This narrative review outlines the shift in chronic kidney disease (CKD) management from renin-angiotensin system inhibitor monotherapy to a four-pillar combination approach incorporating SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists. Evidence and the 2024 KDIGO guidelines indicate that these complementary therapies significantly reduce kidney failure risk in diabetic patients while improving safety and tolerability, notably by mitigating hyperkalemia. Clinicians should consider early integration of this multimodal strategy, with ongoing research focusing on non-diabetic CKD populations and novel agents like aldosterone synthase inhibitors.
Chronic kidney disease (CKD) management has evolved from supportive care with renin-angiotensin system inhibitors (RASi) alone to multi-target combination therapies. While RASi remain foundational, their limited efficacy in fully preventing disease progression (e.g. residual albuminuria) and safety concerns, such as hyperkalemia, have underscored the need for novel therapeutic agents. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and nonsteroidal mineralocorticoid receptor antagonists (nsMRA) demonstrate complementary nephroprotective effects by targeting metabolic, hemodynamic and inflammatory pathways within the cardiovascular-kidney-metabolic (CKM) syndrome framework. Evidence from large-scale studies demonstrates that combination four-pillar therapies are superior to monotherapy in reducing the risk of kidney failure in patients with diabetes and also exhibit complementary safety profiles that enhance tolerability and long-term patient adherence. For example, combining SGLT2i with RASi mitigates hyperkalemia risk and reduces RASi discontinuation, thereby enhancing treatment persistence. The KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of CKD emphasizes patient-centered, team-based management integrating these therapies. Future directions include expanding evidence for non-diabetic CKD populations, more rapid implementation of these four-pillar therapies and new therapies such as aldosterone synthase inhibitors in this vulnerable group.
