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

Abstract

-The objective of this study was to investigate the availability of novel urinary biomarkers (BMs) such as total protein, albumin, β 2 -microglobulin, clusterin, cystatin C, neutrophil gelatinaseassociated lipocalin (NGAL) for the detection of acute nephrotoxicity in cynomolgus monkeys. Animals (total 9 males/3 groups) were administered gentamicin (GM) subcutaneously at 40 mg/kg for 7 days, cisplatin (CDDP) intravenously at 3 mg/kg once and puromycin aminonucleoside (PAN) intravenously at 20 mg/kg for 7 days. Two-hr urine on Days 0, 3, and 6, and 16-hr urine and blood on Days 1, 4, and 7 were collected. Novel urinary BMs and conventional clinical pathology parameters were evaluated in parallel to histopathological and electron microscopic examinations on the kidneys at termination. Urinary BMs and enzymes increased earlier than serum creatinine and blood urea nitrogen, particularly in 2-hr urine after dosing on Day 0, urinary albumin was increased in all groups and urinary NGAL with the highest magnitude of change rate among urinary BMs was observed in the GM and CDDP groups. Degeneration/necrosis and hyaline droplet of renal tubule, cellular cast and dilatation of renal tubule, and hypertrophy of podocytes were observed in the GEN, CDDP, and PAN groups, respectively. These results showed that the increases of urinary BMs reflected the agent-specific renal damages and these urinary BMs could be useful for the detection of segment-specific nephrotoxicity. Urinary albumin and NGAL are the most useful BMs to estimate glomerular and distal tubular damages, respectively, as well as proximal tubular damage in cynomolgus monkeys.

Evaluation of 10 Urinary Biomarkers for Renal Safety With 5 Nephrotoxicants in Nonhuman Primates

“…8 Neutrophil gelatinase-associated lipocalin was found to be increased as early as 2 hours after gentamicin treatment. 9 Everninomicin/gentamicin elicited the largest fold changes in urinary biomarkers relative to all of the other toxicants, notably, cystatin C, a poor performer in other studies, increased over 100-fold which may be explained by its competition for megalin, a transporter that is used for gentamicin uptake as well. 29,30 The inclusion of a recovery phase in the study design allowed for monitoring biomarker changes during the treatment-free period.…”

“…22 Biomarkers of kidney toxicity in cynomolgus monkeys treated with cisplatin were studied previously. 9,23 Uchino et al 9 reports no degenerative tubular changes at SD 7 following a single dose of 3 mg/kg IV. Due to the very mild nature of the tubular injury, the response of urinary biomarkers in the study by Uchino et al is not very strong, however of interest are very acute biomarker increases most notably for NGAL (at 2 hours at SD 1) and clusterin (at 16 hours at SD 1).…”

“…7 Recent efforts have demonstrated the added value of novel kidney biomarkers in monitoring kidney injury, relative to the traditional blood biomarkers such as blood urea nitrogen (BUN) and serum creatinine (SCr). [8][9][10][11][12][13][14] Here, we provide a detailed characterization of drug-induced histomorphologic changes in the NHP kidney and conventional clinical chemistry alterations in blood following dosing with nephrotoxic pharmaceuticals and provide further insight to the corresponding performance of 10 urinary biomarkers. The urinary biomarkers selected included albumin, clusterin, cystatin C, KIM-1, livertype fatty acid-binding protein (L-FABP), N-acetyl-b-Dglucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), retinol binding protein 4 (RBP4), and total protein.…”

Predicting the Need for a Tier II Ototoxicity Study From Early Renal Function Data

“…35 Serum creatine and blood urea nitrogen have been used as biomarkers for the detection of drug-induced acute kidney injury (AKI); however, these are insensitive or nonspecific to diagnose AKI because both parameters are easily influenced by many other physiological functions, for example, gastrointestinal bleeding, without negative impact on the kidneys. [36][37][38][39] Traditionally, AKI has been indicated by a diminished urine output coincident with an elevated serum creatinine concentration. For example, Waring and Moonie 40 proposed a diagnostic threshold of an elevated serum creatinine concentration of !150 mmol/L (1.69 mg/dL) or !50% increase from baseline for a diagnosis of AKI, but the rate of increase in serum concentrations after AKI is quite variable, and the thresholds may not be detected until 2 or more days from chemical insult.…”

“…Expected urine output from rats over a standard collection period of 16 to 24 hours lends suspect to the accuracy and predictability of any set of parameters predictive of drug-induced kidney injury. However, according to Uchino et al, 36 these 7 biomarkers are considered “acceptable” in the context of nonclinical drug development programs for the detection of drug-induced acute toxicity in renal tubule and glomeruli in rats. The EMA and FDA have accepted KIM-1, ALB, CLU, and TFF3 changes as potential markers for drug-induced acute renal tubular alterations, while TP, B2M, and Cys C changes may suggest acute glomerular alterations/damage and/or impairment of kidney tubular or impairment of renal tubular absorption in rats (EMA 57 –60 ; FDA 61,62 ).…”