Evaluation of novel acute urinary rat kidney toxicity biomarker for subacute toxicity studies in preclinical trials.

Novel urinary protein biomarkers for the detection of acute renal damage, recently accepted by the U.S. Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency (Japan), now have to be validated in practice. Limited data regarding the performance of these acute markers after subacute or subchronic treatment are publicly available. To increase the area of applicability of these markers, it is important to evaluate the ability to detect them after 28 days of treatment or even longer. Wistar rats were treated with three doses of cisplatin, vancomycin, or puromycin to induce renal damage. Twelve candidate proteins were measured by Luminex xMAP-based WideScreen assays, MesoScale Discovery-based MULTI-SPOT technology, or RENA-strip dipstick assay after 28 days. Treatment with all three model compounds resulted in a dose-dependent increase in urinary biomarkers, specific for the observed areas within the nephron, determined histopathologically. The most promising biomarkers in this study were NGAL, Kim-1, osteopontin, clusterin, RPA-1, and GSTYb1, detected by multiplexing technologies. The RENA-strip dipstick assay delivered good diagnostic results for vancomycin-treated but not for cisplatin- or puromycin-treated rats. Taken together, the data show that these new biomarkers are robust and measurable for longer term studies to predict different types of kidney toxicities.

Preclinical perspective of urinary biomarkers for the detection of nephrotoxicity: what we know and what we need to know.

The assessment of kidney damage is a challenge and must incorporate assessment of the functional capacity of the kidney, as well as a comprehensive understanding of the kidney's role. Multiple parameters have been used for many years to measure renal functionality to assess renal damage. It is astonishing that, beside histopathology, the most common traditional parameters are serum based. However, urine is also used to obtain additional information regarding the health status of the kidneys. Since 2008, several novel urinary protein biomarkers have been qualified by the US FDA and the European Medicines Agency in conjunction with the Predictive Safety Testing Consortium in a specially developed qualification process. Subsequently, the Pharmaceuticals and Medical Devices Agency accepted the qualification of these seven urinary biomarkers. This review will give an overview of the state-of-the-art detection based on urinary biomarkers, which will enhance toxicological research in the future. In addition, the qualification process that leads to acceptance of these biomarkers will be described because of its uniqueness and importance for the field of biomarker research.