Emerging Strategies for Cardio-Renal Protection Beyond RAAS Blockade: Emphasis on Non-diabetic CKD and Resistant Hypertension

Non-diabetic chronic kidney disease (ND-CKD) complicated by resistant hypertension remains a high-risk phenotype even when renin-angiotensin system blockade is optimized. This review synthesizes contemporary evidence for cardio-renal protection beyond traditional renin-angiotensin-aldosterone system inhibition (RAASi), with emphasis on mechanisms, clinical trial data, and pragmatic sequencing. Sodium-glucose cotransporter 2 inhibitors provide hemodynamic and tubular benefits that translate into renal and heart failure risk reduction in many patients with ND-CKD. Non-steroidal mineralocorticoid receptor antagonism (MRA) like finerenone targets inflammatory and fibrotic signaling and may add incremental benefit when potassium is proactively managed. The GLP-1 receptor agonists offer cardiometabolic advantages with emerging kidney signals, particularly in patients with obesity and high cardiovascular risk. Modern potassium binders can preserve RAASi/MRA intensity, and device-based blood pressure strategies (including renal denervation) may be considered in carefully selected resistant hypertension. We propose a stepwise implementation framework to maximize efficacy while minimizing adverse events through structured monitoring and multidisciplinary care.