Where Did We Leave Off in 2008? Conclusions From The 8th International Symposium

Although short-term outcomes following kidney transplantation have improved in recent years, allograft viability beyond 1 year has changed little since the introduction of cyclosporine (CsA)-based immunosuppression. Chronic allograft nephropathy (CAN) is a continuing threat to improved long-term outcomes, and regimens that involve calcineurin inhibitors (CNI) are implicated as a result of the progressive fibrosis they promote in renal allografts. Although strategies to reduce the nephrotoxic effects of CNI exposure have shown some success, alternative approaches to reducing nephrotoxicity and graft failure are needed. Sirolimus (SRL) suppresses immune reactions in a mechanism distinct from that of other immunosuppressants and may therefore hold potential for reducing the risk of CAN and improving long-term graft survival. The Rapamune Maintenance Regimen study randomized patients at 3 months either to continue with a regimen of SRL, CsA, and steroids or to have CsA withdrawn and the dose of SRL increased. Patients who were randomized to CsA withdrawal had superior graft and patient survival, demonstrated improved renal function, better blood pressure control, and a lower rate of skin and nonskin posttransplantation malignancy. A key barrier to the wider clinical implementation of SRL in kidney transplantation has, however, been the understanding of its optimal incorporation into standard immunosuppressive protocols. The CONVERT study examined the late conversion (approximately 3 years posttransplantation) from CNI to SRL. Late conversion was associated with inferior outcomes in patients with poor graft function or significant proteinuria following conversion. In addition, a number of short-term adverse events, such as prolongation of delayed graft function and abnormal wound healing, have been more commonly associated with de novo approaches. In designing the optimal approach to achieving long-term CNI-free immunosuppression with SRL, it should therefore be considered how these adverse events may be avoided or minimized. This brings into focus the optimal timing for the introduction of SRL and the potential for a two-stage approach to immunosuppression, minimizing the different short- and long-term risks to both the graft and the patient.