Optimum tacrolimus trough levels for enhanced graft survival and safety in kidney transplantation: a retrospective multicenter real-world evidence study

Background: The current study aimed to determine the optimal tacrolimus trough levels for balancing graft survival and patient safety following kidney transplantation. Materials and Methods: We conducted a retrospective cohort study involving 11,868 kidney transplant recipients from five medical centers. The association between tacrolimus exposures (periodic mean trough level, coefficient of variability, time in therapeutic range) and composite allograft outcome (de novo donor specific antibody, biopsy-proven rejection, kidney dysfunction, and graft failure), as well as safety outcomes (severe infection, cardiovascular events, malignancy, and mortality) were assessed. Data were sourced from Clinical Data Warehouses and analyzed using advanced statistical methods, including Cox marginal structural models with inverse probability treatment weighting. Results: Tacrolimus levels of 5.0–7.9 ng/mL and 5.0–6.9 ng/mL during the 2–12 month and 12–72 month post-transplantation periods, respectively, were associated with reduced risks of composite allograft outcomes. During the first post-transplant year, the adjusted hazard ratios (aHR) for composite allograft outcomes were: 0.69 (95% CI 0.55–0.85, P <0.001) for 5.0–5.9 ng/mL; 0.81 (95% CI 0.67–0.98, P =0.033) for 6.0–6.9 ng/mL; and 0.73 (95% CI 0.60–0.89, P =0.002) for 7.0–7.9 ng/mL (compared to levels ≥8.0 ng/mL). For the 6-year composite outcomes, aHRs were 0.68 (95% CI 0.53–0.87, P =0.002) for 5.0–5.9 ng/mL and 0.65 (95% CI 0.50–0.85, P =0.001) for 6.0–6.9 ng/mL. These optimal ranges showed reduced rates of severe infection (6 y), malignancy (6 y), and mortality (1 y). Conclusion: This multicenter study provides robust evidence for optimal tacrolimus trough levels during the periods 2–12 and 12–72 months following kidney transplantation.