Optimizing the long-term outcome of renal transplants: opportunities created by sirolimus.
This review focuses upon the sirolimus-based cyclosporine elimination studies and the light they shed on choice of the best long-term immunosuppressive strategy for managing the balance between prevention of loss of grafts from antigen specific immune responses or from chronic nephrotoxicity. The underlying strategy of both cyclosporine elimination studies was to treat patients with a uniform therapy for the first 3 months and then wean off the cyclosporine therapy in one cohort. The Phase II study was conducted in 246 recipients in 17 centers in the USA and Europe. Thus 97 patients were treated with full-dose cyclosporine, fixed-dose sirolimus and corticosteroids, and 100 patients received reduced-dose cyclosporine and trough concentration controlled sirolimus with corticosteroids until 3 months when the dose of cyclosporine was tapered progressively. The phase III study was undertaken in 525 patients in 57 centers in Australia, Canada and Europe with randomization for cyclosporine elimination undertaken at 3 months and implemented over the next 4-6 weeks. The primary outcome of renal function was better in the elimination arms of both studies and, in the phase III study, continued to improve for up to 2 years. Both studies demonstrated better renal function, equivalent patient and graft survival and no difference in acute rejection rates. These studies have shown that one of the successful strategies for improving the longer term graft survival rates includes the continuous use of sirolimus and steroids, without calcineurin inhibitors.
Westmead Hospital and University of Sydney, Sydney, Australia.
J R
JR
Chapman
D000328:Adult; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D005006:Ethnicity; D005060:Europe; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus