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Iron-Related Proteins: Candidate Urine Biomarkers in Childhood HIV–Associated Renal Diseases

Ángel A. Soler-García^*,,, Douglas Johnson, Yetrib Hathout^,, and Patricio E. Ray^*,,

^* Division of Nephrology, Center for Cancer and Immunology Research, Center for Genetic Medicine, Children's National Medical Center, and Department of Pediatrics, The George Washington University, Washington, DC

Correspondence: Dr. Patricio E. Ray, Children's National Medical Center, Children's Research Institute, Center for Cancer and Immunology Research, Division of Nephrology, R-5111, 111 Michigan Avenue, NW, Washington, DC 20010. Phone: (202) 476-2912; Fax: (202) 476-4477; E-mail: pray{at}cnmc.org

Background: Because of the risk of performing renal biopsies in children with co-morbid conditions, we carried out this study to identify candidate protein biomarkers in the urine of HIV-infected children with renal disease.

Design, setting, participants & measurements: Urine samples from HIV-infected children with biopsy proven HIV-nephropathy (HIVAN; n = 4), HIV-associated Hemolytic Uremic Syndrome (HIV-HUS; n = 2), or no renal disease (n = 3) were analyzed by two-dimensional electrophoresis (2-DE) and proteomic methods. Positive findings were confirmed in HIV-infected children with (n = 20) and without (n = 10) proteinuria using commercially available assays.

Results: By 2-DE analysis, a single urine marker was not sufficient to distinguish children with HIVAN from the others. High urine levels of β₂-microglobulin and retinol-binding protein (RBP) suggested the presence of tubular injury. In addition, we found elevated urine levels of iron and the iron-related proteins, transferrin, hemopexin, haptoglobin, lactoferrin, and neutrophil gelatinase-associated lipocalin (NGAL), in children with HIVAN and HIV-HUS. Furthermore, we detected a significant accumulation of iron in the urine and kidneys of HIV-transgenic (Tg) rats with renal disease.

Conclusion: These findings suggest that iron and iron-related proteins might be promising candidate urine biomarkers to identify HIV-infected children at risk of developing HIVAN and HIV-HUS. Moreover, based on the results of previous studies, we speculate that the release or accumulation of iron in the kidney of HIV-infected children may contribute to the rapid progression of their renal disease, and could become a new therapeutic target against HIVAN and HIV-HUS.