What is Successful Islet Transplantation in 2006?

Three general transplantation approaches are most common, namely, simultaneous pancreas and kidney (SPK); pancreas after kidney (PAK); and pancreas transplant alone (PTA). The one-year, post-transplant pancreas survival rates for these procedures are 79%, 69%, and 69%, respectively, while the five-year organ survival rates are 70%, 45%, and 45%, respectively.The one- and five-year patient survival rates are 95%, 96%, and 97%, respectively, and the five-year patient survival rates are 90%, 89%, and 91%, respectively.

Three general transplantation approaches are most common, namely, simultaneous pancreas and kidney (SPK); pancreas after kidney (PAK); and pancreas transplant alone (PTA). The one-year, post-transplant pancreas survival rates for these procedures are 79%, 69%, and 69%, respectively, while the five-year organ survival rates are 70%, 45%, and 45%, respectively.The one- and five-year patient survival rates are 95%, 96%, and 97%, respectively, and the five-year patient survival rates are 90%, 89%, and 91%, respectively. Since patient deaths usually do not occur within three months of the procedures and are usually cardiovascular in etiology, it seems likely that the mortality is more related to chronic diabetes than the surgery.

Successful islet transplantation was first reported in 1980 (see Figure 1). Although numerous reports of single successes appeared thereafter up to 20005, oneyear, post-transplant success rates were less than 10%. Success was defined simply as freedom from exogenous insulin for longer than one year with no reference to the degree of glycemic control.Thus, it is likely that by modern standards the value of <10% would be closer to <1%. No uniformly successful series was reported until 2000 when the Edmonton group reported 100% of seven islet transplant recipients were insulin-free for an average of one year post-transplant with normal hemoglobin A1c (HbA1c) and fasting glucose levels. The Edmonton Era—The Present
The distinguishing features of the Edmonton approach were to redesign the immunosuppressive regimen (avoid glucocorticoids, include daclizumab) and to infuse intrahepatically multiple preparations of islets (see Figure 2). Although seven of seven recipients were insulin-free with normal levels of HbA1c and fasting glucose levels at an average of one year posttransplant, as a group they had impaired glucose tolerance.They also had clinical complications, such as elevated liver function studies, serum creatinine, and hepatic bleeding secondary to the liver puncture required for infusing islets via the hepatic portal vein. After this series was published, the Edmonton group reported that successful islet transplantation two years post-transplant had decreased to 65% and by five years had decreased to 8% (see Figure 3). Most recently, the results of the Immune Tolerance Network multicenter trial have been reported. These results are consistent with those reported by the Edmonton group in terms of one-year success rates, but clearly demonstrated a ‘center effect’. Of the nine participating centers, three were highly successful in maintaining insulin-free normoglycemia, three were moderately successful, and three had no successes. The clear trend was that the more experienced centers were more successful than the less experienced ones. This indicates that the current methods of islet isolation and intrahepatic infusion provide variable outcomes and thus need to be refined before they will yield reproducible success rates across centers.

Whether these data indicate failure or success is a subject of debate. The pessimistic view is that islet transplantation is still not clinically useful and lags far behind pancreas transplantation in terms of success. The optimistic view is that islet transplantation has made major strides beyond the dismal success rates that existed before 2000 and, if nothing else, the recipients who are still C-peptide positive are at less risk for hypoglycemia.

Another layer of argument is whether islet transplant recipients who use ancillary drug therapy to aid the control of glycemia, such as traditional oral hypoglycemia agents, insulin sensitisers, or small amounts of insulin, should be termed partial successes or failures. In any event, the prudent approach is to use traditional medical approaches to help maintain normoglycemia rather than overstress transplanted islets that are clearly functional as determined by measurable circulating C-peptide levels. Taken into the context of success rates over time for pancreas transplantation, islet transplantation is actually making good headway. The average length of islet graft survival for the Edmonton group is 15 months, a result obtained after six years of procedural development. The similar value for pancreas transplantation required over 20 years to obtain (see Figure 4). Post-Edmonton—the Future
Future efforts in islet transplantation will be focused on what went wrong with the initially impressive clinical outcomes reported by the Edmonton group. Although two obvious candidates are immunorejection of the engrafted islets and return of autoimmune-based beta cell destruction, no convincing evidence to support either of these possibilities has been reported. However, and more optimistically, there is ample room to suspect technology-based difficulties. Possibilities include use of islet isolation procedures that damage islets, as well as islet-toxic immunosuppressive drugs that highly concentrate in the hepatic portal vein and hence liver tissue.These considerations have prompted research on the use of non-hepatic sites, which will avoid the need for purification and consequent islet damage, as well as avoiding toxic concentrations of immunosuppressive drugs. This will also obviate the problem of liver bleeding caused by liver puncture.

Other approaches will include attempts to protect islets during isolation by infusing donors with antioxidants during procurement of the pancreas and using antioxidants in the islet isolation media, adenoviral overexpression of any number of cDNAs designed to protect islets against apoptosis and use of various growth factors designed to enhance islet graft vascularisation in situ. If nothing else, islet transplantation has moved into an exciting new era wherein optimism will again build as researchers discover new approaches that will lead to new successes built on the insights provided during the past six years.