3 years ago

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

Sara Bremer, Karsten Midtvedt, Morten Skauby, Stein Bergan, Nils T. Vethe, Elisabet D. Johansson, Margrete Kasbo
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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13367

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