2008 Clinical Practice Guidelines - Canadian Diabetes Association

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2008 CLINICAL PRACTICE GUIDELINES S88 Pancreas and Islet Transplantation Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Breay W. Paty MD FRCPC, Erin Keely MD FRCPC and Charlotte McDonald MD FRCPC KEY MESSAGES • Pancreas transplant can result in prolonged insulin independence and a possible reduction in the progression of secondary complications of diabetes. • Islet transplant can result in transient insulin independence and can reliably stabilize blood glucose concentrations in people with glycemic lability. • The risks of chronic immunosuppression must be carefully weighed against the potential benefits of pancreas or islet transplant for each individual. INTRODUCTION Beta cell replacement as a means of restoring endogenous insulin secretion, either by whole organ pancreas transplant or islet transplant, has a number of potential advantages over standard exogenous insulin therapy for the treatment of type 1 diabetes, including improved glycemic control and the potential for insulin independence. However, any advantages must be weighed against the risks and adverse effects of surgery and chronic immunosuppressive therapy that accompany these treatments. Unfortunately, the absence of data from randomized controlled trials (RCTs) makes it difficult to draw firm conclusions regarding the efficacy of these therapies compared with intensive medical management of diabetes. Nevertheless, some general recommendations can be made regarding the role of pancreas and islet transplant in the context of current clinical experience. WHOLE PANCREAS TRANSPLANTATION Pancreas transplantation has progressed significantly in terms of surgical technique and immunosuppression since it was first introduced in the 1960s (1). It is most commonly categorized on the basis of the presence or absence of a kidney transplant and the relative timing of the procedures: simultaneous pancreas kidney (SPK) transplant; pancreas after kidney (PAK) transplant; or pancreas transplant alone (PTA), in the absence of a kidney transplant. Worldwide, noncontrolled pancreas graft and patient survival rates differ slightly among these 3 categories (2). However, in the absence of large RCTs, it is unclear whether these differences are clinically significant. Metabolic studies demonstrate a marked improvement in glycemic control and glycated hemoglobin (A1C) after successful whole pancreas transplant, with most recipients achieving insulin independence that can last for many years (3,4). A reduction in albuminuria has been shown at 1 year posttransplant (5). Similarly, improvements in the histologic changes of diabetic nephropathy have been reported after 5 to 10 years posttransplant (6). Studies also show an improvement and/or stabilization of diabetic retinopathy (7) after an initial risk of worsening due to a rapid reduction in glycemia (8). The benefits of pancreas transplant are less clear in patients with advanced retinal disease (9). Peripheral sensory and motor neuropathies have been shown to improve after pancreas transplant (10,11). Improvements in autonomic neuropathy are less consistent and may take longer to achieve (12,13). There is growing evidence that pancreas transplant improves cardiovascular (CV) function (14) and may reduce cardiac events (15). However, studies have generally been small and nonrandomized. It remains uncertain whether pancreas transplant improves overall mortality rates (16). Finally, diabetes-related quality of life appears to improve after pancreas transplant, although overall quality of life may not change (17). ISLET TRANSPLANTATION Islet transplantation is a less invasive procedure than pancreas transplantation. It involves the infusion of islets isolated from cadaveric pancreata via the portal vein into the liver (18). Unlike whole pancreas transplant recipients, most islet transplant recipients require at least 2 islet infusions to achieve insulin independence, although there has been recent shortterm success using single islet donors in some centres (19). The rate of posttransplant insulin independence at the most experienced centres is approximately 80% at 1 year, but declines to about 10% at 5 years (20-22). Rates of insulin independence may be lower at less experienced centres (23,24). Most transplant recipients continue to have some endogenous insulin secretion even after insulin independence is lost. However, there are very few long-term data regarding function of the transplanted islets after 5 years. Most published studies involve islet transplant in the absence of a kidney transplant (islet transplant alone [ITA]).There is some evidence suggesting that islet transplant performed at the same time as a kidney transplant (simultaneous islet kidney [SIK]) or after a kidney transplant (islet after kidney [IAK]) may have comparable results (25,26).
The principal benefit of islet transplant is stabilization of blood glucose control in individuals with severe glycemic lability or hypoglycemia unawareness.This benefit is evident and persists in most recipients, even in the absence of insulin independence (27,28).The impact of islet transplantation on diabetes complications remains uncertain. Renal function appears to decline after ITA in patients with significant preexisting renal dysfunction, although the degree of decline can vary (29,30). For this reason, particular caution may be warranted for patients with pre-existing renal dysfunction.There is some evidence that IAK transplant recipients show improved endothelial and CV function compared to kidney transplant recipients (31,32). Kidney graft survival rates also appear to improve with concomitant islet transplant (33). The impact of islet transplantation on diabetic retinopathy and neuropathy is still uncertain. Quality of life appears to improve initially after islet transplantation, due primarily to a reduced fear of hypoglycemia, but declines with the loss of insulin independence (34,35). RISKS OF PANCREAS AND ISLET TRANSPLANTATION Pancreas transplantation is associated with significant perioperative risks, including graft pancreatitis, peripancreatic abscess, duodenal stump leak, venous or arterial thrombosis, and conversion from bladder to enteric drainage (36). Islet transplantation is associated with fewer procedural risks, which may include intraperitoneal hemorrhage, partial portal vein thrombosis, gallbladder puncture and a transient elevation of liver enzymes (37). Both pancreas and islet transplantation require chronic immunosuppression, which is associated with a number of risks and side effects, including increased risk of infection and malignancy, nephrotoxicity, diarrhea, oral ulcers (in the case of islet transplant) and many others. These risks must be carefully weighed against the potential benefits of transplant for each individual. RECOMMENDATIONS 1. For individuals with type 1 diabetes and end-stage renal disease who are undergoing or have undergone successful kidney transplant, pancreas transplant should be considered [Grade D, Consensus]. 2. For individuals with type 1 diabetes and preserved renal function, but with persistent metabolic instability characterized by severe glycemic lability and/or severe hypoglycemia unawareness despite best efforts to optimize glycemic control, pancreas transplant [Grade D, Level 4 (4)] or islet transplant [Grade D, Level 4 (21)] may be considered. REFERENCES 1. Larsen JL. Pancreas transplantation: indications and consequences. Endocr Rev. 2004;25:919-946. 2. 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) as of June 2004. Clin Transplant. 2005;19:433-455. 3. Robertson RP, Abid M, Sutherland DE, et al. Glucose homeostasis and insulin secretion in human recipients of pancreas transplantation. Diabetes. 1989;38(suppl 1):97-98. 4. Robertson RP, Sutherland DE, Lanz KJ. Normoglycemia and preserved insulin secretory reserve in diabetic patients 10-18 years after pancreas transplantation. Diabetes. 1999;48:1737- 1740. 5. Coppelli A, Giannarelli R,Vistoli F, et al.The beneficial effects of pancreas transplant alone on diabetic nephropathy. Diabetes Care. 2005;28:1366-1370. 6. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med. 1998;339:69-75. 7. Giannarelli R, Coppelli A, Sartini M, et al. Effects of pancreaskidney transplantation on diabetic retinopathy. Transpl Int. 2005;18:619-622. 8. Landgraf R, Nusser J, Scheuer R, et al. Metabolic control and effect on secondary complications of diabetes mellitus by pancreatic transplantation. Baillieres Clin Gastroenterol. 1989;3: 865-876. 9. Bandello F,Vigano C, Secchi A, et al. Effect of pancreas transplantation on diabetic retinopathy: a 20-case report. Diabetologia. 1991;34(suppl 1):S92-S94. 10. Kennedy WR, Navarro X, Goetz FC, et al. Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med. 1990; 322:1031-1037. 11. Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol. 1997;42:727-736. 12. 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;41:946-951. 13. Tydén G, Bolinder J, Solders G, et al. Improved survival in patients with insulin-dependent diabetes mellitus and endstage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation. 1999;67:645-648. 14. Coppelli 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;76:974-976. 15. La Rocca E, Fiorina P, di Carlo V, et al. Cardiovascular outcomes after kidney-pancreas and kidney-alone transplantation. Kidney Int. 2001;60:1964-1971. 16. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA. 2003;290:2817-2823. 17. Sureshkumar KK, Mubin T, Mikhael N, et al. Assessment of quality of life after simultaneous pancreas-kidney transplantation. Am J Kidney Dis. 2002;39:1300-1306. S89 MANAGEMENT
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2008 Clinical Practice Guidelines - Canadian Diabetes Association

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