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

Abstract

Aims: 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 the present study was to characterize 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 h after Tac dosing at approximately 1 week, 6 weeks and 1 year post-Tx. Tac concentrations were measured by immunoassay, while the expression of genes encoding NFAT-regulated cytokines [interleukin 2 (IL2), interferon gamma (IFNG), colony stimulating factor 2 (CSF2)] and cytochrome P450 3A5 (CYP3A5) genotyping were determined by real-time polymerase chain reaction.

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 h postdose (C1.5 ) >15 μg l-1 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 viraemia (n = 3) had relatively strong inhibition of cytokines (RGE 2.5-32.5%). By contrast, there was no association between Tac exposure and rejection or viraemia.

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 viraemia.

Keywords: NFAT-regulated gene expression; acute rejection; calcineurin inhibitors; pharmacodynamic drug monitoring; renal transplantation; tacrolimus; viraemia.

© 2017 The British Pharmacological Society.

Figures

Figure 1

Residual gene expression (RGE) of nuclear factor of activated T cells‐regulated cytokines at 1 week (n = 29), 6 weeks (n = 24) and 1 year (n = 24) after transplantation. Data are shown as median ± interquartile range

Figure 2

Correlation between tacrolimus (Tac) concentrations 1.5 h post‐dose (C1.5) and the residual gene expression (RGE) of nuclear factor of activated T cells(NFAT)‐regulated cytokines at 1 week (A), 6 weeks (B) and 1 year (C) after transplantation (Tx). rs, Spearman's rank correlation coefficient