PROJECT SUMMARY Chronic kidney disease (CKD) affects 37 million Americans, costs tens of billions of dollars annually, and can lead to kidney failure, cardiovascular disease (CVD), and early mortality. CKD is not a single entity but rather a heterogeneous condition with a wide spectrum of underlying causes, pathologic and clinical manifestations, and varying rates of loss of kidney function. Because of the paucity of kidney biopsy samples from patients with common forms of CKD and the acknowledged limitations of animal models, our understanding of the pathology and molecular mechanisms of CKD is limited. Improved understanding of human CKD due to hypertension and diabetes will require investigation of kidney tissue from patients with CKD, using rapidly evolving techniques in molecular pathology. We are responding to RFA-DK-20-026 to continue as a multicenter CKD recruitment site for the Kidney Precision Medicine Project (KPMP) that builds upon the accomplishments of our established multidisciplinary research group in the UG3/UH3 phase. We propose to continue to participate as a successful CKD recruitment site in Boston, MA including four clinical sites: Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, and Boston Medical Center. The proposal builds upon an established infrastructure and our experience recruiting and retaining KPMP participants. In addition, our site has an outstanding safety record for participants with no major post-biopsy complications as well as exceeding the quality biospecimen metrics. For the U01 phase we propose to obtain repeat kidney biopsies in selected individuals as well as increase the focus on social determinants of health. We also will continue to biopsy individuals with longstanding Type 1 diabetes mellitus with no evidence of kidney pathology (‘resistors') to identify molecular underpinnings of protection against diabetic kidney disease. We are committed to continued collaborative protocol development, sharing best practices, and team science to achieve the KPMP’s objectives of advancing precision medicine to improve the lives of our patients with and at risk for CKD. The proposed research plan, by improving our understanding of CKD pathophysiology, has the potential to dramatically impact public health.