Maintenance immunosuppression: new agents and persistent dilemmas

Since the approval of cyclosporine in 1983, only 3 drugs, mycophenolate mofetil, tacrolimus, and sirolimus, have been approved for maintenance immunosuppression in renal transplant recipients. All 3 agents decrease the incidence of early acute allograft rejection. An increase in intermediate and long-term graft survival has not been shown. However, survival data from these clinical trials should be interpreted with caution because the studies were not designed for this purpose. All 3 drugs have significant, albeit different, safety profiles. It remains to be seen whether, the lower incidence of hypertension and hyperlipidemia seen in tacrolimus-treated patients will reduce the incidence and severity of the cardiovascular disease experienced by renal transplant recipients. Sirolimus causes severe hyperlipidemia, and the long-term consequences both on the pathogenesis of cardiovascular disease and on lipid-associated renal injury have yet to be determined. Tacrolimus and mycophenolate mofetil appear to increase graft survival in pancreas-kidney recipients but their efficacy in another high-risk group, African-American recipients, has not yet been clearly shown. However, the trend toward improved graft survival in African-American recipients treated with tacrolimus is encouraging. Steroid-withdrawal remains a goal in the posttransplant period. The available data from steroid-withdrawal and steroid-avoidance clinical trials are mixed. Steroid withdrawal can be achieved in about 50% of patients on a cyclosporine-based immunosuppression regimen. Steroid-withdrawal under coverage of tacrolimus, mycophenolate mofetil or Neoral (Novartis Pharmaceuticals, East Hanover, NJ) may be more successful than that achieved in patients receiving Sandimmune (Novartis Pharmaceuticals). Further studies are needed in this area.