HIV-infected persons are at greater risk of accelerated aging complications, including premature kidney, heart, and bone diseases. In the presence of HIV infection, the effect of aging on the kidney appears to be accelerated by 1-2 decades. HIV-infected persons have a 10-fold prevalence of impaired kidney function and risk of end-stage renal disease (ESRD) compared with matched controls. In addition, kidney disease adversely affects bone health and is associated with fracture risk. These effects may be compounded by the nephrotoxic effects of tenofovir, a first-line treatment of HIV infection, which has been associated with decreased bone mineral density;tenofovir's bone toxicity is likely due to kidney tubular injury and resulting impairments in bone mineral homeostasis. It is widely agreed that the key strategy to prevent the complications of kidney disease is early diagnosis and provision of care. However, a major challenge in clinical practice is the current reliance on serum creatinine and albuminuria testing to detect kidney injury and disease. Kidney function estimates based on creatinine are unreliable until the glomerular filtration rate (GFR) has been substantially reduced;by this time, kidney disease is established and the primary prevention window has closed. Albuminuria captures only a small fraction of the kidney injury in HIV-infected persons and is therefore insufficient as a screening tool for kidney disease. This proposal envisions a new paradigm for early diagnosis of kidney disease in persons with HIV-infection. The strategy will be to use targeted serum and urine biomarkers to detect kidney injury at its earliest stages at multiple sites within the kidney, and to determine whether early kidney injury adversely effects bone mineral metabolism in ways that lead to accelerated osteoporosis. To address these key issues related to kidney disease in the aging HIV-infected population, we will add novel biomarkers of injury to the microvasculature, tubules, and interstitium of the kidney and of bone mineral metabolism to the ongoing Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). Our first objective will be to compare kidney injury markers among HIV-infected and uninfected participants cross-sectionally, and their association with age, tenofovir use, and GFR. The second objective will be to examine the link between HIV-infection, advancing age, declining GFR, and tenofovir use with the disorders of mineral metabolism and reduced bone mineral density. The third objective will be to evaluate longitudinally whether baseline and follow-up markers of kidney injury are independently associated with accelerated declines in kidney function during follow-up.

Public Health Relevance

Age-related declines in kidney function appear to be accelerated by nearly two decades in HIV-infected persons, and the resulting kidney disease predisposes to higher risk of death and bone disease. Current strategies for detecting kidney disease are narrowly focused, providing a diagnosis in only a small fraction of affected individuals or diagnosing the disease late in its course. This proposal envisions a new paradigm for early detection of kidney injury in persons with HIV-infection through the use of novel, site-specific serum and urine biomarkers to detect injury at multiple locations within the kidney at their earliest, preclinical stage.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034853-04
Application #
8463084
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Zieman, Susan
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2013-06-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$451,564
Indirect Cost
$86,708
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Jotwani, Vasantha; Scherzer, Rebecca; Abraham, Alison et al. (2014) Does HIV infection promote early kidney injury in women? Antivir Ther 19:79-87
Lang, Joshua; Scherzer, Rebecca; Tien, Phyllis C et al. (2014) Serum albumin and kidney function decline in HIV-infected women. Am J Kidney Dis 64:584-91
Baxi, Sanjiv M; Greenblatt, Ruth M; Bacchetti, Peter et al. (2014) Common clinical conditions - age, low BMI, ritonavir use, mild renal impairment - affect tenofovir pharmacokinetics in a large cohort of HIV-infected women. AIDS 28:59-66
Peralta, Ca; Scherzer, R; Grunfeld, C et al. (2014) Urinary biomarkers of kidney injury are associated with all-cause mortality in the Women's Interagency HIV Study (WIHS). HIV Med 15:291-300
Banerjee, Tanushree; Scherzer, Rebecca; Powe, Neil R et al. (2014) Race and other risk factors for incident proteinuria in a national cohort of HIV-infected veterans. J Acquir Immune Defic Syndr 67:145-52
O'Seaghdha, Conall M; Tin, Adrienne; Yang, Qiong et al. (2014) Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality. Am J Kidney Dis 63:16-22
Park, Meyeon; Vittinghoff, Eric; Ganz, Peter et al. (2014) Role of soluble endothelial cell-selective adhesion molecule biomarker in albuminuria and kidney function changes in patients with coronary artery disease: the Heart and Soul Study. Arterioscler Thromb Vasc Biol 34:231-6
Lang, Joshua; Scherzer, Rebecca; Weekley, Cristin C et al. (2013) Serum albumin and short-term risk for mortality and cardiovascular disease among HIV-infected veterans. AIDS 27:1339-43
Shlipak, Michael G; Day, Erica C (2013) Biomarkers for incident CKD: a new framework for interpreting the literature. Nat Rev Nephrol 9:478-83
Phair, John; Palella, Frank (2011) Renal disease in HIV-infected individuals. Curr Opin HIV AIDS 6:285-9

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