Tissue Expression and Correlation of a Panel of Urinary Biomarkers Following Cisplatin-induced Kidney Injury

Abstract

In recent years, there has been considerable activity to identify urinary biomarkers of nephrotoxicity as noninvasive measurements with greater sensitivity and specificity than traditional biomarkers, such as serum creatinine and blood urea nitrogen. Our study aimed to use cisplatin-treated rats to evaluate the use of immunohistochemistry directed at multiple urinary biomarkers in kidney tissue. Tissue levels were compared to urinary levels of these biomarkers to demonstrate tissue specificity and sensitivity. These techniques could also be used in studies where urine samples are not available, such as retrospective studies in drug safety testing, to demonstrate the potential utility of using these biomarkers in future preclinical or clinical studies. All of the biomarkers investigated showed either an increase (kidney injury molecule [KIM-1], osteopontin [OPN], and, clusterin) or a decrease (alpha-glutathione S-transferase and trefoil factor 3) except beta 2 microglobulin (b2MG) that showed no significant changes 5 days after 1.0 mg/kg or 2.5 mg/kg cisplatin treatment. All of the biomarkers except b2MG showed utility as tissue biomarkers, but KIM-1 and OPN expression correlated closely with urinary biomarker measurements and reflect tissue damage. Future studies are needed to determine the wider application of these two markers for detecting renal toxicity following administration of other nephrotoxicants.

Participation of bone morphogenetic protein (BMP)-6 and osteopontin in cisplatin (CDDP)-induced rat renal fibrosis

“…OPN immune-reactivity may be seen in renal tubules, particularly in the loop of Henley, in normal rats (Wadey et al, 2014); however, the reactivity of OPN was faint and limited in the present control rats. In CDDP-injected rats, OPN immune-expression began to be seen in injured renal tubules, and its expression was gradually increased in renal epithelial cells of the dilated or atrophied tubules; some of them showed dual labeling to OPN and Ki-67, suggesting regenerating epithelial cells (Regner et al, 2011).…”

“…OPN is used as a biomarker for renal injury; its expression is related to the extent of renal damage (Kashiwagi et al, 2014;Wadey et al, 2014). OPN immune-reactivity may be seen in renal tubules, particularly in the loop of Henley, in normal rats (Wadey et al, 2014); however, the reactivity of OPN was faint and limited in the present control rats.…”

Sequencing of LRP2 Reveals Multiple Rare Variants Associated with Urinary Trefoil Factor-3

“…15 However, it was subsequently discovered that TFF3 is expressed in all mucussecreting tissues, including the renal tubules. 16 Although the exact role of TFF3 in the kidney is uncertain, changes in urinary TFF3 levels have been associated with AKI in animal models 16,17 and incident CKD in a population-based study. 18 Thus, TFF3 has been explored as a potential biomarker of acute kidney disease and CKD.…”

Drug safety testing paradigm, current progress and future challenges: an overview

“…Various groups are further validating the usefulness of these biomarkers in preclinical studies Ozer et al, 2010;Tonomura et al, 2010Tonomura et al, , 2012. There is also a significant ongoing effort to characterize and qualify a panel of safety biomarkers by various groups, and their clinical bringing validation is also underway John-Baptiste et al, 2012;Wadey et al, 2012;Xie et al, 2013). Measurement of a panel of safety biomarkers in parallel would help maximally capture all potential safety signals for a more informative decision to be made in drug research and development as well as for optimal selection of the drug and its dose in clinical practice.…”