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Optimizing the long-term outcome of renal transplants: opportunities created by sirolimus
1Westmead Hospital and University of Sydney, Sydney, Australia.
Abstract:
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.
Insights
Eliminating calcineurin inhibitors like cyclosporine improved long-term kidney transplant outcomes. Sirolimus-based immunosuppression without cyclosporine enhances renal function and graft survival.
Area of Science:
- Nephrology
- Immunology
- Transplantation
Background:
- Calcineurin inhibitors (e.g., cyclosporine) are standard immunosuppressants post-transplant.
- Chronic nephrotoxicity from calcineurin inhibitors can impair long-term graft survival.
- Alternative immunosuppressive strategies are needed to balance efficacy and toxicity.
Purpose of the Study:
- To evaluate sirolimus-based immunosuppression strategies with cyclosporine elimination.
- To determine the optimal long-term immunosuppressive regimen for kidney transplant recipients.
- To assess the impact on renal function, graft survival, and rejection rates.
Main Methods:
- Two studies (Phase II and III) involving kidney transplant recipients.
- Patients received uniform therapy for 3 months, followed by cyclosporine withdrawal in one arm.
- Comparison of cyclosporine elimination versus continuous calcineurin inhibitor use alongside sirolimus and corticosteroids.
Main Results:
- Improved renal function was observed in the cyclosporine elimination groups in both studies.
- Renal function continued to improve for up to 2 years in the Phase III elimination arm.
- Equivalent patient and graft survival rates and no difference in acute rejection were noted.
Conclusions:
- Continuous sirolimus and steroid use without calcineurin inhibitors is a successful strategy.
- This approach improves long-term graft survival by enhancing renal function.
- Cyclosporine elimination offers a viable alternative for long-term immunosuppression in kidney transplantation.