Drugs to Slow Progression of Chronic Kidney Disease: It’s a Whole New World!

Chronic kidney disease (CKD) affects approximately 14% of adults in the United States and about 10% worldwide and remains a major public health concern. Diabetes and hypertension are the leading causes of CKD and contribute to progressive nephron loss through disturbances in glomerular hemodynamics and filtration barrier, tubular and vascular function, and pathways of inflammation and fibrosis. Over the past two decades, an expanding set of therapeutic interventions has been developed that target key mechanisms of CKD progression. Renin–angiotensin–aldosterone system (RAAS) blockers remain foundational and are now complemented by sodium–glucose cotransporter-2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (nsMRAs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and emerging therapies including endothelin receptor antagonists (ERAs) and angiotensin receptor–neprilysin inhibitors (ARNIs). These agents act across multiple renal compartments to reduce hyperfiltration, proteinuria, inflammation, and fibrosis. This review outlines a unified framework of CKD pathophysiology, summarizes disease-specific mechanisms in diabetic and hypertensive kidney disease, and integrates mechanistic and clinical evidence for current and emerging therapies. It also provides a structured approach to combination therapy, highlighting how complementary mechanisms can be leveraged to slow CKD progression and improve kidney and cardiovascular outcomes.