Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

Abstract

-Urinary biomarkers have been used widely in preclinical toxicity studies to detect dysfunctions and injuries of the kidney caused by drugs under development. While they have been well studied for evaluating nephrotoxicity, knowledge of sex differences in excretion levels of urinary biomarkers remains inadequate. We conducted experiments focused on effects of endogenous sex hormones on urinary biomarkers using intact and castrated male and female rats. Comparisons of the urinary biomarker excretion levels between intact male and female rats at 5, 7, 9 and 12 weeks of age revealed higher excretion levels of leucine aminopeptidase (LAP), γ-glutamyl transpeptidase (γGTP), total protein, liver-type fatty acid-binding protein (L-FABP), cystatin C (Cys-C) and β2-microglobulin (β2-MG), and lower excretion level of kidney injury molecule 1 (Kim-1), in male rats as compared to female rats. Orchidectomized male rats showed lower urinary excretion levels of alkaline phosphatase (ALP), LAP, γGTP, N-acetyl-β-D-glucosaminidase (NAG), glucose, total protein, L-FABP, Cys-C, β2-MG and neutrophil gelatinaseassociated lipocalin (NGAL), and higher urinary excretion levels of clusterin (CLU) and Kim-1, than sham-operated male rats. On the other hand, no significant differences in the urinary biomarker excretion levels excluding ALP were observed between ovariectomized and sham-operated female rats. In the present study, we demonstrated the existence of sex differences in excretion levels of urinary biomarkers that are universally used in preclinical toxicity studies, and also that these differences, especially in relation to the urinary excretions of ALP, LAP, γGTP, total protein, L-FABP, Cys-C, and β2-MG, may closely relate to the endogenous testosterone.

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

“…Its soluble form is a 90 kDa molecule (as compared to the membrane bound 104 kDa form) found in the urine of both animals and humans with renal injury. Its presence was associated with AKI in several experimental studies [34,41,42,43,44,45,46,47,48,49,50] and some authors suggest that it may be predictive of cisplatin nephrotoxicity [119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135]. Anti-KIM-1 antibodies have been developed as a potential therapy in neoplasia characterized by KIM-1 overexpression (renal, ovarian, and lung carcinomas) [167,168].…”

“…In predicting AKI, authors reported an area under the receiver operator curve (AUC) of 0.93 for KIM-1 and interleukinIL-18 [48]. Interestingly, male rats with AKI showed greater increase in KIM-1 levels as compared to females [49,50].…”

Equine urinary N-acetyl-β-D-glucosaminidase assay validation and correlation with other markers of kidney injury

“…A significant effect of sex on urine NAG index has been identified in humans and clinically normal dogs, but no clear difference in urine NAG index between males and females was demonstrated in studies of juvenile rats and healthy cats. 4,24,30,37 Potential effects of sex in the overall findings of our study were likely minimized by the similar sex composition of group N and group A.…”

Urinary Reference Values and First Insight into the Urinary Proteome of Captive Giraffes

“…The comparison between sexes revealed higher values for uTP and uCr in males, albeit not significant, than in females, as in the urine of rat [ 39 ]. Urinary creatinine is likely higher in men than in women [ 40 ] since the excretion of this metabolite is related to body mass [ 41 ]. Accordingly, giraffe males’ average weight is about 1200 kg, while the average weight observed in females is around 800 kg [ 42 ].…”