Review Article
Review of the state of renal nerve ablation for patients with severe and resistant hypertension

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Abstract

Through modulation of renin secretion, glomerular filtration rate, and renal absorption of sodium, the sympathetic innervation of the kidneys plays an important role in the pathogenesis of hypertension. Renal nerve ablation technology is being developed for treatment of drug-treatment-resistant hypertension worldwide. Preliminary research with the use of radiofrequency-based renal denervation systems have demonstrated encouraging results with significant reduction of blood pressure in patients inadequately controlled despite nearly maximal drug therapy regimens. From work done thus far, the renal denervation procedure has not been associated with serious adverse effects. Long-term efficacy and safety still needs to be established for renal nerve ablation. This review focuses on the impact of the renal sympathetic system on blood pressure regulation, the clinical rationale for renal nerve ablation in severe and drug-treatment-resistant hypertension, and current evidence from the more advanced renal denervation devices.

Introduction

Inadequate blood pressure (BP) control is the most common attributable risk for death worldwide, being responsible for 62% of cerebrovascular disease and 49% of ischemic heart disease.1 Despite the availability of several effective drugs for control of BP, approximately 50% of patients have suboptimal control of their BP.2 Resistant hypertension has been defined as failure to achieve goal BP when a patient adheres to maximum tolerated doses of three antihypertensive drugs, including a diuretic.3 It is estimated that the prevalence of resistant hypertension in the U.S. varies from 8% to 20%.4, 5 Until recently, therapeutic options for patients with resistant hypertension were limited to drug therapies. However, insights into the pathophysiology of resistant hypertension and understanding of the role of the sympathetic nervous system have led to the development of renal nerve denervation as a potential management option.

Section snippets

Early Experience with Lumbar Sympathectomy for the Treatment of Hypertension

Recognizing that the sympathetic nervous system played an important role in the pathogenesis of hypertension led to a surgical approach known as radical lumbo-dorsal splanchnicectomy to disrupt catecholamine discharges.6 This technique, developed by Smithwick in 1938, lowered BP and reduced mortality, but at the cost of severe and incapacitating side effects.6, 7 Several uncontrolled trials of surgical sympathectomy demonstrated profound improvement in BP control along with reduction in cardiac

Renal Sympathetic Nervous System

Sympathetic innervation of the kidneys plays a major role in the pathogenesis of hypertension through modulation of renin secretion, glomerular filtration rate, and renal absorption of sodium.11, 12 The preganglionic sympathetic neurons originate in the intermediolateral column of the spinal cord at thoracic and lumbar levels (T10 to T12, L1 to L2) and extend via splanchnic nerves to synapse with the postganglionic neurons in the pre- and paravertebral ganglia.13 The renal sympathetic system

Clinical Rationale for Renal Denervation

The concept of renal denervation was initiated from observations made in patients undergoing nephrectomy or renal transplantation and animal models of renal sympathectomy. Increased sympathetic activity has been demonstrated in patients with end-stage renal disease requiring dialysis and normalization of that activity following bilateral nephrectomy.19 In contrast, sympathetic overactivity persists in patients whose native diseased kidneys are not removed, further supporting the hypothesis that

Technical Development of Renal Sympathetic Denervation

Sobotka and Esler pioneered the technique of percutaneous renal sympathetic denervation, and performed the first studies of catheter-based renal nerve ablation using radiofrequency (RF) energy.23 The catheter-based approach was developed to directly target the sympathetic nerves adjacent to the renal artery. The procedure involves insertion of an endovascular catheter under fluoroscopic guidance via the femoral artery using a 6F or 8F guide and advancing it towards the distal renal artery.

RF Ablation (RFA) Technology

Catheter-based renal denervation for drug resistant hypertension using a standard electrophysiology catheter has already demonstrated significant reductions in clinic BP in patients resistant to drug therapy.25 These data have paved the way for development of numerous proprietary systems that are presently undergoing clinical assessment. At present, four systems using RFA technology have been approved for phase 3 clinical study programs in the U.S., Europe, and other countries around the world:

Ultrasonic Ablation Technology

Ultrasound energy consists of high-frequency sound waves that are emitted circumferentially by the cylindrical transducer. These sound waves pass through the surrounding fluids and generate frictional heating of soft tissues, resulting in a temperature increase and nerve damage at depth. It induces a targeted injury pattern to the renal sympathetic nerves within the adventitia of renal artery.

Bullfrog Microinfusion Catheters

The Mercator Bullfrog microinfusion catheter (Mercator MedSystems Inc, San Leandro, CA) is a catheter-guided system designed to inject therapeutic agents directly, non-systemically, and safely through blood vessel walls into adventitial tissues. It has received U.S. Food and Drug Administration 510(k) clearance. Thus far, the sympatholytic agent guanethidine has been studied for injection in the renal arteries. Given locally, guanethidine induces autonomic denervation directly and through an

Safety Concerns for Renal Nerve Ablation in Humans

All the modalities available for renal sympathetic nerve denervation either approved by European regulatory agencies or in the final stages of development and testing use intravascular techniques for delivery of energy. Besides any physiological changes occurring due to renal denervation, being an invasive procedure, complications may occur due to the procedure itself. There were two procedure-related complications in the initial cohort of Symplicity 1 trial: one renal artery dissection related

Heart Failure

The sympathetic nervous system is the driving force behind several compensatory pathophysiologic processes in cardiovascular disorders. For example, neurohumoral activation is a negative prognostic marker in chronic heart failure, and the use of beta-blockers significantly reduces cardiovascular morbidity and mortality.38 High renal sympathetic activity in heart failure patients on treatment with beta-adrenergic blockade has shown to predict early death.39 Of interest, studies in animal models

Potential Limitations of Renal Denervation

While studies have shown beneficial effects of the procedure, there are no long-term controlled data on the efficacy or sustainability of the procedure. There is also limited data on the impact of renal denervation on out-of-office BP. Data from the Symplicity HTN-2 trial shows that renal denervation might not reduce ambulatory BP nearly as effectively as the doctor's office BP. Data from 10 European hypertension clinics within the European network coordinating research on renal denervation

Conclusions

Treatment of drug-resistant hypertension has entered into an interesting historical phase with the emergence of renal nerve ablation therapy. Current evidence from the phase I and 2 clinical trials suggests that the use of catheter-based RFA of renal nerves could be successful in a small, but important subset of patients with severe and resistant hypertension. However, the mechanisms governing BP control are complex and multi-factorial. Long-term safety and efficacy data using controlled

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      Additionally, following the completion of primarily uncontrolled studies in Europe and Australia, RDN has been performed in clinical practice in these regions when secondary forms of hypertension and pseudo-resistance, such as medication nonadherence, or white-coat hypertension based on ambulatory blood pressure (BP) monitoring (ABPM), have been excluded. Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent sympathetic renal nerves (RDN) has become relatively widespread outside the US for the management of RH.2 Clinical study data available thus far have been obtained primarily in patients whose RH is defined as clinic systolic BPs (SBPs) of ≥160 mm Hg or ≥150 mm Hg in patients with type 2 diabetes mellitus, despite pharmacologic treatment with at least three antihypertensive drugs at maximally tolerated doses, one of which must be a thiazide or loop diuretic.

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