Errata: Addendum Volume 36, Issue 5, 303, Article first published online: 13 May 2013
Hypertension is a leading cause of cardiovascular morbidity and mortality. Drug-resistant hypertension remains common despite the availability of several classes of effective antihypertensive agents. Sympathetic hyperactivity has long been recognized as a major contributor to resistant hypertension, but radical sympathectomy was abandoned several decades ago due to its significant side effects. The newly developed, minimally invasive, catheter-based renal sympathetic denervation procedure has been shown in recent trials to produce impressive blood pressure reductions and a favorable safety profile in drug-resistant hypertension. Although the long-term efficacy and safety of renal denervation remains to be determined, emerging data suggest that the benefits of renal denervation may extend beyond blood pressure control.
Dr. Cohen is the principal investigator for Symplicity 3 study funded by Medtronic; Dr. Huan is the subinvestigator for Symplicity 3 study funded by Medtronic.
Hypertension is a growing public health problem worldwide and a leading cause of cardiovascular morbidity and mortality.1 The majority of hypertension cases are considered essential as no secondary causes can be identified. Despite the availability of several classes of effective antihypertensive agents, uncontrolled hypertension remains common, resulting in related adverse cardiovascular outcomes including stroke, coronary heart disease, heart failure, vascular disease, and renal failure.2,3 The sympathetic nervous system has long been recognized to play an important role in hypertension,4 and splanchnicectomy or radical sympathectomy had been considered an effective way of treating severe hypertension and related cardiovascular morbidities several decades ago.5 Modern pharmacological therapy for hypertension, with several classes of effective antihypertensive agents, has made splanchnicectomy and radical sympathectomy obsolete because of the unfavorable side effect profiles including orthostatic hypotension, impotence, and incontinence. The recent development of minimally invasive, catheter-based, renal denervation presents an innovative and promising new approach to localized therapeutic renal sympathectomy in the treatment of drug-resistant hypertension. Clinical trials thus far have shown impressive blood pressure reduction and favorable side effect profile of catheter-based renal denervation. This review will address the role of the renal sympathetic nervous system, recent trial results of catheter-based renal denervation, and the potential role of renal denervation in the treatment of hypertension.
Renal Sympathetic System in Hypertension
Increased sympathetic nervous system activity has been implicated in the development and perpetuation of hypertension, and the sympathetic nervous system activity increases in parallel to the severity of hypertension.4 Preferential and local activation of sympathetic outflows to different organs fine tunes sympathetic activity. In essential hypertension, the activation of renal sympathetic nerves is often greater than the sympathetic activation in other organs.
The autonomic control of the kidneys is mostly sympathetic, and the renal nerves enter the renal hilus along the main renal artery.6 The efferent and afferent renal sympathetic nerve fibers are located within and immediately adjacent to the wall of the renal artery. The Figure1 is a schematic depiction of the physiological effects of the efferent and afferent renal sympathetic activation. The efferent renal sympathetic nerves originate from postganglionic sympathetic neurons and carry the central sympathetic outflow to the kidneys through a dense network of fibers to the renal vasculature, tubules, and juxtaglomerular apparatus. The efferent renal sympathetic nerve activity is regulated by several factors including central sympathetic outflow, vagal tone, and renorenal reflexes. Activation of efferent renal sympathetic nerves results in increased renal noradrenaline production and release, greater renal vasoconstriction, increased renin activity, and enhanced sodium and water retention.
The afferent renal sympathetic nerves are sensory nerves with cell bodies located in the ipsilateral dorsal root ganglia. They modulate the central sympathetic outflow by sending sensory information from the chemoreceptors in renal interstitium and mechanoreceptors in the renal pelvic wall to the central nervous system. Activation of afferent renal sympathetic nerves with renal injuries, including ischemia and hypoxia, stimulates sympathetic centers in the brain and increases central sympathetic outflows to the kidneys and other organs involved in cardiovascular control, resulting in higher blood pressure.
Renal Denervation in the Treatment of Hypertension
Renal sympathectomy has been used since the 1930s to reduce blood pressure in patients with severe hypertension.7 The use of radical surgical sympathectomy and therapeutic splanchnicectomy in severe hypertension and related cardiovascular conditions,5,8 was largely abandoned in the mid to late 1960s due to the significant side effects after the advent of modern pharmacotherapy with effective and well-tolerated antihypertensive agents.9 The neural control of the kidney plays an important role in blood pressure control by regulating volume and sodium homeostasis, and renin release.6 Adequate renal function, however, does not seem to depend on intact sympathetic renal nerves, as seen in transplanted kidneys that have complete renal denervation.
The recently developed catheter-based renal denervation procedure attempts to avoid side effects associated with nonspecific sympathectomy by targeting bilateral renal nerves specifically based on the fact that renal nerves enter the renal hilus along the wall of the main renal artery. An ablation device is placed in the renal main artery by percutaneous femoral catheter. The device then delivers radiofrequency energy to generate heat to ablate the renal sympathetic nerves located in the outer layer and adventitia of the renal artery wall. The denervation procedure appears minimally invasive and has a short procedure and recovery time. The initial trials on renal denervation have shown impressive blood pressure reduction and minimal systemic side effects. The Table 1 summarizes the recent major trials on catheter-based renal denervation in blood pressure reduction.
Table 1. Major Trials of Renal Denervation on BP Reduction
The first-in-man and proof-of-concept study on catheter-based renal sympathetic denervation used Symplicity Renal Denervation System (Medtronic, Inc., Mountain View, CA) and enrolled an uncontrolled cohort of 50 patients with resistant hypertension.10 After excluding 5 patients from the renal denervation procedure due to dual renal artery systems, 45 patients who had a mean baseline office blood pressure of 177/101 mm Hg while on an average number of 4.7 antihypertensive agents, and preserved renal function with mean estimated glomerular filtration rate of 81 mL/min/1.73 m2, underwent bilateral renal denervation using a radiofrequency ablation device placed at the main renal artery through a femoral percutaneous catheter. The effectiveness of renal sympathetic denervation by this approach was confirmed by a 47% reduction in renal noradrenaline production following denervation, as experimental studies have shown that renal sympathetic activation enhances renal noradrenaline production, whereas renal denervation results in a marked reduction in renal noradrenaline production.6 Compared to the group of 5 patients who were unable to have the renal denervation and had no reduction in their office blood pressure during the follow-up, the group who underwent the bilateral renal denervation had significant reduction in office blood pressure with mean of 14/10, 21/10, 22/11, 24/11, and 27/17 mm Hg by 1, 3, 6, 9, and 12 months following denervation, respectively. Except for 1 patient with intraoperative renal artery dissection occurring before the radiofrequency ablation and 1 patient with a pseudoaneurysm at the femoral access site, no other significant operative complications were noted. Repeat renal angiogram and magnetic resonance angiogram showed no significant procedure-related renovascular changes, and estimated glomerular filtration rate showed no deterioration of renal function up to 6 months following bilateral renal denervation.
A case report by the same group of researchers demonstrated significant blood pressure reduction of 20/17 and 34/26 mm Hg, respectively, by 30 days and 12 months following denervation in a 59-year-old male with longstanding resistant hypertension and 2 episodes of transient ischemic attacks.11 In addition, the researchers showed that bilateral renal denervation significantly lowered both renal and overall noradrenaline levels and decreased renin activity. By 12 months following renal denervation, the cardiac baroreflex sensitivity also improved, and muscular sympathetic nerve firing decreased gradually toward the normal level.
Based on the promising results of the initial studies, the randomized controlled Symplicity HTN-2 Trial (Renal Denervation in Patients With Uncontrolled Hypertension) was conducted to further examine the efficacy of renal sympathetic denervation.12 It enrolled 106 patients with resistant hypertension and preserved renal function, and assigned them randomly to either renal denervation (n = 52) or control (n = 54) group. The renal denervation and control groups had almost identical mean baseline office blood pressures of 178/97 and 178/98 mm Hg, respectively. Although the control group had no significant reduction in their office blood pressure, the renal denervation group had impressive mean office blood pressure reduction of 20/7, 24/8, and 32/12 mm Hg by 1, 3, and 6 months following denervation, respectively. There were no serious procedure- or device-related complications noted during the study.
The initial proof-of-concept study expanded to enroll 153 subjects with resistant hypertension, who had mean baseline office blood pressure of 176/98 mm Hg while on an average number of 5.1 antihypertensive agents.13 It showed impressive blood pressure reductions with a mean of 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months following denervation, respectively, supporting the durable blood pressure reduction by renal denervation at least up to 2 years following denervation. The safety of the renal denervation procedure is again supported by the low rate of procedure- and device-related complications, including only 3 cases of groin pseudoaneurysms and 1 case of renal artery dissection, and absence of renovascular injury or renal function deterioration up to 2 years following renal denervation.
Because currently available results on the catheter-based renal denervation procedure are all based on trials conducted outside of the United States, including Australia, New Zealand, and Europe, the ongoing Symplicity HTN-3 Trial is being carried out at multiple centers in the United States to gain the regulatory approval of the catheter-based renal denervation procedure in the United States.14 The trial is designed as a prospective, randomized, single-blind, masked procedure trial to further evaluate the safety and efficacy of catheter-based, bilateral, renal denervation in the treatment of drug-resistant hypertension in patients with relatively preserved renal function.
Drug-resistant hypertension is defined as blood pressure ≥140/90 mm Hg on 3 different classes of antihypertensive agents with 1 being a diuretic. Adding an additional aldosterone antagonist has shown both efficacy and safety in lowering blood pressure in a significant portion of drug-resistant hypertension cases.15–17 A recent analysis of the National Health and Nutrition Examination Survey data from 2003 to 2008 showed that 12.8% of drug-treated hypertensive patients met the criteria of drug-resistant hypertension.18 However, inadequate diuretic therapy appears common in this population of drug-resistant hypertension, because hydrochlorothiazide (a weak thiazide diuretic) was the only diuretic used in more than 50% of cases, and aldosterone antagonist was only used in 3% of cases. A recent Spanish registry study showed that 12.2% of the database met the criteria of drug-resistant hypertension by office blood pressure, but 37.5% of them had normal ambulatory blood pressure, indicating white coat hypertension.19
To ensure enrollment of patients with true drug-resistant hypertension, the Symplicity HTN-3 Trial is limited to patients with uncontrolled blood pressure confirmed by both office and ambulatory blood pressure despite being compliant with maximally tolerated antihypertensive regimens of at least 3 agents of different classes and 1 agent being a diuretic. However, there is no specified inclusion requirement for aldosterone antagonist therapy. The primary efficacy end point is the change in office blood pressure by 6 months, and a major secondary efficacy end point is the change in average 24-hour systolic blood pressure at 6 months. The primary safety end point is the incidence of major adverse events.
The Simplicity HTN-3 study is expected to enroll 530 patients in a 2:1 treatment design. It is expected to provide the strongest evidence on the catheter-based renal denervation procedure, because it will be the largest trial on renal denervation and will compare the catheter-based renal denervation to a catheter-based sham procedure. In anticipation of the potential benefits of renal denervation, patients who are enrolled in the sham procedure arm will be offered catheter-based renal denervation upon completion of the 6-month follow-up.
A recently published study of catheter-based renal sympathetic denervation examined the effects on renal hemodynamics and function in patients with resistant hypertension.20 Compared to the control group of 12 participants who had no significant changes while remaining on medical therapy, the intervention group of 88 subjects had significant reductions in systolic, diastolic, and pulse pressure of 22.7/7.7/15.1 mm Hg and 26.6/9.7/17.5 mm Hg at 3 and 6 months, respectively, following renal denervation. In addition, the renal denervation resulted in a decrease in the renal resistive index from baseline of 0.691 to 0.674 and 0.670 at 3 and 6 months, respectively, but with no effects on cystatin C-based glomerular filtration rate and urinary albumin excretion. There were no renal artery stenoses, dissections, or aneurysms during the 6 months of follow-up.
In a recent small pilot study, 15 patients who had resistant hypertension and moderate to severe renal function impairment with mean estimated glomerular filtration rate of 31 mL/min/1.73 m2 underwent the same catheter-based bilateral renal denervation procedure and had similarly impressive mean blood pressure reductions of 34/14, 25/11, 32/15, and 33/19 mm Hg at 1, 3, 6, and 12 months following denervation, respectively.21 In addition, nighttime ambulatory blood pressure decreased significantly, restoring a more physiologic nocturnal dipping pattern. Renal function assessed by estimated glomerular filtration rate did not change significantly up to 12 months following denervation. This pilot study supports the potential utility of catheter-based renal denervation in patients with impaired renal function.
Another recent study examined the effects of renal denervation on blood pressure and sleep apnea severity in 10 patients with severe hypertension and sleep apnea. Antihypertensives were not changed during 6 months of follow-up, but the office blood pressure was reduced significantly by 34/13 mm Hg at 6 months following denervation. In addition, apnea-hypopnea index decreased significantly, and glucose tolerance improved with lower plasma glucose and hemoglobin A1c levels at 6 months following renal denervation,22 suggesting potential benefits of renal denervation in other conditions associated with sympathetic hyperactivity beyond resistant hypertension.
A more recent study of 46 patients with resistant hypertension examined the effects of renal denervation on blood pressure and associated cardiac conditions including left ventricular hypertrophy and diastolic function.23 Besides the impressive blood pressure reduction, significant reductions in interventricular septum thickness and left ventricular mass index, along with improvement in diastolic function, were also noticed at 1 and 6 months following denervation. Cardiac ejection fraction also improved significantly at 6 months following denervation. More importantly, the improvement of left ventricular hypertrophy seemed to be somewhat independent of blood pressure lowering effects, suggesting possible benefits of renal denervation in cardiovascular conditions beyond blood pressure.
Based on the available data on the catheter-based renal denervation procedure, a position statement in 2012 by the European Society of Hypertension advocates the use of renal denervation but recommends that renal denervation should only be used in patients with truly drug-resistant hypertension and be performed in very experienced centers at this time.24 In a swine model, the short-term efficacy and safety of catheter-based radiofrequency ablation using the Symplicity Renal Denervation System was confirmed by the presence of renal nerve injury, primarily nerve fibrosis with replacement of nerve fascicles with fibrous connective tissue, and thickening of the epineurium and perineurium, whereas the changes of renal arteries only included fibrosis of 10% to 25% of media and adventitia, mild disruption of the external elastic lamina, but no significant smooth muscle hyperplasia or inflammation.25 In addition, there was no angiographic or histological evidence of renal artery stenosis or thrombosis at 6 months following ablation. Consistent with the animal data, the clinical data so far have demonstrated impressive efficacy, durability, and safety of the Symplicity Renal Denervation System.10,12,13 However, the optimism of renal denervation will remain guarded given the complicated mechanism of hypertension and the lack of long-term outcome.26
Drug-resistant hypertension remains common despite the availability of effective antihypertensive agents. The recently developed catheter-based renal denervation procedure has shown impressive blood pressure reduction and favorable safety profile with thus far no significant procedure or device-related complications. Efferent renal sympathetic nerves are known to be able to regenerate fairly quickly, whereas regeneration of afferent renal sympathetic nerves remains less clear.27 How this will affect the long-term effects of renal denervation in blood pressure reduction remains to be determined. Despite the promising data so far, ongoing follow-up is needed to confirm the long-term efficacy and safety of renal denervation. While awaiting answers from the ongoing studies on renal denervation, including the Symplicity HTN-3 trial, we expect the field of catheter-based renal denervation to expand with the emergence of new ablation devices using different configurations and ablation energy/methods.28,29 With the reduction in both renal and overall sympathetic activity, it is possible that the benefits of renal denervation can extend beyond blood pressure control to other cardiovascular conditions affected by overall sympathetic hyperactivity.