In renal transplantation blood cyclosporine levels soon after surgery act as a major determinant of rejection: Insights from the MY.S.S. Trial

Abstract

Target organs express antigens recognized directly by antigen-specific T cells, and their recognition is crucial to precipitate rejection. Then, the earliest T-cell activation is inhibited by cyclosporine A (CsA), the lowest would be the risk of rejection. Here, we aimed to assess this possibility in a large cohort of de novo kidney transplant recipients participating in an ongoing clinical trial, the Mycophenolate Steroid-Sparing (MY.S.S.) Trial. Three-hundred-thirty-four patients entered the prospective, multicenter MY.S.S. trial. The main aim of the study was to assess the predictive value of serial evaluation of blood CsA trough concentration (C0) and 2-hour postdose drug (C2) levels alone or in combination, and to identify which is the critical posttransplant measurement to target CsA therapy in order to minimize the risk of acute rejection. A very large number of CsA trough (N= 2236) and C2 (N= 2128) measurements during the first 6 months postsurgery were available for analysis. Patients with delayed graft function were excluded. CsA trough levels measured at day 2 posttransplant were the strongest predictor of acute graft rejection over 6-month follow-up. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while for levels lower than 300 ng/mL, the risk of acute rejection was more than doubled. Higher levels failed to provide any further protection from graft rejection. CsA trough values predicted allograft rejection with an accuracy of 74%, while C2 levels considered alone had no predictive values at all. Findings that among serial daily measurements posttransplant those taken as early as at day 2 have by far the highest capacity to predict rejection episodes, underline the need of targeting CsA therapy very early posttransplant with the goal to modulate early enough T-cell activation at the interface between the recipient's blood and the graft where alloimmune response actually initiates.