S100–2. 93. Solders G, Tydén G, Persson A, et  al. Improvement of nerve conduction in diabetic neuropathy. A follow-up study 4 yr after combined pancreatic and renal transplantation. Diabetes. 1992;41:946–51. 94. Müller-Felber W, Landgraf R, Sheuer R, et al. Diabetic neuropathy 3 years after successful pancreas and kidney transplantation. Diabetes. 1993;42:1482–6. 95. Trojaborg W, Smith T, Jakobsen J, et  al. Effect of pancreas and kidney transplantation on the neuropathic profile in insulin-­ dependent diabetes with end-stage nephropathy. Acta Neurol Scand. 1994;90:5–9. 96. Martinenghi S, Comi G, Galardi G, et al. Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas. Diabetologia. 1997;40:1110–2.

844 97. Remuzzi G, Ruggenenti P, Mauer SM. Pancreas and kidney/pancreas transplants: experimental medicine or real improvement? Lancet. 1994;343:27–31. 98. Krendel DA, Costigan DA, Hopkins LC.  Successful treatment of neuropathy in patients with diabetes mellitus. Arch Neurol. 1995;52:1053–61. 99. Navarro X, Kennedy WR.  Benefit of pancreatic transplantation on diabetic neuropathy. Euglycemia or immunosuppression? Ann Neurol. 1998;44:149–50. 100. Najarian JS, Kaufman DB, Fryd DS, et  al. Long-term survival following kidney transplantation in 100 type I diabetic patients. Transplantation. 1989;7:106–13. 101. Sutherland DER, Kendall DM, Moudry KC, et  al. Pancreas transplantation in nonuremic, type I diabetic recipients. Surgery. 1988;104:453–64. 102. Laftavi MRA, Chapuis F, Vial C, et al. Diabetic polyneuropathy outcome after successful pancreas transplantation: 1 to 9 year follow up. Transplant Proc. 1994;27:1406–9. 103. Solders G, Tydén G, Tibell A, et al. Improvement in nerve conduction 8 years after combined pancreatic and renal transplantation. Transplant Proc. 1995;27:3091. 104. Allen RDM, Al-Harbi IS, Morris JGL, et  al. Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation. 1997;63:830–8. 105. Tydén G, Bolinder J, Solders G, et  al. Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation. 1999;67:645–8. 106. Sutherland DER, Goetz FC, Najarian JS.  Pancreas transplantation at the University of Minnesota: donor and recipient selection, operative and postoperative management, and outcome. Transplant Proc. 1987;19(Suppl 4):63–74. 107. Gruessner RWG, Sutherland DER, Najarian JS, et al. Solitary pancreas transplantation for nonuremic patients with labile insulin-­ dependent diabetes mellitus. Transplantation. 1997;64:1572–7. 108. Navarro X, Kennedy WR, Aeppli D, et al. Neuropathy and mortality in diabetes: influence of pancreas transplantation. Muscle Nerve. 1996;19:1009–16. 109. Boucek P, Saudek F, Adamec M, et al. Spectral analysis of heart rate variation following simultaneous pancreas and kidney transplantation. Transplant Proc. 2003;35:1494–8. 110. Azmi S, Jeziorska M, Ferdousi M, et al. Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation. Diabetologia. 2019;62:1478–87. 111. Argente-Pla M, Pérez-Lázaro A, Martinez-Millana A, et  al. Simultaneous pancreas kidney transplantation improves cardiovascular autonomic neuropathy with improved Valsalva ratio as the most precocious test. J Diabetes Res. 2020;2020:7574628. 112. Havrdova T, Boucek P, Saudek F, et  al. Severe epidermal nerve fiber loss in diabetic neuropathy is not reversed by long-term normoglycemia after simultaneous pancreas and kidney transplantation. Am J Transplant. 2016;16:2196–201. 113. Beggs JL, Johnson PC, Olafsen AG, et al. Signs of nerve regeneration and repair following pancreas transplantation in an insulin-­ dependent diabetic with neuropathy. Clin Transpl. 1990;4:133–41.

X. Navarro and W. R. Kennedy 114. Kennedy WR, Wendelschafer-Crabb G, Johnson T.  Quantitation of epidermal nerves in diabetic neuropathy. Neurology. 1996;47:1042–8. 115. Navarro X, Kennedy WR.  Neuropathy. In: Gruessner RWG, Sutherland DER, editors. Transplantation of the pancreas. New York: Springer; 2005. 116. Gross CR, Zehrer CL. Health-related quality of life outcomes of pancreas transplant recipients. Clin Transpl. 1992;6:165–71. 117. Nakache R, Tyden G, Groth CG. Long-term quality of life in diabetic patients after combined pancreas-kidney transplantation or kidney transplantation. Transplant Proc. 1994;26:510–1. 118. Hathaway DK, Abell T, Cardoso S, et  al. Improvement in autonomic and gastric function following pancreas-kidney versus kidney-­alone transplantation and the correlation with quality of life. Transplantation. 1994;57:816–22. 119. Martins LS, Outerelo C, Malheiro J, et  al. Health-related quality of life may improve after transplantation in pancreas-kidney recipients. Clin Transpl. 2015;29:242–51. 120. Gibbons A, Cinnirella M, Bayfield J, et al. Changes in quality of life, health status and other patient-reported outcomes following simultaneous pancreas and kidney transplantation (SPKT): a quantitative and qualitative analysis within a UK-wide programme. Transpl Int. 2020;33:1230–43. 121. Ewing DJ, Campbell IW, Clarke BF. Mortality in diabetic autonomic neuropathy. Lancet. 1976;1:601–3. 122. O’Brien IA, McFadden JP, Corrall RJM.  The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Quart J Med. 1991;79:495–502. 123. Stephenson JM, Fuller JH. Microalbuminuria is not rare before 5 years of IDDM. EURODIAB IDDM Complications Study Group and the WHO Multinational Study of Vascular Disease in Diabetes Study Group. J Diabet Complications. 1994;8:166–73. 124. Navarro X, Kennedy WR, Loewensen RB, et al. Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction, and mortality in diabetes mellitus. Diabetes. 1990;39:802–6. 125. Becker BN, Brazy PC, Becker YT, et al. Simultaneous pancreas-­ kidney transplantation reduces excess mortality in type I diabetic patients with end-stage renal disease. Kidney Int. 2000;57:2129–35. 126. Klein R, Moss SE, Klein BEK, et  al. Relation of ocular and systemic factors to survival in diabetes. Arch Intern Med. 1989;149:266–72. 127. Sundkvist G, Lilja B. Autonomic neuropathy predicts deterioration in glomerular filtration rate in patients with IDDM. Diabetes Care. 1993;16:773–9. 128. Morel P, Gillingham KJ, Moudry-Munns KC, et al. Factors influencing pancreas transplant outcome: Cox proportional hazard regression analysis of a single institution’s experience with 357 cases. Transplant Proc. 1991;23:1630–3. 129. van Dellen D, Worthington J, Mitu-Pretorian OM, et al. Mortality in diabetes: pancreas transplantation is associated with significant survival benefit. Nephrol Dial Transplant. 2013;28:1315–22. 130. Ito T, Kenmochi T, Aida N, et al. Impact of pancreas transplantation on the patient survival - an analysis of the Japanese Pancreas Transplants Registry. J Clin Med. 2020;9:2134.

60

Retinopathy Yoon Jeon Kim, Arthur W. Walsh, and Rainer W.G. Gruessner

Contents Introduction 

 845

Description of Diabetic Retinopathy  Early Changes 

 846  846

Nonproliferative Diabetic Retinopathy 

 846

Proliferative Diabetic Retinopathy 

 846

Diabetic Macular Edema 

 847

Other Ocular Effects of Diabetes 

 847

Treatment of Diabetic Retinopathy 

 847

The Impact on Retinopathy of Blood Sugar Control Improvement by Medical Means: DCCT 

 848

DCCT Results 

 848

Impact of Pancreas Transplantation on Retinopathy 

 850

DCCT Versus Pancreas Transplantation 

 853

Ophthalmic Complications After Transplant  Opportunistic Infections 

 853  853

Medication Effects 

 854

Other Effects 

 854

Conclusions 

 855

Recommendations 

 855

Future Considerations 

 856

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Y. J. Kim Department of Ophthalmology, Asan Medical Center, Seoul, South Korea A. W. Walsh Ophthalmic Consultants of the Upper Valley, Lebanon, NH, USA R. W.G. Gruessner (*) Department of Surgery, State University of New York (SUNY), Downstate Health Sciences University, Brooklyn, NY, USA e-mail: [email protected]

Introduction Diabetic retinopathy, a common microvascular complication of diabetes mellitus (DM), is a leading cause of vision loss worldwide. It is the most common cause of legal blindness in the United States in adults [1]. Retinal microvascular changes visible on ophthalmoscopy typically develop years after the onset of diabetes. Approximately 75% of type 1 diabetics and 50% of type 2 diabetics have some

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 R. W.G. Gruessner, A. C. Gruessner (eds.), Transplantation of the Pancreas, https://doi.org/10.1007/978-3-031-20999-4_60

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form of diabetic retinopathy (DR) at 10  years after their diabetes has been d­ iagnosed. Approximately 30% of type 1 diabetics and 8% of type 2 diabetics have proliferative diabetic retinopathy (PDR), the most serious form, at 15 years after diagnosis [1]. The progression of early retinopathy to the proliferative form may be rapid in some patients and can be accelerated by pregnancy or the hormonal changes of puberty. The pathogenesis of DR is yet to be fully elucidated, but chronic hyperglycemia has been noted as a core pathogenic cause of the disease. It is associated with increased permeability of retinal vessels, areas of capillary closure in the retina, and retinal hypoxia. The damage to the retina is evidenced by changes to the vessels themselves (dilation, areas of closure, increased tortuosity); hemorrhages; exudation of serous fluid, lipids, and proteins; and growth of new vessels from the surface of the retina. The development of these new vessels (neovascularization) typically causes hemorrhage into the vitreous jelly, which results in reduced vision and scar tissue formation within the eye. Such scarring, if not controlled, may cause retinal detachment and even loss of vision and the eyeball.

Description of Diabetic Retinopathy Early Changes Histopathologic studies suggest that one of the earliest changes caused by diabetes in retinal vessels is thickening of the capillary basement membranes. Other early alterations include loss of capillary endothelial cells and intramural pericytes, which are thought to be contractile and play a role in autoregulation of the retinal microvasculature. These changes probably cause microaneurysms, which are the first clinically visible manifestation of DR.  Microaneurysms are focal dilations of the capillary walls, appearing as tiny red dots with the magnification of ophthalmoscopy. Another process in DR is breakdown of the blood–retinal barrier. The actual mechanism is still debated, but breakdown may begin early in the process of retinopathy. Ultimately, the result is the leakage of serous fluid, proteins, and lipids out of the retinal microvasculature, which ordinarily has “tight” junctions. The leakage causes retinal edema.

Nonproliferative Diabetic Retinopathy Nonproliferative diabetic retinopathy (NPDR) includes many phenomena visible on ophthalmoscopy. Initially, microaneurysms are found, usually with small hemorrhages

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(“dot/blot hemorrhages”) present in the nerve fiber layer or deeper in the retina. These hemorrhages are due to rupture of capillaries. Both hemorrhages and microaneurysms are typically transient, disappearing in a few weeks, with new ones developing elsewhere in the retina. The patient’s vision is not affected at this stage. Progression of the retinopathy includes increased exudation from the retinal vasculature, resulting in retinal edema and “hard exudates.” The latter are irregular yellowish deposits of lipoproteins within the retina. Hard exudates ordinarily do not directly affect vision. However, the retinal edema caused by transparent, serous fluid can cause blurring of the vision, in particular if located in the macula. Capillary closure throughout the retina results in scattered areas of ischemia, ordinarily invisible on clinical examination. If the ischemia is in the nerve fiber layer, however, it results in swelling of the axons, producing fluffy white patches referred to as cotton wool spots. Eventually, usually after a period of years, more gross changes to the retinal vessels themselves become visible, including irregular dilation and constriction (known as venous beading), closure of some visible vessels, and unusual loops or other figures. Examination of a patient with retinopathy will typically reveal a mixture of the previously described findings. The actual level of retinopathy can be graded through a series of steps developed in the Early Treatment Diabetic Retinopathy Study (ETDRS), a national multicenter collaborative effort launched in the 1980s. The ETDRS steps involve careful quantification of the size, number, and extent of lesions and determination of the grade on a published scale [2–4]. Surprisingly, most patients with severely advanced NPDR remain asymptomatic. For this reason, among others, annual ophthalmic evaluation is recommended for patients with diabetes. Even though patients with NPDR are not treated unless they develop clinically significant macular edema, regular observation ensures that treatment can be instituted promptly if progression to PDR occurs. When the level termed “severe NPDR” is reached, the risk of progression to PDR within 1 year is 50%.

Proliferative Diabetic Retinopathy PDR is defined by the development of neovascularization. These new vessels, which sprout from the retinal vasculature, may grow along the surface of the retina or ascend into the vitreous jelly as individual vessels, loops, or fronds. The development of such vessels is associated with considerable progressive pathology and vision loss, primarily due to the tendency for these vessels to hemorrhage easily, as well as their association with increasing fibrosis.

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Neovascularization is attributed to generalized retinal ischemia, probably secondary to areas of capillary closure scattered throughout the retina. It is believed that an angiogenic factor is elaborated by ischemic retinal tissue and that this factor, diffusing through the vitreous, acts on the retinal vessels. The growth of these vessels seems to be misdirected, with random growth occurring across the retinal surface or into the vitreous, rather than toward the actual source of the angiogenic factor. Unfortunately, neovascularization usually occurs in the central posterior portion of the retina, almost certainly involving the macula (which is critical for central vision) in the processes of hemorrhage and fibrosis. The Diabetic Retinopathy Study (DRS) identified specific risk factors as ominous harbingers of severe vision loss. Of PDR patients who progress to these so-called high-risk characteristics, more than 40% will develop blindness within 3 years if not treated [5].

Diabetic Macular Edema Diabetic macular edema (DME), defined as macular thickening from DR, results from increased retinal vascular permeability. DME results in swelling of the retina and deposition of lipid and protein and represents one of the most common causes of vision loss among people with DM. If the swelling occurs in the central portion of the macula, vision is reduced. Usually, the reduction is on the order of a few lines on the Snellen chart, but it can be to the level of legal blindness. The occurrence of DME is unpredictable and can be found at any severity of DR; some patients develop it despite only minimal DR, yet others show no signs of it despite high-risk PDR. Optical coherence tomography (OCT) is now routinely used as a fast, noninvasive tool for quantitatively mapping macular thickening areas. In addition, fluorescein angiography helps distinguish those vessels that are the primary sources of leakage. Leakage can be quite focal or diffuse. Often, clusters of microaneurysms or other fine vascular abnormalities are found near the center of the area of edematous retina (Fig. 60.1).

Fig. 60.1  Diabetic macular edema in nonproliferative diabetic retinopathy. Scattered retinal hemorrhages and microaneurysms in the posterior pole show profound leakage on fluorescein angiography. Optical

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Other Ocular Effects of Diabetes Other effects on the eyes attributable to long-term diabetes include extraocular muscle palsies, ischemic optic neuropathy, and lens changes. Of these, lens changes such as cataracts are by far the most common and frequently impact the patient’s vision and quality of life. The natural lens of the eye is nearly transparent in childhood and progressively becomes cloudier over the course of one’s life. This opacification is referred to as a cataract when it has occurred to a degree that significantly reduces vision. This often occurs relatively early in life in diabetics. A common cause of fluctuation in vision in diabetics results from alternating swelling and dehydration of the lens, over a period of hours or days. A high blood glucose level, even if comparatively transient, is believed to increase levels of sorbitol in the lens. The result is osmotic swelling or tumescence that may persist for 2 days or more, even after the blood glucose level has returned to normal. The swelling increases the refractive power of the lens, altering the focusing power of the eye. Diabetics will often observe cycles, over several days, of worsening and improved vision. Similarly, changes in vision may be observed with any significant alteration in the mean glucose level or with reduction in blood glucose fluctuations.

Treatment of Diabetic Retinopathy Scattered laser photocoagulation over the retina, mostly in the periphery, was proven by the DRS to have great benefit in halting the progression of PDR.  This laser treatment is referred to as panretinal photocoagulation (PRP). In patients who reached high-risk characteristics and were treated with PRP, the incidence of blindness at 3 years was reduced from more than 40 to 20% [5]. It is believed that the scattered laser burns reduce the overall metabolic demand of the retina, thereby reducing ischemia and reducing the production of angiogenic factors. In a small percentage of patients, PRP is ineffective; in a larger percentage, the degree of retinopathy is too far advanced when diagnosed for the laser to be helpful. In such

coherence tomography demonstrates subretinal and intraretinal fluid accumulation involving the fovea

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patients, vitrectomy may be performed to remove the opacified vitreous and the fibrovascular fronds or sheets that typically cause traction on the retinal surface. This surgery, usually accompanied by additional laser placement in the operating room, is often effective in restoring vision and preventing future neovascularization. Treatment paradigms for DME have evolved considerably over time. Intravitreous injection of medications inhibiting the activity of vascular endothelial growth factor (VEGF) has become the first-line treatment for eyes with DME involving the foveal center after a number of pivotal clinical trials demonstrating the safety and efficacy of locally administered drugs for this indication. In addition, intravitreous injection of various corticosteroid formulations has shown efficacy for treatment of DME with the cautious use of adverse effects, i.e., cataract, ocular hypertension, and glaucoma. Laser treatment of DME was established as being effective by the ETDRS and still has a role in selective cases. The laser is either used to photocoagulate individual leaking vessels or placed in a grid pattern over an area of diffuse leakage. Among patients who have reached the threshold level of DME established by the ETDRS, 24% will suffer significant vision loss in 3 years if untreated, but only 12% of laser-treated patients suffer such loss [6]. Even without treatment, PDR eventually stabilizes after a period of years. Unfortunately, the untreated endpoint usually involves blindness due to vitreous opacification, with contracted fibrous sheets dragging and elevating the macula. Laser treatment seems to stabilize eyes quickly, before the deleterious effects of neovascularization occur. Stabilization, whether due to laser treatment or simply end-stage PDR, prevents measurable improvement through achievement of normoglycemia.

 he Impact on Retinopathy of Blood Sugar T Control Improvement by Medical Means: DCCT The Diabetes Control and Complications Trial (DCCT) was designed to determine whether prolonged intensive blood sugar control could prevent DR from developing or progressing, among other objectives. The study began in 1982; a series of reports were published in the mid-1990s, several of which addressed retinopathy [3, 4, 7, 8]. Studies prior to the DCCT investigating the effects of intensive blood sugar control on the progression of retinopathy were, in hindsight, of too short duration. These included the Kroc, Steno, and Oslo studies, none of which included follow-up of more than 2  years [9–12]. Given our current knowledge, it is not surprising that the benefits of intensive blood sugar control were not demonstrated. A surprising and consistent observation made in these studies was that reti-

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nopathy often worsened shortly after intensive blood sugar control began [13]. The DCCT was designed to answer two primary underlying questions regarding retinopathy: Would intensive treatment (IT) to bring blood sugar levels in diabetics as close to the nondiabetic range as safely possible (1) reduce the risk of development of DR or other diabetic complications and (2) reduce the progression of such complications in patients who already exhibited them? Another goal was to assess the risks of such treatment. The DCCT patients were enrolled in two cohorts. The primary prevention cohort consisted of 726 insulin-dependent diabetes mellitus (IDDM) patients who had no retinopathy. The secondary intervention cohort consisted of 715 patients with mild to moderate NPDR. It is notable that the baseline level of retinopathy in the secondary intervention cohort was mild compared with the level of retinopathy found in studies of pancreas transplant patients; PDR was excluded in the DCCT. The level of retinopathy was assessed at baseline and on follow-up visits through fundus photographs graded by blinded evaluators at a remote reading center. The scale used for retinopathy assessment was the same one established and used in the ETDRS [2–4]. It has 23 steps, with the first 11 dedicated to stages of NPDR and the remaining 12 to PDR [3]. Thus, evaluation and study of relatively subtle changes in the degree of retinopathy were feasible. The enrolled patients of both cohorts were randomly assigned to undergo either conventional or IT of blood sugar. Conventional treatment included one or two daily insulin injections, with daily monitoring of urine or blood glucose levels. IT included three or more daily insulin injections (or administration by a pump), with blood glucose levels measured at least four times daily. The follow-up period was 3–9  years, considerably longer than those in prior studies. Compliance and follow-up were excellent: 98% of all scheduled fundus photographs were taken. The mean glycosylated hemoglobin levels were approximately 7.2% (IT) and 9.1% (conditional treatment) and remained separated by about two percentage points throughout the follow-up period [3].

DCCT Results Figure 60.2 shows the cumulative percentage of patients whose retinopathy progressed by three or more steps on the ETDRS scale through the years of the DCCT study. Both the upper (primary prevention cohort) and lower (secondary intervention cohort) portions show a divergence of the conventional treatment (broken lines) and IT (solid lines) groups after close to 3  years. Beyond 3  years, the conventional-­ treatment group had an increasing incidence of progression of retinopathy [3]. After 6  years of follow-up, retinopathy had progressed at least three steps in 35.1% of the primary

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Fig. 60.3  Absolute risk of sustained retinopathy progression (hazard rate per 100 patient-years) in DCCT treatment groups as function of updated mean HbA1c. The risk continues to fall as the glycosylated hemoglobin is decreased. (Reprinted with permission from the Diabetes Control and Complications Trial Research Group [8])

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Fig. 60.2  Cumulative incidence of sustained progression of retinopathy by three or more steps in conventional (broken lines) and intensive (solid lines) treatment groups of primary prevention (top) and secondary intervention (bottom) cohorts in DCCT. The beneficial effects of intensive treatment become evident at about 3  years in each cohort. (Reprinted with permission from the Diabetes Control and Complications Trial Research Group. Copyright 1995. American Medical Association [3])

prevention cohort on conventional treatment versus only 11.3% on IT. Similarly, in the secondary intervention cohort, retinopathy had progressed at least three steps in 30.8% on conventional treatment versus only 11.1% on IT. In the DCCT, IT had a beneficial effect on all levels of DR studied. That effect began after 3 years of IT. Although IT did not entirely prevent retinopathy from developing, it definitely reduced its incidence in patients who began the study without it and distinctly reduced its progression once it developed [3, 4]. An interesting finding of the DCCT was the absence of a glycemic threshold for the development of long-term complications. The previous belief was that a threshold might be

present, below which the development or progression of retinopathy would be greatly reduced. However, in fact, the DCCT showed that every reduction in hemoglobin A1c (HbA1c) was accompanied by a proportional reduction in the risk of sustained progression of retinopathy—clearly the case even with HbA1c below 8%. Figure  60.3 depicts the absolute risk of sustained progression of retinopathy in the combined treatment groups versus the mean glycosylated Hb percentage. As can be seen, the risk of progression continues to fall even as HbA1c is reduced below 6.5% [8]. This finding suggests that a pancreas transplant, with the resulting euglycemia, may provide the maximum reduction in risk of progression. After the first year of the DCCT, the number of patients in both cohorts whose retinopathy had progressed at least three steps was higher in the IT group (vs. the conventional-­ treatment group). This phenomenon of early worsening on IT was also observed in earlier studies. At 3 years, however, the number of patients whose retinopathy had progressed at least three steps was considerably higher than in the conventional-­ treatment group (vs. the IT group); after 3 years, the two groups continued to separate [3]. The DCCT found that total glycemic exposure was the dominant factor associated with the risk of progression of retinopathy, including HbA1c levels at baseline and throughout follow-up, as well as the baseline duration of IDDM [7]. Elevated screening levels of HbA1c were associated with persistent risk of progression of retinopathy—a risk that was not completely eliminated through IT.  These findings suggest an inherent momentum in the retinopathic process and accentuate the lasting deleterious effects of hyperglycemia. Anecdotal observations indicate that normalizing blood sugar has less effect on more advanced cases of retinopathy.

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This has implications regarding expectations of improvement in retinopathy in transplant patients, who typically have a long-standing history of glycemic exposure and diabetic complications. The beneficial effect of improved blood sugar control on the progression of retinopathy, as found in the DCCT, also was accompanied by an increased risk of severe hypoglycemia, including coma and seizure. The risk of severe hypoglycemia rose 26% for each 10% reduction in HbA1c in the IT group, with an even higher percentage rise in the conventional-­ treatment group [8]. In addition, in the IT group, the rate of severe hypoglycemia with coma or seizure was 16.7 events per 100 patient-years, with an HbA1c of 7.0%, and was predicted to rise to 21.3 events per 100 patient-years (equivalent to an event every 5 years) with an HbA1c of 6.0% [7]. Summarizing the early DCCT trial results, it is apparent that intensive insulin therapy is most effective when initiated early in the course of DM, demonstrating a beneficial effect over the course and progression of retinopathy. The long-­ term benefits of intensive therapy greatly outweigh the risk of “early worsening.” As shown, control of HbA1c, hypertension, and hypercholesterolaemia can slow progression of retinopathy and other DM endpoints. Furthermore, tobacco use and diet, particularly the consumption of fatty acids and dietary fiber, are significantly associated with the rate of progression of DR and retinopathy-related risk factors. Follow-up studies over the subsequent 3 decades confirmed the original results regarding the impact of glucose metabolism on the development and progression of retinopathy. The persistence of the original treatment effects 10 years after the DCCT was examined in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. Of note, after 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs. 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional-­ treatment group, the former IT group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse. The persistent difference in DR between former intensive and conventional therapy (“metabolic memory”) appeared to continue for at least another 10 years, but it may be waning [14]. With over 18 years of follow-up in EDIC, the risk of further progression of retinopathy, progression to PDR, clinically significant macular edema, and the need for intervention (photocoagulation or anti-VEGF) was studied. The cumulative incidence of each retinal outcome continued to be lower in the former IT group. However, the year-to-year incidence of these outcomes was similar, owing in large part to a reduction in risk in the former conventional-treatment group [15]. An additional benefit of intensive therapy was also shown in one of the follow-up studies. Of patients enrolled in the DCCT/EDIC study, intensive therapy was associated with a

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substantial reduction in the long-term risk of ocular surgery; in addition, the costs of surgery were 32% lower in the intensive-­therapy group [16]. Finally, when potential retinopathy risk factors (modifiable and nonmodifiable) were examined over more than 30 years of follow-up in DCCT/EDIC, the mean HbA1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated albumin excretion rate and diastolic blood pressure were other modifiable risk factors associated with the progression of retinopathy [17].

Impact of Pancreas Transplantation on Retinopathy Numerous studies have examined retinopathy in groups of diabetics who have undergone pancreas transplants, typically with kidney transplants. Many such studies were limited by their relatively short duration (3 years or less), and most of them unavoidably included predominantly patients with advanced retinopathy. In fact, most of the patients in all of these studies had already undergone laser treatment for PDR prior to transplantation. Most of the studies showed little impact on the progression of retinopathy—not surprisingly, considering the factors mentioned earlier. However, results pointed to the possibility that the beneficial effects on retinopathy appeared by about 3 years after transplant, that a transplant was probably more helpful if performed at earlier stages of retinopathy, and that a transplant might have a benefit regarding macular edema. The studies differed in the parameters measured: visual acuity in some, for example, and various measures of DR in others. There is no simple means of measuring the benefit or impact on a patient of one treatment or another regarding retinopathy. If authors choose to document, say, visual acuity as the primary determinant of patient benefit, it can fluctuate widely over a relatively short term according to the presence and spontaneous clearing of vitreous hemorrhage, or the development of cataracts may reduce visual acuity considerably, yet such a reduction may be completely reversible. Alternatively, even though the degree of PDR can be measured and “quantified” with precision by standards such as those set by the ETDRS, such findings may have little direct impact on a patient’s vision and functioning. One of the larger studies on retinopathy after transplant was performed by Ramsay et  al. at the University of Minnesota and presented in the New England Journal of Medicine in 1988 [18]. This study involved 22 patients with successful pancreas transplants and 16 control patients with unsuccessful pancreas transplants. The findings of this study are relatively similar to those of many that followed. The average patient already had advanced PDR with elevated

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fronds of neovascularization at the time of the transplant; in fact, of the 44 study group eyes, 10 were irreversibly blind at baseline. Of the remaining 34 eyes, 20 had already undergone laser treatment. The mean follow-up was 24  months. No significant difference in the rate of progression of retinopathy or loss of visual acuity was found between the two groups. Nonetheless, the authors’ analysis suggested a late beneficial effect after 3 years of euglycemia. More advanced retinopathy was less likely to progress after successful pancreas transplant. In one patient with a successful transplant, the rate of progression of retinopathy accelerated within 6 months after transplant, but his eyes did respond to laser treatment. Several other studies of relatively short duration were performed, including work by Petersen and Vine (mean follow­up: 24.5  months) [19] and Wang et  al. (mean follow-up: 12.7  months) [19, 20]. These authors found that pancreas transplants had no beneficial effect on the progression of retinopathy. However, again, most of their patients had already had advanced retinopathy before their transplant. Several studies of longer duration (more than 3 years) by Bandello et al. comparing simultaneous pancreas and kidney (SPK) transplant versus kidney transplant alone (KTA) recipients found no significant difference in retinopathy [21– 24]. In all of these studies, the mean level of retinopathy was advanced prior to transplantation, and a high percentage of patients had already undergone laser treatment. Caldera et al. commented that when end-stage diabetic nephropathy develops, they believe that severe retinal damage is also present and that at this late stage of the disease, normoglycemia is unable to exert a positive effect on DR [24]. Two other studies with follow-up of more than 3  years showed no significant effect on DR between patients who had undergone a successful SPK transplant versus those who had lost their pancreas graft [25, 26]. In both studies, 79% or more of the study patients had already undergone photocoagulation, and both concluded that the potential benefits of euglycemia could not be separated from the effects of laser treatment in such late-stage diabetic patients. A number of studies with follow-up of more than 3 years showed benefits after transplant for patients with DR. In particular, patients who seem to improve are in earlier stages of retinopathy or have macular edema. For example, a study by Königsrainer et al. [27] compared 25 patients with functioning pancreas grafts (mean observation time: 43.2  months) with 14 controls who had lost their pancreas graft during the first 4 years after transplant. As is typical of these studies, a large proportion (71%) of patients had such advanced retinopathy that they had already undergone photocoagulation. The authors concluded that the course of DR, as graded by the ETDRS system, was positively influenced by a successful pancreas transplant. Notably, the two patients enrolled with preproliferative retinopathy saw regression of their reti-

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nopathy after transplant—a finding that suggests earlier transplant may be of greater benefit. Di Landra et  al. and Königsrainer et al. also noted improvements in retinopathy, but only if it was at a comparatively early stage at the time of the transplant [28, 29]. Pearce et al., in a study of SPK transplant recipients, found that eight eyes with only mild DR at the time of transplant remained stable at 5 years after transplant [30]. They found one patient with early acceleration of retinopathy. Ulbig et  al., in a study of 25 successful SPK transplant recipients (average follow-up: 38  months), concluded that DR tended to stabilize after about 3 years. They also found reabsorption of macular edema, but whether this was due to the pancreas or kidney transplant was unclear [31]. As early as 1981, one report of a diabetic SPK transplant recipient described a reduction in macular edema in a diabetic patient and considerable improvement in visual acuity [32]. Friberg et al. reported on four SPK transplant recipients (follow-up of at least 48 months) [33]. Of the six seeing eyes, all had previously undergone laser photocoagulation, yet four improved significantly during the follow-up period. The improvement was attributed to the resolution of macular edema. Tsai et al. reported on six female pancreas transplant recipients who developed acute macular edema and peripapillary soft exudate with rapid progression to PDR within 3 months after transplant [34]. Notably, the patients had no or only mild pretransplant DR. Their mean HbA1c levels had rapidly decreased from 13.4% before transplant to 6.5% within 2 months after transplant. All macular edema resolved either with or without treatment. Five cases progressed to PDR and received PRP. DR remained stable in all eyes after treatment, and the visual prognosis was good, except in one eye that had macular branch retinal artery occlusion with foveal involvement. It appears that acute macular edema after pancreas transplantation has a favorable treatment outcome despite rapid progression to PDR. The authors hypothesized that high pretransplant HbA1c and abrupt blood sugar normalization may be related to the disease course [34]. By definition, almost all patients involved in the previously cited transplant studies had had end-stage diabetic renal disease, which unfortunately selects for patients who in all likelihood already have advanced PDR.  Most such patients previously underwent laser treatment, so their retinopathy was stable. Obviously, then, the studies tend to show no significant benefit from a transplant. The minority of patients who have earlier-stage retinopathy and are thus most likely to show benefit after transplant are, in effect, lost in the much larger pool of patients whose retinopathy is unlikely to worsen regardless of their future blood sugar control. In subsets of patients within the studies, however, evidence of benefit after transplant can be found. Although a number of studies on the effect of pancreas transplantation on retinopathy have been published since the

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beginning of the new millennium, most of these studies drew conclusions similar to those of the aforementioned earlier studies. Koznarová et al. performed a prospective study in normoglycemic SPK transplant recipients (SPK group; n  =  43, follow-up 44.9 ± 35.1 months) versus SPK transplant recipients of a nonfunctioning pancreas transplant and recipients of a KTA (control group; n = 45, follow-up 60.3 ± 34.2 months) [35]. Fundoscopic findings at the end of follow-up were improved, stabilized, or deteriorated in the SPK group in 21.3, 61.7, and 17.0%, respectively. The respective figures in the control group were 6.1, 48.8, and 45.1% (p  8) and median follow-up was 65 months. After adjusting for age, gender, smoking and transplant type and history of dialysis and diabetes, for each point increase in abdominal aortic calcification score, the hazard ratio for cardiovascular events was 1.07 (95% CI 1.02–1.12) and mortality was 1.09 (1.04–1.13). Overall, those with high abdominal aortic calcifications scores were found to have 3× higher cardiovascular and mortality risk even in SPK recipients with slower progression of vascular atherosclerosis. Most importantly, higher scores also seem to be associated with graft loss. The authors made an argument that abdominal aortic calcification scoring can be a safe, simple, cost effective and accurate way of risk stratifying those at highest risk and identifying those who could potentially benefit most from intense cardiovascular intervention [41]. Clearly, larger, prospective studies of pre-transplantation noninvasive cardiovascular testing [stress myocardial perfusion imaging, stress echocardiography, coronary calcium computed tomography (CT) scanning, cardiac magnetic resonance imaging (MRI)] are necessary to determine the ­optimal method of evaluating cardiac risk in this patient population.

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Glycemic Control and Cardiovascular Disease As cardiovascular-related mortality is so pervasive in diabetic patients, aggressive treatment of any modifiable cardiovascular specific risk factor is critical. As such, diabetes is considered a coronary artery disease equivalent, as patients with diabetes are as likely to die from coronary artery disease without prior cardiac history as those without diabetes having prior history of coronary artery disease itself [15, 42]. Intuitively, the elimination of chronic hyperglycemia and renal failure for patients with long-standing type 1 diabetes and uremia should attenuate the markedly excessive rates of cardiovascular morbidity and mortality found in this patient population. Previous epidemiological studies have established a strong correlation between glycemic control and cardiovascular event rates [43–45]. However, limited data are available to suggest that an improvement in glycemic control can lead to a reduction in cardiovascular disease in patients with diabetes. The Diabetes Control and Complications Trial (DCCT) was a prospective, randomized clinical trial of intensive insulin therapy vs. conventional treatment in 1441 patients with type 1 diabetes [46]. The marked reductions in the development or progression of microvascular complications of diabetes (retinopathy, nephropathy, neuropathy) observed in this trial established the utility of intensive glycemic control. However, although the risk of macrovascular events (myocardial infarction, stroke, peripheral vascular disease) was reduced by 40%, due to the low number of events this reduction did not achieve statistical significance (p = 0.08) [47]. When interpreting these results, it should be pointed out that patients with known cardiovascular disease, hypertension, and hyperlipidemia were excluded from this trial. More importantly, most of these patients were only in their early 30s at the completion of the study, too early to observe whether an intervention trial can reduce cardiovascular events in this vulnerable population. The DCCT proved that intensive insulin therapy not only slows the progression but also delays the onset of some diabetic complications. Improved long-term results were observed in reduction of early microvascular disease and lower HbA1 given an intensive insulin therapy comprising of three or more insulin injections a day or with a programmed insulin pump [21, 48, 49]. While the risks of diabetic-related complications improved, these were not universally eliminated, and the challenge of reaping full benefits by mimicking normal beta cell derived glycemic control remain. The UK Prospective Diabetes Study (UKPDS) was a randomized study evaluating the effects of glycemic control in patients with type 2 diabetes [50]. The study included 3867 newly diagnosed patients with type 2 diabetes, who after 3  months of diet treatment were randomly assigned either intensive treatment with an oral agent or insulin or conven-

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tional therapy with diet. The median follow-up for endpoint analysis was 10 years. A modest 16% relative risk reduction for myocardial infarction (p = 0.052) was observed for the patients assigned to the intensive treatment group. One of the limitations of this study and potential explanations for the absence of a more robust reduction in macrovascular events was the lack of a marked difference in glycemic control between the two groups (hemoglobin [Hb]A1c, 7% vs. 7.9%). The objective of the Diabetes Insulin Glucose Infusion in Acute Myocardial Infarction study was to determine whether intensive metabolic treatment with a 24-h insulin–glucose infusion followed by multidose insulin treatment for at least 3  months in patients with diabetes and acute myocardial infarction improves prognosis [51]. The study consisted of 620 patients with type 2 diabetes admitted with acute myocardial infarction randomized to conventional or intensive insulin (with 24-h insulin–glucose infusion) treatment, and the mean follow-up was 3.4 years. At 1 year, a greater reduction in HbA1c was observed in the intensive group compared with the conventional group (0.9  ±  1.6% vs. 0.4  ±  1.8%, p