Evaluation of novel biomarkers of nephrotoxicity in Cynomolgus monkeys treated with gentamicin

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

“…2 shown) were observed. Interestingly, higher urinary α-1M protein was more specific than rises in BUN and/or sCr in detecting proximal tubular injury in gentamicin-treated cynomolgus monkeys (Gautier et al, 2016). Future studies may reveal the usefulness of transient changes in urinary α-1M protein concentrations when monitoring for acute, progressive and/or reversible AmpB-induced proximal tubular toxicity in cynomolgus monkeys.…”

“…This study was conducted by the Critical Path Institute's PSTC/Nephrotoxicity Working Group to systematically evaluate the cross-reactivity of commercial human-specifi c analytical assays in NHPs (Sauer et al, 2015) and test the diagnostic performance of monkey-specifi c assays (Ennulat and Adler, 2015) to support prospective preclinical and clinical exploratory studies to demonstrate the translatable context of use for nephron-specifi c toxicity biomarkers (Gautier et al, 2016). The objective of this study was to induce acute dose-related AmpB nephrotoxicity to demonstrate immunolocalization of novel corticomedullary tubule injury markers in male cynomolgus monkeys.…”

“…Earlier investigations revealed constitutive OPN immunostaining in distal convoluted tubules and distal straight tubules in corticomedullary regions in normal kidneys from healthy adult cynomolgus monkeys (Ogbureke and Fisher, 2005). In a recent report, male cynomolgus monkeys that received intramuscular administrations of gentamicin for 10 days showed minimal to mild tubular lesions and highly increased levels of kidney injury molecule 1 (KIM-1), osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) gene expression in representative macrodissected kidney cortices (Gautier et al, 2016). We sought to identify α1-microglobulin (α1-M), KIM-1, OPN and NGAL immunopositivity in nephron segments with corresponding kidney lesions in monkeys that received amphotericin B (AmpB) to enable future systematic characterization of translatable context of use for nephron-specific toxicity biomarkers.…”

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

“…Many investigations of novel urinary BMs for the early detection of the segment-specific nephrotoxicity in rats have been reported but only a few investigations were conducted in cynomolgus monkeys with agents such as GM and triple reuptake inhibitor (Guha et al, 2011;Gautier et al, 2016). The early detection of nephrotoxicity in rodent and non-rodent species, particularly nonhuman primates, is extremely useful for early strategic decision in drug development because toxicity studies generally require non-rodent and rodent species.…”

“…There is a need to investigate the availability of novel urinary BMs for the early detection of the xenobiotic-induced segmentspecific nephrotoxicity in comparison to the conventional clinical pathology parameters such as sCRN, BUN, and urinary enzymes in cynomolgus monkeys. Therefore, we selected GM, CDDP, and PAN to investigate the early detection of the segment-specific nephrotoxicity because it has been well known that GM damages the proximal tubules, CPPD damages both the proximal and distal tubules, and PAN damages the glomeruli in cynomolgus monkeys (Robertson, 1998;Working et al, 1998;Gautier et al, 2016).…”