African Americans (AA) have a greater than three-fold higher lifetime risk of end stage renal disease (ESRD) as compared to non-Hispanic Whites (7.8% to 2.8%) secondary to a higher prevalence of both chronic kidney disease (CKD) and glomerulonephritides (GN). Recent studies suggest that Blacks living in Sub-Saharan Africa (SSA) (African Blacks) may have a similarly high predilection to kidney disease as do AA and that underlying this similarity in the two populations (American and African Blacks) may be common genetic predispositions to kidney disease; the most notable of which are the APOL1 kidney risk variants that encode for apolipoprotein L1. Circulating apolipoprotein L1 acts as a trypanolytic factor capable of killing trypanosome parasites in human serum and may be protective against trypanosomiasis (African sleeping sickness) which is endemic in 36 African countries. It is estimated that more than three million AA and greater than 50 million African Blacks have CKD due to clinically defined nephropathies (from hypertension, diabetes mellitus, sickle disease, etc.) and GN. A significant fraction of these will progress to ESRD which is a harbinger of imminent death in the African setting due to the scarcity of dialysis or kidney transplantation. Building on our work in AA (Parsa A. N Eng J Med 2013;369(23):2183-960 & Lipkowitz MS. Kidney Int 2013;83(1):114-20) as well as in African Blacks (Science 2014;344(6190):1346-9 & Tayo BO. Int Urol Nephrol 2013;45(2)485-94), we herein propose to leverage the resources and expertise in the ongoing, NIH-funded, case-controlled H3Africa Kidney Disease Study to conduct a multinational prospective cohort study in 3,000 participants with clinically defined nephropathies and in 1,000 participants with biopsy-confirmed incident glomerular disease (for a total sample size of 4,000 HIV-negative African Blacks with kidney disease) to accomplish the following research objectives: (1) determine whether APOL1 risk variants independently predict kidney disease progression and identify modifiable risk factors for kidney disease progression in African Blacks; (2) elucidate the causative role of gene-environment interactions (APOL1-infections) and their joint and several effects on the outcomes of GN among African Blacks by country (n=4) and region (East vs. West Africa) and (3) establish a high quality resource (data and specimen repository of blood, urine, DNA, RNA and kidney tissue) for basic, clinical and translational research in kidney disease and other chronic diseases. The proposed study is innovative in that it is the first adequately powered prospective cohort study to both identify the genetic determinants and characterize the phenotype for kidney disease progression in SSA. The overall impact of the study is likely to be very high as it would: (i) yield new information relevant for the development of kidney disease screening programs, preventative strategies and therapeutic intervention trials and (ii) create a new platform essentia for basic, clinical and translational studies of kidney disease in all people of African ancestry. o wit, this unique research resource would be made readily accessible to researchers worldwide.

Public Health Relevance

Chronic kidney disease (CKD) is estimated to affect 50 million African Blacks, with more than 500,000 of these individuals progressing annually to end stage renal disease, and death, shortly thereafter. The studies proposed in this application will leverage the resources of the ongoing NIH-funded Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network, to identify genetic variants and modifiable environmental and clinical factors that cause the progression of kidney disease in Blacks, thus potentially pinpointing new screening and prevention strategies for end stage renal disease in both African Blacks and African Americans.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1)
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Parsa, Afshin
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University of Arizona
Internal Medicine/Medicine
Schools of Medicine
United States
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Chen, Teresa K; Estrella, Michelle M; Parekh, Rulan S (2016) The evolving science of apolipoprotein-L1 and kidney disease. Curr Opin Nephrol Hypertens 25:217-25