Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium

Abstract

Sensitive biomarkers are needed to detect kidney injury at the earliest stages. The objective of this study was to determine whether the appearance of kidney injury molecule-1 (Kim-1) protein ectodomain in urine and kidney injury molecule-1/hepatitis A viral cellular receptor-1 (Kim-1/ Havcr1) gene expression in kidney tissue may be more predictive of renal injury after exposure to nephrotoxicants when compared to traditionally used biomarkers. Male Sprague-Dawley rats were injected with a range of doses of gentamicin, mercury (Hg; HgCl 2 ), or chromium (Cr; K 2 Cr 2 O 7 ). The results showed that increases in urinary Kim-1 and kidney Kim-1/Havcr1 gene expression paralleled the degree of severity of renal histopathology and were detected at lower doses of nephrotoxicants when compared to blood urea nitrogen (BUN), serum creatinine, and urinary Nacetyl-β-D-glucosaminidase (NAG). In a time course study, urinary Kim-1 was elevated within 24 h after exposure to gentamicin (100 mg/kg), Hg (0.25 mg/kg), or Cr (5 mg/kg) and remained elevated through 72 h. NAG responses were nephrotoxicant dependent with elevations occurring early (gentamicin), late (Cr), or no change (Hg). At 72 h, after treatment with any of the three nephrotoxicants, there was increased Kim-1 immunoreactivity and necrosis involving ∼50% of the proximal tubules; however, only urinary Kim-1 was significantly increased, while BUN, serum creatinine, and NAG were not different from controls. In rats treated with the hepatotoxicant galactosamine (1.1 mg/kg), serum alanine aminotransferase was increased, but no increase in urinary Kim-1 was observed. Urinary Kim-1 and kidney Kim-1/Havcr1 expression appear to be sensitive and tissue-specific biomarkers that will improve detection of early acute kidney injury following exposure to nephrotoxic chemicals and drugs. Keywordsacute kidney injury; nephrotoxicity biomarkers; kidney injury molecule-1; mercury; chromium; gentamicin 1To whom correspondence should be addressed at Center for Devices and Radiological Health, U.S. Food and Drug Administration, White Oak Life Sciences Laboratory, WO64-4064, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002. Fax: 301-796-9826. E-mail: peter.goering@fda.hhs.gov.. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptRenal insufficiency, in some form, has been reported to occur in ∼11% of the U.S. population (Nally, 2002). Acute kidney injury (AKI) or acute renal failure (ARF) occurs in 2-5% of patients admitted to general hospitals in the United States, and AKI is associated with a high rate (up to 50%) of mortality (Chertow et al., 2005;Nally, 2002). The annual health care expenditures attributable to hospital-acquired AKI based on conservative assumptions are estimated to exceed $10 billion (Chertow et al., 2005). Patients with subclinical renal injury may be more sensitive to AKI following exposure to potentially nephrotoxic drugs and/or compounds released unintentionally from medical device materials (e.g., residues, le...

Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

“…The most prominent gene with an up-regulation of 38-fold after gentamicin administration was the Kim-1 (Kidney injury molecule-1, also known as HAVCR1) gene. This type I cell membrane glycoprotein serves as an earlier urinary diagnostic marker for proximal tubule injury (Zhou et al, 2008;Han et al, 2002, Vaidya et al, 2006.In addition SPP1 (Osteopontin), ATF3…”

Proximal tubular dysfunction as an indicator of chronic graft dysfunction

“…Moreover, Kim-1 co-localized with signs of inflammation and renal fibrosis. The potential of Kim-1 as a biomarker of proximal tubular injury was illustrated in several other models and in human studies of drug toxicity (43,44), heavy metal nephropathy (43,45), protein-overload nephropathy (46), and polycystic kidney disease (47).…”

Rapid colorimetric detection of Hg2+ ion by green silver nanoparticles synthesized using Dahlia pinnata leaf extract

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