title: Nuclear Factor of Activated T Cells-Regulated Gene Expression as Predictive Biomarker of Personal Response to Calcineurin Inhibitors.
abstract: BACKGROUND
  Calcineurin inhibitors (CNIs) represent the most widely used immunosuppressive agents in kidney transplantation. Both CNIs show a narrow therapeutic window; thus, monitoring is necessary to balance efficacy and toxicity. Several approaches have been undertaken to measure the biological effects of CNI-based immunosuppression.
  
  
  METHODS
  A quantitative analysis of gene expression was established to calculate the functional effects of calcineurin inhibition, the assessment of nuclear factor of activated T cells (NFAT)-regulated gene expression. This assay is based on the quantitative analysis of interleukin-2, interferon-γ, and granulocyte macrophage colony-stimulating factor gene expression in whole blood samples collected at the time cyclosporine A/tacrolimus troughs (C0) and 2 hours after oral uptake (C2).
  
  
  RESULTS
  In this comprehensive review, analytical aspects of the assay and also clinical benefits and limitations are presented and discussed. Several observational studies underline the beneficial effect of NFAT-regulated gene expression as biomarker of personal response on CNI therapy, especially in infectious complications, malignancies, and acute rejection episodes. Data are more comprehensive in cyclosporine A compared with tacrolimus therapy. However, results on prospective interventional studies are sparse. A randomized controlled study evaluating the opportunity for NFAT-guided immunosuppression is ongoing.
  
  
  CONCLUSIONS
  NFAT-regulated gene expression is a promising biomarker in CNI therapy concerning infectious complications, malignancies, and acute rejection. Prospective interventional studies and randomized controlled studies are ongoing to confirm the encouraging results.
authors.affiliation: Departments of *Nephrology, and †Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommerer
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
mesh_terms: D015415:Biomarkers / Q000097:blood*; D065095:Calcineurin Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D016903:Drug Monitoring / Q000379:methods; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000379:methods; D050778:NFATC Transcription Factors / Q000235:genetics*; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D016559:Tacrolimus