Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience

Abstract

Background and objective: Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C₀/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C₀/D, the study aimed to estimate the combined effect of tacrolimus IPV and C₀/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods.

Methods: The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C₀/D during 6-12 months post-transplantation.

Results: The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C₀/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C₀/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C₀/D. Patients with high IPV/low C₀/D had significantly reduced graft survival compared to the other tacrolimus IPV/C₀/D combination groups (i.e., high IPV/high C₀/D, low IPV/low C₀/D, low IPV/high C₀/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint.

Conclusion: The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C₀/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.