PROJECT SUMMARY: Persons of African descent have a disproportionate risk for several forms of kidney disease including diabetic nephropathy, arterionephrosclerosis (hypertension-attributed kidney disease), focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN), a distinct form of FSGS. Kopp and Winkler et al have shown that variants in the apolipoprotein-1 (APOL1) gene confer sizeable odds ratios (OR) for FSGS (OR = 17), HIVAN (OR = 29 in the US; 89 in South Africa), and hypertension-attributed kidney disease (OR = 7). These variants are present only on African-origin chromosomes and represent an evolutionary protective mechanism against African trypanosomiasis. The presence of these risk genotypes is highest in West Africa, and specifically in Nigeria among persons of Hausa, Fulani, Igbo, and Asante descent. Markers of kidney disease include microalbuminuria, proteinuria, and/or reduced estimated glomerular filtration rate (eGFR). All three have been associated with increased mortality in HIV-infected adults. Increased urinary albumin excretion has diagnostic and prognostic value in the initial identification and confirmation of renal disease, and changes in albuminuria can be useful in assessing the effectiveness of therapy as well as the progression of the disease. The renin-angiotensin aldosterone system (RAAS) is recognized as the central player in the pathophysiology of CKD based on numerous clinical trials in diabetics. The blockade of RAAS with angiotensin converting enzyme inhibitors (ACE-I) is a well-recognized strategy to slow down renal disease progression in diabetic patients with CKD. Aldosterone, together with angiotensin II, has been shown to mediate oxidative stress, inflammation and tissue fibrosis. Therefore by more aggressively blocking RAAS via the addition of an aldosterone receptor antagonist to an ACE-I, one may be able to elicit a more potent and durable response thereby altering their risk trajectory for the development of potentially serious kidney complications. To evaluate this at-risk population more in-depth and to determine the optimal means to reduce their risk for renal complications, we plan to screen 2,200 HIV-infected adults receiving suppressive ART (? 6 months) at the Aminu Kano Teaching Hospital; to conduct the following Specific Aims: 1) To determine the prevalence of APOL1 variants and assess whether their presence correlates with prevalent albuminuria, median eGFR, and/or CKD. 2) To assess whether RAAS inhibition (with the ACE-I lisinopril) compared to placebo will significantly reduce the risk of kidney complications; and 3) To evaluate whether more aggressively blocking the RAAS system via the addition of the mineralocorticoid antagonist spironolactone (in addition to lisinopril) is an even more potent means of sustainably reducing the risk of kidney complications in this population.
NIH ExPorter
NIH ExPorter