Reframing renal denervation: from blood pressure reduction to autonomic disease modification—a state-of-the-art review

Figures

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  Fig. 1. Conceptual framework of RDN as an autonomic disease-modifying therapy. RDN interrupts both afferent and efferent renal sympathetic signaling, resulting in attenuation of central sympathetic outflow and downstream neurohumoral activation. Through modulation of autonomic pathways, RDN may influence multiple biological mechanisms, including renin–angiotensin–aldosterone system activation, inflammation, oxidative stress, endothelial dysfunction, and target-organ remodeling. These effects may contribute to disease modification across a spectrum of cardiovascular, renal, and metabolic disorders extending beyond hypertension. RDN, renal denervation.

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  Fig. 2. Mechanisms of disease modification beyond blood pressure reduction. Potential biological pathways through which RDN exerts effects beyond blood pressure lowering. Sympathetic modulation influences neurohumoral signaling, immune activation, oxidative stress, endothelial function, cardiac remodeling, and renal injury. These interconnected mechanisms may explain the broader cardiovascular and renal benefits observed following RDN. RDN, renal denervation; RAAS, renin–angiotensin–aldosterone system; LV, left ventricular; AF, atrial fibrillation.

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  Fig. 3. A precision-based clinical framework for identification of the autonomic responder phenotype before RDN. The proposed framework integrates sequential clinical, physiological, anatomical, and procedural assessments to facilitate individualized patient selection for RDN. Following confirmation of uncontrolled or resistant hypertension and exclusion of secondary causes, patients undergo ambulatory blood pressure monitoring to identify nocturnal hypertension, non-dipping or reverse-dipping patterns, morning blood pressure surge, and increased blood pressure variability. Subsequent evaluation incorporates autonomic biomarkers, including resting heart rate and heart rate variability, while direct measures of sympathetic activity, such as muscle sympathetic nerve activity and renal norepinephrine spillover, remain research tools. Evidence of sympathetic target-organ injury, including left ventricular hypertrophy, chronic kidney disease, atrial fibrillation, heart failure, obstructive sleep apnea, and metabolic dysfunction, is then integrated with renal artery anatomy and procedural feasibility. Patients demonstrating a multidimensional autonomic phenotype and appropriate anatomical…

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  Fig. 4. Technological evolution of RDN from anatomical ablation toward precision-guided autonomic intervention. The figure illustrates the anticipated evolution of RDN technologies across 4 developmental stages. Early-generation catheter systems relied primarily on anatomical renal artery ablation without objective confirmation of sympathetic nerve interruption. Contemporary technologies employ multi-electrode RF and ultrasound-based platforms with improved circumferential energy delivery and greater procedural consistency. Future technological development is expected to focus on objective verification of successful denervation through physiological assessment, intraprocedural biomarkers, renal nerve mapping, and advanced imaging techniques. Ultimately, integration of computational planning, AI, patient-specific anatomical modeling, and biological feedback systems may enable precision-guided autonomic intervention with individualized procedural optimization. RDN, renal denervation; RF, radiofrequency; AI, artificial intelligence.

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  Fig. 5. Roadmap for the future clinical development of RDN beyond conventional BP reduction. The proposed roadmap illustrates the anticipated evolution of RDN from a BP-lowering intervention toward a precision-based autonomic therapy. Future progress depends on sequential integration of phenotype-guided patient selection, procedural optimization, validation of autonomic biomarkers, standardized denervation techniques, and disease-specific clinical trials. Expansion into cardiovascular, renal, metabolic, and sleep-related disorders should be guided by objective evidence of sympathetic overactivity and supported by sham-controlled outcome trials incorporating clinically meaningful endpoints beyond BP reduction. Ultimately, validated responder phenotypes and mechanistically informed trial designs may facilitate transition from empirical antihypertensive treatment toward precision autonomic disease modification. RDN, renal denervation; BP, blood pressure; HRV, heart rate variability; HFpEF, heart failure with preserved ejection fraction.