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Reduced residual gene expression of nuclear factor of activated T cells‐regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation
Author(s) -
Steinebrunner N.,
Sandig C.,
Sommerer C.,
Hinz U.,
Giese T.,
Stremmel W.,
Zahn A.
Publication year - 2014
Publication title -
transplant infectious disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.69
H-Index - 67
eISSN - 1399-3062
pISSN - 1398-2273
DOI - 10.1111/tid.12206
Subject(s) - nfat , medicine , calcineurin , tacrolimus , immunology , transplantation , pharmacology , gastroenterology
Background Pharmacokinetic monitoring of calcineurin inhibitors ( CNI s) is unsatisfactory because, at comparable blood concentrations, side effects vary considerably. We recently confirmed the applicability of a pharmacodynamic ( PD ) assay that measures the suppression of CNI target genes, specifically the suppression of nuclear factor of activated T cells ( NFAT )‐regulated genes in liver transplant ( LT ) recipients. The aim of this prospective study was to prove the clinical reliability of this assay. Therefore, we quantified the residual gene expression ( RGE ) of NFAT ‐regulated genes and evaluated the association between the RGE of NFAT ‐regulated genes and the incidence of cytomegalovirus ( CMV ) infection. Patients and methods In 20 LT recipients, 10 patients on cyclosporine (CsA) and 10 patients on tacrolimus (Tac) therapy, who presented with CMV infection, the RGE s of interleukin‐2, interferon‐γ ( IFN γ), and granulocyte–monocyte colony‐stimulating factor were measured and compared with the RGE s of these cytokines in 40 healthy dose‐matched LT controls. Results CsA‐treated CMV patients demonstrated a lower RGE of all NFAT ‐regulated genes compared with controls (30 ± 17 vs. 44 ± 20, P  = 0.067). For IFN γ, the level of significance was reached (26 ± 17 vs. 43 ± 17, P  = 0.0125). Daily CsA dosage, CsA baseline (C 0 ) and 2 h (C 2 ) concentrations were comparable (CsA dosage 169 mg/day vs. 165 mg/day; CsA C 0 94 μg/L vs. 85 μg/L; CsA C 2 389 μg/L vs. 381 μg/L). In addition, Tac‐treated CMV patients demonstrated a lower RGE of all NFAT ‐regulated genes compared with controls (68 ± 25 vs. 84 ± 22, P  = 0.0769). Analogous to CsA‐treated CMV patients, the level of significance was reached for IFN γ (61 ± 24 vs. 88 ± 29, P  = 0.0154). Daily Tac dosage and Tac 1.5 h concentrations (C 1.5 ) were comparable in both groups (Tac dosage 4 mg/day vs. 4 mg/day; Tac C 1.5 8 μg/L vs. 10 μg/L), whereas Tac C 0 concentrations were significantly higher in controls (Tac C 0 4 μg/L vs. 6 μg/L, P  = 0.0276). Conclusion Measuring the RGE of NFAT ‐regulated genes is appropriate to assess the risk of infections in LT recipients. Measuring the RGE of IFN γ is particularly suitable to assess the risk of CMV infection. PD monitoring of CNI s in LT recipients is an approach to individualize immunosuppression, which may help to reduce infectious complications.

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