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

Abstract

IntroductionThe 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.AimTo 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, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology.MethodsBetween 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 tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 monthsResultsCNI 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 patient (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17).ConclusionCNI (tacrolimus) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in steroid-free low immunological risk renal transplant patients.Trial RegistrationClinicalTrials.gov NCT00556933

Tailored Rabbit Antithymocyte Globulin Induction Dosing for Kidney Transplantation

“…Single-dose administration of rATG 6 mg/kg has also been evaluated. For example, Stevens et al 11 , 12 reported results of their experience of rATG 6 mg/kg single dose versus same total dose divided in 4 days. Again, low rejection rates with favorable safety parameters were obtained using higher doses than we report.…”

“… 8 - 10 Single dose (6 mg/kg) versus divided doses (1.5 mg/kg on four consecutive days) have yielded similar outcomes in terms of graft and rejection-free survival. 11 , 12 Most recently (April 2017), the Food and Drug Administration approved rATG as antibody induction therapy with doses ranging from 6 to 10.5 mg/kg. The efficacy of rATG induction when compared with various alternate strategies has been clearly defined, a detailed discussion of which is beyond the scope of this report.…”

A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation

“…However, in primates, an intensive administration schedule of fewer, larger doses conferred more-comprehensive lymphocyte depletion than did a less-intensive regimen, both in the bloodstream and in secondary lymphoid structures (2). Improved early renal function with deceased donor kidneys was reported when rATG administration was initiated before reperfusion (8), and in nonrandomized studies, single-dose rATG (SD-rATG) induction appeared to enable calcineurin inhibitor maintenance minimization and even complete withdrawal (9)(10)(11). In a blinded single-center trial that compared induction with rabbit versus equine DD-ATG, there was less rejection and superior graft survival in the rATG group after 10 years (12).…”