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Human Kidney Injury Molecule-1 Is a Tissue and Urinary Tumor Marker of Renal Cell Carcinoma

Won K. Han^*,,**, Anwar Alinani^*, Chin-Lee Wu^,, Dror Michaelson^||,**, Massimo Loda^,,, Francis J. McGovern^¶,, Ravi Thadhani^,** and Joseph V. Bonventre^*,,**

^* Renal; Pathology Divisions, Brigham and Women’s Hospital; Medical; Pathology; ^|| Oncology; ^¶ Urology Services, Massachusetts General Hospital; and Departments of; ^** Medicine,; Pathology; Urology, Harvard Medical School; and Pathology Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

Address correspondence to: Dr. Joseph V. Bonventre, Harvard Institutes of Medicine, 4 Blackfan Circle, Renal Division, Room 550, Boston, MA 02115. Phone: 617-525-5969; Fax: 617-525-5965; joseph_bonventre{at}hms.harvard.edu

Received for publication July 6, 2004. Accepted for publication January 17, 2005.

Human kidney injury molecule-1 (hKIM-1) is a type 1 transmembrane protein that is not detectable in normal kidney tissue but is expressed at high levels in human and rodent kidneys with dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury. Therefore, it was hypothesized that renal tumors express hKIM-1 and release this protein into the urine. Forty renal cell carcinoma (RCC) and 484 nonrenal tumors were analyzed by immunohistochemistry for expression of hKIM-1 (group 1). Urine samples before nephrectomy and nephrectomy tissue samples were collected from an additional 42 patients with renal tumors, from 30 normal control subjects, and also from 10 patients with prostate carcinoma (group 2). In five additional patients with RCC, urine was collected before and after nephrectomy (group 3). Tissue was examined for expression of hKIM-1, and cell-free urine supernatants were analyzed for hKIM-1 by ELISA. Urinary hKIM-1 was normalized to the urinary creatinine concentration (U_Cr). Expression of hKIM-1 was present in 32 tissue sections (91%) of 35 clear cell RCC (group 1). In group 2, the normalized urinary hKIM-1 levels were significantly higher in patients with clear cell RCC (0.39 ± 0.08 ng/mg U_Cr; n = 21), compared with levels in patients with prostate carcinoma (0.12 ± 0.03 ng/mg U_Cr; P < 0.02; n = 10), or normal control subjects (0.05 ± 0.01 ng/mg U_Cr; P < 0.005; n = 30). Tissue sections from 28 (82%) of 34 primary RCC stained positively for the expression of hKIM-1. In all patients with a detectable prenephrectomy urinary hKIM-1 level, there was either complete disappearance or marked reduction after nephrectomy (group 3). In conclusion, the cleaved ectodomain of hKIM-1 can be detected in the urine of patients with RCC and may serve as a new biomarker for early detection of RCC.

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