PROJECT SUMMARY / ABSTRACT The overall goal of the Discovery Science Collaborative for CKDu Renal Science Core is to bring the best investigative methods and scientific technology to the problem of CKDu. We will work closely with Field Epidemiology Sites, the Scientific Data Coordinating Center, NIDDK Leadership, the External Oversight Committee, and HHEAR to design clinical phenotyping studies and perform discovery science experiments. We will then integrate this data to elucidate the etiology and progression factors of CKDu occurring in diverse agricultural communities. The Renal Science Core is a multi-institutional collaborative organized around six Core components: Genomics, Pathology, Transcriptomics, Biomarkers, Physiology, and Bioinformatics. The specific aims of the RSC are to: (1) characterize the clinical phenotypes and natural history of patients with CKDu and unaffected individuals in CKDu-endemic regions, comparing features across CKDu sites and determining the degree of similarities and differences across sites and regions; (2) introduce cutting-edge molecular technologies to compare the risk factors and pathophysiology of CKDu across and within study sites to understand both shared and unique aspects of the etiology of disease; (3) define the relationship between AKI and CKDu in endemic regions; and (4) build a flexible, adaptable infrastructure for both hypothesis- and non-hypothesis-based approaches to understanding etiology that will form the core of ongoing CKDu studies. The leadership team of the RSC has extensive experience working on CKDu, a history of collaboration on international working groups, and leadership roles on other major NIDDK consortia. This group brings together expertise in nephrology, genomics, nephropathology, machine learning algorithms for digital pathology, single- cell transcriptomics, biomarker development, proteomics, metabolomics, renal physiology, bioinformatics, and data integration. We have also enlisted several advisors with expertise in novel pathogen discovery, novel imaging technologies, and environmental sampling. These studies will result in a greater understanding of the underlying pathophysiology of CKDu.