Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation

Background, The adoption of calcineurin inhibitors (CNI) as We mainstay of immunosuppression has resulted in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients. Methods, Ninety-eight patients of primary cadaver or Living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study, The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2R alpha), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 months and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNP, The primary efficacy endpoint was biopsy-proven rejection during the first 6 months posttransplant, Results. Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection, At 1 year, patient survival was 97% and graft survival was 96%, Only two grafts were lost secondary to rejection. At I-year posttransplant, 62% of patients had received CM for more than 7 days, At 1-year posttransplant, the mean serum creatinine in the nonrejectors with mo GM use was 113 mu mol/L (95%, confidence interval [CI], 100.7 to 125.3 mu mol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 mu mol/L (95% CI, 135.0 to 173.0 mu mol/L), In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2R alpha saturation. Conclusions. This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI, however, because complete IL-2R alpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.