ABSTRACT Half of all Americans will develop chronic kidney disease (CKD) during their lifetime. Risk for progressive CKD is particularly high among African Americans: an estimated 7-8% will eventually require kidney replacement therapy, such as dialysis or transplant. Existing treatment for CKD is inadequate, and far greater mechanistic insight is required to explain and address heterogeneity in disease progression. The proposed study will use a combination of innovative methods and omics data to identify biomarkers and pathways that are clinically relevant, linking blood protein and metabolite levels to kidney outcomes and kidney histology. The first phase of this grant focused on integrating genetic and metabolomic data in two cohorts of African Americans, the African American Study of Kidney Disease and Hypertension (AASK) and a subset of BioME, an electronic medical record-linked biorepository. The initial grant period was highly productive, with more than 22 publications, and a focus on rigorous replication of findings in multiple research and clinical cohorts. The renewal proposal requests funds for integrating novel proteomic data with existing metabolomic and genomic data in AASK (proteomic profiling of 7,000 proteins at the baseline visit funded in year 5 of the initial grant period) and expansion to the Boston Kidney Biopsy Cohort Study (BKBC), a clinical cohort with adjudicated histological scores of CKD pathology. Our overarching hypothesis is that an integrated approach combining genetics, proteomics, metabolomics, and histological correlates can yield novel insights into the pathogenesis and prognosis of CKD. Additional investigation using data from genetics consortia and the Kidney Precision Medicine Project will permit corroboration of potential causal roles in disease development and compartment- specific expression of select markers highlighted by our BKBC analyses at single cell resolution, respectively. If successful, these studies should (a) identify key metabolites, proteins, and networks that provide information about risk of CKD progression independent of GFR, albuminuria, and other confounders; (b) identify blood metabolite and protein markers of specific renal histopathologic findings, including interstitial fibrosis/tubular atrophy (IFTA), glomerular sclerosis, and arterial/arteriolar sclerosis; and (c) determine the potential causal role of metabolite and protein markers in CKD pathogenesis. The data generated from this grant would be largely unprecedented in scope, connecting histology and omics, and work in AASK greatly increases the diversity of populations represented in omic investigations. Methods developed will have broad applicability, and the investigators are well poised to extend and replicate findings in other cohorts. Finally, this proposal will be executed by a team with a track record of collaboration and published expertise in each of the methods outlined in the application, demonstrating a high leve...