PROJECT ABSTRACT Diabetes is the leading cause of chronic kidney disease (CKD). When combined, diabetes with CKD exponentially increases risk for cardiovascular disease and death. Preventing or delaying CKD in diabetes would substantially decrease these adverse outcomes, save billions in healthcare expenditures, and improve quality of life for those at high-risk for dialysis-dependent kidney failure. Emerging evidence strongly indicates that primary aldosteronism (PA) pathophysiology is a causative mechanism for the development and progression of CKD in diabetes. PA pathophysiology is characterized by relatively non-suppressible and renin-independent aldosterone production that causes excessive activation of the mineralocorticoid receptor (MR). This maladaptive activation of the MR induces inflammation and fibrosis that contributes to CKD and cardiovascular disease. Our work in R01DK115392 has re-defined primary aldosteronism. We have shown that PA pathophysiology exists across a broad continuum of severity, from mild (or subclinical) to overt (or severe); in this regard, PA is better considered to be a pathophysiologic syndrome. The prevalence of PA pathophysiology is high and almost entirely unrecognized. Our work, and that of others, has demonstrated that PA pathophysiology can be detected in 10-25% of the general population; however, despite this alarming prevalence, the rates of testing for PA, or empiric MR antagonist use, in these high-risk populations is abysmal and rarely exceeds 2%. The scope of this problem is magnified by the fact that randomized clinical trials in patients with diabetes have established the exceptional efficacy of MR antagonists for reducing albuminuria, lowering the risk of CKD progression, incident end-stage kidney disease, and incident cardiovascular outcomes. Despite demonstrating this efficacy, these landmark trials did not investigate the role of PA pathophysiology. Our results from R01DK115392 represent the most likely hypothesis to explain the reno-protective benefits of MR antagonists: there is a prevalent, progressive, and unrecognized, spectrum of PA pathophysiology and MR activation in people with diabetes that increase their risk for CKD. In this renewal, we will extend our work in R01DK115392 by conducting a mechanistic cohort study to deeply characterize PA pathophysiology and MR activation in individuals with diabetes and at-risk for incident or progressive CKD. A thorough understanding of PA pathophysiology as an early mechanistic contributor to CKD in diabetes will provide critical evidence to support broader use of MR antagonists to prevent CKD development and progression in diabetes. Participants with diabetes and CKD3A, or at high-risk for developing CKD, will undergo characterization of PA pathophysiology using profiling of steroids indicative of dysregulated aldosterone synthase activity, measurement of urinary extracellular vesicles containing proteins indicative of pathology MR activation,...