A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: XXXX -Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology.

@entity1 @entity3446 @entity281 @entity618 @entity1140 @entity479
INTRODUCTION: The two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand. AIM: To determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology-surrogates for graft and, therefore, @entity1 survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer @entity281 , and improved @entity1 survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology. METHODS: Between April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of @entity1140 , a CNI, and @entity3446 , a @entity1 target of @entity3446 inhibitor. We report here the outcome of converting @entity1 after six months either to minimized @entity1140 / @entity3446 or @entity618 / @entity3446 . Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 months. RESULTS: CNI withdrawal (on-treatment analysis) associated with better graft function (p <0.001) and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003) and 24 (p = 0.013) months, without affecting @entity1 (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17). CONCLUSION: CNI ( @entity1140 ) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in @entity479 -free low immunological risk renal transplant @entity1 . TRIAL REGISTRATION: ClinicalTrials.gov NCT00556933.
