title: Monitoring of calcineurin inhibitors by NFAT-regulated gene expression in de novo renal allograft recipients on cyclosporine A.
abstract: BACKGROUND
  Calcineurin inhibitors are critical-dose drugs with a narrow therapeutic range and optimal monitoring strategies are discussed in terms of safety and efficacy. A new pharmacodynamic monitoring tool - assessing the expression of nuclear factor of activated T-cells (NFAT)-regulated genes - has been established to directly measure the functional effect of cyclosporine A (CsA) in an individual patient. Until now, only sparse data on NFAT-regulated gene expression within the early post-transplant period have been available.
  
  
  METHODS
  Altogether 80 de novo renal transplant patients were enrolled in this non-interventional cohort-study. Immunosuppression consisted of interleukin (IL)-2 receptor antagonist induction, CsA, mycophenolic acid and steroids. Expression of NFAT-regulated genes (IL-2, granulocyte-macrophage colony stimulating-factor (GM-CSF), interferon-γ (IFN-γ)) was determined by qRT-PCR (real-time reverse transcription-PCR) at CsA C0 (prior to CsA intake) and C2 (2 hours after CsA intake) at regular follow-up visits within 6 months after transplantation.
  
  
  RESULTS
  The median age of all patients was 47.9 ± 13.7 years (54 male). Residual NFAT-regulated gene expression showed a high interindividual variability. Inversely to reduction of CsA doses, NFAT-regulated genes increased from 1.78 ± 1.33% to 8.04 ± 7.36% in month 1 to month 6. Despite comparable CsA C0 levels, NFAT-regulated gene expression was significantly less inhibited in patients with treated biopsy-proven acute rejections (2.9 ± 2.2% vs. 2.0 ± 1.7%, p = 0.047). Patients with very low residual expression of NFAT-regulated genes were at an increased risk for early infectious episodes. Residual expression of IFN-γ and GM-CSF genes correlated significantly with clinical outcomes.
  
  
  CONCLUSIONS
  NFAT-regulated gene expression is highly inhibited in the early post-transplant period in renal allograft recipients on CsA treatment. High residual NFAT-regulated gene expression was related to acute rejection episodes and low residual expression with infectious complications. Thus, NFAT-monitoring has the potential to support pharmacokinetic monitoring during the early post-transplant period.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommerer
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Stefan
authors.initials: S
authors.lastname: Meuer
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
mesh_terms: D000328:Adult; D065095:Calcineurin Inhibitors / Q000032:analysis / Q000378:metabolism; D015331:Cohort Studies; D016572:Cyclosporine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; D016572:Cyclosporine