Evaluation of Novel Renal Biomarkers with a Cisplatin Model of Kidney Injury: Gender and Dosage Differences

Abstract

A number of novel urinary biomarkers have been identified and partially qualified for use as markers for renal injury in rats. We use two novel multiplex assays to quantify biomarker concentration in multiple urine collections made prior to and following administration of cisplatin, a common nephrotoxicant, to rats. We investigate the correlation of the magnitude of biomarker changes with the severity of histopathological observations and explore the relationship of these to both dose and sex. The novel biomarkers evaluated are urinary albumin, alpha glutathione s-transferase (α-GST), glutathione S-transferase-yb1 (GSTYb1), lipocalin-2, kidney injury molecule-1 (KIM-1), osteopontin, and renal papillary antigen 1 (RPA-1) and plasma cystatin C, alongside the traditional biomarkers of plasma urea, creatinine, and urinary n-acetyl-beta-d-glucosaminidase (NAG), total protein, and glucose. We show for all time points, and for almost all doses, that male rats consistently had either more severely graded or a higher incidence of histologically observed lesions than females; that changes in urinary glucose, total urinary protein, NAG, and the novel urinary biomarkers albumin, osteopontin, and KIM-1 are clearly temporally associated; and that changes are related to the severity of injury. We also found that receiver operating characteristic curve analysis and area under the curve are significantly higher than urea or creatinine for all new biomarkers except aGST, GSTYb1, cystatin c, and total protein in both sexes.

Morphological Study of Progressive Glomerulonephropathy in Common Marmosets (Callithrix jacchus)

“…Moreover, the relationship between the histopathological grade of glomerulonephropathy and our routine examination parameters remains unclear. We suggest that measuring sensitive biomarkers of glomerular injury such as plasma cystatin C, urinary b2-microglobulin, and kidney injury molecule-1 may facilitate the ability to judge the degree of progressive glomerulonephropathy in common marmosets (Pinches et al 2012a(Pinches et al , 2012b(Pinches et al , 2012c. …”

Evaluation of Novel Urinary Renal Biomarkers with a Cisplatin Model of Kidney Injury: Effects of Collection Period

“…Initially we calculated the fold change over predose value for each biomarker value (corrected for creatinine). This was then determined either to be ''elevated'' or ''normal'' depending upon whether the value exceeded the reference change values outlined in the first article in this series (Pinches et al 2012a) (the reference change value is the cut off value at which any greater sequential change is considered significant). We then used a method previously described by Fleiss (1981) to determine the agreement between the two collection periods.…”

“…A detailed methodology for this study was reported in the first article in this series (Pinches et al 2012a). In brief, 85 male HsdHAN Wistar rats supplied by Harlan UK were acclimatized for at least 6 days prior to dosing.…”

“…A similar protocol was followed for analysis of lipocalin-2, osteopontin, albumin, and KIM-1 1 using kidney injury panel 1 assay kit (MSD, Gaithersburg, MD, USA). Details of the methodology used to analyze urinary and plasma biomarkers and to perform creatinine correction have been described previously (Pinches et al 2012a). …”

“…A full description and images of the lesions can be found in Pinches et al (2012b). In brief, there was dose dependent tubular necrosis (principally to the S3 segment) followed by subsequent tubular regeneration and repair.…”