Pancreas and Islet Transplantation

Abstract

Key Messages•Simultaneous pancreas kidney transplantation in persons with type 1 diabetes and end stage renal disease can improve kidney graft survival and result in prolonged insulin independence.•Successful pancreas or islet allotransplantation can stabilize glucose and possibly result in insulin independence in persons with type 1 diabetes and glycemic lability or recurrent hypoglycemia.•Islet autotransplantation can stabilize glucose and possibly result in insulin independence in people undergoing total pancreatectomy for benign pancreatic disease. •Simultaneous pancreas kidney transplantation in persons with type 1 diabetes and end stage renal disease can improve kidney graft survival and result in prolonged insulin independence.•Successful pancreas or islet allotransplantation can stabilize glucose and possibly result in insulin independence in persons with type 1 diabetes and glycemic lability or recurrent hypoglycemia.•Islet autotransplantation can stabilize glucose and possibly result in insulin independence in people undergoing total pancreatectomy for benign pancreatic disease. Restoring endogenous insulin secretion by whole pancreas or islet transplantation has been established as an alternative to insulin injection therapy in select individuals with type 1 diabetes (1White S.A. Shaw J.A. Sutherland D.E.R. Pancreas transplantation.Lancet. 2009; 373: 1808-1817Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 2Halban P.A. German M.S. Kahn S.E. et al.Current status of islet cell replacement and regeneration therapy.J Clin Endocrinol Metab. 2010; 95: 1034-1043Crossref PubMed Scopus (71) Google Scholar). Nonrandomized studies demonstrate that both pancreas and islet transplantation can result in insulin independence and glucose stability, especially in the setting of glucose lability or frequent, severe hypoglycemia. Unfortunately, the absence of prospective randomized controlled trials makes it difficult to draw firm conclusions about the overall efficacy and safety of these therapies compared with exogenous insulin treatment. Also, the limited number of specialized islet and pancreas transplantation centres and the relatively small number of donor pancreases limit the availability of these treatments. Nevertheless, general recommendations regarding the role of pancreas and islet transplantation may be made in the context of current clinical experience. Pancreas transplantation can result in complete independence from exogenous insulin in the majority of cases (3Robertson R.P. Abid M. Sutherland D.E. et al.Glucose homeostasis and insulin secretion in human recipients of pancreas transplantation.Diabetes. 1989; 38: 97-98Crossref PubMed Google Scholar). As shown in Table 1, worldwide, noncontrolled 1- and 3-year mean pancreas graft and patient survival rates differ slightly among the 3 major types of transplantations (4Waki K. Kadowaki T. An analysis of long-term survival from the OPTN/UNOS Pancreas Transplant Registry.Clin Transplant. 2007; : 9-17Google Scholar). Long-term pancreas graft survival declines with time, with a median graft survival of 9 years and <10% survival at 21 years (5Everly M.J. Pancreas transplant in the United States: an analysis of the UNOS registry.Clin Transplant. 2009; : 75-81PubMed Google Scholar).Table 1Reported graft survival rates according to type of pancreas transplantation 4Waki K. Kadowaki T. An analysis of long-term survival from the OPTN/UNOS Pancreas Transplant Registry.Clin Transplant. 2007; : 9-17Google ScholarTransplantation type1 year5 years10 years15 yearsSPK83%69%51%33%PAK74%45%24%13%PTA78%54%28%9%SPK, simultaneous pancreas kidney; PAK, pancreas after kidney; PTA, pancreas transplant alone. Open table in a new tab SPK, simultaneous pancreas kidney; PAK, pancreas after kidney; PTA, pancreas transplant alone. Glycemic control and glycated hemoglobin (A1C) are markedly improved after successful pancreas transplantation, with most recipients achieving normal glucose tolerance, albeit with hyperinsulinemia (6Robertson R.P. Sutherland D.E. Kendall D.M. et al.Metabolic characterization of long-term successful pancreas transplants in type 1 diabetes.J Investig Med. 1996; 44: 549-555PubMed Google Scholar, 7Lauria M.W. Figueiro J.M. Machado L.J. et al.Metabolic long-term follow-up of functioning simultaneous pancreas-kidney transplantation versus pancreas transplantation alone: insights and limitations.Transplantation. 2010; 89: 83-87Crossref PubMed Scopus (14) Google Scholar). A reduction in albuminuria has been noted at 1 year (8Coppelli A. Giannarelli R. Vistoli F. et al.The beneficial effects of pancreas transplant alone on diabetic nephropathy.Diabetes Care. 2005; 28: 1366-1370Crossref PubMed Scopus (77) Google Scholar), and improvements in the histological changes associated with diabetic nephropathy have been reported 5 to 10 years posttransplantation (9Fioretto P. Steffes M.W. Sutherland D.E. et al.Reversal of lesions of diabetic nephropathy after pancreas transplantation.N Engl J Med. 1998; 339: 69-75Crossref PubMed Scopus (1016) Google Scholar, 10Fioretto P. Sutherland D.E.R. Najafian B. et al.Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients.Kidney Int. 2006; 69: 907-912Crossref PubMed Scopus (122) Google Scholar). Whether successful simultaneous pancreas kidney (SPK) transplantation improves renal graft survival is unclear. In 1 study, recipients of SPK transplantations had better renal graft survival over 72 months than deceased-donor kidney transplantations but lower graft survival than living-donor kidney transplantations (11Young B.Y. Gill J. Huang E. Takemoto S.K. et al.Living donor kidney versus simultaneous pancreas-kidney transplant in type I diabetics: an analysis of the OPTN/UNOS database.Clin J Am Soc Nephrol. 2009; 4: 845-852Crossref PubMed Scopus (78) Google Scholar). The impact of pancreas transplantation on overall patient survival also is uncertain. Studies suggest lower short-term survival in the perioperative period up to 18 to 24 months after SPK, but for patients with successful functioning pancreas grafts at 12 months post-transplantation, survival was similar or improved compared to living- or deceased-donor kidney transplantation (12Ojo A.O. Meier-Kriesche H.U. Hanson J.A. et al.The impact of simultaneous pancreas-kidney transplantation on long-term patient survival.Transplantation. 2001; 71: 82-90Crossref PubMed Scopus (280) Google Scholar, 13Reddy K.S. Stablein D. Taranto S. et al.Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure.Am J Kidney Dis. 2003; 41: 464-470Abstract Full Text PDF PubMed Scopus (184) Google Scholar, 14Weiss A.S. Smits G. Wiseman A.C. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation.Clin J Am Soc Nephrol. 2009; 4: 988-995Crossref PubMed Scopus (73) Google Scholar). A retrospective cohort study of individuals with diabetes and preserved kidney function who received a solitary pancreas transplantation suggested that overall survival was worse compared with wait-listed patients receiving conventional medical therapy (15Venstrom J.M. McBride M.A. Rother K.I. et al.Survival after pancreas transplantation in patients with diabetes and preserved kidney function.JAMA. 2003; 290: 2817-2823Crossref PubMed Scopus (263) Google Scholar). Improvement and/or stabilization of diabetic retinopathy have been demonstrated (16Giannarelli R. Coppelli A. Sartini M.S. et al.Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients.Diabetologia. 2006; 49: 2977-2982Crossref PubMed Scopus (84) Google Scholar). Peripheral sensory and motor neuropathies also have been shown to improve after pancreas transplantation (17Mehra S. Tavakoli M. Kallinikos P.A. et al.Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes.Diabetes Care. 2007; 30: 2608-2612Crossref PubMed Scopus (192) Google Scholar, 18Kennedy W.R. Navarro X. Goetz F.C. et al.Effects of pancreatic transplantation on diabetic neuropathy.N Engl J Med. 1990; 322: 1031-1037Crossref PubMed Scopus (382) Google Scholar), but these findings are not consistent and may take years to achieve (19Solders 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: 946-951Crossref PubMed Google Scholar, 20Tydén 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: 645-648Crossref PubMed Scopus (227) Google Scholar, 21Boucek P. Havrdova T. Voska L. et al.Epidermal innervation in type 1 diabetic patients: a 2.5-year prospective study after simultaneous pancreas/kidney transplantation.Diabetes Care. 2008; 31: 1611-1612Crossref PubMed Scopus (43) Google Scholar). Pancreas transplantation appears to improve cardiovascular (CV) function, carotid intimal medial thickness, blood pressure and lipid parameters (22Coppelli A. Giannarelli R. Mariotti R. et al.Pancreas transplant alone determines early improvement of cardiovascular risk factors and cardiac function in type 1 diabetic patients.Transplantation. 2003; 76: 974-976Crossref PubMed Scopus (46) Google Scholar, 23Larsen J.L. Colling C.W. Ratanasuwan T. et al.Pancreas transplantation improves vascular disease in patients with type 1 diabetes.Diabetes Care. 2004; 27: 1706-1711Crossref PubMed Scopus (74) Google Scholar, 24Luan F.L. Miles C.D. Cibrik D.M. et al.Impact of simultaneous pancreas and kidney transplantation on cardiovascular risk factors in patients with type 1 diabetes mellitus.Transplantation. 2007; 84: 541-544Crossref PubMed Scopus (32) Google Scholar). A single, small, nonrandomized study showed a reduction in CV events in SPK recipients compared to those undergoing kidney transplantation alone (25La Rocca E. Fiorina P. di Carlo V. et al.Cardiovascular outcomes after kidney-pancreas and kidney-alone transplantation.Kidney Int. 2001; 60: 1964-1971Crossref PubMed Scopus (117) Google Scholar); however, this has not been examined in a randomized controlled fashion. Finally, diabetes-related quality of life (QOL) appears to improve after pancreas transplantation, although overall QOL appears to be unchanged (26Sureshkumar K.K. Patel B.M. Markatos A. et al.Quality of life after organ transplantation in type 1 diabetics with end-stage renal disease.Clin Transplant. 2006; 20: 19-25Crossref PubMed Scopus (81) Google Scholar, 27Speight J. Reaney M.D. Woodcock A.J. et al.Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in Type 1 diabetes: a systematic review.Diabet Med. 2010; 27: 812-822Crossref PubMed Scopus (40) Google Scholar). Islet allotransplantation involves the infusion of islets isolated from cadaveric pancreata via the portal vein into the liver (28Robertson R.P. Islet transplantation as a treatment for diabetes: a work in progress.N Engl J Med. 2004; 350: 694-705Crossref PubMed Scopus (360) Google Scholar), either alone or in association with a renal transplantation (29Gerber P.A. Pavlicek V. Demartines N. et al.Simultaneous islet-kidney vs pancreas-kidney transplantation in type 1 diabetes mellitus: a 5-year single centre follow-up.Diabetologia. 2008; 51: 110-119Crossref PubMed Scopus (58) Google Scholar, 30Deng S. Markmann J.F. Rickels M. et al.Islet alone versus islet after kidney transplantation: metabolic outcomes and islet graft survival.Transplantation. 2009; 88: 820-825Crossref PubMed Scopus (23) Google Scholar). Successful islet transplantation can result in stable, near-normal glycemic control (A1C, glycemic variability) with a reduction or elimination of hypoglycemia (31Ryan E.A. Paty B.W. Senior P.A. et al.Five year follow-up after clinical islet transplantation.Diabetes. 2005; 54: 2060-2069Crossref PubMed Scopus (1367) Google Scholar) over and above what can be achieved with insulin injections or even insulin pump therapy (32Vantyghem M.C. Marcelli-Tourvieille S. Fermon C. et al.Intraperitoneal insulin infusion versus islet transplantation: comparative study in patients with type 1 diabetes.Transplantation. 2009; 87: 66-71Crossref PubMed Scopus (27) Google Scholar). The ability of transplant recipients to achieve and maintain insulin independence varies between transplantation centres and is influenced by both donor and recipient factors (33Shapiro A.M. Ricordi C. Hering B.J. et al.International trial of the Edmonton protocol for islet transplantation.N Engl J Med. 2006; 355: 1318-1330Crossref PubMed Scopus (1548) Google Scholar, 34Alejandro R. Barton F.B. Hering B.J. et al.2008 update from the Collaborative Islet Transplant Registry.Transplantation. 2008; 86: 1783-1788Crossref PubMed Scopus (200) Google Scholar). Insulin independence can be achieved in most recipients but often requires 2 or more transplantation procedures. Insulin independence rates decline with time from approximately 70% at 1 year posttransplantation to approximately 10% after 5 years (31Ryan E.A. Paty B.W. Senior P.A. et al.Five year follow-up after clinical islet transplantation.Diabetes. 2005; 54: 2060-2069Crossref PubMed Scopus (1367) Google Scholar). However, patients who are not able to maintain insulin independence may still benefit from more stable blood glucose control (35Paty B.W. Senior P.A. Lakey J.R. et al.Assessment of glycemic control after islet transplantation using the continuous glucose monitor in insulin-independent versus insulin-requiring type 1 diabetes subjects.Diabetes Technol Ther. 2006; 8: 165-173Crossref PubMed Scopus (48) Google Scholar) that results from ongoing graft function, as evidenced by the sustained secretion of C peptide and the reduced requirement for exogenous insulin (33Shapiro A.M. Ricordi C. Hering B.J. et al.International trial of the Edmonton protocol for islet transplantation.N Engl J Med. 2006; 355: 1318-1330Crossref PubMed Scopus (1548) Google Scholar). Small, short-term studies also suggest stabilization of retinopathy (36Thompson D.M. Begg I.S. Harris C. et al.Reduced progression of diabetic retinopathy after islet transplantation compared with intensive medical therapy.Transplantation. 2008; 85: 1400-1405Crossref PubMed Scopus (65) Google Scholar) and neuropathy (37Del Carro U. Fiorina P. Amadio S. et al.Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis.Diabetes Care. 2007; 30: 3063-3069Crossref PubMed Scopus (72) Google Scholar) with islet allotransplantation. Renal outcomes vary, but recent reports suggest that the glomerular filtration rate achieved with the procedure does not differ significantly from that observed in the nondiabetic population (38Senior P.A. Zeman M. Paty B.W. et al.Changes in renal function after clinical islet transplantation: four-year observational study.Am J Transplant. 2007; 7: 91-98Crossref PubMed Scopus (88) Google Scholar, 39Fung M.A. Warnock G.L. Ao Z. et al.The effect of medical therapy and islet cell transplantation on diabetic nephropathy: an interim report.Transplantation. 2007; 84: 17-22Crossref PubMed Scopus (47) Google Scholar). Successful islet transplantation can improve QOL by reducing the fear of hypoglycemia (40Poggioli R. Faradji R.N. Ponte G. et al.Quality of life after islet transplantation.Am J Transplant. 2006; 6: 371-378Crossref PubMed Scopus (97) Google Scholar) but can be negatively impacted by adverse effects from immunosuppressive agents (27Speight J. Reaney M.D. Woodcock A.J. et al.Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in Type 1 diabetes: a systematic review.Diabet Med. 2010; 27: 812-822Crossref PubMed Scopus (40) Google Scholar). In islet autotransplantation, islets are isolated from an individual's own resected pancreas following pancreatectomy for benign pancreatic disease (e.g. chronic, painful pancreatitis) (41Robertson R.P. Lanz K.J. Sutherland D.E. et al.Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis.Diabetes. 2001; 50: 47-50Crossref PubMed Scopus (136) Google Scholar, 42Bellin M.D. Sutherland D.E. Pediatric islet autotransplantation: indication, technique, and outcome.Curr Diab Rep. 2010; 10: 326-331Crossref PubMed Scopus (25) Google Scholar). Islet yields from a resected, diseased pancreas may be lower than those from cadaveric donors, but immunosuppression is not required. Even if insulin independence is not achieved, islet autotransplantation may result in reduced exogenous insulin requirements and a lower risk of hypoglycemia (43Blondet J.J. Carlson A.M. Kobayashi T. et al.The role of total pancreatectomy and islet autotransplantation for chronic pancreatitis.Surg Clin North Am. 2007; 87: 1477-1501Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). As a result, the ratio of benefit to risk of this procedure may exceed that noted with islet allotransplantation (44Sutherland D.E. Gruessner A.C. Carlson A.M. et al.Islet autotransplant outcomes after total pancreatectomy: a contrast to islet allograft outcomes.Transplantation. 2008; 86: 1799-1802Crossref PubMed Scopus (140) Google Scholar). Pancreas transplantation is associated with significant perioperative risks, including graft thrombosis, hemorrhage, pancreatitis, wound infection, peripancreatic abscesses and duodenal stump leakage (45Troppmann C. Complications after pancreas transplantation.Curr Opin Organ Transplant. 2010; 15: 112-118Crossref PubMed Scopus (123) Google Scholar). Islet transplantation is associated with fewer procedural risks, which may include intraperitoneal hemorrhage, partial portal vein thrombosis or gallbladder puncture. These complications occur in <10% of procedures and usually are self-limited (31Ryan E.A. Paty B.W. Senior P.A. et al.Five year follow-up after clinical islet transplantation.Diabetes. 2005; 54: 2060-2069Crossref PubMed Scopus (1367) Google Scholar, 34Alejandro R. Barton F.B. Hering B.J. et al.2008 update from the Collaborative Islet Transplant Registry.Transplantation. 2008; 86: 1783-1788Crossref PubMed Scopus (200) Google Scholar). Both pancreas and islet transplantations require long-term immunosuppression, which is associated with a number of risks and side effects (46Gruessner R.W. Sutherland D.E.R. Gruessner A.C. Mortality assessment for pancreas transplants.Am J Transplant. 2004; 4: 2018-2026Crossref PubMed Scopus (252) Google Scholar). Drug side effects are generally mild and often respond to dose or agent adjustment. Although rare, life-threatening opportunistic infections and malignancies have been reported (34Alejandro R. Barton F.B. Hering B.J. et al.2008 update from the Collaborative Islet Transplant Registry.Transplantation. 2008; 86: 1783-1788Crossref PubMed Scopus (200) Google Scholar, 46Gruessner R.W. Sutherland D.E.R. Gruessner A.C. Mortality assessment for pancreas transplants.Am J Transplant. 2004; 4: 2018-2026Crossref PubMed Scopus (252) Google Scholar). These risks must be carefully weighed against the potential benefits of transplantation for each individual. See Table 2 for a detailed comparison of pancreas vs. islet transplantation.Recommendations1.Individuals with type 1 diabetes and ESRD who are being considered for kidney transplantation should also be considered for simultaneous pancreas transplantation [Grade D, Level 4 (12Ojo A.O. Meier-Kriesche H.U. Hanson J.A. et al.The impact of simultaneous pancreas-kidney transplantation on long-term patient survival.Transplantation. 2001; 71: 82-90Crossref PubMed Scopus (280) Google Scholar, 14Weiss A.S. Smits G. Wiseman A.C. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation.Clin J Am Soc Nephrol. 2009; 4: 988-995Crossref PubMed Scopus (73) Google Scholar)].2.Individuals with type 1 diabetes with preserved renal function, or who have undergone successful kidney transplantation but have persistent metabolic instability characterized by severe glycemic lability and/or severe hypoglycemia despite best efforts to optimize glycemic control, may be considered for pancreas or islet allotransplantation [Grade D, Consensus].3.Individuals undergoing total pancreatectomy for benign pancreatic disease may be considered for islet autotransplantation but only in the context of an experienced islet transplantation centre [Grade D, Consensus].Abbreviation:ESRD, end stage renal disease.Table 2Comparison of beta cell replacement modalitiesIsletPancreasOutcomesReduce or eliminate hypoglycemiaYesYesImprove A1CYesYesInsulin independenceYes∗More than 1 islet infusion may be required.YesEffect on diabetes-related complicationsMicrovascularMay be stabilized†Retinopathy and neuropathy may be stabilized.ImprovedMacrovascularNot knownMay be improvedRisksProcedural risksMinor procedural riskMajor surgical riskImmunosuppressionSimilar agents,‡Steroids are avoided in islet transplantation but may be used in whole pancreas transplantation. life-long immunosuppressionOther considerationsESRDAvoidConsider SPKFunctioning renal transplantConsider IAK if glycemic lability or hypoglycemia§No additional risk from immunosuppression.Consider PAK if glycemic lability or hypoglycemia§No additional risk from immunosuppression.A1C, glycated hemoglobin; ESRD, end stage renal disease; IAK, islet after kidney; PAK, pancreas after kidney; SPK, simultaneous pancreas kidney.∗ More than 1 islet infusion may be required.† Retinopathy and neuropathy may be stabilized.‡ Steroids are avoided in islet transplantation but may be used in whole pancreas transplantation.§ No additional risk from immunosuppression. Open table in a new tab 1.Individuals with type 1 diabetes and ESRD who are being considered for kidney transplantation should also be considered for simultaneous pancreas transplantation [Grade D, Level 4 (12Ojo A.O. Meier-Kriesche H.U. Hanson J.A. et al.The impact of simultaneous pancreas-kidney transplantation on long-term patient survival.Transplantation. 2001; 71: 82-90Crossref PubMed Scopus (280) Google Scholar, 14Weiss A.S. Smits G. Wiseman A.C. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation.Clin J Am Soc Nephrol. 2009; 4: 988-995Crossref PubMed Scopus (73) Google Scholar)].2.Individuals with type 1 diabetes with preserved renal function, or who have undergone successful kidney transplantation but have persistent metabolic instability characterized by severe glycemic lability and/or severe hypoglycemia despite best efforts to optimize glycemic control, may be considered for pancreas or islet allotransplantation [Grade D, Consensus].3.Individuals undergoing total pancreatectomy for benign pancreatic disease may be considered for islet autotransplantation but only in the context of an experienced islet transplantation centre [Grade D, Consensus].Abbreviation:ESRD, end stage renal disease. A1C, glycated hemoglobin; ESRD, end stage renal disease; IAK, islet after kidney; PAK, pancreas after kidney; SPK, simultaneous pancreas kidney.