title: Assessing the metabolic effects of calcineurin inhibitors in renal transplant recipients by urine metabolic profiling.
abstract: BACKGROUND
  Biomarkers that can predict graft function and/or renal side effects of calcineurin inhibitors (CNI) at each stage of treatment in kidney transplantation are still lacking. We report the first untargeted GC-MS-based metabolomic study on urines of renal transplant patients. This approach would bring insight in biomarkers useable for graft function monitoring.
  
  
  METHODS
  All consecutive patients receiving a kidney allograft in our transplantation department over a 6-month period were prospectively included and followed up for 12 months. We collected urine samples on the seventh day (D7) after transplantation, then at month 3 (M3) and month 12 (M12), and obtained mass-spectrometry-based urinary metabolic profiles. Multivariate analyses were conducted to compare metabolic profiles at the 3 different periods and to assess potential differences between cyclosporine and tacrolimus. Differences in metabolic signatures were also assessed according to graft function at D7 and renal function at M3 and M12.
  
  
  RESULTS
  The urinary metabolic patterns varied over time in cyclosporine- and tacrolimus-treated patients and were somewhat different at D7, M3, and M12 between the 2 treatment groups. Principal metabolites that differed, regardless of the treatment used, were mainly sugars, inositol, and hippuric acid. Interestingly, among tacrolimus-treated patients, different metabolic signatures were found between patients with immediate or delayed graft function at D7.
  
  
  CONCLUSIONS
  Urinary metabolomics represents a noninvasive way of monitoring immunosuppressive therapy in renal transplant patients. Although it is too early to consider it as a biomarker of CNI-induced injury or graft function, metabolomics appears a promising evaluation tool in this area.
authors.affiliation: 1 INSERM U930, Université François-Rabelais, Tours, France. 2 Service de néphrologie-immunologie Clinique, CHU Tours, France. 3 EA 4245, Université François-Rabelais, Tours, France. 4 Laboratoire de biochimie et biologie moléculaire, CHU Tours, France. 5 PPF "Analyses des Systèmes Biologiques", Université François Rabelais, Tours, France. 6 Address correspondence to: Chantal Le Guellec, PharmD, Ph.D., Laboratoire de biochimie et biologie moléculaire, CHU Tours, France.
authors.forename: Binta
authors.initials: B
authors.lastname: Diémé
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Halimi
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Matthias
authors.initials: M
authors.lastname: Büchler
authors.forename: Lydie
authors.initials: L
authors.lastname: Nadal-Desbarat
authors.forename: Hélène
authors.initials: H
authors.lastname: Blasco
authors.forename: Chantal
authors.initials: C
authors.lastname: Le Guellec
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016030:Kidney Transplantation / Q000009:adverse effects; D016018:Least-Squares Analysis; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D025341:Principal Component Analysis; D011446:Prospective Studies; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus