Catheter-Based Renal Nerve Ablation as a Novel Hypertension Therapy: Lost, and Then Found, in Translation.

Abstract

The hypothesis that renal nerves mediate, at least in part, the pathogenesis and maintenance of hypertension is based on decades of preclinical studies and, to a certain extent, recent clinical trials of catheter-based renal nerve ablation (CBRNA) in humans. The first 2 clinical trials for CBRNA, Symplicity HTN-1 and Symplicity HTN-2, reported sustained reductions in arterial pressure in patients with drug-resistant hypertension and set the stage for the first blinded US trial, Symplicity HTN-3. However, Symplicity HTN-3 failed to reach its 6-month efficacy end point, thus jeopardizing the clinical application of CBRNA in the United States. The goal of this article is to reexamine the feasibility of CBRNA to treat hypertension. Preclinical studies on the role of renal nerves in hypertension have been extensively reviewed,1,2 as have the Symplicity HTN-1, 2, and 3 trials.3–7 Therefore, we will review these topics only briefly to provide context for the primary purpose of this article which is to answer the following question: is the outcome of Symplicity HTN-3 because of the failure to translate preclinical knowledge to the clinic, or is our basic understanding of the mechanisms by which renal nerves contribute to hypertension flawed? The kidney is innervated by sympathetic efferent fibers that modulate 3 pharmacological targets for the treatment of hypertension: renin release, tubular sodium reabsorption, and renal vascular resistance.1,2 Although conventional pharmacological treatments of these targets lower arterial pressure, patients often present with negative side effects which may lead to drug incompliance. One rationale for CBRNA is that this treatment would suppress renin release, tubular sodium reabsorption, and renal vasoconstriction, while avoiding the side effects associated with more globally acting pharmacotherapies. The kidney is also innervated by renal afferent fibers that provide the central nervous system sensory information related to the …