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Pancreas Versus Islet Transplantation in Diabetes Mellitus: How to Allocate Deceased Donor Pancreata?
Pancreas Versus Islet Transplantation in Diabetes Mellitus: How to Allocate Deceased Donor Pancreata? R. Kandaswamy and D.E.R. Sutherland ABSTRACT Transplant options for the diabetic recipient include pancreas and islet transplantation. Pancreas transplantation has been increasingly performed in the last 3 decades with increasing success rates. Nevertheless, islet transplantation offers the advantage of being less invasive with fewer complications. However, current experience shows that multiple transplants are required to achieve and maintain insulin-independence in the intermediate term, and long-term function remains a problem even with multiple transplants. Early successes with single-donor islet transplants are encouraging and if maintained will largely substitute pancreas transplants. Currently, single-donor islet transplants have been shown to work in recipients with low insulin requirements who receive a pancreas from a donor with high body mass index. However, pancreas transplants from obese donors are associated with increased surgical risk. Therefore, it is logical to preferentially allocate obese donor pancreata to islet recipients. In addition, older donor (50 to 65 years) pancreata could be preferentially allocated to islets since their islet yield is still good, whereas they are associated with decreased survival in whole-organ pancreas transplants. With increasing efficiency and success of islet transplants the criteria for pancreas allocation for islets will need to be periodically reviewed.
D
IABETES MELLITUS whether type 1 or 2, is a disease of absolute or relative deficiency of insulinproducing beta cells in the islets of Langerhans within the pancreas relative to insulin needs. Beta-cell replacement to eliminate the need for exogenous insulin in diabetic patients can be accomplished by either pancreas or islet allotransplantation.1 Conceptually, pancreas transplantation is an islet transplant—just a big islet. An obvious advantage of islet transplantation is that it is minimally invasive for the recipient, although it is logistically more difficult.2 Thus, pancreas transplantation is still more widely applied than islet transplantation, although advances in surgical techniques have contributed to the ever-increasing success rate of pancreas transplantation.3 With either pancreas or islet transplantation, the recipients require immunosuppression, and various regimens are in current use.4 Of course, the ultimate objective of beta-cell replacement is to mitigate the complications associated with diabetes and to improve quality of life in the recipients, and a recent review documents the degree to which this objective is achieved.5 The issue of pancreas allocation for whole-organ pancreas versus islets should take into consideration the following factors. Even though pancreas transplantation has a © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 365–367 (2006)
high success rate, it is associated with surgical morbidity. Islet transplantation has a low morbidity but is inefficient because of the attrition during isolation and engraftment. This problem creates the need for more than one donor (retransplantation) to achieve a sufficient beta-cell mass in many recipients and limits the number of candidates that can benefit, given the number of donor pancreata available (less than the theoretical demand). Ideally, beta-cell replacement should be done by the least invasive way possible. However, if one is to maximize the number of recipients in the face of a scarce resource, deceased donor organ allocation for pancreas and islet allotransplantation has to be integrated in a way that balances the two objectives: treat as many as possible and minimize morbidity.6 Recipient characteristics should be included in the decision as to whether a beta-cell replacement candidate should From the Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA. Address reprint requests to Raja Kandaswamy, MD, Assistant Professor, Director of Organ Procurement, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC 195, Minneapolis, MN 55455. E-mail: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.01.005 365
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receive an immediately vascularized pancreas graft or an injection of isolated islets.7 Exogenous insulin requirement is a rough guide to the number of beta cells required to induce insulin-independence; the lower the requirement, the fewer islets that will be needed. Thus, beta-cell replacement candidates with high insulin requirements would be better suited for a pancreas transplant, while those with low insulin requirements might get by with a single-donor islet transplant. We also know that nondiabetic, obese (body mass index [BMI] ⬎ 30) individuals have more islets than lean individuals, because the beta-cell mass increases to cope with the increased insulin needs associated with obesity. Transplantation of a pancreas from an obese donor has an increased rate of technical complications such as thrombosis and intra-abdominal infections.8 Thus, recipients of pancreata from obese donors experience morbidity more often than the recipients from lean donors. This means that pancreata from obese donors could be assigned preferentially to recipients suitable to receive islet transplants because of their low insulin requirements, while the pancreata from lean donors would be used for whole pancreas transplants to recipients with high insulin requirements. A deceased donor pancreas allocation policy for beta-cell replacement should be designed to foster efficiency and, thus, minimize the use of multiple islet donors (retransplants) for a single recipient. A high insulin-requiring candidate could opt for an islet transplant, but if insulinindependence is not achieved with a primary graft, no priority should be given for a retransplant over those already queued (listed) for a primary graft. Exceptions could be made for medical reasons, such as candidates with vascular disease precluding a pancreas transplant or otherwise at high risk for major surgery. In the United States, organ allocation policies are set by the United Network for Organ Sharing (UNOS). Pancreas allocation is complicated by the need for two lists: one for those only in need of beta-cell replacement and one for those who also need a kidney. The priority varies according to the policies of local organ procurement organizations (OPOs). In some OPOs, uremic diabetic patients waiting for a kidney-pancreas (KP) transplant have no priority over uremic patients waiting for a kidney alone; a KP is allocated only when a uremic diabetic is at the top of the list. In other OPOs, the highest ranked uremic diabetic gets priority for a KP, no matter what the rank; in still others, a level of rank is specified, above which the highest ranked KP gets priority. In all OPOs, if no KP candidate is ranked high enough for an offer of both organs, the pancreas is offered to the highest ranked candidate for solitary pancreas or islet transplantation. In regard to UNOS policy on solitary transplants, organs from donors ⬍50 years old are first offered to pancreas candidates and those from donors ⬎50 (generally up to 65 years of age) first to islet candidates, primarily because intact pancreas transplants from donors over 50 years of age have increased technical complication rates in most pan-
KANDASWAMY AND SUTHERLAND
creas programs. It is now proposed that pancreata from obese donors also be first allocated for islets, because of both the increased technical complication rate with pancreas transplants from such donors and the fact that the absolute number of islets isolated is proportional to donor size.9 UNOS has not made the proposal a general policy yet, but has allowed individual OPOs to do so as a variance. Advances are being made in isolation of islets to increase the proportion of islets that remain viable for transplantation, for example, the use of agents that prevent apoptosis after isolation.10 As these advances are applied clinically, the insulin requirement threshold below which a single donor islet transplant would be sufficient to induce insulinindependence could be raised, increasing the proportion of beta-cell replacements done by the minimally invasive technique. Conversely, the BMI requirements to be an islet donor could be progressively lowered as the islet isolation efficiency in terms of viability increases. Ultimately, such improvements would result in a fully integrated list of pancreas and islet candidates, each being able to accept nearly all donors regardless of characteristics, and most beta-cell replacement therapy would be done by islet transplantation. We are, of course, not at that point yet. Besides improving the efficiency of islet isolation, other alterations in strategies may allow a lower number of isolated islets to induce insulin-independence in recipients than is currently the case, for example, using a truly nondiabetogenic immunosuppressive regimen (even the Edmonton protocol is diabetogenic with its inclusion of a calcineurin-inhibitor). In the pancreas transplant program at the University of Minnesota, our immunosuppressive regimen is free of calcineurin-inhibitor as well as steroids.11 We give periodic anti-T-cell agents for maintenance, rather than solely for induction immunosuppression. In regard to the islet transplant program at the University of Minnesota, we have combined several aspects of the recipient and donor selection criteria, technical improvements in islet isolation, and immunosuppressant selection, as outlined above. By doing so, we have been able to consistently achieve insulin-independence in our recipients with islets from a single donor.12 If one deceased donor pancreas could consistently yield enough islets to induce insulin-independence in a diabetic recipient, regardless of donor characteristics or recipient’s exogenous insulin requirements, islet transplantation would largely replace pancreas transplantation. An exception would be candidates who also have exocrine deficiency, for example, those who became diabetic as a result of pancreatectomy for benign disease. Islet autotransplantation performed at the time of pancreatectomy for chronic pancreatitis can preserve insulin-independence in some patients,13 but for those in whom it does not or in whom it was never attempted, and in whom labile diabetes ensues, it makes sense to transplant a pancreas (rather than simply islets) with enteric drainage of the exocrine secretions, so that normal intestinal absorption can also be restored.14
PANCREAS VERSUS ISLET TRANSPLANTATION
The shortage of deceased donors for those in need of organ replacement therapy of all kinds has led to the use of living donors, including for the pancreas. At the University of Minnesota we have done segmental pancreas transplants from living donors since 1979,15 and had an even earlier experience with two cases of islet allografts from living donors.16 –18 In countries where deceased organ donors are in even shorter supply, the incentive to use living donors is particularly strong. For example, in Japan the number of living donor liver transplants greatly exceeds that from deceased donors, and, as reported very recently in the news media, the Japanese group in Kyoto has now done a living donor islet transplantation. However, it is unlikely that the use of both deceased and living donors can meet the demand for beta-cell replacement therapy any better than it has for any other organ, even in countries with relatively high numbers of both types. Thus, in the long-term, either islet xenografts or induction of endogenous beta-cell regeneration will be the answer.6 Meanwhile, we must use the resources at hand: a limited number of allogeneic donor pancreata for beta-cell replacement therapy. To answer the questions posed in the title, beta-cell replacement therapy should be done in insulindependent diabetic patients who are either obligated to immunosuppression (nearly all diabetic renal allograft recipients should be candidates) or in those whose problems with achieving sufficient metabolic control of diabetes using exogenous insulin (primarily those with hypoglycemic unawareness) exceed the potential side effects of immunosuppression. For candidates in whom the insulin requirements are low enough so that islets isolated from a single donor would predictably induce insulin-independence, perform an islet transplant; in those whose requirements are so high that more than one donor would be needed for the islet approach and who are not at high risk for surgical complications, perform a pancreas transplant. If the surgical risk is unacceptable in high insulin-requiring candidates, then do an islet transplant with the expectation that islet retransplants can be done over time to eventually achieve insulinindependence. With this approach beta-cell replacement can be done in the most patients with the highest insulinindependent rate possible, while allowing minimally invasive surgery to be done in some candidates at no expense to those who require more (a solid organ). It is foreseeable that islet transplant successes will improve to the point where it will be performed as the predominant transplant procedure for diabetics. Obviously, as this evolves we need to review allocation criteria for pancreas versus islets and revise as appropriate.
367
REFERENCES 1. Sutherland DER: Beta-cell replacement by transplantation in diabetes mellitus. Current Opinion in Organ Transplantation 10: 147, 2005 2. Stock P: Beta-cell replacement for type 1 diabetes mellitus— islet verus solid organ pancreas. Curr Opin Organ Transplant 10:70, 2005 3. Boggi U, Vistoli F, DelChiaro M, et al: Surgical techniques for pancreas transplantation. Curr Opin Organ Transplant 10:75, 2005 4. Kaufmann D, Salvalaggio PRO: Immunosuppression for pancreas transplantation. Curr Opin Organ Transplant 10:88, 2005 5. Robertson RP: 2005 update: impact of pancreas and islet transplantation on acute and chronic complications of diabetes. Curr Opin Organ Transplant 10:88, 2005 6. Sutherland DER, Gruessner A, Hering J: Beta-cell replacement therapy (pancreas and islet transplantation): an integrated approach. Endocrinol Metab Clinics North America 33:135, 2004 7. Sutherland DER: Pancreas and islet transplant population. In Gruessner RWG, Sutherland DER (eds): Transplantation of the Pancreas. New York: Springer-Verlag; 2004, p 91 8. Humar A, Ramcharan T, Kandaswamy R, et al: The impact of donor obesity on outcomes after cadaver pancreas transplantation. Am J Transplant 4:605, 2004 9. Matsumoto I, Sawada T, Nakano M, et al: Improvements in islet yield from obese donors for human islet transplants. Transplantation 78:880, 2004 10. Nakano M, Matsumoto I, Sawada T, et al: Capsase-3 inhibitor prevents apoptosis of human islets immediately after isolation and improves graft function. Pancreas 29:104, 2004 11. Sutherland DER, Kandaswamy R, Humar A, et al: Calcineurininhibitor-free protocols: use of the anti-T-cell agent Campath H-1 for maintenance immunosuppression in pancreas and pancreas/ kidney recipients. Clin Transplant 18(suppl 13):14, 2004 12. Hering BJ, Kandaswamy R, Ansite J, et al: Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes mellitus. JAMA 293:830, 2005 13. Sutherland DER, Gruessner RW, Jie T, et al: Pancreatic islet auto-transplantation for chronic pancreatitis. Clin Transplant 18(suppl 13):17, 2004 14. Gruessner RWG, Sutherland DE, Dunn DL, et al: Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis. J Am Coll Surg 198:559, 2004 15. Sutherland DE, Gruessner RW, Dunn DL, et al: Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 233:463, 2001 16. Sutherland DER, Matas AJ, Goetz FC, Najarian JS: Transplantation of dispersed pancreatic tissue in humans: autografts and allografts. Diabetes 29 (Suppl):31, 1980 17. Gores PF, Najarian JS, Sutherland DER: Clinical Islet Allotransplantation. The University of Minnesota experience. In: Ricordi C, ed. Pancreatic Islet Cell Transplantation. Austin: R.A. Lavides Company, 1992, p 423 18. Sutherland DER, Gores PF, Farner AL et al. Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota. Am J Surg 166:456, 1993
D
IABETES MELLITUS whether type 1 or 2, is a disease of absolute or relative deficiency of insulinproducing beta cells in the islets of Langerhans within the pancreas relative to insulin needs. Beta-cell replacement to eliminate the need for exogenous insulin in diabetic patients can be accomplished by either pancreas or islet allotransplantation.1 Conceptually, pancreas transplantation is an islet transplant—just a big islet. An obvious advantage of islet transplantation is that it is minimally invasive for the recipient, although it is logistically more difficult.2 Thus, pancreas transplantation is still more widely applied than islet transplantation, although advances in surgical techniques have contributed to the ever-increasing success rate of pancreas transplantation.3 With either pancreas or islet transplantation, the recipients require immunosuppression, and various regimens are in current use.4 Of course, the ultimate objective of beta-cell replacement is to mitigate the complications associated with diabetes and to improve quality of life in the recipients, and a recent review documents the degree to which this objective is achieved.5 The issue of pancreas allocation for whole-organ pancreas versus islets should take into consideration the following factors. Even though pancreas transplantation has a © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 365–367 (2006)
high success rate, it is associated with surgical morbidity. Islet transplantation has a low morbidity but is inefficient because of the attrition during isolation and engraftment. This problem creates the need for more than one donor (retransplantation) to achieve a sufficient beta-cell mass in many recipients and limits the number of candidates that can benefit, given the number of donor pancreata available (less than the theoretical demand). Ideally, beta-cell replacement should be done by the least invasive way possible. However, if one is to maximize the number of recipients in the face of a scarce resource, deceased donor organ allocation for pancreas and islet allotransplantation has to be integrated in a way that balances the two objectives: treat as many as possible and minimize morbidity.6 Recipient characteristics should be included in the decision as to whether a beta-cell replacement candidate should From the Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA. Address reprint requests to Raja Kandaswamy, MD, Assistant Professor, Director of Organ Procurement, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC 195, Minneapolis, MN 55455. E-mail: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.01.005 365
366
receive an immediately vascularized pancreas graft or an injection of isolated islets.7 Exogenous insulin requirement is a rough guide to the number of beta cells required to induce insulin-independence; the lower the requirement, the fewer islets that will be needed. Thus, beta-cell replacement candidates with high insulin requirements would be better suited for a pancreas transplant, while those with low insulin requirements might get by with a single-donor islet transplant. We also know that nondiabetic, obese (body mass index [BMI] ⬎ 30) individuals have more islets than lean individuals, because the beta-cell mass increases to cope with the increased insulin needs associated with obesity. Transplantation of a pancreas from an obese donor has an increased rate of technical complications such as thrombosis and intra-abdominal infections.8 Thus, recipients of pancreata from obese donors experience morbidity more often than the recipients from lean donors. This means that pancreata from obese donors could be assigned preferentially to recipients suitable to receive islet transplants because of their low insulin requirements, while the pancreata from lean donors would be used for whole pancreas transplants to recipients with high insulin requirements. A deceased donor pancreas allocation policy for beta-cell replacement should be designed to foster efficiency and, thus, minimize the use of multiple islet donors (retransplants) for a single recipient. A high insulin-requiring candidate could opt for an islet transplant, but if insulinindependence is not achieved with a primary graft, no priority should be given for a retransplant over those already queued (listed) for a primary graft. Exceptions could be made for medical reasons, such as candidates with vascular disease precluding a pancreas transplant or otherwise at high risk for major surgery. In the United States, organ allocation policies are set by the United Network for Organ Sharing (UNOS). Pancreas allocation is complicated by the need for two lists: one for those only in need of beta-cell replacement and one for those who also need a kidney. The priority varies according to the policies of local organ procurement organizations (OPOs). In some OPOs, uremic diabetic patients waiting for a kidney-pancreas (KP) transplant have no priority over uremic patients waiting for a kidney alone; a KP is allocated only when a uremic diabetic is at the top of the list. In other OPOs, the highest ranked uremic diabetic gets priority for a KP, no matter what the rank; in still others, a level of rank is specified, above which the highest ranked KP gets priority. In all OPOs, if no KP candidate is ranked high enough for an offer of both organs, the pancreas is offered to the highest ranked candidate for solitary pancreas or islet transplantation. In regard to UNOS policy on solitary transplants, organs from donors ⬍50 years old are first offered to pancreas candidates and those from donors ⬎50 (generally up to 65 years of age) first to islet candidates, primarily because intact pancreas transplants from donors over 50 years of age have increased technical complication rates in most pan-
KANDASWAMY AND SUTHERLAND
creas programs. It is now proposed that pancreata from obese donors also be first allocated for islets, because of both the increased technical complication rate with pancreas transplants from such donors and the fact that the absolute number of islets isolated is proportional to donor size.9 UNOS has not made the proposal a general policy yet, but has allowed individual OPOs to do so as a variance. Advances are being made in isolation of islets to increase the proportion of islets that remain viable for transplantation, for example, the use of agents that prevent apoptosis after isolation.10 As these advances are applied clinically, the insulin requirement threshold below which a single donor islet transplant would be sufficient to induce insulinindependence could be raised, increasing the proportion of beta-cell replacements done by the minimally invasive technique. Conversely, the BMI requirements to be an islet donor could be progressively lowered as the islet isolation efficiency in terms of viability increases. Ultimately, such improvements would result in a fully integrated list of pancreas and islet candidates, each being able to accept nearly all donors regardless of characteristics, and most beta-cell replacement therapy would be done by islet transplantation. We are, of course, not at that point yet. Besides improving the efficiency of islet isolation, other alterations in strategies may allow a lower number of isolated islets to induce insulin-independence in recipients than is currently the case, for example, using a truly nondiabetogenic immunosuppressive regimen (even the Edmonton protocol is diabetogenic with its inclusion of a calcineurin-inhibitor). In the pancreas transplant program at the University of Minnesota, our immunosuppressive regimen is free of calcineurin-inhibitor as well as steroids.11 We give periodic anti-T-cell agents for maintenance, rather than solely for induction immunosuppression. In regard to the islet transplant program at the University of Minnesota, we have combined several aspects of the recipient and donor selection criteria, technical improvements in islet isolation, and immunosuppressant selection, as outlined above. By doing so, we have been able to consistently achieve insulin-independence in our recipients with islets from a single donor.12 If one deceased donor pancreas could consistently yield enough islets to induce insulin-independence in a diabetic recipient, regardless of donor characteristics or recipient’s exogenous insulin requirements, islet transplantation would largely replace pancreas transplantation. An exception would be candidates who also have exocrine deficiency, for example, those who became diabetic as a result of pancreatectomy for benign disease. Islet autotransplantation performed at the time of pancreatectomy for chronic pancreatitis can preserve insulin-independence in some patients,13 but for those in whom it does not or in whom it was never attempted, and in whom labile diabetes ensues, it makes sense to transplant a pancreas (rather than simply islets) with enteric drainage of the exocrine secretions, so that normal intestinal absorption can also be restored.14
PANCREAS VERSUS ISLET TRANSPLANTATION
The shortage of deceased donors for those in need of organ replacement therapy of all kinds has led to the use of living donors, including for the pancreas. At the University of Minnesota we have done segmental pancreas transplants from living donors since 1979,15 and had an even earlier experience with two cases of islet allografts from living donors.16 –18 In countries where deceased organ donors are in even shorter supply, the incentive to use living donors is particularly strong. For example, in Japan the number of living donor liver transplants greatly exceeds that from deceased donors, and, as reported very recently in the news media, the Japanese group in Kyoto has now done a living donor islet transplantation. However, it is unlikely that the use of both deceased and living donors can meet the demand for beta-cell replacement therapy any better than it has for any other organ, even in countries with relatively high numbers of both types. Thus, in the long-term, either islet xenografts or induction of endogenous beta-cell regeneration will be the answer.6 Meanwhile, we must use the resources at hand: a limited number of allogeneic donor pancreata for beta-cell replacement therapy. To answer the questions posed in the title, beta-cell replacement therapy should be done in insulindependent diabetic patients who are either obligated to immunosuppression (nearly all diabetic renal allograft recipients should be candidates) or in those whose problems with achieving sufficient metabolic control of diabetes using exogenous insulin (primarily those with hypoglycemic unawareness) exceed the potential side effects of immunosuppression. For candidates in whom the insulin requirements are low enough so that islets isolated from a single donor would predictably induce insulin-independence, perform an islet transplant; in those whose requirements are so high that more than one donor would be needed for the islet approach and who are not at high risk for surgical complications, perform a pancreas transplant. If the surgical risk is unacceptable in high insulin-requiring candidates, then do an islet transplant with the expectation that islet retransplants can be done over time to eventually achieve insulinindependence. With this approach beta-cell replacement can be done in the most patients with the highest insulinindependent rate possible, while allowing minimally invasive surgery to be done in some candidates at no expense to those who require more (a solid organ). It is foreseeable that islet transplant successes will improve to the point where it will be performed as the predominant transplant procedure for diabetics. Obviously, as this evolves we need to review allocation criteria for pancreas versus islets and revise as appropriate.
367
REFERENCES 1. Sutherland DER: Beta-cell replacement by transplantation in diabetes mellitus. Current Opinion in Organ Transplantation 10: 147, 2005 2. Stock P: Beta-cell replacement for type 1 diabetes mellitus— islet verus solid organ pancreas. Curr Opin Organ Transplant 10:70, 2005 3. Boggi U, Vistoli F, DelChiaro M, et al: Surgical techniques for pancreas transplantation. Curr Opin Organ Transplant 10:75, 2005 4. Kaufmann D, Salvalaggio PRO: Immunosuppression for pancreas transplantation. Curr Opin Organ Transplant 10:88, 2005 5. Robertson RP: 2005 update: impact of pancreas and islet transplantation on acute and chronic complications of diabetes. Curr Opin Organ Transplant 10:88, 2005 6. Sutherland DER, Gruessner A, Hering J: Beta-cell replacement therapy (pancreas and islet transplantation): an integrated approach. Endocrinol Metab Clinics North America 33:135, 2004 7. Sutherland DER: Pancreas and islet transplant population. In Gruessner RWG, Sutherland DER (eds): Transplantation of the Pancreas. New York: Springer-Verlag; 2004, p 91 8. Humar A, Ramcharan T, Kandaswamy R, et al: The impact of donor obesity on outcomes after cadaver pancreas transplantation. Am J Transplant 4:605, 2004 9. Matsumoto I, Sawada T, Nakano M, et al: Improvements in islet yield from obese donors for human islet transplants. Transplantation 78:880, 2004 10. Nakano M, Matsumoto I, Sawada T, et al: Capsase-3 inhibitor prevents apoptosis of human islets immediately after isolation and improves graft function. Pancreas 29:104, 2004 11. Sutherland DER, Kandaswamy R, Humar A, et al: Calcineurininhibitor-free protocols: use of the anti-T-cell agent Campath H-1 for maintenance immunosuppression in pancreas and pancreas/ kidney recipients. Clin Transplant 18(suppl 13):14, 2004 12. Hering BJ, Kandaswamy R, Ansite J, et al: Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes mellitus. JAMA 293:830, 2005 13. Sutherland DER, Gruessner RW, Jie T, et al: Pancreatic islet auto-transplantation for chronic pancreatitis. Clin Transplant 18(suppl 13):17, 2004 14. Gruessner RWG, Sutherland DE, Dunn DL, et al: Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis. J Am Coll Surg 198:559, 2004 15. Sutherland DE, Gruessner RW, Dunn DL, et al: Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 233:463, 2001 16. Sutherland DER, Matas AJ, Goetz FC, Najarian JS: Transplantation of dispersed pancreatic tissue in humans: autografts and allografts. Diabetes 29 (Suppl):31, 1980 17. Gores PF, Najarian JS, Sutherland DER: Clinical Islet Allotransplantation. The University of Minnesota experience. In: Ricordi C, ed. Pancreatic Islet Cell Transplantation. Austin: R.A. Lavides Company, 1992, p 423 18. Sutherland DER, Gores PF, Farner AL et al. Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota. Am J Surg 166:456, 1993