POSTTRANSPLANT DIABETES-MELLITUS - THE ROLE OF IMMUNOSUPPRESSION

Immunosuppressive agents increase the risk of death due to coronary di sease or stroke by their ability to cause 3 different adverse effects: dyslipidaemia, hypertension and hyperglycaemia. Post-transplant diabe tes mellitus has emerged as a major adverse effect of immunosuppressan ts. As recipients of organ transplants survive longer, the secondary c omplications of diabetes mellitus have assumed greater importance. The re is a need for a precise definition of post-transplant diabetes mell itus to facilitate inter-centre comparison and to study the natural hi story of post-transplant diabetes mellitus. We recommend broad criteri a to define hyperglycaemia, as a fasting blood glucose level of >400 m g/dl at any point or >200 mg/dl for 2 weeks, or a need for insulin tre atment for at least 2 weeks. We also recommend serial measurements of HbA(1c). Cyclosporin and tacrolimus cause post-transplant diabetes mel litus by a number of mechanisms, including decreased insulin secretion , increased insulin resistance or a direct toxic effect on the beta ce ll. For corticosteroids, the induction of insulin resistance seems to be the predominant factor. However, few studies have examined the mech anism of diabetogenicity at the molecular level. This may hold the key for pharmacological manipulation of current immunosuppressive regimen s which may result in decreased metabolic complications. Corticosteroi d sparing regimens have been shown to reduce the metabolic complicatio ns of immunosuppressants including post-transplant diabetes mellitus. However, their use should be balanced against the increased incidence of transplant rejections. Post-transplant diabetes mellitus may be org an-specific, irrespective of the immunosuppressant used. Tacrolimus ca uses a high incidence of post-transplant diabetes mellitus in recipien ts of kidney transplants (up to 20% in some reports); the diabetogenic ity of cyclosporin-based regimens is comparable with that of tacrolimu s-based regimens in recipients of liver transplants. A few clinical st udies in which attempts were made to discontinue cyclosporin resulted in an unacceptable loss of the transplant. In the case of tacrolimus, complete withdrawal of immunosuppression may be possible in selected p atients with liver transplants. However, post-transplant recipients wh o may benefit from this approach are difficult to identify. In some ea rly series, patients received doses of tacrolimus that were approximat ely 2 to 3 times higher than those currently used, which may have resu lted in a higher incidence of post transplant diabetes mellitus. More recently, it has been shown that tacrolimus was successful in salvagin g whole pancreatic grafts which were maintained on cyclosporin. Tacrol imus-based immunosuppression as primary therapy was also used with rem arkable success in solitary whole pancreas transplants. Strategies to reduce the metabolic complications of immunosuppressants should be pur sued aggressively as this will directly lead to a decrease in long ter m cardiovascular adverse effects.