KEYSTONE, COLO. — Formidable obstacles continue to prevent pancreatic islet transplantation from having a major impact on type 1 diabetes despite the spectacular technical advances of the past 4 years, Ronald G. Gill, Ph.D., said at a conference on management of diabetes in youth.
The breakthrough in islet transplantation began in 2000 with the success of what since has come to be known as the Edmonton protocol.
Previously, only about 10% of recipients of islet transplants ever achieved insulin independence. But investigators at the University of Alberta, Edmonton, discarded the standard islet-toxic immunosuppressive regimen routinely used in whole-organ transplants in favor of a gentler sirolimus- and tacrolimus-based, corticosteroid-free regimen utilizing daclizumab, a monoclonal antibody directed against the interleukin-2 receptor on activated lymphocytes. They also boosted the islet dose, infusing islets harvested from two donor pancreases per recipient.
They electrified the diabetes and transplant communities, reporting that their novel protocol had rendered seven consecutive type 1 diabetic patients insulin independent.
“The Edmonton protocol was something drastically different. It's probably the single most important advance in transplant biology in all of the transplant literature,” said Dr. Gill, an immunologist at the university.
The Edmonton experience has been replicated in an as yet unpublished 10-center study, conducted by the National Institutes of Health-sponsored Immune Tolerance Network, that underscored the importance of extensive experience in isolating and handling pancreatic islets as the key to transplant success.
The experience at the universities of Alberta, Minnesota, Miami, Pennsylvania, and other highly experienced centers is that roughly 80% of islet recipients remain insulin independent at 1 year, and 65%-70% at 2 years. Those results are as good as for whole-organ pancreatic transplantation, a mature procedure reimbursed by Medicare. There now are more than 100 islet transplant recipients off of exogenous insulin, with complete reversal of hypoglycemia and normal glycosylated hemoglobin values. However, the grafts do not counter regulate.
The islet graft is placed in the liver via intraportal infusion. Acute complications have included moderate to severe portal vein bleeding. Long-term complications have consisted of fatty liver, hypertension, hypertriglyceridemia, and mouth ulcers secondary to immunosuppressive therapy, he said at the conference, sponsored by the University of Colorado and the Children's Diabetes Foundation at Denver.
Medicare soon will begin reimbursing for islet transplants in kidney transplant recipients. The federal National Center for Research Resources has funded 10 U.S. centers to serve as regional islet resource centers in anticipation of a ramping-up of islet transplants.
Dr. Gill noted an ethical distinction between islet and other forms of transplantation.
“We know for sure there's tremendous long-term collateral damage and toxicities from immunosuppressive drugs. In conventional organ transplantation, you endanger the host with toxic drugs in order to preserve the graft because the graft is important to their life. In islet transplantation, we must be willing to endanger the graft in order to preserve the host because diabetes is not an immediately life-threatening disease.”
Only about 2,000 cadaveric pancreases per year are available for islet harvesting and two pancreases are typically required per transplant. The procedure in its current form will remain beyond the reach of most of the nation's 1.4 million type 1 diabetic patients.