Although HIV-infected individuals are achieving greater life-expectancy, the population is experiencing a growing burden of chronic kidney disease (CKD). CKD develops at much younger ages in HIV-infected than uninfected persons, and is associated with substantially higher risks for cardiovascular disease, heart failure, and mortality. These already elevated risks of kidney disease and its complications are amplified by the widespread use of tenofovir disoproxil fumarate (TDF), which is currently used by approximately two-thirds of HIV-infected persons in the US, and is independently associated with a doubling in risk for CKD compared with alternative regimens. Both in the United States and worldwide, TDF-containing therapies are first-line for long- term therapy of HIV. Despite the importance of CKD as a complication of HIV and the kidney risks of TDF, current practices for kidney disease screening and diagnosis remain essentially unchanged since the beginning of the HIV epidemic. As a consequence we lack effective strategies to detect early kidney damage from TDF, to distinguish kidney damage caused by TDF from other CKD risk factors, or to quantify risk accurately for the onset and progression of CKD. During our initial funding period, our research team demonstrated the remarkable potential of several urine biomarkers of kidney injury to detect and quantify subclinical kidney damage, to characterize the influence of specific risk factors, and to forecast subsequent declines in kidney function. This novel approach could dramatically transform the process of screening, diagnosing and treating kidney disease in HIV-infected persons. In this renewal R01 application, we have the practice-changing objectives of developing and validating two distinct multiplex urine biomarker panels: the Tenofovir Injury Panel and the CKD Risk Panel. We will evaluate 15 candidate urine biomarkers that quantify damage and dysfunction within distinct compartments of the kidney, and we will select the optimal combinations to maximize: 1) detection of kidney abnormalities at their earliest stages; 2) discernment of TDF specific damage; and 3) prognosis of kidney disease risk. To accomplish both development and validation stages for our biomarker combinations, we will conduct our research across five multi-center studies that have available biological specimens and that have welcomed our collaboration on this proposal: the Preexposure Prophylaxis Initiative trial (iPrEx), the Women's Interagency HIV Study (WIHS), the Multicenter AIDS Cohort Study (MACS), the Biopsy Examination of AIDS Nephropathy (BEANS), and the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN). Our multi-disciplinary team of expert investigators will ensure the success of this project. At its conclusion we will design a randomized clinical trial to determine whether our advanced methods to detect, diagnose and stage kidney disease can improve the safety of HIV therapy without sacrificing its clinical effectiveness.

Public Health Relevance

Although kidney disease is growing as a major health problem for the HIV-infected population, clinicians cannot detect it early or diagnose its etiology with currently available diagnostic tests. This proposal will develop novel strategies for diagnosing early kidney disease by building multiplex panels that combine several novel urine biomarkers. These diagnostic panels will be developed to quantify medication adverse effects on the kidney and to predict risks of progressive kidney disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Eldadah, Basil A
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Northern California Institute Research & Education
San Francisco
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Jotwani, Vasantha; Scherzer, Rebecca; Glidden, David V et al. (2018) Pre-exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Kidney Tubular Dysfunction in HIV-Uninfected Individuals. J Acquir Immune Defic Syndr 78:169-174
Ascher, Simon B; Scherzer, Rebecca; Estrella, Michelle M et al. (2018) Association of Urinary Biomarkers of Kidney Injury with Estimated GFR Decline in HIV-Infected Individuals following Tenofovir Disoproxil Fumarate Initiation. Clin J Am Soc Nephrol 13:1321-1329
Baxi, Sanjiv M; Scherzer, Rebecca; Jotwani, Vasantha et al. (2017) Changes in Urinary Biomarkers Over 10 Years Is Associated With Viral Suppression in a Prospective Cohort of Women Living With HIV. J Acquir Immune Defic Syndr 74:e138-e145
Park, Meyeon; Maristany, Daniela; Huang, Debbie et al. (2017) Associations of tumor necrosis factor alpha receptor type 1 with kidney function decline, cardiovascular events, and mortality risk in persons with coronary artery disease: Data from the Heart and Soul Study. Atherosclerosis 263:68-73
Ascher, Simon B; Scherzer, Rebecca; Peralta, Carmen A et al. (2017) Association of Kidney Function and Early Kidney Injury With Incident Hypertension in HIV-Infected Women. Hypertension 69:304-313
Chau, Katherine Hsin-Yu; Scherzer, Rebecca; Grunfeld, Carl et al. (2017) CHA2DS2-VASc Score, Warfarin Use, and Risk for Thromboembolic Events Among HIV-Infected Persons With Atrial Fibrillation. J Acquir Immune Defic Syndr 76:90-97
Jotwani, Vasantha; Scherzer, Rebecca; Estrella, Michelle M et al. (2017) Association of HIV infection with biomarkers of kidney injury and fibrosis in the Multicenter AIDS Cohort Study. Antivir Ther 22:421-429
Kim, Julie E; Scherzer, Rebecca; Estrella, Michelle M et al. (2016) Tenofovir exposure alters associations of serum bicarbonate with chronic kidney disease risk in HIV-infected veterans. AIDS 30:1049-57
Jotwani, Vasantha; Scherzer, Rebecca; Estrella, Michelle M et al. (2016) HIV Infection, Tenofovir, and Urine ?1-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study. Am J Kidney Dis 68:571-581
Scherzer, Rebecca; Lin, Haiqun; Abraham, Alison et al. (2016) Use of urine biomarker-derived clusters to predict the risk of chronic kidney disease and all-cause mortality in HIV-infected women. Nephrol Dial Transplant 31:1478-85

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