Monitoring Long-term Tacrolimus Exposure: Metrics, Trajectories, and Associations with Outcomes after Kidney Transplantation in the Wisconsin Allograft Recipient Database (WisARD)

Background There is no consensus on the optimal metric for long-term tacrolimus monitoring after kidney transplantation. It remains unknown how tacrolimus exposure changes over time and how tacrolimus monitoring metrics are related to long-term outcomes. Methods We examined tacrolimus exposure beyond the first year after kidney transplantation, as assessed by multiple monitoring metrics (i.e., mean trough level, intra-patient variability [IPV], time in therapeutic range [TTR], time below range, time above range), in the Wisconsin Allograft Recipient Database. We examined associations of these metrics with late graft outcomes (late rejection, uncensored and death-censored graft failure [DCGF]) and mortality (death with a functioning graft [DWFG]). Results A total of 1994 kidney transplant recipients, who received tacrolimus-based immunosuppression and survived at least 12 months with a functioning graft, were included. We observed a decreasing trend of tacrolimus exposure over median follow-up of 5.3 years. A high tacrolimus IPV (coefficient of variation ≥30%) in the second year was most strongly associated with outcomes, including a 45% higher risk of uncensored graft failure (adjusted hazard ratio =1.45; 95% confidence interval: 1.22, 1.72; p <0.01). A higher IPV also was associated with a higher risk of death-censored graft failure, mortality, and late rejection. Cumulative high tacrolimus IPV in the past 5 years was associated with higher risk of graft failure and mortality. Conclusion Metrics of tacrolimus exposure assessed beyond the first year after kidney transplantation, especially IPV, remain informative for long-term outcomes.