Evaluation of the Relative Performance of 12 Urinary Biomarkers for Renal Safety Across 22 Rat Sensitivity and Specificity Studies

Abstract

Novel urinary kidney safety biomarkers have been identified recently that may outperform or add value to the conventional renal function biomarkers, blood urea nitrogen (BUN) and serum creatinine (SCr). To assess the relative performance of the growing list of novel biomarkers, a comprehensive evaluation was conducted for 12 urinary biomarkers in 22 rat studies including 12 kidney toxicants and 10 compounds with toxicities observed in organs other than kidney. The kidney toxicity studies included kidney tubular toxicants and glomerular toxicants. The 12 urinary biomarkers evaluated included Kim-1, clusterin, osteopontin, osteoactivin, albumin, lipocalin-2, GST-α, β2-microglobulin, cystatin C, retinol binding protein 4, total protein, and N-acetyl-β-D-glucosaminidase. Receiver operator characteristic (ROC) curves were generated for each biomarker and for BUN and SCr to compare the relative performance of the 12 biomarkers in individual animals against the microscopic histomorphologic changes observed in the kidney. Among the kidney toxicity biomarkers analyzed, Kim-1, clusterin, and albumin showed the highest overall performance for detecting drug-induced renal tubular injury in the rat in a sensitive and specific manner, whereas albumin showed the highest performance in detecting drug-induced glomerular injury. Although most of the evaluated kidney biomarkers were more sensitive in detecting kidney toxicity compared with BUN and SCr, all biomarkers demonstrated some lack of specificity, most notably NGAL and osteopontin, illustrating the need for caution when interpreting urinary biomarker increases in rat samples when organ toxicity is unknown.

Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases

“…Furthermore, plasma β 2 M changes paralleled changes in urinary β 2 M, but correlations between the biomarker values varied according to the nephrotoxin. Nevertheless, a more extensive evaluation of 12 markers for sensitivity (renal toxicity) and specificity (non-renal organ toxicity) in 22 rat studies, reveal that β 2 M (and cystatin C) had relatively poor area under the curve (AUC) for both tubular (AUC = 0.72) and glomerular (AUC = 0.85) toxicities (162). In the same study, urinary albumin had one of the best performance for both tubular (AUC = 0.90 vs. AUC = 0.96 of the best performing KIM-1) and glomerular (AUC = 0.99, best performing) toxicity.…”

“…Such studies are urgently needed, because the urinary β 2 M appears to have a much larger utility than previously recognized. Animal toxicology experiments conducted under rigorously controlled conditions (160, 162) and provocative observations in glomerular diseases (163, 164) suggest that urinary β 2 M may in fact be a better marker of glomerular than tubular damage. This finding, backed by controlled experiments in hundreds of animals and observations in a much smaller number of humans, seems to go against textbook dogma.…”

Acute biomarker panel changes associated with amphotericin B nephrotoxicity in female Sprague-Dawley rats

“…To date, most investigations of DIKI biomarkers in rat preclinical studies (Xie et al, 2013) were in male rats (Xie et al, 2001;Gautier et al, 2010;Hoffmann et al, 2010;Betton et al, 2012;Vlasakova et al, 2014;Vinken et al, 2012). Common characteristics of AmpB nephrotoxicity in animal models and humans has been reviewed elsewhere (Fanos and Cataldi, 2000;Bagnis and Deray, 2002).…”

“…Pharmaceutical companies have continued to integrate DIKI biomarkers in rat toxicology studies (Hoffmann et al, 2010;Burt et al, 2014;Phillips et al, 2016). Yet, relative performances of the qualified DIKI biomarkers have been evaluated mostly in male SD rats and male Han-Wistar rats (Vlasakova et al, 2014). Given the well-recognized sex differences in drug disposition and nephrotoxicity outcomes, investigations are needed to further demonstrate context of use for the next-generation DIKI biomarkers specifically in female rats as indicators that may outperform or add value to traditional kidney safety function biomarkers (Ennulat and Adler, 2015).…”

Usefulness of urinary biomarkers for nephrotoxicity in cynomolgus monkeys treated with gentamicin, cisplatin, and puromycin aminonucleoside

“…Furthermore, EMA and FDA qualified an additional 2 novel urinary BMs: NGAL (lipocalin-2) and osteopontin (OPN) which showed elevations by proximal tubular degeneration/necrosis in rats (EMA, 2014;FDA, 2014). The urinary increases in TP, ALB, B2M, and CysC are derived from the damage of glomerulus and proximal tubule, while CLU and NGAL are from that of the proximal and distal tubules in humans Vlasakova et al, 2014).…”