Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers

Abstract

BackgroundSeveral 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.MethodsSpot 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.ResultsConfidence 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 r2≥0.700 for five of six biomarkers when evaluating biomarker concentration, but for only two biomarkers when evaluating concentration normalized to creatinine.ConclusionConfidence 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.

Cisplatin nephrotoxicity in male beagle dogs: next-generation protein kidney safety biomarker tissue expression and related changes in urine

“…Endogenous OPN protein in kidneys is responsible for binding to calcium salts to prevent the formation of calcium oxalate crystals. 38 Yet, the value of Ur OPN and spatial localization when monitoring for CDDP nephrotoxicity in dogs has not been previously defined. 34 Ur OPN protein was recently recognized as a candidate DIKI biomarker in non-clinical studies in rats treated with CDDP; 35 rats 36 nonhuman primates 37 and dogs 8 treated with gentamicin; and other paradigm and/or proprietary compounds that induce DIKI 2,7 and early clinical drug development studies.…”

Interactions between osteopontin and vascular endothelial growth factor: Implications for skeletal disorders

“…VEGF and OPN are up-regulated in acute kidney injury [86]. In nephrogenic systemic fibrosis (induced by gadodiamide), OPN and VEGF are persistently elevated.…”

Immunolocalization of novel corticomedullary tubule injury markers in Cynomolgus monkeys treated with amphotericin B

“…Ultimately, the aim of these collaborative studies is to obtain regulatory qualification of translational DIKI biomarkers as innovative drug safety testing tools (Matheis et al, 2011;Brott et al, 2014). Interestingly, the spatial localization of DIKI biomarkers in monkey kidney tissues has been infrequently assessed (Bauchet et al, 2011;Guha et al, 2011).…”