NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation

SUMMARYAIMS Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of this study was to characterize the nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy. METHODS In 29 renal allograft recipients samples were drawn once pre-Tx, and before and 1.5 hours after Tac-dosing at approximately 1 week, 6 weeks and 1 year post-Tx. Tac concentrations were measured by immunoassay, while the expression of NFAT-regulated cytokines (IL2, IFNG, CSF2) and CYP3A5 genotyping was determined by real-time PCR. RESULTS The cytokine response after Tac dosing varied up to 46-fold between patients and changed significantly with time post-engraftment. Tac concentrations 1.5 hours post-dose (C1.5) >15 μg/L were associated with strong cytokine inhibition and residual gene expression (RGE) ≤10 %, while lower Tac C1.5 resulted in more variable responses (RGE 2.5–68.7%). Patients with ongoing subclinical acute rejection (n=5) demonstrated limited cytokine inhibition (RGE 39.7–72.6%), while patients with polyoma virus viremia (n=3) had relatively strong inhibition of cytokines (RGE 2.5–32.5%). In contrast, there was no association between Tac exposure and rejection or viremia. CONCLUSIONS The findings of our study support the potential of NFAT-regulated gene expression measurements as a pharmacodynamic tool for additional monitoring of Tac therapy, especially in the context of overimmunosuppression and viremia.