A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function

Abstract

The Predictive Safety Testing Consortium's first regulatory submission to qualify kidney safety biomarkers revealed two deficiencies. To address the need for biomarkers that monitor recovery from agent-induced renal damage, we scored changes in the levels of urinary biomarkers in rats during recovery from renal injury induced by exposure to carbapenem A or gentamicin. All biomarkers responded to histologic tubular toxicities to varied degrees and with different kinetics. After a recovery period, all biomarkers returned to levels approaching those observed in uninjured animals. We next addressed the need for a serum biomarker that reflects general kidney function regardless of the exact site of renal injury. Our assay for serum cystatin C is more sensitive and specific than serum creatinine (SCr) or blood urea nitrogen (BUN) in monitoring generalized renal function after exposure of rats to eight nephrotoxicants and two hepatotoxicants. This sensitive serum biomarker will enable testing of renal function in animal studies that do not involve urine collection.

Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

“…An investigation of leading pharmaceutical companies, together with the nonprofit Critical Path Institute (C-Path), led to the discovery and subsequent evaluation of 23 urinary proteins and a large number of transcriptional biomarkers in the rat (Dieterle et al 2010;Ozer et al 2010). Only eight of these markers have been accepted for the detection of AKI in preclinical studies up to 14 days.…”

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“…Notably, there was no correlation between activity of each enzyme in the serum and in the urine. Since, according to literature data [21], the main source of above enzymes in the urine is the epithelium of the proximal channels of the nephron, we consider that enzymuria analysis can provide information about its injury level. Increase of the urine ALP and GGT activities may evidence about damage of brush border of the epithelium [7,29] where these enzymes are predominantly localized and thus accompany all stages of injury of the epithelial cell.…”

“…It has been found that serum and urine interleukin (ІL-2, ІL-8 and ІL-10) concentrations are indicative of the functional activity of various types of immune-competent cells, severity of inflammatory process at RAT and can have diagnostic and prognostic value [1,9,23]. At the same time opinions differ as to where one should better estimate interleukin concentrations at RAD: in the patient's peripheral blood or in the urine [9,21].…”

“…Neither has been sufficiently studied the diagnostic value of combinations of various biochemical parameters [12,16]. The published results of investigations are rather contradictory [21,32]. Many methods used (for instance, moleculargenetic) are expensive [14,17] for routine clinical diagnosis.…”

Testes sanguíneos de biomarcadores para diagnóstico e tratamento de desordens mentais: foco em esquizofrenia

“…The PSTC was founded by the FDA to act as a liaison between the FDA, pharmaceutical companies and academia in biomarker qualification for preclinical and clinical use. The nephrotoxicity subgroup of the PSTC identified seven kidney safety biomarkers for limited use in preclinical and clinical drug development 60,63 . A Rat KidneyMAP TM has now been developed as a multiplexed immunoassay by Rules Based Medicine in collaboration with the PSTC for early detection of renal damage, which is common in drug development programs (http://www.…”