Pancreas Transplantation for Diabetes Mellitus

TRANSPLANTATION FOR THE NEPHROLOGIST

Pancreas Transplantation for Diabetes Mellitus John D. Pirsch, MD, Charles Andrews, MD, Donald E. Hricik, MD, Michelle A. Josephson, MD, Alan B. Leichtman, MD, Christopher Y. Lu, MD, Larry B. Melton, MD, PhD, Venkateswara K. Rao, MD, Robert R. Riggio, MD, Robert J. Stratta, MD, and Matthew R. Weir, MD (Kidney-Pancreas Committee of the American Society of Transplant Physicians) • Pancreas transplantation has become a viable option for the patient with insulin-dependent diabetes mellitus with progressive renal failure. The most common type of pancreas transplantation is a simultaneous pancreas and kidney transplantation performed from a single cadaver donor (SPK). The next most common is pancreas transplantation after successful kidney transplantation (PAK). A few centers are performing pancreas transplantation alone (PTA) in diabetic recipients without renal disease but who have significant complications from their diabetes. Pancreas transplantation is associated with a higher morbidity than kidney transplantation alone. Most pancreas transplantation centers report a significant increase in acute rejection, which can lead to increased hospitalization and risk of opportunistic infection. In addition, the early era of pancreas transplantation was associated with significant surgical complications. However, with bladder drainage of the pancreas exocrine secretions, the surgical complication rate has decreased significantly. Despite medical and surgical complications, the overall results for pancreas transplantation are excellent, with 1-year graft survival of 75% for SPK transplantations and 48% for PAK and PTA transplant recipients. The effects of a pancreas transplantation on the secondary complications of diabetes have been studied extensively. Most studies have shown a modest improvement in secondary complications with the exception of diabetic retinopathy. The major benefit of pancreas transplantation appears to be enhanced quality of life for patients successfuUy transplanted. For these reasons, the Kidney-Pancreas Committee of the American Society of Transplant Physicians believes the current results of pancreas-kidney transplantation justify its use as a valid option for insulin-dependent diabetic transplant recipients. © 1996 by the National Kidney Foundation, Inc. INDEX WORDS: Pancreas transplantation; secondary complications; quality of life; surgical complications; rejection; results.

IABETES MELLITUS is the leading cause of renal failure and blindness in adults, the leading disease cause of amputations and impotence, and one of the leading chronic diseases of childhood, l In addition, diabetes mellitus is associated with accelerated atherosclerosis, ab-

D

From the University of Wisconsin Hospital, Madison, W1; Harris Methodist Fort Worth, Fort Worth, TX; University Hospital, Cleveland, OH; University of Chicago Medical Center, Chicago, 1L; University of Michigan, Ann Arbor, M1; University of Texas Southwestern Medical School Dallas, TX; Baylor University Medical Center, Dallas, TX; Hennepin County Medical Center, Minneapolis, MN; The New York Hospital New York, NY; University of Nebraska Medical Center, Omaha, NE; and University of Maryland Hospital Baltimore, MD. Received June 7, 1995; accepted in revised form August 22, 1995. Address reprint requests to John D. Pirsch, MD, Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Ave, Madison, WI 53792-7375. © 1996 by the National Kidney Foundation, Inc. 0272-6386/96/2703-002253.00/0

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normal lipid metabolism, and cardiovascular disease. It accounts for more than 160,000 deaths per year in the United States. Exogenous insulin therapy is life saving, controlling glucose metabolism and preventing acute metabolic decompensation. Results of a recent landmark multicenter trial, the Diabetes Control and Complication Trial, 2 have shown that tight glucose control is even more important than previously recognized. The consequences are that most individuals with insulin-dependent diabetes mellitus (IDDM) develop one or more end-stage organ complications during their lifetime. In patients who suffer progressive complications despite intensive insulin therapies, pancreas transplantation is the best treatment option, for it is the single most effective method of achieving tight glucose control. The first vascularized pancreas transplantation was pioneered by Kelly et al in 1966 at the University of Minnesota? Most grafts functioned immediately, but technical complications and rejection arose, and none of the initial pancreas

American Journal of Kidney Diseases, Vol 27, No 3 (March), 1996: pp 444-450

PANCREAS TRANSPLANTATION

transplants were successful. The major surgical problem to be overcome was appropriate exocrine drainage of the transplanted pancreas. This was largely solved in the 1980s with the introduction of the bladder drainage technique. 4'5 The use of this technique gained wide acceptance in the transplant community and became the preferred technique for exocrine drainage. 6 Despite improvements in surgical technique, pancreas transplantation was associated with complications and morbidity from anastomotic leak and abscess formation, increased frequency of rejection requiring additional immunosuppression, and opportunistic infection] -9 The incidence of these complications has declined with the use of University of Wisconsin solution for preserving the pancreas, 1° improved surgical techniques, 8'11 and better monitoring of the transplanted pancreas for rejection. 12-16These improvements have resulted in a significant increase in patient and graft survival and reduced morbidity. ]7-2] The improved survival has made pancreas transplantation an increasingly important option for the insulin-dependent diabetic patient with end-stage renal disease. RATIONALE FOR PANCREAS TRANSPLANTATION

Vascularized pancreas transplantation was first developed to provide an autoregulating endogenous source of insulin responsive to normal feedback controls. Successful pancreas transplantation is currently the only known therapy that establishes an insulin-independent euglycemic state with complete normalization of glycosylated hemoglobin levels. 22-25After two decades of kidney transplantation alone for diabetic nephropathy, the secondary complications of diabetes continue to cause significant disability and death. Providing a pancreas transplant to the diabetic recipient is an attempt to slow down or reverse the relendess progression of diabetic complications. Because the insulin-dependent diabetic patient with end-stage renal disease will be undergoing a kidney transplantation and will be subjected to the risks of immunosuppression, a pancreas transplantation simultaneously or after the kidney transplantation provides an opportunity to cure the insulin deficiency of the diabetic recipi-

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ent. The costs of this mechanism for normalizing glucose homeostasis are the operative risks of the transplantation procedure and the need for long-term immunosuppression. 26 It is hoped that, by restoring normal glucose homeostasis with a pancreas transplantation, secondary complications of diabetes would be stabilized or significantly improved. TYPES OF PANCREAS TRANSPLANTS

Pancreas transplantation is being performed in three clinical settings. The most common type of pancreas transplantation is a simultaneous pancreas and kidney transplantation performed from a single donor (SPK). In 1993, 37% of diabetic patients younger than 50 years of age who received kidney transplants had SPK transplants; this percentage continues to increase. 18 The next most common type is a pancreas transplantation after successful kidney transplantation (PAK). Finally, a few centers perform pancreas transplantation alone (PTA) in patients who do not have end-stage renal disease but have other significant complications from their diabetes. 26'27 Living-donor pancreas transplantation have also been performed. 28 Living-donor pancreas transplantation have a decreased incidence of rejection, but the technical failure rate is similar to that of cadaver transplantations. Because of the improved results with cadaver pancreas transplantation, the enthusiasm for living-donor transplantation has decreased, although living-donor transplantation may be indicated for patients who are highly sensitized. OUTCOME

Patient and graft survival after pancreas transplantation has improved dramatically since the early 1980s. SPK transplantation is associated with the best overall survival. One-year graft survival is poorer with PAK transplantations, but patient survival is equivalent to that for SPK transplantations. PTA yields patient and pancreas transplant survival equivalent to that for PAK transplantation. 6 The International Pancreas Transplant Registry (IPTR) was organized in 1980 to provide historical and current data on clinical pancreas transplantation. From December 16, 1966 to August 1, 1994, 6,016 pancreas transplantations

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Table 1. Patient and Graft Survival for Diabetic Recipients of Kidney Transplant Alone Versus Simultaneous Kidney-Pancreas Transplant (One-Year Survival)

Kidney alone SPK

Patient

Kidney

Pancreas

(%)

(%)

(%)

90 91

79 84

-75

were performed worldwide and reported to the IPTR. 29 More than 75% of these procedures have been performed since September 30, 1987. Since that time, all United States cases have been reported to the United Network for Organ Sharing (UNOS) through a subcontract with the IPTR. Most (84%) pancreas transplantations have been performed as SPK procedures in patients who have had imminent or projected renal failure (preemptive) or were on dialysis. The remaining transplantations were performed as a sequential PAK procedure (8%), as PTA (6%), or in conjunction with a single organ other than the kidney or with multiple organs ( 2 % ) . 6 Survival statistics for the period October 1, 1987 to April 30, 1994 show overall actual 1year graft survival rates of 75% for simultaneous pancreas transplantations; patient survival was 91%29 Pancreas transplantation did not adversely affect kidney graft survival; 1-year kidney graft survival for diabetic recipients who underwent a kidney transplantation alone was 79% versus 84% for diabetics undergoing SPK transplantation j8 (Table 1). One-year patient survival in diabetic recipients was 90%, similar to that for all pancreas transplant recipients. 29 PAK and PTA both have 1-year graft survival of 48%, which is significantly less than S P K . 29 MORBIDITY

Any pancreas transplantation is associated with a higher morbidity than kidney transplantation alone. 7-9'1821 The most frequent problem after pancreas transplantation is acute rejection, 8'9 which leads to additional hospitalization and an increased risk for opportunistic infections. Fortunately, surgical complications have been decreasing with improvements in pancreas preservation and surgical techniques. Because the

pancreas is now commonly drained into the bladder, metabolic and urologic complications can be frequent in both early and later posttransplantation years. 26'3° Occasionally, conversion to enteric drainage is undertaken to relieve urologic complications; this, of course, necessitates an additional operative intervention. 31'32 The major challenge in the posttransplantation setting is the prevention and treatment of acute rejection. Despite significant improvements in the immunosuppressive regimens and their use, rejection is very common (60% to 80%) after pancreas transplantation and is the leading cause of pancreas graft lOSS.6 It is difficult to monitor for rejection, because the loss of glycemic control is late evidence and usually indicates significant destruction of the islet cells in the graft. Current monitoring techniques such as following serum lipase and amylase or urinary amylase are helpful but not sufficiently sensitive or specific to diagnose graft rejection.14 Urine cytology33 and serum anodal trypsinogen are showing promise as noninvasive markers of rejection. 34 Cystoscopic and percutaneous pancreatic allograft biopsy with sonographic guidance are becoming more common tools to evaluate allograft dysfunction. ~5'35-37It is hoped that newer immunosuppressive agents such as FK506 or mycophenolate mofetil will provide better immunosuppression in the near future. EFFECTS OF PANCREAS TRANSPLANTATION ON SECONDARY COMPLICATIONS

The effects of pancreas transplantation on secondary complications have been studied extensively. The major benefit of a pancreas transplantation over a kidney transplantation alone is enhanced quality of life. 38-4j Other advantages over kidney transplantation alone include reversal in neuropathy,42-45 prevention of diabetic nephropathy, 46'47 and lower lipid levels. 48 It does not appear that pancreas transplantation ameliorates retinopathy, but retinopathy often stabilizes.49'50 An area of investigational interest is the effect of pancreas transplantation on microvascular disease; preliminary reports appear to show improvements in the microvasculature of the pancreas recipient. 5~ PATIENT SELECTION

Recipient selection and evaluation for vascularized pancreas transplantation was reported re-

PANCREAS TRANSPLANTATION

cently.52 Because of the increased morbidity of pancreas transplantation compared with kidney transplantation alone, recipients selected for pancreas transplantation are usually healthier than diabetic recipients receiving a kidney transplant alone. 9 In general, candidates for pancreas transplantation should be free of significant noncorrectable, cardiovascular disease. 52 In addition, severe vascular disease, psychiatric illness, the lack of well-defined diabetic complications, and significant obesity may be considered to be relative contraindications to pancreas transplantation. In general, pancreas transplantation is only recommended for type I diabetes mellitus, although there are anecdotal cases by transplant centers of successful transplantation in the presence of non-insulin-dependent diabetes mellitus. Because of the high morbidity of diabetic recipients on dialysis and the increasing waiting time for successful transplantation, most large pancreas transplant centers prefer preemptive transplantation before the onset of the need for dialysis. COST

The charges associated with pancreas transplantation are comparable to those for kidney transplantation and less than those for other solid organ transplant procedures. Charges for pancreas transplantation are slightly lower than for kidney transplantation alone. In 1993, estimated total first-year charges for pancreas transplantations was $65,000 (v $87,700 for kidney transplantation alone) by actuarial analysis.53 Projected total 5-year charges are $70,300 for pancreas transplantation versus $124,900 for kidney transplantation based on 1993 actuary data. These data are actuarial and may not accurately reflect the long-term charges associated with pancreas transplantation. In addition, many of the charges for SPK transplants may be covered under the Diagnosis-Related Group for kidney transplantation, making it difficult to accurately estimate the charge for pancreas transplantation. Late hospitalizations or reoperations for pancreas-related problems could also add to the total cost of pancreas transplantation. Despite the costs of pancreas transplantation procedures, the number of health maintenance organizations paying for pancreas transplantation has grown from 43% in 1986 to 55% in 1992. 5~

447 OBSERVATIONS AND RECOMMENDATIONS

Pancreas transplantation in the United States has been limited by a reluctance in the medical community to accept transplantation as a valid and effective treatment option in selected IDDM patients. A recent review questioned the appropriateness of pancreas transplantation in view of increased morbidity and the lack of a substantial effect on secondary complications. 54 A major concern is the lack of controlled trials that demonstrate unequivocal evidence of the superiority of pancreas transplantation over kidney transplantation alone, particularly on secondary complications of diabetes. Most studies have been comparative trials of concurrent transplant recipients or recipients of a failed graft. Although uncontrolled, there has been consistency of findings of improvement in pancreas recipients compared with kidney recipients alone regarding most secondary complications and quality of life. Unfortunately, given the excellent results of SPK in the current era, it is doubtful that controlled randomized trials will ever be conducted. Morbidity and cost is an important consideration when recommending pancreas transplantation. In the 1980s, much of the morbidity was related to the surgical procedure and complications arising from the transplant itself. Improvements in the surgical approach has decreased postsurgical complications greatly. Rejection, although frequent, is almost always treatable but may require aggressive therapy with antilymphocyte therapy. 9 Surprisingly, in the University of California at Los Angeles database, acute rejection has not led to an increased frequency of late graft loss when compared with kidney transplantation alone, is Overall, whether the patient undergoes SPK transplant or a sequential PAK transplant, he or she receives clearly established benefits in quality of life and alleviation of some secondary complications of diabetes over kidney transplantation alone. In each of these patient categories, it appears that the benefit-to-risk ratio favors pancreas transplantation over diabetes with a kidney transplantation alone. With regard to solitary PTA before any establishment of a need for a kidney transplantation, data are still being generated. PTA might be indicated for those patients who have been failed by

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exogenous insulin therapy because of hyperlability, hypoglycemic unawareness, or poor quality of life. Furthermore, P T A might be an effective therapeutic option in the I D D M patient who is b e g i n n i n g to experience early diabetic complications and has, therefore, b y definition, suffered long-term failure of exogenous insulin therapy. That patient is at high risk for developing progressive and eventual irreversible complications from diabetes such as blindness, heart disease, kidney failure, or amputations. On the basis of available data, the A m e r i c a n Society of Transplant Physicians agrees with the policy statements from the A m e r i c a n Diabetes Associationss and the A m e r i c a n Society of Transplant Surgeons 56 recognizing the benefits of pancreas transplantation for I D D M patients with end-stage renal disease. The A m e r i c a n Society of Transplant Physicians strongly r e c o m m e n d s universal coverage for suitable pancreas transplant recipients b y third-party payers and Medicare. REFERENCES

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Ramsay RC, Steffes MW, Mauer SM, Gruessner R, MoudryMunns KC, Morel P, Viste A, Robertson RP, Najarian JS: A 10-year experience with 290 pancreas transplants at a single institution. Ann Surg 210:274-288, 1989 9. Sollinger HW, Knechtle SJ, Reed A, D'Alessandro AM, Kalayoglu M, Belzer FO, Pirsch JD: Experience with 100 consecutive simultaneous kidney-pancreas transplants with bladder drainage. Ann Surg 214:703-711, 1991 10. D'Alessandro AM, Stratta RJ, Sollinger HW, Kalayoglu M, Pirsch JD, Belzer FO: Use of UW solution in pancreas transplantation. Diabetes 38:7-9, 1989 11. Soilinger HW, Pirsch JD, D'Alessandro AM, Kalayoglu M, Belzer FO: Advantages of bladder drainage in pancreas transplantation:A personal view. Clin Transplant 4:3236, 1990 12. Stratta RI, Sollinger HW, Pedman SB, D'Alessandro AM, Groshek M, Kalayoglu M, Pirsch JD, Belzer FO: Early detection of rejection in pancreas transplantation. Diabetes 38:63-67, 1989 13. Nakhleh RE, Gruessner RWG, Swanson PE, Tzardis PJ, Brayman K, Dunn DL, Sutherland DER: Pancreas transplant pathology: A morphologic, inununohistochemical,and electron microscopic comparison of allogeneic grafts with rejection, syngeneic grafts, and chronic pancreatitis. Am J Surg Pathol 15:246-256, 1991 14. Abendroth D, Capalbo M, Itlner WD, Landgraf R, Land W: Critical analysis of rejection markers sIL-2R, urinary amylase, and lipase in whole-organpancreas transplantation with exocrine bladder drainage. Transplant Proc 24:786787, 1992 15. Allen RDM, Wilson TG, Grierson JM, Greenberg ML, Earl MJ, Nankivell BJ, Pearl TA, Chapman JR: Percutaneous biopsy of bladder-drained pancreas transplants. Transplantation 51:1213-1216, 1991 16. Lowell JA, Bynon JS, Nelson N, Hapke MR, Morton JJ, Brennan DC, Radio SJ, Stratta RJ, Taylor RJ: Improved technique for transduodenal pancreas transplant biopsy. Transplantation 57:752-753, 1994 17. US Renal Data System: USRDS 1992 Annual Report: Simultaneous kidney-pancreas transplantation versus kidney transplantation alone: Patient survival, kidney graft survival, and post-transplant hospitalization.Am J Kidney Dis 20:6167, 1992 18. Hirata M, Terasaki PI: The long-termeffect of primary disease on cadaver-donorrenal transplant recipients, in Terasaki PI, Cecka JM (eds): Clinical Transplants 1993 (ed 9). Los Angeles, CA, UCLA Tissue Typing Laboratory, 1993, pp 485-498 19. Cheung AH, Sutherland DEll, Gillingham KJ, McHugh LE, Moudry-Munns KC, Dunn DL, Najarian JS, Matas AJ: Simultaneous pancreas-kidney transplant versus kidney transplant alone in diabetic patients. Kidney Int 41:924-929, 1992 20. Stratta RJ, Taylor RJ, Ozaki CF, Bynon JS, Miller SA, Baker TL, Lykke C, Krobot ME, Langnas AN, Shaw BW Jr: Tile analysis of benefit and risk of combined pancreatic and renal transplantation versus renal transplantation alone. Surg Gynecol Obstet 177:163-171, 1993 21. SchulakJA, Mayes JT, Hricik DE: Kidney transplantation in diabetic patients undergoing combined kidney-pan-

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Burke K, Sollinger HW: The influence of combined kidney-pancreas transplantation on the progression of diabetic retinopathy: A case series. Ophthalmology 10 l: 1071-1076, 1994 51. Gfesser M, Nusser J, Muller-Felber W, Abendroth D, Land W, Landgraf R: Cross-sectional study of peripheral microcirculation in diabetic patients with microangiopathy: Influence of pancreatic and kidney transplantation. Acta Diabetol 30:79-84, 1993 52. Stratta RJ, Taylor RJ, Wahl TO, Duckworth WC, Gallagher TF, Knight TF, Fischer JL, Neumann TV, Miller S, Langnas AN, Ozaki CF, Bynon JS, Larsen JL, Weide LG, Cassling RS, Taylon AJ, Shaw BW Jr: Recipient selection and evaluation for vascularized pan-

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creas transplantation. Transplantation 55:1090-1096, 1993 53. Evans RW: Organ transplantation and the inevitable debate as to what constitutes a basic health care benefit, in Terasaki PI, Cecka JM (eds): Clinical Transplants 1993 (ed 9). Los Angeles, CA, UCLA Tissue Typing Laboratory, 1994, pp 359-391 54. Remuzzi G, Ruggenenti P, Mauer SM: Pancreas and kidney/pancreas transplants: Experimental medicine or real improvement? Lancet 343:27-31, 1994 55. American Diabetes Association: Position statement: Pancreas transplantation for patients with diabetes mellitus. Diabetes Care 16:21, 1993 (suppl 2) 56. Sutherland DER: Medicare coverage: Pancreas transplantation. Chimera 3:27, 1991