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1 Medical Services, Massachusetts General Hospital and Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
2 Medical Services, Massachusetts General Hospital and Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Lilly Research Laboratories, Greenfield, IN, USA
3 Medical Services, Massachusetts General Hospital and Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: tichimura{at}partners.org.
Nephrotoxicity is a common side effect of therapeutic interventions, environmental insults and exposure to toxicants in the workplace. Although biomarkers for nephrotoxicity are available, they often lack sensitivity and are not specific as indicators of epithelial cell injury. Kidney Injury Molecule-1 (Kim-1) is a type-1 membrane protein with extracellular immunoglobulin and mucin domains. The mRNA and protein for Kim-1 are expressed at very low levels in normal rodent kidney, but expression increases dramatically after injury in proximal tubule epithelial cells in postischemic rodent kidney and in humans during ischemic acute renal failure. To evaluate the utility of Kim-1 as a biomarker for other types of renal injury, we analyzed tissue and urinary expression in response to three different types of nephrotoxicants in the rat: S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), folic acid and cisplatin. Marked increases of Kim-1 expression were confirmed by immunoblotting in all three models. The protein was shown to be localized to the proximal tubule epithelial cell by immunofluorescence. Furthermore, Kim-1 protein was detected in urine of toxicant-treated rats. The temporal pattern of expression in response to TFEC is similar to the Kim-1 expression pattern in the postischemic kidney. In folic acid-treated kidneys, Kim-1 is clearly localized to the apical brush border of the well-differentiated proximal tubular epithelial cells. After folic acid treatment, expression of Kim-1 is present in the urine despite no significant increase in serum creatinine. Cisplatin treatment results in early detection of urinary Kim-1 protein, and a delayed and diffuse Kim-1 expression in S3 cells of the proximal tubule. Kim-1 can be detected in the tissue and urine on days 1 and 2 after cisplatin administration, occurring prior to an increase in serum creatinine. The upregulation of expression of Kim-1 and its presence in the urine in response to exposure to various types of nephrotoxicants suggests that this protein may serve as a general biomarker for tubular injury and repair processes.
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