IMMUNOSUPPRESSIVE EFFECTS AND SAFETY OF A SIROLIMUS CYCLOSPORINE COMBINATION REGIMEN FOR RENAL-TRANSPLANTATION/

Background. Sirolimus, a novel immunosuppressant that inhibits cytokin e-driven. cell proliferation and maturation, prolongs allograft; survi val in animal models. After a phase I trial in stable renal transplant recipients documented that cyclosporine and sirolimus have few overla pping toxicities, we conducted an open-label, single-center, phase I/I I dose-escalation trial to examine the safety and efficacy of this dru g combination. Methods. Forty mismatched living-donor renal transplant recipients were sequentially assigned to receive escalating initial d oses of sirolimus (0.5-7.0 mg/m(2)/day), in addition to courses of pre dnisone and a concentration-controlled regimen of cyclosporine. We con ducted surveillance for drug-induced side effects among sirolimus-trea ted patients and compared their incidence of acute rejection episodes as well as mean laboratory values with those of a historical cohort of 65 consecutive, immediately precedent, demographically similar recipi ents treated with the same concentration-controlled regimen of cyclosp orine and tapering doses of prednisone. Results. The addition of sirol imus reduced the overall incidence of acute allograft; rejection episo des to 7.5% from 32% in the immediately precedent cyclosporine/prednis one-treated patients, At 18- to 47-month follow-up periods, both treat ment groups displayed similar rates of patient and graft survival, as well as morbid complications. Although sirolimus-treated patients disp layed comparatively lower platelet and white blood cell counts and hig her levels of serum. cholesterol and triglycerides, sirolimus did not augment the nephrotoxic or hypertensive proclivities of cyclosporine. The degree of change in the laboratory values was more directly associ ated with whole blood trough, drug concentrations than with doses of s irolimus. Conclusions. Sirolimus potentiates the immunosuppressive eff ects of a cyclosporine-based regimen by reducing the rate of acute rej ection episodes.