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

Background: Renal denervation (RDN) has re-emerged as an evidence-based treatment for uncontrolled and resistant hypertension following consistent findings from contemporary sham-controlled randomized trials. Because renal sympathetic signaling plays a central role in cardiovascular (CV), renal, and metabolic homeostasis, the therapeutic effects of RDN may extend beyond blood pressure (BP) reduction. This review reframes RDN within a precision autonomic medicine framework by integrating contemporary mechanistic evidence, phenotype-guided patient selection, and future directions for outcome-oriented clinical trials. Methods: A comprehensive literature search was conducted in PubMed/MEDLINE for studies published between January 2009 and 30 June 2026. Randomized controlled trials, observational studies, mechanistic investigations, systematic reviews, consensus statements, and major international guidelines evaluating the mechanisms, clinical effects, procedural aspects, and emerging applications of RDN were reviewed. Evidence was synthesized narratively with emphasis on autonomic modulation, target-organ protection, precision phenotyping, and future trial design. Results: Contemporary evidence demonstrates that RDN provides durable reductions in ambulatory BP with an acceptable long-term safety profile. Experimental and clinical studies further suggest favorable effects on sympathetic activity, neurohumoral activation, inflammation, oxidative stress, endothelial function, and cardiac, renal, and metabolic remodeling. We propose an autonomic responder phenotype integrating ambulatory BP characteristics, autonomic biomarkers, target-organ involvement, and anatomical suitability to facilitate precision-guided patient selection. We also outline a framework for phenotype-enriched clinical trials incorporating standardized procedural verification and clinically meaningful CV and renal outcomes beyond BP reduction. However, evidence supporting autonomic disease modification remains preliminary, with most studies relying on surrogate endpoints. Conclusions: RDN is an established therapy for appropriately selected patients with hypertension, whereas its broader role as a precision-guided autonomic disease-modifying intervention remains investigational. Future progress requires validated responder phenotypes, objective confirmation of successful denervation, standardized procedural methodologies, and adequately powered randomized outcome trials.