title: Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers.
abstract: BACKGROUND
  Several preclinical urinary biomarkers have been qualified and accepted by the health authorities (US Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency) for detecting drug-induced kidney injury during preclinical toxicologic testing. Validated human assays for many of these biomarkers have become commercially available, and this study was designed to characterize some of the novel clinical renal biomarkers. The objective of this study was to evaluate clinical renal biomarkers in a typical Phase I healthy volunteer population to determine confidence intervals (pilot reference intervals), intersubject and intrasubject variability, effects of food intake, effect of sex, and vendor assay comparisons.
  
  
  METHODS
  Spot urine samples from 20 male and 19 female healthy volunteers collected on multiple days were analyzed using single analyte and multiplex assays. The following analytes were measured: α-1-microglobulin, β-2-microglobulin, calbindin, clusterin, connective tissue growth factor, creatinine, cystatin C, glutathione S-transferase-α, kidney injury marker-1, microalbumin, N-acetyl-β-(D) glucosaminidase, neutrophil gelatinase-associated lipocalin, osteopontin, Tamm-Horsfall urinary glycoprotein, tissue inhibitor of metalloproteinase 1, trefoil factor 3, and vascular endothelial growth factor.
  
  
  RESULTS
  Confidence intervals were determined from the single analyte and multiplex assays. Intersubject and intrasubject variability ranged from 38% to 299% and from 29% to 82% for biomarker concentration, and from 24% to 331% and from 10% to 67% for biomarker concentration normalized to creatinine, respectively. There was no major effect of food intake or sex. Single analyte and multiplex assays correlated with r (2)≥0.700 for five of six biomarkers when evaluating biomarker concentration, but for only two biomarkers when evaluating concentration normalized to creatinine.
  
  
  CONCLUSIONS
  Confidence intervals as well as intersubject and intrasubject variability were determined for novel clinical renal biomarkers/assays, which should be considered for evaluation in the next steps of the qualification process.
authors.affiliation: Translational Patient Safety and Enabling Sciences, AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brott
authors.affiliation: Translational Patient Safety and Enabling Sciences, AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Adler
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Ramin
authors.initials: R
authors.lastname: Arani
authors.affiliation: AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Lovick
authors.affiliation: Global Safety Assessment, AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Pinches
authors.affiliation: Translational Patient Safety and Enabling Sciences, AstraZeneca Pharmaceuticals, Wilmington, DE, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Furlong
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine*; D004435:Eating; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D012737:Sex Factors
chemical_list: D015415:Biomarkers
keywords: biomarkers; clinical; drug development; healthy volunteers; kidney; qualification