Cell- and biomarker-based assays for predicting nephrotoxicity.
BACKGROUND
Drug-induced nephrotoxicity contributes to the failure rate of investigational drugs during clinical trials. We are still not able to accurately predict drug-induced nephrotoxicity during early drug discovery and development. There is an urgent need for a robust screening system that can identify nephrotoxic compounds before they reach the clinic.


METHODS
This review discusses traditional and emerging kidney injury biomarkers that are used for the determination of nephrotoxicity and for evaluation and diagnosis of other kidney diseases. The potential for in vivo biomarkers to predict renal toxicity in high-throughput in vitro screening assays is discussed. We also compare cell types and highlight novel three-dimensional (3D) culture technologies with potential for in vitro prediction of nephrotoxicity.


CONCLUSIONS
Traditional cell culture methods and cytotoxicity assays are well established as in vitro tests for nephrotoxicity but the correlation with in vivo results is extremely poor. Recently validated renal biomarkers show promise for early in vivo detection of nephrotoxicity, but have yet to be successfully applied for in vitro prediction of drug-induced nephrotoxicity. Advanced culture technologies 'kidney-on-a-chip' and 3D culture can produce biomarker signatures from relevant kidney cell types that show promise as better predictive systems.
The University of Queensland, Institute for Molecular Bioscience , St. Lucia, Brisbane, QLD 4072 , Australia.
Johnny X
JX
Huang
Mark A
MA
Blaskovich
Matthew A
MA
Cooper
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001681:Biological Assay; D015415:Biomarkers / Q000378:metabolism; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D057166:High-Throughput Screening Assays; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015203:Reproducibility of Results; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*
D015415:Biomarkers
adverse drug reaction; biomarker; cell-based assay; drug discovery; kidney; nephrotoxicity; renal failure; screening; three-dimensional culture