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ToxSci Advance Access originally published online on October 13, 2007
Toxicological Sciences 2008 101(1):159-170; doi:10.1093/toxsci/kfm260
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Published by Oxford University Press 2007.

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

Yuzhao Zhou*, Vishal S. Vaidya{dagger}, Ronald P. Brown*, Jun Zhang{ddagger}, Barry A. Rosenzweig{ddagger}, Karol L. Thompson{ddagger}, Terry J. Miller{ddagger}, Joseph V. Bonventre{dagger} and Peter L. Goering*,1

* Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, Maryland 20993 {dagger} Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 {ddagger} Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993

1 To 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{at}fda.hhs.gov.

Received August 28, 2007; accepted October 5, 2007


  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; HgCl2), or chromium (Cr; K2Cr2O7). 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 N-acetyl-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.

Key Words: acute kidney injury; nephrotoxicity biomarkers; kidney injury molecule-1; mercury; chromium; gentamicin.


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