Association of Intrapatient Variability of Tacrolimus Concentration with Early Deterioration of Chronic Histologic Lesions in Kidney Transplantation

Abstract

Background. High intrapatient variability (IPV) of tacrolimus (Tac) is increasingly recognized as a risk factor for poor graft outcomes in kidney transplantation. The timing of onset of its impact on kidney histologic lesions has not been investigated. Methods. We analyzed the adverse effect of Tac IPV using the coefficient of variability from 6 to 12 months posttransplantation on long-term outcomes in a cohort of 671 kidney recipients and on the evolution of chronic histologic lesions in a cohort of 212 recipients for whom paired protocol biopsies at 10 days and 1 year were available. Results. High IPV of Tac (cutoff value of coefficient of variability = median of 20.5%) was associated with an increased risk of graft loss (hazard ratio, 3.28; 95% confidence interval, 1.090-9.849; P = 0.035) in the entire cohort. At 1 year, the high Tac IPV group showed a significantly deteriorated chronicity score (F = 5.912, P = 0.016) compared with the low Tac IPV group in the Histology cohort after controlling for the 10-day scores. In a multivariate analysis, a high IPV of Tac was predictive of the chronicity score (odds ratio, 1.91; 95% confidence interval, 0.215-1.075; P = 0.003) at 1 year posttransplant. Conclusions. These data indicate that high IPV of Tac is associated with early deterioration of chronic histologic lesions as well as poorer long-term outcomes. Large prospective studies of Tac IPV usage as a clinical monitoring tool are needed in the future.