Dissociation Between Whole-Blood and Kidney Tissue Tacrolimus Exposure in Kidney Transplant Recipients

Tacrolimus (TAC) therapeutic drug monitoring (TDM) routinely monitors whole-blood TAC concentrations; however, these measurements may not accurately reflect renal TAC exposure. We investigated the relationship between whole-blood and kidney tissue TAC exposure in kidney transplant recipients receiving long-term TAC therapy. Thirty-five kidney transplant recipients who underwent graft biopsy and TDM, including trough concentration (C₀) and 24-h area under the concentration-time curve (AUC_0-24), were enrolled from 2020-2021. TAC concentrations in kidney tissue (C_T) were quantified using liquid chromatography-tandem mass spectrometry. Recipients were stratified according to their alternative arteriolar hyalinosis (aah) scores (Banff classification) into a Low-aah group (aah 0-1, n = 20) and a High-aah group (aah 2-3, n = 15). Whole-blood TAC concentrations, C_T, and kidney-to-blood TAC concentration ratios (KBRs) were compared. KBRs were calculated using TAC concentrations measured at trough (C₀), biopsy-matched (C_matched), and peak (C_peak) time points. Associations between time since transplantation and KBRs were subsequently assessed. Whole-blood TAC concentrations, C_T, and KBRs were comparable between the two groups. However, a positive relationship between KBRs and time since transplantation was observed in the High-aah group, whereas no such pattern was observed in the Low-aah group. These exploratory findings suggest that the relationship between whole-blood and kidney tissue TAC exposure may differ according to time since transplantation, particularly in recipients with severe arteriolar hyalinosis. Tissue-based assessment of TAC exposure may provide pharmacokinetic information complementary to that from conventional whole-blood monitoring, offering a framework for future mechanistic investigation of TAC nephrotoxicity.