Abstract
Hexachloro-1:3-butadiene (HCBD) causes segment-specific injury to the proximal renal tubule. A time course study of traditional and more recently proposed urinary biomarkers was performed in male Hanover Wistar rats receiving a single intraperitoneal (ip) injection of 45 mg/kg HCBD. Animals were killed on days 1, 2, 3, 4, 5, 6, 7, 10, 14, and 28 postdosing and the temporal response of renal biomarkers was characterized using kidney histopathology, urinary and serum biochemistry, and gene expression. Histopathologic evidence of tubular degeneration was seen from day 1 until day 3 postdosing and correlated with increased urinary levels of α-glutathione S-transferase (α-GST), albumin, glucose, and kidney injury molecule-1 (KIM-1), and increased gene expression of KIM-1, NAD(P)H dehydrogenase, quinone 1, and heme oxygenase (decycling) 1. Histopathologic evidence of tubular regeneration was seen from day 2 postdosing and correlated with raised levels of urinary KIM-1 and osteopontin and increased gene expression of KIM-1 and annexin A7. Traditional renal biomarkers generally demonstrated low sensitivity. It is concluded that in rat proximal tubular injury, measurement of a range of renal biomarkers, in conjunction with gene expression analysis, provides an understanding of the extent of degenerative changes induced in the kidney and the process of regeneration.
Highlights
Regulatory authorities in Europe, the United States, and Japan endorsed the use of a number of novel and established renal biomarkers for the detection of nephrotoxic injury to either the renal tubules or the glomeruli in preclinical safety studies (Dieterle et al 2010; Harpur et al 2011; Ozer et al 2010; Yu et al 2010)
As in previous work (Swain et al 2011), urinary output of a-glutathione S-transferase (a-glutathione S-transferases (GSTs)) was markedly elevated in HCBD-treated animals when compared to matched control animals on day 1, and the levels remained significantly increased until day 4 (Table 2)
In Pinches et al (2012a), it was demonstrated that increases in a-GST may be influenced by the sex of the animals; it was reported that increases in a-GST were limited to male rats, rather than female animals, and it was concluded that a-GST did not perform any better than serum urea or creatinine using receiver–operating characteristic curve analysis (ROC analysis)
Summary
Regulatory authorities in Europe, the United States, and Japan endorsed the use of a number of novel and established renal biomarkers (urinary kidney injury molecule1 [KIM-1], clusterin, albumin, b2-microglobulin, renal papillary antigen, total protein, trefoil factor 3, and serum cystatinC) for the detection of nephrotoxic injury to either the renal tubules or the glomeruli in preclinical safety studies (Dieterle et al 2010; Harpur et al 2011; Ozer et al 2010; Yu et al 2010). In the appraisal of the more recently proposed urinary biomarkers of renal injury, the use of experimental nephrotoxicants to induce site-specific and organ-specific injury allows investigators to assess doseand time-related changes in the more recent biomarkers and compare performance with those biomarkers that have been used traditionally (e.g., urine albumin, total protein, glucose, serum urea, creatinine). By correlating such changes with histopathologic findings, renal-specific biomarkers can be assessed in relation to the criteria mentioned above
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