Adequate cumulative exposure to tacrolimus and low tacrolimus variability decrease the incidence of biliary complications after liver transplantation

Background: Nonearly biliary complications (BCs) after liver transplantation (LT) are highly associated with immunological status. Tacrolimus is the main immunosuppressant. Whether and how tacrolimus bioavailability affects BCs is unclear. Methods: LT recipients receiving tacrolimus-free immunosuppressants or developing BCs within 3 months after LT were excluded. Tacrolimus-related variables included trough concentration (C0), variability and cumulative exposure to tacrolimus (CET). Receiver operating characteristic (ROC) curves defined cutoff values of CET and variability. The values divided patients into adequate and low CET groups, also high and low-variability groups. Inverse probability of treatment weighting (IPTW) was used to reduce bias. Logistic regression identified risk factors. Kaplan-Meier curves were generated for survival comparison. Results: 409 patients were enrolled, and 39 (9.5 %) suffered from BCs. The mean C0 values were 6.9 and 7.2 ng/ mL in the BCs and BCs-free groups, respectively. CET within 3 postoperative months was 550.0 and 608.6 ng. day/mL, while the tacrolimus variability was 0.4 and 0.3, respectively. The cutoff values for CET within 3 months and variability predicting BCs were 660.5 and 0.54, respectively. Multivariable logistic regression revealed that low CET within 3 months (p = 0.005, p = 0.002) and high variability (p < 0.001, p < 0.001) were associated with BCs before and after IPTW. Appropriate CET and low variability were associated with better overall survival (p = 0.009 and 0.029). Subgroup analysis indicated that long cold ischemia time (CIT), high bilirubin and low CET had a higher relative risk and raised the incidence of BCs. Conclusions: Adequate CET and low variability of tacrolimus ameliorated nonearly BCs incidence and improved survival.