HIV-infected individuals have a 10-fold higher risk of developing end-stage renal disease (ESRD) than HIV- seronegative individuals. In the general population, albuminuria is typically the earliest detectable marker of chronic kidney disease (CKD), and even very low levels of albuminuria are predictive of future cardiovascular events and mortality. Cross-sectional studies in the era of highly active antiretroviral therapy (HAART) indicate that the prevalence of albuminuria is 3- to 5-times higher in HIV-infected individuals than in HIV-seronegative persons. However, few data are available regarding the natural history of albuminuria over time or of the implications of albuminuria for loss of kidney function or cardiovascular disease in this population. We propose to conduct an intensive cohort study that includes equal numbers of HIV-infected and HIV-negative individuals with normal kidney function (estimated glomerular filtration rate (GFR) >60 mL/min/1.73 m2), recruited from the Johns Hopkins HIV Clinical Cohort and the AIDS Link to the Intravenous Experience (ALIVE) study. These cohorts have high rates of illicit drug use and hepatitis C infection, which have been linked to increased CKD risk. Albuminuric subjects will be over-sampled, so that approximately equal numbers of albuminuric and normoalbuminuric subjects will be followed in the HIV-infected and HIV-negative groups. The aims of our study are to 1) determine the implications of HIV infection and albuminuria for changes in GFR (determined by serial measures of iohexol clearance) and for changes in carotid intima-media thickness (a surrogate marker of cardiovascular disease), 2) evaluate novel biomarkers of kidney injury and GFR in this population, and 3) assess potential pathogenic mechanisms of HIV-related CKD (including viral burden measured in urine and immune activation). Our plan to characterize longitudinal changes in GFR with a 'gold standard'measurement technique is novel and will be a key complement to the many studies of HIV-related CKD that are based on estimated GFR. Our proposal targets the natural history and pathogenesis of early-stage CKD in HIV-infected individuals, a phase of disease that is both understudied and potentially most amenable to intervention. PUBLIC HEALTH RELEVANCE: People who are infected with HIV have a high risk of developing kidney disease leading to kidney failure. Chronic kidney disease is also a strong risk factor for heart disease. In a sample of HIV-infected and HIV- negative research participants, we propose to study clinical markers and contributing factors in the progression of kidney disease, and the association between kidney disease and heart disease.