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Pharmacodynamic monitoring of nuclear factor of activated T cell-regulated gene expression in liver allograft recipients on immunosuppressive therapy with calcineurin inhibitors in the course of time and correlation with acute rejection episodes – a prospective study

Niels Steinebrunner, Catharina Sandig, Claudia Sommerer, Ulf Hinz, Thomas Giese, Wolfgang Stremmel, Alexandra Zahn

(Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany)

Ann Transplant 2014; 19:32-40

DOI: 10.12659/AOT.889809

Background: Due to considerable pharmacokinetic (PK) variability, immunosuppression with calcineurin inhibitors (CNIs) remains challenging. The objective of this study was to assess a pharmacodynamic (PD) approach of monitoring nuclear factor of activated T cell (NFAT)-regulated gene expression in the course of time and in correlation with rejection episodes.

Material and Methods: 22 de novo liver allograft recipients were observed for a period of up to 12 months and the residual gene expression (RGE) of NFAT-regulated genes was monitored prospectively and correlated to acute rejection episodes.

Results: There was a significant increase in RGEs between the time points 4–7 months and 1 month (25±7 µg/l vs. 9±5 µg/l, p≤0.0001) and 8–12 months and 1 month (50±8 µg/l vs. 10±7 µg/l, p=0.002) in the cyclosporine A (CsA) group, whereas in the tacrolimus (Tac) group a significant increase in RGEs appeared at the time point 8–12 months first.
Acute rejection episodes occurred in 4 patients within 1 month after transplantation. These patients demonstrated a higher RGE of all NFAT-regulated genes compared to the other patients (CsA-treated patients: 39±0% vs. 11±5%, p=0.0001, Tac-treated patients: 48±12% vs. 18±10%, p=0.0082).
Conclusions: RGE of all NFAT-regulated genes show a relation between acute rejection episodes in the early post transplant period. Thus, this PD method has the potential to aid therapeutic drug monitoring.

Keywords: NFAT-regulated gene expression, Liver Transplantation, pharmacodynamic drug monitoring, calcineurin inhibitors, acute rejection episodes

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