CLINICAL
DIABETES These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly. F E A T U R E A R T I C L E Current Status of Pancreas Transplantation for the Treatment of Type 1 Diabetes Mellitus David E. R. Sutherland,
MD, PhD, and Rainer W. G. Gruessner, MD, PhD
Pancreas or islet transplants are the only treatments of type 1 diabetes that can establish insulin independence.1,2 Currently, only a pancreas graft does so consistently.1 The results with this approach to diabetic management are presented in this article. The Diabetes Control and Complications Trial (DCCT) provided a strong rationale for pancreas and islet transplantation.3 Tight blood glucose control reduces the incidence and severity of secondary complications, but at the expense of an increased frequency of insulin reactions and hypoglycemic episodes. The rigor required is also difficult (finger sticks for blood glucose determinations at least 4 times per day and multiple insulin injections daily). Even with intense insulin treatment, mean glycosylated hemoglobin levels were a gram percent above normal.3 Furthermore, some individuals have extreme oscillations of blood glucose no matter what the regimen, and others develop secondary complications even when glycosylated hemoglobin levels are only moderately elevated. Thus, good control is not good enough in everyone. Perfect control is only provided by beta cell replacement. The penalty of both islet and pancreas transplantation is the need for immunosuppression. A pancreas transplant also requires major surgery. However, when successful, a pancreas graft makes the recipient euglycemic, and glycosylated hemoglobin levels are normal for as long as the graft functions. Because of the need for immunosuppression, most pancreas transplants are performed either simultaneously or subsequent to a kidney transplant in diabetes patients with advanced nephropathy. Nearly everyone agrees that a kidney transplant is preferable to dialysis in the treatment of uremia, particularly in diabetes patients. Thus, in a patient already obligated to immunosuppression, there is very little reason not to add a pancreas, and only the surgical risks need to be considered. Unfortunately, in uremic diabetes patients, retinopathy and neuropathy are usually far advanced, and the DCCT did not study the effect of instituting strict control on established lesions. Thus, the main value of adding a pancreas to a kidney is the additional improvement in quality of life that accompanies being insulin independent, as well as dialysis free.4 This is not to say that pancreas transplantation has no effect on secondary complications, and improvement in neuropathy has been documented following pancreas transplantation.5,6 Recurrence of diabetic nephropathy in a new kidney is also prevented by a successful pancreas transplant.7,8 Nevertheless, advanced retinopathy and vascular disease are unlikely to be affected. A pancreas transplant ideally should be applied before complications occur. But since it is difficult to discern who will get complications (even with poor glucose control not all patients get complications), as well as what the individual side effects of immunosuppression will be, very few pancreas transplants have been done soon after onset of disease. Instead, pancreas transplants alone have largely been employed in patients with very labile diabetes and hypoglycemic unawareness, a syndrome that may emerge many years after onset of diabetes, particularly in those with neuropathy. In this situation, a pancreas transplant is the most effective treatment, since it completely obviates insulin reactions.9
The first pancreas transplant was performed at the University of Minnesota in 1966.10 By 1996, nearly 9,000 transplants had been performed world wide (Figure 1), including more than 6,700 in the United States.11 A dramatic increase in the number of cases occurred starting in the mid-1980s with the introduction of cyclosporine for immunosuppression. The inception of the United Network for Organ Sharing (UNOS) in 1987, which facilitated organ procurement and placement, was followed by a steady growth in application. Last year, more than 1,000 transplants were done in the United States, approximately 85% simultaneous with a kidney, 10% after a kidney, and 5% as a pancreas transplant alone. New immunosuppressants were introduced in the 1990s, and results in the latest eras are summarized in the following section. Pancreas
Recipient and Graft In an analysis of outcome for all cases during the entire 9-year period, the patient survival rates at 1 and 3 years were 92% and 86%, respectively, and were similar in all categories of transplant. Pancreas graft functional (insulin independence) survival rates over the entire period, however, were ~20% higher in SPK than in the other categories. Graft survival rates were also ~7% higher in BD than in ED cases. For all BD cases done from 1987 to 1996, 1-year and 3-year pancreas graft survival rates (death with functioning graft [DWFG] counted as graft failure) were 79% and 71%, respectively, for SPK (n = 3,989), 60% and 40%, respectively, for PAK (n = 375), and 57% and 40%, respectively, for PTA (n = 229). For ED SPK cases, 1- and 3-year pancreas survival rates were 72% and 64%, respectively. Kidney graft survival rates at 1 and 3 years for all SPK cases done during the 1987–96 period were 86% and 79%, respectively. In contrast, for cadaver kidney transplants alone (KTA) in type 1 diabetic recipients reported to UNOS from 1987 to 1996, 1- and 3-year patient survival rates were 91% and 81%, respectively. Renal allograft survival rates were 80% and 68%, respectively.12 The higher patient and kidney graft survival rates in the SPK cases may reflect either selection of healthier patients for the combined procedure or a positive impact of adding the pancreas on outcome. Pancreas graft functional survival rates have improved over time. The insulin-independence survival rates for all BD cases done during the 1994–96 era by category are shown in Figure 2. At 1 year, 81% of BD SPK (n = 1,516), 77% of ED SPK (n = 221), 71% of PAK (n = 141), and 64% of PTA (n = 64) were functioning. Patient and kidney graft survival rates in the largest category, BD SPK, are given in Figure 3. At 1 year, they were 93% and 88%, respectively. The improved graft functional survival rates for pancreas transplants reflect a decrease in both the technical failure and rejection rates. The technical failure rate fell from 16% for 1987–89 to 9% for 1994–96. The rejection rate at 1 year for SPK cases was 5–7% for 1987–93 but only 3% for 1994–96 cases. For PAK and PTA cases, the rejection loss rate declined even more dramatically between the 1987–93 and 1994–96 eras, from 25% to 9% and from 28% to 5%, in the respective categories. Indeed, for technically successful cases in which DWFG was censored, the 1-year pancreas function rates were more than 90% in all three categories (SPK, PAK, and PTA) for 1994–96. Thus, with current immunosuppressive regimens (see below) the pancreas allograft rejection rate is now lower than the technical failure rate. Most recipients of a successful graft can expect to remain insulin independent for years or until they die. Surgical
Technique
BD was first used by Sollinger with direct anastamosis, but was modified by Nhgiem using a whole pancreas duodenal graft with a side-to-side duodenocystostomy—a secure, safe technique. In addition, BD gave the opportunity to directly measure exocrine secretions (amylase in the urine), and a decrease was found to be a sensitive if nonspecific marker of pancreas allograft rejection episodes that could be treated before the occurrence of hyperglycemia. For solitary pancreas transplants (PAK and PTA), BD greatly facilitates monitoring for rejection episodes. In SPK cases, however, an increase in serum creatinine is a marker for rejection of the kidney, and an increase in creatinine occurs before a decrease in pancreas allograft exocrine function more than 90% of the time. Although the occasional patient will have an isolated rejection of the pancreas that could be missed in the absence of BD, the statistical impact on outcome is small, and bladder-specific complications (dysuria, hemturia, and metabolic acidosis from bicarbonate loss) are avoided. About 10% of BD pancreas transplants are eventually converted to ED. Serum pancreatic enzyme levels can also be used to monitor for rejection. An increase is a marker, but it is probably less sensitive than urinary amylase and no more specific. Nearly all groups who perform solitary pancreas transplants prefer the BD technique, while for SPK transplants, ED is becoming increasingly popular. Immunosuppression All immunosuppressants have side effects, including increased susceptibility to infection, nephrotoxicity for FK506 and cyclosporine, body habitués, and bone changes with steroids. With the new immunosuppressives, steroid doses have been reduced and in some programs eventually stopped.13 At this time, there are no protocols that will allow discontinuance of immunosuppressants altogether. The side effects must be accepted as a trade off for insulin independence and must be taken into account in recipient selection (see below). Effects
of Pancreas Transplant on Metabolism and Secondary
Complications Minor metabolic perturbations can exist in some pancreas recipients. Most pancreas transplants are drained via the systemic venous system and thus induce a degree of systemic hyperinsulinemia. Portal drainage of the graft has become more popular in the 1990s, but it is more difficult technically. A clear advantage of one technique over the other has not been shown. In regard to the effect of secondary complications, given the DCCT results it is clear that a successful pancreas transplant performed early in the course of diabetes would prevent occurrence of secondary complications. The effect on established lesions is less certain, but neuropathy clearly improves in most patients after a successful pancreas transplant.
Numerous quality-of-life studies have been performed in pancreas transplants.1 All show that patient satisfaction is higher in SPK and PAK than KTA recipients in regard to many factors, including dietary management and impact on family.4 In PTA recipients, more than 90% of the recipients have stated that management of immunosuppression is easier than management of diabetes. It should be noted, of course, that in this patient group nearly all were extremely labile and very dissatisfied with their situation before the transplant. Recipient
Selection The PAK option is probably vastly underutilized, particularly given the high insulin-independence rates now achieved with this approach. An LD kidney followed later by a cadaver pancreas avoids long waiting times to get a patient off dialysis or avoids the need for dialysis altogether. This method also gives the highest probability of remaining dialysis-free over the long term.14 The option of a simultaneous kidney and segmental pancreas transplant from a living donor also exists.15 Of more than 100 LD pancreas transplants performed at the University of Minnesota since 1978, 20 have been SPK. One hundred percent of the LD SPK recipients are currently alive with functioning kidneys, and 85% have a functioning pancreas.16 In regard to either SPK or PAK transplants, age may be a factor in selection. The patient and graft functional survival rates are not as high in those older than 45 years than in those younger than 45 years of age.11,17 However, patient and kidney survival rates in KTA are also lower in those >45 years than in those <45 years of age, and patient survival rates are still higher for those who receive a transplant than for diabetes patients who remain on dialysis. Thus, although results of SPK and PAK transplants are not as good in those >45 as in those <45 years old, it is a matter of informed consent as to what a uremic diabetes patient chooses to do in an attempt to improve quality of life as fully as possible by a pancreas transplant. In regard to pancreas transplants alone,18 there is no satisfactory medical treatment for patients with hypoglycemic unawareness. Less strict control is really the only alternative strategy, resulting in high glycosylated hemoglobin levels and an increased risk for secondary complications. A successful pancreas transplant allows such patients to avoid hypoglycemia and to gain the freedom of insulin independence. Again, this treatment is probably vastly underutilized. Should pancreas transplants alone be done early in the course of diabetes before complications occur? No randomized studies have been done to compare long-term complication rates of immunosuppression versus diabetes in comparable populations. However, in patients who have difficulty with blood glucose control and are not able to maintain near-normal glycosylated hemoglobin levels, the risk of secondary complications could well be greater than the risk of complications from immunosuppression. In this situation, a pancreas transplant alone may be a reasonable choice. Summary Pancreas transplants alone are less commonly applied because of the need for immunosuppression, but the trade-off to achieve an insulin-independent state may be worthwhile for selected patients, particularly those who are labile with hypoglycemic unawareness. This option should certainly be a part of the treatment armamentarium of modern diabetologists. A positive effect on secondary complications will certainly occur with an early transplant, and even late transplants can have an impact, as has been shown for neuropathy. Whether the simpler procedure of islet transplantation will replace pancreas transplants remains to be seen. Of the >200 islet allografts performed in the 1990s, <10% of the recipients have achieved insulin-independence at 1 year.2 Clinical islet trials are ongoing but limited to patients who accept a low individual probability of success to assist in development or to those in whom the surgical risks of a pancreas transplant are high. Islet transplantation has held promise for more than 25 years, but candidates for endocrine replacement therapy must honestly be told the difference in success rates, which are currently much higher with the pancreas transplant. References 1Sutherland DER, Gruessner RWG, Gores PF, Brayman KL, Wahoff DC, Gruessner A: Pancreas transplantation: an update. Diabetes Metab Rev 11:337-63, 1995. 2Sutherland DER, Gores PF, Hering BJ, Wahoff DC, McKeehen DA, Gruessner RWG: Islet transplantation: an update. Diabetes Metab Rev 12:137-50, 1996. 3The 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 329:977-86, 1993. 4Gross CR, Kangas JR, Lemieux AM, Zehrer CL: One year change in quality of life profiles in patients receiving pancreas and kidney transplants. Transplant Proc 27:3067-68,1995. 5Kennedy WR, Navarro X, Goetz FC, Sutherland DER, Najarian JS: Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 322:1031-37, 1990. 6Allen DM, Al-Harbi IS, Morris JGL, Clouston PD, O’Connell PJ, Chapman JR, Nankivell BJ: Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation 63:830-38, 1997. 7Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes MW: The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 321:80-85, 1989. 8Bohman SO, Tydén G, Wilezek A: Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man. Diabetes 34:306-308, 1985. 9Bolinder J, Wahrenberg H, Linde B, Tydén G, Groth CG, Ostman S: Improved glucose counterregulation after pancreas transplantation in diabetic patients with unawareness of hypoglycemia. Transplant Proc 23:1667-69, 1991. 10Kelly WD, Lillehei RC, Merkel FK, Idezuki T, Goetz FC: Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 61:827-837, 1967. 11Gruessner AC, Sutherland DER: Pancreas transplantation in the United States (US) and Non-US as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). In Clinical Transplants—1996. Cecka M, Terasaki PI, Eds. Los Angeles, UCLA Tissue Typing Laboratory, Regents University of California, 1997, p.47-67. 12Cecka M, Terasaki PI (Eds.): Clinical Transplants—1996, Los Angeles, UCLA Tissue Typing Laboratory, Regents University of California, 1997. 13Gruessner RWG, Burke GW, Stratta R, Sollinger H, Benedetti E, Marsh P, Stock PG, Boudreaux JP, Martin M, Drangstveit MD, Sutherland DER, Gruessner A: A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 61:261-73, 1996. 14Sutherland DER: Pancreas and islet cell transplantation: now and then. Transplant Proc 28:2131-33, 1996. 15Gruessner RWG, Sutherland DER: Simultaneous kidney and segmental pancreas transplants from living related donors—the first two successful cases. Transplantation 61:1265-68, 1996. 16Gruessner RWG, Sutherland DER: Combined kidney and pancreas transplant from live donors. Ann Surg In press. 17Gruessner RWG, Dunn DL, Gruessner AC, Matas AJ, Najarian JS, Sutherland DER: Recipient risk factors have an impact on technical failure and patient and graft survival rates in bladder-drained pancreas transplants. Transplantation 57:1598-1606, 1994. 18Sutherland DER, Gruessner RWG, Moudry-Munns KC, Gruessner A, Zehrer C, Gross C, Najarian JS: Pancreas transplants alone in nonuremic patients with labile diabetes. Transplant Proc 26:446-47,1994. David E. R. Sutherland, MD, PhD, is a professor of surgery, head of the Division of Transplantation, and director of the Diabetes Institute for Immunology and Transplantation at the University of Minnesota in Minneapolis. Rainer W.G. Gruessner, MD, PhD, is a professor of surgery, co-director of the Pancreas Transplant Program, and director of the Intestinal Transplant Program at the University of Minnesota in Minneapolis. Copyright © 1997 American Diabetes Association Last updated: 9/97 For Technical Issues
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