Early Tacrolimus Underexposure Predicts Acute Rejection After Renal Transplantation

Area of Science:

• Nephrology
• Pharmacology
• Immunology

Background:

• Tacrolimus is crucial for immunosuppression post-renal transplant but has a narrow therapeutic index.
• Early pharmacokinetic data is vital for predicting transplant outcomes.
• Identifying early exposure metrics is key for effective therapeutic drug monitoring.

Purpose of the Study:

• To evaluate if early tacrolimus underexposure predicts 12-month acute rejection (AR) in kidney transplant recipients.
• To assess the association between early tacrolimus exposure and the month 3 metabolizer phenotype.

Main Methods:

• Retrospective single-center study of 609 kidney transplant recipients (2007-2018).
• Analyzed pharmacokinetic data for month 3 concentration-to-dose (C/D) classification and rejection analyses.
• Defined early underexposure as trough levels <8 ng/mL during postoperative days 1-10.

Main Results:

• A threshold of 0.29 for the proportion of early days with low tacrolimus levels independently predicted 12-month AR.
• Early tacrolimus exposure showed limited ability to discriminate the month 3 metabolizer phenotype.
• Biopsy-proven AR within 12 months was the primary endpoint.

Conclusions:

• Early tacrolimus underexposure is a clinically relevant predictor of 12-month AR.
• This finding complements existing C/D-ratio risk stratification at 3 months.
• Optimizing early tacrolimus dosing is supported by these findings, as high early clearance and low exposure increase AR risk.