Background: Concentration to dose ratio (CDR) of tacrolimus (TAC) is an index of inter-patient variability that reflects TAC metabolism, and whether it influences allograft outcomes is controversial in kidney transplantation (KT). This study analyzed the effect of TAC interpatient variability combined with TAC intrapatient variability (IPV) on allograft outcomes.
Methods: In total, 1,080 patients with low immunologic risk were enrolled. Interpatient variability was calculated as the mean value of CDRs up to 3 months after KT, and was defined as rapid metabolizer (RM) if it was lower than 1.05 IPV was calculated as the time-weighted coefficient variability (TWCV) of the TAC-trough level (C0) up to 1 year after KT, and was defined as high IPV group if it was higher than 30%. According to CDR and TWCV, patients were divided into four groups: non-rapid metabolizer (NRM)/low IPV, RM/low IPV, NRM/high IPV, and RM/high IPV, and allograft outcomes were analyzed.
Results: Death-censored graft loss (DCGL) rates were 5.5% in the NRM/low IPV group, 5.7% in the RM/low IPV group, 10.5% in the NRM/high IPV group, and 19.1% in the RM/high IPV group, which was the significantly highest in the RM/high IPV group. In Cox regression analysis, the hazard ratio (HR) of RM/high IPV was 3.06, which was observed as a significant risk factor. In the analysis in which the TAC time weighted average value was adjusted, RM/high IPV was remained as a significant risk factor with HR 2.49. In the subgroup analysis of the panel reactive antibody (PRA) (–) and (+) groups, the risk for DCGL of RM/high IPV was higher in the PRA (+) group (HR 3.75 in PRA [+] group vs. 2.79 in PRA [–] group).
Conclusions: High TAC-IPV in patients with low CDRs in the early posttransplantation period is thought to have a significant adverse effect on the allograft outcomes.