Beyond the 4 pillars: aldosterone synthase inhibition as a fifth frontier in chronic kidney disease management

Chronic kidney disease (CKD) is highly prevalent globally and affects approximately 1 in 10 adults, with a prevalence of 10% globally and ∼14.4% in North America. High blood pressure (BP) is one of the most common causes for the development of CKD. Conversely, hypertension occurs more frequently in patients with CKD and is found to be uncontrolled in 60%-80% of these patients. The rates of resistant hypertension are amongst the highest for any patient population, with estimates ranging between 40% and 50%. Deteriorating renal function is associated with increasing risk for co-morbid conditions including cardiac disease and stroke. Appropriate management of hypertension is important in patients with CKD but poses frequent challenges in clinical care with the need to balance the desired BP lowering and ideally reno-protective effects against increased risks for nephrotoxicity and medication side effects. Established therapeutic principles in the context of CKD include renin-angiotensin-aldosterone system (RAAS) blockade using either ACE inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose transport 2 (SGLT-2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (nsMRAs), and glucagon-like-peptide-1 (GLP-1) agonists. Aldosterone dysregulation is emerging as another key driver of persistently uncontrolled BP and deteriorating kidney function, not only through the associated sodium and fluid retention but also through BP-independent effects on endothelial function, inflammatory pathways, tissue fibrosis, and hypertrophic responses. The new drug class of aldosterone synthase inhibitors (ASIs), highly selective agents inhibiting CYP11B2 and thereby reducing circulating aldosterone levels, may offer a novel opportunity to effectively lower BP and reduce organ damage mediated by dysregulated aldosterone. Indeed, recently published data from phase 3 randomized controlled hypertension trials with various ASIs have demonstrated substantial office and ambulatory BP lowering efficacy with an acceptable safety profile. A reduction in albuminuria in early phase 2 trials in patients with hypertension and CKD may indicate reno-protective properties of ASIs. Dedicated outcome trials are ongoing to explore these prospects in detail.