Impact of High Tacrolimus Exposure on Graft Function and Development of a Prediction Model in Kidney Transplant Recipients: A Single-Center Retrospective Cohort Study

Wenyu Yang,1,2,* Renfei Xia,3,* Peijin Zhao,1,2 Juanhua Du,4 Rumin Liu,3 Wenli Zeng,3 Yan Chen,1,2 Xin Luo,1,2 Ping Zheng,1,2 Yilei Li,1,2 Liqian Mo1,2 1Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yilei Li, Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Email [email protected] Liqian Mo, Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Email [email protected]: To evaluate the association between early supratherapeutic tacrolimus exposure (trough concentration > 20 ng/mL within the first postoperative week) and graft outcomes in kidney transplant recipients, and to develop a prediction model for this early high exposure.Patients and Methods: This single-center retrospective cohort study included 210 kidney transplant recipients (105 exposed, 105 non-exposed) after propensity score matching. Renal function (eGFR, cystatin C) and infection rates over the first year were compared using linear mixed-effects models with multiple imputation. A Cox proportional hazards model with LASSO variable selection was developed to predict the risk of high exposure.Results: The exposed group had significantly lower eGFR at 7 days, 1, and 3 months (adjusted mean differences: − 11.32, − 10.20, − 10.75 mL/min/1.73 m2) and higher cystatin C (0.83, 0.36, 0.36 mg/L). At 1 year, eGFR remained lower (− 7.54 mL/min/1.73 m2, P=0.038) and cystatin C higher (0.40 mg/L, P=0.043) in the exposed group. The 1-year infection rate was higher in the exposed group (80.0% vs 52.3%; adjusted OR=4.27, P< 0.001). The prediction model identified CYP3A5 *3/*3 genotype (HR=2.19), elevated C-reactive protein on day 1 (HR=1.27), and higher weight-adjusted tacrolimus dose (HR=1.58) as key predictors (C-index=0.716; optimism-corrected C-index=0.728).Conclusion: Early high tacrolimus exposure is associated with impaired renal function and increased infection risk in the first year after transplantation. A prediction model incorporating genetic, inflammatory, and dosing factors could aid in early risk stratification.Keywords: therapeutic drug monitoring, pharmacogenomics, predictive model, early exposure, risk prediction