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The first clinical pancreas transplantation was in 1966, simultaneous with a kidney transplant in a uremic diabetic patient at the University of Minnesota (4). In the last third of the 20th century more than 1,000 pancreas transplants were done at this institution (5).

Over 100 institutions in the United States of America (USA) and nearly the same number outside the USA have performed pancreas transplants (1). The International Pancreas Transplant Registry (IPTR) was founded in 1980 to analyze the cases (6). In 1987, reporting of USA cases became obligatory through the United Network for Organ Sharing (UNOS), and annual reports have been made thereafter (7).

The success rate (long-term insulin independence) with pancreas transplantation was initially low, but increased dramatically in the 1980s. By the 1990s, more than 1000 pancreas transplant a year were being done worldwide, the majority in the USA.

The alternative to pancreas transplantation for treatment of diabetes is islet transplantation (8). The first clinical allograft was in 1974 in a diabetic recipient of a previous kidney transplant (9). Islet autotransplantation to prevent diabetes after a total pancreatectomy for benign disease has been successful since the first case in the 1970s (10, 11). Sustained insulin independence with islet allotransplantation was not achieved until the early 1990s (12), and consistent success in sequential recipients was not achieved until very recently (13).
Obviously, for correction of diabetes, a simple cell transplant is preferable to the major surgery of pancreas transplantation, but islet isolation requires a specialized facility, while pancreas transplantation can be done at virtually any hospital with a transplant program and appropriately trained surgeons. Thus, though a transition from pancreas to islet transplantation as the dominant form of beta cell replacement therapy will occur over the next few years, pancreas transplantation will never disappear entirely. For example, diabetic patients with exocrine deficiency would best be served by an enteric drained pancreas transplant. In addition, in patients who have very high insulin requirements or who have insulin resistance (Type II diabetes), an intact organ may be needed to obtain a sufficient islet mass to induce insulin independence from a single donor.
At the moment, generalized immunosuppression is needed to prevent rejection of either and intact immediately vascularized pancreas allograft or an islet allograft. However, protocols designed to induce immunological tolerance specific to the donor can tested more readily in islet than in solid organ recipients since the magnitude of the surgical procedure and the consequences of rejection failure are less.
Nevertheless, at the moment, pancreas transplantation remains dominant and the results of the latest analysis of the Pancreas Transplant Registry are summarized below:

There are 3 categories of pancreas transplant recipients: 1) uremic diabetic patients who receive a simultaneous pancreas and kidney (SPK) transplant from either a cadaver or living donor (14); 2) pancreas after kidney (PAK) transplant, in nephropathic patients who already have had renal insufficiency corrected, usually by a living donor transplant; 3) pancreas transplants alone (PTA) in non-uremic diabetic recipients. Current outcomes with pancreas transplantation according to recipient categories, surgical technique, and immunosuppression protocol are given here for USA cases. The annual number of USA cases since 1980 is shown in Figure 1. The historical outcomes are given elsewhere (7). Here only the outcome for contemporary cases from 1996 to October, 2000 are summarized.

From 1996 to October 2000, >5200 pancreas transplants were reported to UNOS, including >4200 SPK transplants, >750 PAK transplants and >300 PTAs. Patient survival rates at 1 year in the 3 categories were 95%, 94% and 98% respectively.

Of the 1996-2000 pancreas grafts, 8% failed for technical reasons, with thrombosis being the biggest risk for technical loss (5%), infection, pancreatitis and anastamotic leak making up the rest. Rejection losses at 1 year were 2% in the SPK, 6% in the PAK and 8% in the PTA categories (P=0.0001). Overall, at 1 year, 84% of SPK, 72% of PAK and 71% of PTA grafts were functioning (recipients insulin independent).

In regard to management of pancreatic duct exocrine secretions, enteric drainage (ED) predominated for SPK transplants (55%), and bladder drainage (BD) for PAK (55%) and PTA (60%). Overall, the technical failure rate was only slightly higher for ED (9%) than BD (6%). However, in regard to graft survival rates there was no difference for BD (n=1541) versus ED (n=1940) SPK transplants, 84% versus 83% at 1 year. However, there was a significantly higher graft survival rate for BD (n=359) versus ED (n=306) PAK transplants, 77% versus 67% at 1 year (P=0.002); and for BD (n=174) versus ED (n=120) PTA transplants, 75% versus 65% at 1 year (p=0.009).

The lack of a difference in graft survival rates for BD versus ED in the SPK category probably reflects the fact that in most cases both grafts come from the same donor, and monitoring of serum creatinine serves as a surrogate marker for rejection in the pancreas transplant, allowing easy detection and reversal by treatment. In contrast, for solitary pancreas transplants (PAK and PTA) serum creatinine cannot be used as a marker of pancreas rejection; hyperglycemia is a late manifestation of rejection and exocrine markers must be used. Although serum amylase and lipase may elevate during a rejection episode, this does not occur in all cases, but for BD grafts, a decrease in urine amylase always eventually always accompanies rejection (100% sensitive, even though it is not specific), and nearly always precedes hyperglycemia, so a rejection episode is more likely to be diagnosed in a bladder drained graft and lead to treatment and reversal.

Another variation in surgical techniques that has gained some popularity is portal drainage of the pancreas graft versus effulent (15). It is more physiological, and some groups have reported that portally enteric drained grafts are less prone to rejection (16,17). However, the latest Registry analysis did not show a difference in pancreas graft survival rates for portal vs. enteric drained SPK transplants (7).

In regard to immunosuppression, graft survival rates are slightly higher in all categories when anti-T cell agents are used for induction immunotherapy (7). For maintenance immunosuppression, most groups use both cyclosporine and tacrolimus (TAC) in combination with mycophenolate mofetil (MMF) with or without prednisone. In the SPK category, graft survival rates are similar with either combination, while in the PAK and PTA categories the TAC-MMF combination has been associated with the highest graft survival rates. The Registry analysis of pancreas graft survival rates in the three recipient categories, according to whether the graft was BD or ED, in recipients given anti-T cell agents for induction and TAC-MMF for initial maintenance immunosuppression, is shown in Figure 2. The highest graft survival rates are in the SPK category, but they are also still over 70% at 1 year in the PAK and PTA categories, and only slightly higher with BD with this immunosuppressive combination.

In regard to the logistics of pancreas transplantation, the Registry shows that organ preservations times up 24 hours are well tolerated, although there is a slight increase in technical failure rates as preservation time increases (7). HLA matching has virtually no impact on SPK grafts, but matching at least at the B locus still has a beneficial effect in PAK and the PTA categories. Recipient age has a modest effect on outcome, with slightly lower patient and graft survival rates in the SPK and PAK categories for those >45 years old. However, in the PTA category, graft survival rates are actually higher in the older recipient, reflecting the decrease in immunocompetency as we age (7).

Only 5500 cadaver donors are available each year in the United States, of which it is estimated that maybe at most 70% are suitable for pancreas donation. Thus, the maximum number of pancreas transplants that could be done in the U.S.A.is 10,000 per year, assuming that each cadaver pancreas could be split for use in two recipients (18) and the living donors would be used for segmental pancreas transplantation (14) to the extent that they have been for kidney transplants (~4000 per year in the U.S.A.). This scenario has not yet materialized, but the potential is there. The numbers would be the same if all pancreases were used for islet transplants unless more than two recipients could be done with one donor. At the moment, the opposite is the case. The team at the University of Alberta in Edmonton showed that if >1 donor pancreas is used for islet transplantation, insulin independence can be routinely achieved in non-uremic diabetic recipients with the modern immunosuppressants available (13). Other centers, including the University of Minnesota, have had success with a single donor (19), but no one has been able to use 1 donor for multiple islet recipients. However, at least the potential for this scenario exists in the future. Other options would include the use of xenografts (pig islets) or stem cells (8).

There is no doubt that pancreas transplantation has a profound effect on quality of life in diabetic recipients by achieving insulin independence per se (20). However, there is also a dramatic beneficial effect of pancreas transplant patients with secondary complications, particularly neuropathy (21) and nephropathy (22). In patients with labile diabetes and hypoglycemic unawareness, a pancreas transplant can be life saving (23,24). Pancreas transplantation, and eventually islet transplantation, should be in the armamentarium of every transplant center for the treatment of diabetic patients.