Late Conversion of Kidney Transplant Recipients from Ciclosporin to Tacrolimus Improves Graft Function: Results from a Randomized Controlled Trial

Abstract

Background: Tacrolimus (TAC) to ciclosporin A (CSA) conversion studies in stable kidney transplant recipients have reported varying effects on graft function. Here we study graft function (eGFR) trajectories using linear mixed models, which provide effect estimates on both slope and baseline level of GFR and offer increased statistical power.

Methods: Secondary analysis of a randomized controlled trial of CSA treated kidney transplant recipients with stable graft function assigned to receive 0.1 mg/kg/day TAC (target 5-8 ng/ml) or to continue CSA based immunosuppression (target 70-150 ng/ml) at a 2:1 ratio. Renal graft function was estimated via the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) formulas.

Results: Forty-five patients continued CSA and 96 patients were converted to TAC with a median follow up of 24 months. Baseline demographics (except for recipient age) including native kidney disease, transplant characteristics, kidney graft function, medication use and comorbid conditions did not differ between groups. In respect to long-term renal graft function, linear mixed models showed significantly improved eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001) in the TAC versus CSA group over 24 months of follow up. Estimated eGFRCKD-EPI group differences between TAC and CSA were -3.49 (p = 0.019) at 3 months, -5.50 (p<0.001) at 12 months, and -4.48 ml/min/1.73m2 (p = 0.003) at 24 months of follow up. Baseline eGFR was a significant predictor of eGFR trajectories (eGFRMDRD: p<0.001, eGFRCKD-EPI: p<0.001). Significant effects for randomization group were evident despite short-term trough levels in the supratherapeutic range (27% (n = 26) of TAC patients at week one). Median TAC trough levels were within target range at week 4 after conversion.

Conclusion: Conversion of CSA treated kidney transplant recipients with stable graft function to TAC (target 5-8 ng/ml) showed significantly improved long-term eGFR trajectories when compared to CSA maintenance (target 70-150 ng/ml).

Trial registration: ClinicalTrials.gov NCT00182559 EudraCT identifier: 2004-004209-98.

Conflict of interest statement

Competing Interests: GSP received speaker fees from Astellas, Novartis, and Roche. GSP also received an unrestricted grant from Fujisawa/Astellas in support of this study. WCW served as external randomization officer to the trial investigators at the Medical University of Vienna in 2005 and 2006 and received honoraria directly from Fujisawa/Astellas for that activity and has served as a scientific advisor to Amgen, Affymax, and Fibrogen or their respective contractors in the past year. MR has received research and travel funds from Astellas. Fujisawa/Astellas issued an unrestricted grant to GSP in support of this study. The results presented in this paper have not been published previously in whole or part, except in abstract format. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Consort flow diagram.

Fig 2. TAC group eGFR and trough level fluctuations.

Mean eGFRCKD-EPI (solid line) and trough levels (dashed line) for the TAC study group at baseline, weeks 1, 2, 4, 8, and 3, 12 and 24 months after conversion.

Fig 3. CSA and TAC group eGFR courses compared.

Mean eGFRCKD-EPI for the CSA (solid black line) and TAC study group (solid grey line) at baseline, 3, 12 and 24 months after conversion. Ciclosporin trough levels (dashed line) at the same timepoints.

Fig 4. TAC trough level distributions at different follow-up timepoints.

Tacrolimus trough level distributions at 1, 2 and 4 weeks, as well as, 24 months after conversion shown as density plots.