Etiology of Persistent Microalbuminuria in Nigeria

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ABSTRACT: Microalbuminuria is an independent risk factor for cardiovascular and kidney disease and a predictor of end organ damage, both in the general population and in persons living with HIV (PLWH). Microalbuminuria, defined as an albumin-to-creatinine ratio (uACR) 30-300 mg/g, can signify either early glomerular damage or microvascular endothelial dysfunction and has been used in the early detection of kidney disease. Microalbuminuria is also an important risk factor for mortality in PLWH treated with antiretroviral therapy (ART), likely as a marker for inflammation and endothelial activation. In the ongoing Renal Risk Reduction (R3) study in Nigeria, 36.9% had microalbuminuria confirmed by two measurements 4- 8 weeks apart, and 2.8% had macroalbuminuria (uACR >300 mg/g). The median duration on ART was 9 years [IQR 6,12], median CD4 cell count was 482 cells/mm3 [IQR 324–661], 95.7% were virally suppressed, and 12.7% had stage 1 or 2 hypertension (22.1% with pre-hypertension). In contrast, other traditional risk factors for albuminuria and kidney disease, including diabetes (2.1%), APOL1 high-risk genotype (6.2%), and smoking (5%) were uncommon. A significant proportion (~59%) were currently receiving potentially nephrotoxic ARV medications, specifically tenofovir disoproxil fumarate. Lastly, endemic co-infections, including viral (e.g. hepatitis B and C, Cytomegalovirus), parasitic (e.g. Plasmodium falciparum, Schistosoma species, Strongyloides stercoralis, Onchocerca volvulus, Loa loa, Wuchereria bancrofti), and bacterial (Mycobacterium tuberculosis) co-infections, may be potential contributors to albuminuria. To better understand this, we plan to test the following overarching hypothesis: Hypertension, immune activation from co-infections, and cumulative, long-term exposure to potentially nephrotoxic ARV medications contribute to the high rates of microalbuminuria in these ART-experienced adults. To test this hypothesis, we propose the following Specific Aims: 1) To compare the prevalence of albuminuria and established kidney disease risk factors in a large cohort of PLWH to age- and sex-matched HIV-negative adults presenting for routine medical care at the Aminu Kano Teaching Hospital in Kano, Nigeria. We will leverage data and stored specimens from 2500 R3 participants who were previously screened for microalbuminuria and will prospectively enroll an additional 300 PLWH recently initiated on ART (≤ 12 months) and 750 age- and sex-matched HIV-negative adults. 2) To determine the role that hypertension and other comorbid medical conditions (e.g. sickle cell trait or disease, immune activation/inflammation from parasitic infestations and tuberculosis, and exposure to potentially nephrotoxic ARV medications), have on the risk for development of albuminuria. We will enroll 1000 HIV-positive, ART-treated normoalbuminuric adults and 500 HIV-negative normoalbuminuric adults from Aim 1 and follow them longitudinally for three years.