Immunosuppression in pancreas transplantation: progress, problems and perspective

Abstract

Through 1997, over 10 000 pancreas transplants have been performed world-wide, with 88% being simultaneous kidney-pancreas transplants (SKPTs). Current 1-year patient survival exceeds 90% and pancreas graft survival (complete insulin independence) exceeds 80% for SKPT, 70% for sequential pancreas after kidney transplant (PAKT), and 65% for pancreas transplant alone (PTA). According to Registry data, rejection account for 32% of graft failures in the first year after pancreas transplantation. However, improving outcomes are expected to continue with the evolution of treatment protocols. Most pancreas transplant centres employ quadruple drug immunosuppression with anti-lymphocyte induction, using either a monoclonal or polyclonal antibody agent. In recent years, there has been an overall decline in the use of antibody-induction therapy from 90% during 1987–93, to 83% of pancreas transplants performed during 1994–97. Maintenance immunosuppression is triple therapy consisting of a calcineurin inhibitor (cyclosporine or tacrolimus), corticosteroids, and an anti-metabolite such as azathioprine (AZA) or mycophenolate mofetil (MMF). Prior to 1995, nearly all p ancreas transplant recipients were managed with Sandimmune. Since 1986, tacrolimus-based therapy has been used in approximately 20% of cases, and a new microemulsion formulation of cyclosporine (Neoral) has replaced Sandimmune in contemporary post-transplant immunosuppression. In addition, MMF is replacing AZA as part of the standard immunosuppressive regimen following pancreas transplantation. At present, a number of centres are conducting various trials with new drug combinations including either Neoral or tacrolimus in combination with steroids and MMF, with or without antibody-induction therapy. From 1994 to 1997, the 1-year rates of immunologic graft loss have decreased to 2% after SKPT, 9% after PAKT, and 16% after PTA. The current array of new immunosuppressive agents are providing more effective control of rejection and permitting solitary pancreas transplantation to become an accepted treatment option in diabetic patients without advanced complications. The apparent potency of new drug combinations has also resulted in a resurgence of interest in steroid withdrawal. Immunosuppressive strategies will continue to evolve to achieve effective control of rejection while minimizing injury to the allograft and risk to the patient. In addition, new regimens must not only address the issue of specific drug toxicities, but also long-term economic, metabolic, and quality of life outcomes. Pancreas transplantation will remain an important alternative in the treatment of diabetic patients until other strategies are developed that can provide equal glycaemic control with less immunosuppression and overall morbidity.