Early Tacrolimus Underexposure Predicts Acute Rejection After Renal Transplantation

Background: Tacrolimus is a key component of immunosuppressive therapy after renal transplantation but is characterized by a narrow therapeutic index and considerable pharmacokinetic variability. Although the month 3 concentration-to-dose (C/D) ratio identifies fast metabolizers at an increased risk of inferior outcomes after transplantation, very early C/D ratios lack prognostic value. Therefore, identifying early exposure metrics that capture cumulative tacrolimus exposure rather than single time-point concentrations represents an important challenge for therapeutic drug monitoring. This study evaluated whether early tacrolimus underexposure (trough concentration <8 ng/mL during postoperative days 1–10) predicts 12-month acute rejection (AR) and examined its association with the month 3 metabolizer phenotype. Methods: This retrospective single-center study analyzed 374 kidney transplant recipients with complete pharmacokinetic data for the month 3 C/D classification and an extended cohort of 609 recipients transplanted between 2007 and 2018 for rejection analyses. Results: The primary end point was biopsy-proven AR within 12 months. A threshold of 0.29 for the proportion of postoperative days 1–10 with trough levels <8 ng/mL provided the highest sensitivity-specificity balance. Values above this cutoff independently predicted 12-month AR. Early tacrolimus exposure patterns showed only a modest ability to discriminate the month 3 metabolizer phenotype. Conclusions: Early tacrolimus underexposure is a simple and clinically relevant predictor of 12-month AR, complementing C/D-ratio-based risk stratification at 3 months. These findings align with the evidence that high early tacrolimus clearance and low tacrolimus exposure increase AR risk and support the recommendations for optimizing early tacrolimus dosing.