Subclinical Primary Aldosteronism in Diabetes At-Risk for Kidney Disease

Diabetes is the leading cause of chronic kidney disease (CKD). When combined, diabetes with CKD exponentially increases risk for cardiovascular disease (CVD) 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 suggests 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 hypertension (HTN), CKD, cardiovascular disease, and death. PA has traditionally been considered to be a rare and categorical disorder. However, it has been 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 origins of PA pathophysiology can be observed in normotensive and pre-hypertensive people, which consequently increases the risk for developing HTN, developing CKD and progression of CKD to end-stage kidney disease, structural heart disease, and adverse CVD outcomes. Thus, early identification of PA pathophysiology is of critical importance since widely available targeted therapies (such as MR antagonists) can mitigate these adverse outcomes. The prevalence of PA pathophysiology is high and almost entirely unrecognized. It can be detected in 10-25% of the general population. In high-risk populations, such as those with resistant hypertension and/or hypertension with hypokalemia, the prevalence of PA exceeds 25%. 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 have established the exceptional efficacy of MR antagonists. Landmark trials have established the efficacy of MR antagonist therapy for treating PA, controlling resistant HTN, reducing adverse outcomes in heart failure, reducing albuminuria, and most germane to this proposal, for lowering the risk of CKD progression and incident end-stage kidney disease in patients with diabetes and incident CVD outcomes despite the use of ACEi/ARBs. GAPS IN CURRENT UNDERSTANDING: What is the mechanism by which MR antagonists impart reno-protective benefits in patients with type 2 diabetes? Ground-breaking results of clinical trials led to the FDA approval of the MR antagonist finerenone and changes to clinical practice guidelines to employ MR antagonists to prevent CKD progression in type 2 diabetes; however, the role of PA pathophysiology was not directly investigated. The investigators hypothesize that there is a prevalent, progressive, and unrecognized, spectrum of PA pathophysiology and MR activation in people with diabetes who have, or are vulnerable to developing, CKD. The aim of this protocol is to assess the presence and severity of primary aldosteronism pathophysiology in patients with type 2 diabetes who have, or are at-risk for developing, chronic kidney disease.