Monitoring intracellular tacrolimus concentrations and its relationship with rejection in the early phase after renal transplantation

Abstract

Introduction: After kidney transplantation, rejection and drug-related toxicity occur despite tacrolimus whole-blood pre-dose concentrations ([Tac]_blood) being within the target range. The tacrolimus concentration within peripheral blood mononuclear cells ([Tac]_cells) might correlate better with clinical outcomes. The aim of this study was to investigate the correlation between [Tac]_blood and [Tac]_cells, the evolution of [Tac]_cells and the [Tac]_cells/[Tac]_blood ratio, and to assess the relationship between tacrolimus concentrations and the occurrence of rejection.

Methods: In this prospective study, samples for the measurement of [Tac]_blood and [Tac]_cells were collected on days 3 and 10 after kidney transplantation, and on the morning of a for-cause kidney transplant biopsy. Biopsies were reviewed according to the Banff 2019 update.

Results: Eighty-three [Tac]_cells samples were measured of 44 kidney transplant recipients. The correlation between [Tac]_cells and [Tac]_blood was poor (Pearson's r = 0.56 (day 3); r = 0.20 (day 10)). Both the dose-corrected [Tac]_cells and the [Tac]_cells/[Tac]_blood ratio were not significantly different between days 3 and 10, and the median inter-occasion variability of the dose-corrected [Tac]_cells and the [Tac]_cells/[Tac]_blood ratio were 19.4% and 23.4%, respectively (n = 24). Neither [Tac]_cells, [Tac]_blood, nor the [Tac]_cells/[Tac]_blood ratio were significantly different between patients with biopsy-proven acute rejection (n = 4) and patients with acute tubular necrosis (n = 4) or a cancelled biopsy (n = 9; p > 0.05).

Conclusion: Tacrolimus exposure and distribution appeared stable in the early phase after transplantation. [Tac]_cells was not significantly associated with the occurrence of rejection. A possible explanation for these results might be related to the low number of patients included in this study and also due to the fact that PBMCs are not a specific enough matrix to monitor tacrolimus concentrations.

Keywords: Kidney transplantation; Peripheral blood mononuclear cell; Pharmacokinetics; Tacrolimus; Therapeutic drug monitoring.