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 (AUC0–24), were enrolled from 2020–2021. TAC concentrations in kidney tissue (CT) 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, CT, and kidney-to-blood TAC concentration ratios (KBRs) were compared. KBRs were calculated using TAC concentrations measured at trough (C0), biopsy-matched (Cmatched), and peak (Cpeak) time points. Associations between time since transplantation and KBRs were subsequently assessed. Whole-blood TAC concentrations, CT, 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.