New Therapies for the Management of Chronic Kidney Disease

Abstract

A major public health concern gripping the nation is chronic kidney disease (CKD), and for individuals concomitantly diagnosed with type 2 diabetes mellitus (T2DM), the coexistence significantly increases the cardiovascular morbidity and mortality by two to three times higher than patients diagnosed without CKD. CKD management encompasses both non-pharmacological approaches, such as dietary sodium restriction and lifestyle modification for blood pressure control, and pharmacological approaches. Current pharmacological management focuses on four key pillars: renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and mineralocorticoid receptor antagonists (MRAs), all of which have shown renoprotective and cardiovascular benefits. An incomplete block of aldosterone activity remains a challenge and is one of the factors contributing to the progression of kidney damage. Aldosterone synthase inhibitors (ASIs), such as vicadrostat, may represent a new horizon in selectively inhibiting aldosterone synthesis while preserving cortisol production. Early-phase trials have shown reductions in albuminuria and a potential for renal protection. The question is, could ASIs emerge as a fifth pillar in CKD management and help curb the progression?

Keywords: ace inhibitors; aldosterone; chronic kidney disease; mineralocorticoid receptor antagonists; sglt2 inhibitors.

Figure 1. The RAAS regulates blood pressure and fluid balance. ACE inhibitors reduce angiotensin II synthesis; ARBs block AT₁ receptors; MRAs inhibit aldosterone at its receptor; and ASIs selectively inhibit aldosterone synthase (CYP11B2), directly reducing aldosterone production.

ACE: Angiotensin-converting enzyme; AT1: Angiotensin type 1 receptor (AT1); ASIs: Aldosterone synthase inhibitors; MR: Mineralocorticoid receptor; RAAS: renin-angiotensin-aldosterone system Image credit: Andrew M. Treihaft

Figure 2. The four foundational pillars of CKD management—RAS inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and MRAs—act synergistically to reduce intraglomerular pressure, provide cardio-renal protection, and attenuate inflammation and fibrosis.

CKD: Chronic kidney disease; RASi: Renin-angiotensin system inhibitors; GLP-1RA: Glucagon-like peptide-1 receptor agonist; MRA: mineralocorticoid receptor antagonist Image credit: Andrew M. Treihaft

Figure 3. ASIs are a new class of drugs manufactured to selectively inhibit aldosterone synthase (CYP11B2), an important enzyme catalyzing the final steps of aldosterone synthesis in the zona glomerulosa of the adrenal gland. With the selectivity, these inhibitors are effective in the reduction of aldosterone without affecting cortisol synthesis.

ASI: Aldosterone synthase inhibitor Image credit: Andrew M. Treihaft