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Abstract

Hypertension is a major public health concern that is increasing in prevalence. Lifestyle and pharmacological management are not always sufficient to control blood pressure and treatment-resistant hypertension is a recognized clinical challenge. Renal sympathetic denervation (RSD) represents a new frontier in the treatment of resistant hypertension. Results from the Symplicity HTN-1 and HTN-2 trials have demonstrated evidence that suggests RSD can safely reduce blood pressure in patients with this condition. More research is needed to verify these data, clarify unanswered questions and assess future applications of RSD. This review provides a detailed overview on the history of hypertension, treatment-resistant hypertension, the rationale behind RSD, current evidence and potential future applications of RSD. An overview of current and upcoming RSD devices is also included.

Keywords

renal sympathetic denervation resistant hypertension sympathetic nervous system

Introduction

Hypertension is a major public health concern worldwide and is the leading cause of global mortality accounting for 13% of deaths [World Health Organization, 2009]. The prevalence of hypertension is increasing and it is estimated by 2025, 29% of the world’s population will be affected [Kearney et al. 2005]. Treating hypertension is a priority due to its established associations in the development of cerebrovascular disease, ischemic heart disease and renal impairment [Whitworth, 2003]. In common clinical practice, lifestyle modifications and pharmacological management strategies can be effective treatments, but despite the above, some patients fail to respond. Managing these patients with medical-resistant hypertension poses an increasing clinical challenge to clinicians [Calhoun et al. 2008] and the concept of ‘treatment of resistant hypertension’ has been proposed.

With the further understanding of the pathophysiology of hypertension we have an evolution in the management ranging from surgical, pharmacological, and more recently, endovascular approaches. With recent increased interest and understanding of the sympathetic nervous system’s role in hypertension, renal sympathetic denervation (RSD) has been proposed as an innovative treatment methodology targeting patients with ‘Treatment resistant hypertension’ [Ritz, 2009].

The evidence for RSD is in its early stages but is growing with multiple ongoing clinical trials. Current clinical evidence suggests that catheter-based renal denervation can safely be used to substantially reduce treatment-resistant hypertension [Esler et al. 2010]. Further research is being conducted to ascertain the value of RSD in treating other medical conditions such as congestive cardiac failure. Interest in RSD has sparked the development of devices using a variety of technologies, including radiofrequency (RF) ablation, focused ultrasound and localized pharmacological administration. Given the global hypertension prevalence and the need for innovative ways to manage treatment-resistant hypertension, the renal denervation market is expected to grow from US$17 million in 2011 to US$561 million by 2015 [TechNavio, 2012].

Our review provides the clinician with a detailed overview of the history of hypertension, treatment-resistant hypertension, the rationale behind RSD, current evidence and potential future applications of RSD. One of the challenges for the modern clinician is familiarity with available medical devices and to address this we have also included a short overview of current and upcoming RSD devices (Table 1).

Table 1.

Article learning points.

The history of hypertension and the current role of renal sympathetic denervation

An overview of the renal sympathetic denervation rationale and current evidence

The risks of the procedure and areas in which more research is needed

Current Conformité Européenne (CE) marked renal sympathetic devices and upcoming technologies

Future applications of renal sympathetic denervation

Historical perspective: from 2600 BC to catheter-based renal sympathetic denervation

Numerous reports in history dating back to 2600 BC suggest that hypertension may have been a known phenomenon, but was referred to as hard pulse disease. Initial methods of treatment included venepuncture and bleeding by leeches [Esunge, 1991]. The story of hypertension in modern medicine begins in 1733 with the first documented measurement of intra-arterial pressure in a horse by Stephen Hales [Kotchen, 2011]. The proposed method required pressure measurement via direct arterial puncture and therefore had limited clinical applicability. The first noninvasive sphygmomanometer was developed in 1855 by Vierordt, but underwent significant evolution by von Basch and Riva-Rocci. By 1896 a device was produced that resembles the technology behind present day sphygmomanometers [Booth, 1977]. Several years later in 1905, Korotkoff proposed further innovation on this technique by measuring blood pressure (BP) using the Riva-Rocci cuff combined with auscultation [Korotkoff, 1905; Booth, 1977].

The modern day understanding of hypertension appears to have originated in the early 1800s with the work of Young [Young, 1809] and Bright [Bright, 1836; Freis, 1995]. By the early 1900s, low salt diets and pharmacological use of sodium thiocynate had been developed as proposed treatments for raised BP. The role of the sympathetic nervous system on vasoconstriction was also known as a potential causative factor in the development of hypertension. Therefore, surgical sympathectomy was first performed in 1921 and continued into the 1950s [Freis, 1995]. The procedure was associated with a significant reduction in BP. Patients however suffered severe side effects which led to the abandonment of the procedure as newer pharmacological interventions were introduced [Doumas et al. 2010].

Until the 1950s, some clinicians believed hypertension could be a necessary homeostatic mechanism and needed for adequate perfusion of organs and therefore treatment should be avoided [Moser, 2006; Chobanian, 2009]. This was echoed by prominent individuals, for example, John Hay, Professor of Medicine at Liverpool University, who stated ‘the greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it’ [Hay, 1931, p.46]. Perhaps this paradigm is partially responsible for the delay in development of effective antihypertensive medications.

Initial drug therapy during the 1950s built upon the knowledge of sympathetic input as an etiologic factor in hypertension. Chemical sympathectomy was proposed through a range of medications, including tetraethylamonium chloride, mecamlamine, pentaquine, guanethidine and others [Freis, 1995; Moser, 2006]. However, these drugs had significant side effects limiting their clinical use. Then in the late 1950s, the first thiazide diuretic, chlorothiazide, was introduced and was successful at reducing BP [Beyer, 1958]. This event paved the way for further innovation in pharmacological management and saw the introduction of β blockers in the 1960s [Prichard and Gillam, 1964], converting enzyme inhibitors in the 1970s [Ondetti et al. 1977], calcium channel blockers in the 1980s [Karlsberg, 1982] and angiotensin II receptor blockers in the 1990s [Brunner et al. 1992].

Despite the available pharmacological means of treatment, hypertension is felt to be poorly managed globally [World Health Organization, 2009]. The reasons for this are multifactorial of which the most important is noncompliance to pharmacological treatment as patients may not perceive any symptoms related to hypertension [Krum et al. 2009]. Entering into a new millennium, innovation in the management of hypertension is essential to reduce the global burden of the disease. Drawing upon historical knowledge of surgical sympathectomy and animal models demonstrating the antihypertensive effect of renal denervation, the concept of sympathectomy was revisited in the early 2000s [Mann, 2010]. Rather than using a surgical approach, endovascular RF ablation of renal sympathetic nerves was developed and the first proof-of-concept study using this technology was published in 2009 [Krum et al. 2009].

Rationale of renal sympathetic denervation

The precise pathophysiology of hypertension is multifactorial and continues to be evaluated [Beevers et al. 2001]. However, there is a strong indication to support sympathetic nervous system overactivity as an etiologic and sustaining factor in essential hypertension [Schlaich et al. 2009]. This is evidenced by raised renal overflow of norepinephrine into the plasma in patients with hypertension [Schlaich et al. 2004]. These renal sympathetic nerves serve to regulate sodium and water retention, renin release and renal blood flow [DiBona and Kopp, 1997]. Depending on whether efferent or afferent nerves are stimulated, different outcomes are observed:

Efferent nerves: efferent sympathetic stimulation results in water retention, sodium reabsoprtion (via α₁ adrenoceptors), increased renin release (via β₁ adrenergic receptors) and reduced renal blood flow secondary to renal vessel vasoconstriction [Schlaich et al. 2009; Doumas et al. 2010]. Evidence also demonstrates that efferent sympathetic activity has an established role in the development of hypertension.

Afferent nerves: less is known about renal afferent nerve activity; however, evidence supports a link between renal afferent nerves and sympathetic activity [Schlaich et al. 2012]. In renal disease, these afferent fibres are thought to be activated causing peripheral sympathetic nerve activity to be increased with resultant vasoconstriction and increased arterial pressure [Johns et al. 2011].

Disrupting renal sympathetic nerves through surgical sympathectomy (subdiaphragmatic splanchnicectomy) has historically demonstrated good results in BP reduction [Doumas and Douma, 2009]. Severe side effects of this technique including postural hypotension, syncope, impotence and mobility disturbance meant the procedure was relatively abandoned in the 1950s as newer pharmacological treatments emerged [Doumas et al. 2010]. More recent studies in dogs [Kassab et al. 1995] using open phenol-based chemical renal denervation further confirmed the link between sympathetic nerves and BP control.

Advances in the understanding of neural control of the kidney have demonstrated that nerves are located in the renal vessels, tubules and juxtaglomerular granular cells [ DiBona, 2000]. At the renal arteries, these nerves are situated in the adventitial layer [Pathak et al. 2012]. Therefore, given the clear link between sympathetic renal nerves and BP, a localized endovascular approach to disrupt these nerves should theoretically result in BP reduction without the unwanted side effects demonstrated in surgical sympathectomy. This is the basis for endovascular RSD.

Renal sympathetic denervation: the evidence

Treatment-resistant hypertension is defined as failure to achieve target BP (normally <140/90 mmHg or <130/80mm Hg in patients with diabetes mellitus or chronic kidney disease) despite concomitant full dose use of three antihypertensives, one of which should be a diuretic [Chobanian et al. 2003]. The two largest studies looking at RSD in treatment-resistant hypertension used a modified BP cutoff of 160 mmHg or more (Esler et al. 2010; Symplicity HTN-1 Investigators, 2011].

The majority of evidence for endovascular RSD has been using the Symplicity catheter system invented by Ardian (Mountain View, CA, USA) but acquired by Medtronic (Minneapolis, MN, USA) in 2011 [Medtronic, 2011]. The procedure involves endovascular access via the femoral artery with advancement of the Symplicity catheter into the renal artery. The device is connected to a RF generator which applies RF ablations of 8 W or less lasting up to 2 min each. To ensure maximum nerve ablation, up to six RF ablations are applied at a different longitudinal and rotational position [Krum et al. 2009].

Proof-of-principle trial

The first major body of evidence for RSD was published in 2009 by Krum and colleagues [Krum et al. 2009]. This study was an international proof-of-principle, nonrandomized trial of 50 patients with treatment-resistant hypertension [ClinicalTrial.gov identifier: NCT00483808 and NCT 00664638]. Of the 50 patients, 5 were excluded due to abnormal renal artery anatomy (e.g. dual renal arteries). Therefore 45 patients underwent RSD using the Symplicity catheter system. Primary outcomes measured included BP and safety data. Secondary outcomes were measured in some of the patients and included the effects of the procedure on norepinephrine spill over (a marker of sympathetic overactivity) and renal function. In patients undergoing the procedure (n = 45), BP at enrolment was 177/101 mmHg and they were taking an average of 4.7 antihypertensives.

Primary outcomes

Office BP measurements at 1, 3, 6, 9 and 12 months were −14/−10, −21/−10, −22/−11, −24/−11, −27/−17 mmHg respectively. In comparison, BPs of the five patients who were excluded from the study during 1-, 3-, 6- and 9-month follow up were +3/−2, +2/+3, +14/+9, +26/+17. These numbers appear favourable, but multiple patients were lost to follow up; at 9 months, only n = 9 in the treated group and n = 2 in the untreated group were available. These limited numbers represent one of this trial’s weak points.

Secondary outcomes

Norepinephrine spill over rates were studied in 10 patients, in which a mean reduction of 47% was demonstrated. This group demonstrated a 6-month BP reduction of 22/12 mmHg. Paired baseline with 6-month follow up estimated glomerular filtration rate (eGFR) (ml/min/1.73 m²) measurements in 25 patients demonstrated a change from 79 to 83 ml/min/1.73 m² respectively.

Krum and colleagues acknowledge the weaknesses in their proof-of-principle trial [Krum et al. 2009]. First, 13% of patients had minimal BP reduction, which suggests sympathetic overactivity is not the culprit in all cases of treatment-resistant hypertension, or the Symplicity RSD system failed to ablate the nerves adequately. Second, BP measurements were not all consistent; some were office based while others were ambulatory. The white-coat effect in office-based BP readings has an established etiologic role in treatment hypertension; approximately one-quarter of patients with office-based measurements of resistant hypertension achieve the target BP using ambulatory measurements [Sarafidis and Bakris, 2008; Brown et al. 2001]. The causes of treatment-resistant hypertension are multifactorial. Doumas and colleagues point out that this proof-of-principle trial included patients without clarifying the potential etiology of treatment resistance [Doumas and Douma, 2009]. Thereby, people with white-coat hypertension could have been included in the dataset, which may not only skew results but also place this group at unnecessary risk of an invasive procedure. Third, patients may have adjusted their antihypertensive regime during the follow-up period, which casts a realm of uncertainty on the published data. Certainly, the lack of a control group, low sample size and 12-month follow-up data represent further weaknesses.

Symplicity HTN-1

This study is an expansion in follow up and cohort size of the aforementioned proof-of-principle trial [Symplicity HTN-1 Investigators, 2011]. Study methodology remained nonrandomized with 153 treated patients. Baseline mean office BP was 176/98 mmHg and patients were taking a mean of five antihypertensives. Postprocedure office BP at 1, 3, 6, 12, 18 and 24 months were reduced by 20/10, 24/11, 25/11, 23/11, 26/14 and 32/14 respectively.

This study supports the notion that denervation persists at least until 24 months. Weaknesses in the study are similar to the original proof-of-principle trial. In particular, small follow-up numbers at 24 months (n = 18) and the effect of changes in the antihypertensive regime during the follow-up period need to be considered. The authors present censored data to account for patients who increased their antihypertensive regime, which demonstrates only a small difference in BP change.

Symplicity HTN-2

Symplicity HTN-2 is an international multicentre prospective randomized trial [ClinicalTrials.gov identifier: NCT00888433] [Esler et al. 2010]. Patient inclusion criteria required a baseline BP of at least 160 mmHg or at least 150 mmHg in patients with type 2 diabetes. A total of 106 patients were randomly assigned in a one-to-one ratio using sealed envelopes to the treatment group (n = 52) or control group (n = 54). The treatment group underwent catheter-based renal denervation using the Symplicity catheter system while the control group maintained previous treatment. The primary endpoint of the study was seated office-based measurement of systolic BP at 6 months.

At baseline, the treatment group had a mean BP of 178/97 mmHg and were taking a mean of 5.2 antihypertensives. The control group’s mean baseline BP was 178/98 mmHg while taking a mean of 5.3 antihypertensives.

Follow up at 6 months in 94% (n = 49) of the treatment group demonstrated an office-based BP reduction of 32/12 mmHg. No significant change from baseline was shown in the control group. Interestingly, 20 treatment patients had 24 h ambulatory BP measurements taken which showed a 6-month mean reduction of 11/7 mmHg. Ambulatory measurements in 25 controls showed no average change during the 6 months. Since publication, 12-month follow-up data were presented in 2012 and showed a sustained mean BP reduction of 28.1/9.7 mmHg in the treatment group [Esler et al. 2012].

Like its predecessors, Symplicity HTN-2 has faced critique of its study design. Doumas and colleagues pointed out that potential bias could have been reduced by introducing double blinding with a sham operation [Doumas et al. 2010]. These authors also suggested that secondary and white-coat hypertension as exclusion criteria could improve the study’s methodology.

Procedural safety data

Overall the Symplicity trials have demonstrated a good safety profile for RSD. In the proof-of-principle trial, pain was reported during application of the RF ablation but did not persist post procedure. There were two procedural complications: renal artery dissection upon Symplicity catheter placement (before application of RF energy) and pseudoaneurysm formation at the femoral entry site. Follow-up imaging of the renal vessels using angiography and magnetic resonance angiography (MRA) demonstrated an abnormality on MRA in one patient in the form of a nonobstructive irregularity of the renal vessel in an untreated area.

As Symplicity HTN-1 builds upon the proof- of-principle trial, the previously reported renal artery dissection and pseudoaneurysm formation are included as complications. In addition, two further pseudoaneurysms/haematomas were reported at the femoral access site. Follow-up imaging in 81 patients at 6 months demonstrated an abnormality of the renal vessels in one patient with progression of a pre-existing renal artery stenosis. This abnormality was described as being away from the site of RF energy application.

Symplicity HTN-2 further supports the safety profile of the Symplicity RSD as no serious complications were observed. The authors reported 13% (n = 7) had intraprocedural bradycardia that was successfully managed with atropine. Post procedure the following complications were observed: pseudoaneurysm treated with manual compression (n = 1); drop in BP requiring reduction in antihypertensives (n = 1); urinary tract infection (n = 1); extended hospital stay for evaluation of paraesthesias (n = 1); back pain that resolved with analgesics (n = 1).

Follow up at 6 months of mean renal function showed no change from baseline in the treatment or control group. Imaging in the form of renal duplex, magnetic resonance imaging (MRI) or computed tomography (CT) angiography was undertaken in 43 patients at 6 months. One abnormality was detected: possible progression of a pre-existent atherosclerotic lesion, which was identified at a site away from the location of RF energy application.

Uncertainty and limitations of clinical knowledge

The Symplicity trials demonstrate provocative data, highlighting the potential BP reduction of RSD in the management of treatment-resistant hypertension [Bunte, 2011]. However, there remain areas of concern based on theoretical risks and reported results [Gu et al. 2012].

Renal vessel damage

Follow-up imaging using MRI, CT, renal duplex or catheter angiography has not reported any abnormalities that appear directly related to application of RF energy to the vessel wall. The lack of consistency in use of imaging modality makes direct comparison between studies difficult. Furthermore, no details are provided about how imaging data were interpreted. These imaging modalities can only provide limited information and histological analysis of the renal vessels is necessary to fully ascertain potential damage. In human studies, this poses ethical implications that are difficult to overcome. Rippy and colleagues reported a histological study in seven swine that underwent renal artery RF ablation using the Symplicity catheter system [Rippy et al. 2011]. At 6 months, swine were euthanatized and histological analysis performed of the renal vessels along with examination of the surrounding genitourinary system. The renal vessels demonstrated evidence of nerve damage mainly through fibrosis involving the total media and underlying adventitia (location of sympathetic nerves). This finding supports the effectiveness of RF ablation. No clinically significant adverse sequelae (e.g. renal arterial stenosis or thrombosis) were observed. Furthermore, at 6 months, no inflammatory changes were seen, suggesting healing of the renal vessel was complete. These data are reassuring in supporting the safety profile, but the limited sample size and the lack of further evidence restricts its wider scale applicability. More studies are required and follow-up imaging in patients undergoing the procedure should be standardized.

Ambulatory versus office-based blood pressure measurement

The differences between ambulatory and office-based BP measurement were seen from the initial proof-of-principle trial. Twelve patients had ambulatory BP measurements at follow up longer than 30 days after bilateral denervation; nine demonstrated response to treatment with office-based reduction in systolic BP of −27 mmHg. The 24 h ambulatory systolic BP reduction in this group of patients was −11 mmHg. Symplicity HTN-2 showed a similar trend, with a reported mean office-based BP reduction of 32/12 mmHg, but 24 h ambulatory measurements in 20 patients showed 11/7 mmHg.

Other studies outside the Symplicity trials have demonstrated 6-month ambulatory BP reductions of 11.3/4.1 mmHg [Kaltenbach et al. 2012] and 9/4 mmHg [Plehn, 2012]. Bertog and colleagues suggested the discrepancy between ambulatory and office-based BP may be due to more pronounced activation of the sympathetic nervous system in office-based BP measurement, which results in a greater BP difference after renal denervation [Bertog et al. 2012]. This question will need to be addressed in future research.

Nonresponders

Of further concern is the concept of nonresponse to treatment. The initial proof-of-principle trial defined nonresponders as achieving a BP reduction of less than 10 mmHg, of which six such patients (13%) were identified. Symplicity HTN-2 showed no decrease in systolic BP in five patients (10%) at 6-month follow up. Potential reasons for this could include failure of the Symplicity catheter system, or some subtypes of treatment-resistant hypertension may not respond to RF ablation. The causative factors of nonresponders should be a focus of further research to ensure patients are appropriately selected for treatment. Grouping patients by subtype of resistant hypertension, in particular when secondary or white-coat hypertension is implicated, may help clarify the current ambiguity. Briasoulis and Brakis point out that the study groups in the Symplicity trials were unequal as the treatment group had more men, higher rates of diabetes and coronary artery disease [Briasoulis and Bakris, 2012]. Although this is unlikely to account for the nonresponder rate, it highlights the need for clarification of precise patient groups in which RSD may be effective. Further studies may also wish to assess the value of RSD in duplicate renal artery systems, as this has been an exclusion criterion of current studies.

Combining the risk of nonresponse with the lower BP reductions seen with ambulatory measurements casts a new light on renal denervation data. Patient selection therefore requires careful risk–benefit analysis, and the inclusion criteria of treatment-resistant hypertension may need evolution.

Durability of treatment effect and possible reinnervation

Current follow-up data have reached a range of approximately 24−36 months. Drawing conclusions on a relatively short time period with a limited sample size is difficult. Of particular concern is the concept of treatment durability. Symplicity HTN-1 and HTN-2 have shown sustained BP reduction at 24 months, but how can it be guaranteed to last?

Using historical data, Smithwick and Thompson demonstrated long-term efficacy of surgical sympathectomy for treating hypertension [Smithwick and Thompson, 1953; Smithwick, 1955; Bunte, 2011]. This is further supported by data from Peet demonstrating the maintained antihypertensive effect of surgical sympathectomy [Peet, 1948; Doumas et al. 2010] and together this evidence favours the durability of the Symplicity trial data. However, Newcombe and colleagues, in a series of 212 patients who underwent surgical sympathectomy, add further insight. In Newcombe’s series, almost all patients saw a reduction in diastolic BP of 15–45 mmHg which lasted for weeks to months. Yet on follow up, only 27% maintained a reduction of at least 15 mmHg [Newcombe et al. 1959].

Using the example of transplanted organs, the Symplicity trials point out that nerve fibres may regrow but recovery of sympathetic function has not been demonstrated in humans [Hansen et al. 1994; Esler et al. 2010]. This is further supported by a study in rats that showed some reinnervation may occur in a transplanted kidney, but functionally it remains in a state of persistent sympathetic denervation [Grisk et al. 2001]. So far the Symplicity data are reassuring from a reinnervation stand point. Longer-term follow up will be essential to observe nerve regrowth and its potential consequences as well as other biological mechanisms that could impact the denervation durability.

Renal function: a cause for concern?

Uder and colleagues have raised concerns over RSD’s potential negative impact on renal function [Uder et al. 2011]. In Symplicity HTN-1, at 24-month follow up eGFR data were available in 10 patients, which showed a change by −16.0 ml/min per 1.73 m². In a patient with pre-existing renal impairment, this level of decline could have profound clinical consequences. It is unclear why these patients suffered a deterioration in renal function, but it may have been related to changes in their medications rather than the RSD itself. Are the renal sympathetic nerves needed to preserve renal function? Given that transplanted kidneys (totally denervated) are able to maintain electrolyte and homeostatic balance, it appears these nerves are not needed [Schlaich et al. 2010; Uder et al. 2011].

Symplicity HTN-2 demonstrated that two treatment patients suffered a decrease of more than 25% in their eGFR. These changes in renal function raised important concerns as the aetiology remains unclear. These data highlight the need for even more careful patient selection to ensure adequate renal functional reserve. Recent research has suggested that renal haemodynamics and renal function are not adversely impacted by RSD [Mahfoud et al. 2012]. Further research in patients with chronic kidney disease stage 3 or 4 also supports that RSD can be undertaken safely in these potentially higher risk patient groups [Blankestijn and Joles, 2012]. Despite these reassuring data, larger patient numbers are needed before definitive conclusions can be drawn.

Symplicity HTN-3

With the above-mentioned areas for concern, more research is needed. The Symplicity HTN-3 trial is currently in recruitment and may shed light on previous ambiguity. This trial is a multicentre, prospective, single-blind, randomized, controlled study. The primary outcome is office-based systolic BP at 6 months. The secondary outcome will assess average 24 h ambulatory BP. These data will be of great use to clarify current discrepancies between ambulatory and office-based readings. The HTN-3 trial improves upon previous methodologies: subjects will be blinded to randomization using sedation, sensory isolation and lack of familiarity with the procedure, all patients will undergo screening renal angiography, but only the treatment group will receive RF ablation via the Symplicity catheter system. The estimated completion date is March 2013 [ClinicalTrials.gov identifier: NCT01418261].

Devices

The majority of evidence for RSD has been derived with the Medtronic Symplicity catheter system. Its initial success and large market potential has inspired other companies to develop further methods for renal denervation [Rocha-Singh, 2012]. Anecdotal reports online suggest up to 40 renal denervation devices are currently in development [MedicalDevicesToday, 2012]. From a business perspective, the global renal denervation market is expected to reach US$561 million by 2015. The drivers accounting for this growth include increased prevalence of hypertension, further technological advancement and the application of renal denervation in treating other diseases [TechNavio, 2012].

Reviewing all available devices is beyond the scope of this article. A brief summary of the five devices that currently hold Conformité Européenne (CE) are included and other devices in development using innovative approaches to denervation are introduced. Table 2 provides a brief summary of the CE marked devices.

Table 2.

Conformité Européenne marked renal denervation devices.

Company	Medtronic	ReCor Medical	Covidien	St Jude Medical	Vessix Vascular
Device Name	Symplicity (Figure 1(a, b)	Paradise (Figure 2)	OneShot (Figure 3)	EnligHTN (Figure 4)	V2 (Figure 5)
Catheter size	6 F	6 F	7 F	8 F	Variable
Method of denervation	Radiofrequency ablation	Ultrasound energy	Radiofrequency ablation	Radiofrequency ablation	Radiofrequency ablation

Medtronic Symplicity renal denervation system

The Medtronic Symplicity System, originally developed by Ardian, consists of a catheter and a RF generator. The Symplicity catheter is 6 F compatible and made for access to the renal arteries. Once within the vessel, the RF generator delivers RF energy to ablate the nerves within the wall. The catheter tip requires multiple rotations and application of further RF energy in a spiral pattern to ensure all nerves are evenly exposed [Medtronic, 2012].

Medtronic are current leaders in the RSD market, having been involved in the largest trials to date: Symplicity HTN-1 and HTN-2. Symplicity HTN-3 will add to previous data and Medtronic are also involved in further trials, for example, Symplicity HF to assess the value of RSD in patients with chronic heart failure and renal impairment [Bhatt and Bakris, 2012].

Figure 1(a) and (b) demonstrate the Symplicity handle and RF generator respectively.

Figure 1.

(a) Medtronic Symplicity handle. (b) Medtronic Symplicity generator. Images are provided courtesy of Medtronic.

ReCor Medical Paradise

ReCor Medical Paradise (Menlo Park, CA, USA) uses a component system with a 6 F compatible catheter and a generator. Unlike Symplicity, the Paradise system uses ultrasound instead of RF energy. At the distal end of the catheter is an ultrasound transducer contained within an inflatable balloon that once activated will deliver uniform circumferential ultrasound energy to cause denervation. The proposed advantage of the Paradise system is a shorter energy delivery cycle due to its circumferential nature and therefore less treatment sites are required. Additionally, the catheter balloon allows cooled fluid to circulate during energy delivery, which may theoretically reduce endothelial wall damage [ReCor Medical, 2012b].

Evidence published in 2012 in 11 patients who underwent transcatheter renal denervation using the Paradise system showed a 3-month average reduction of office and home BP of −36/−17 and −22/−12 mmHg respectively [Mabin et al. 2012]. These results are reported to be comparable with BP reductions seen with RF ablation seen in HTN-1 and HTN-2. ReCor Medical has reported 6-month follow-up data in six patients in a company press release demonstrating an average of 33 mmHg systolic BP reduction [ReCor Medical, 2012a]. Further trials are currently recruiting, for example Renal DenervatIon by Ultrasound Transcatheter Emission (REALISE) [Clinical Trials.gov identifier: NCT01529372] and will help to further evaluate this technology.

Figure 2 demonstrates the ReCor Medical Paradise catheter.

Figure 2.

ReCor Paradise. Image provided courtesy of ReCor Medical.

Covidien’s OneShot renal denervation device

The Covidien OneShot system (Dublin, Ireland), previously Maya Medical (Saratoga, CA, USA) is another RF-based system. The system includes the OneShot irrigated RF balloon catheter (7 F) and OneShot RF generator. The catheter can be delivered over a standard 0.014’ guidewire and is available in 5 mm, 6 mm and 7 mm balloon diameter. Energy is delivered via a spiral electrode that is surrounded by irrigation holes to allow cooling of nontreated regions [Covidien, 2012]. It is reported that the OneShot system allows a single RF treatment per vessel with improved treatment pattern consistency due to the spiral electrode configuration [Rocha-Singh, 2012].

No current citable clinical data exist for the Covidien OneShot system. The Rapid Renal Sympathetic Denervation for Resistant Hypertension (RAPID) study is currently recruiting [ClinicalTrials.gov identifier: NCT01520506] and is expected to be completed in December 2013.

Figure 3 demonstrates the Covidien OneShot catheter.

Figure 3.

Covidien OneShot. Image provided courtesy of Covidien.

St Jude Medical EnligHTN

The St Jude Medical EnligHTN renal denervation system (Little Canada, MN, USA) includes an 8 F renal artery ablation catheter that connects to the EnligHTN RF ablation generator. The catheter tip contains four electrodes which are sequentially activated once inside the renal artery. The reported advantage to this shape is a more consistent placement with reproducible ablation patterns. The sequential activation and reported minimal need for catheter repositioning may potentially reduce procedure time [St Jude Medical, 2012a].

There are limited citable clinical data for the EnligHTN system. Currently, the only data are available through a St Jude Medical Press release that reports outcomes in 47 patients with treatment-resistant hypertension. Thirty-day outcomes demonstrated an average 28-point systolic reduction in BP (baseline average of 176/96 mmHg reduced to 148/87 mmHg) [St Jude Medical, 2012b]. Clinical details regarding the trial are limited, therefore appropriate critical appraisal cannot be exercised. St Jude Medical is involved with the Safety and Efficacy Study of Renal Artery Ablation in Resistant Hypertension Patients (EnligHTN 1) [ClinicalTrials.gov identifier: NCT01438229] with an estimated completion date of March 2013.

Figure 4 demonstrates the St Jude EnliHTN catheter.

Figure 4.

St Jude Medical EnligHTN. Image provided courtesy of St Jude Medical.

Vessix Vascular V2 System

The Vessix Vascular V2 System (Laguna Hills, CA, USA) consists of the V2 catheter and a bipolar RF generator. The catheter (size variable) is an inflatable balloon with electrodes which are able to deliver RF into the renal vasculature, thereby causing denervation. The proposed benefits of this system relate to reduced treatment time of 30 seconds per artery [Vessix Vascular, 2012, nd].

No published data are currently available for the V2 system. The Treatment of Resistant Hypertension Using a Radiofrequency Percutaneous Transl uminal Angioplasty Catheter (REDUCE-HTN) trial [ClinicalTrials.gov identifier: NCT01541865] is currently recruiting patients and is estimated to complete in December 2014.

Figure 5 demonstrates part of the Vessix Vascular V2 system.

Figure 5.

Vessix Vascular V2. Image provided courtesy of Vessix Vascular.

The future of renal denervation?

Historically, guanethidine had been used in the management of hypertension but was largely abandoned due to side effects [Moser, 2006]. With improved endovascular delivery mechanisms, smaller doses can be delivered directly to a target side, thereby minimizing systemic side effects. The Bullfrog Microinfusion Catheter by Mercator MedSystems (San Leandro, CA, USA) allows localized administration of guanethidine monosulphate to the renal arteries’ adventitia, resulting in chemical sympathectomy [Rocha-Singh, 2012]. More research is needed to establish the role of this technology.

Kona Medical (Campbell, CA, USA) has proposed a method of externally delivered, noninvasive, focused ultrasound that could ablate renal nerves [Rocha-Singh, 2012; KonaMedical, 2012]. This technology is currently recruiting patients in a phase I clinical trial: A Safety Evaluation of Renal Denervation Using Focused Therapeutic Ultrasound on Patients With Refractory Hypertension [ClinicalTrials.gov identifier: NCT01638195] and is expected to be completed in September 2013.

Pharmacological, RF, ultrasound and more recently cryoablation [Prochnau et al. 2011] are all proposed technologies in the rapidly evolving field of renal denervation. With these innovations, clinicians will have a growing choice of available devices, making appropriate selection a potentially complex process. Despite the excitement associated with these innovative technologies, careful analysis of data through continued rigorous clinical trials must continue to ensure patient safety remains the top priority while hopefully identifying new ways to reduce the global burden of hypertension.

Broader applications of renal sympathetic denervation

Sympathetic overactivity has been implicated in disease other than treatment-resistant hypertension, including heart failure, essential hypertension, insulin resistance, diuretic resistance and cardiorenal disorders [Sobotka et al. 2011; Schlaich et al. 2012; Egan, 2011]. Multiple studies have been carried out to investigate each of these links, and so far, data point to wider applicability of RSD outside of only treatment-resistant hypertension. Table 3 summarizes potential future applications of RSD.

Table 3.

Potential future applications of renal sympathetic denervation.

Heart failure

Sleep apnoea

Glycaemic control

Diuretic resistance

Other cardiorenal disorders

In a study of 46 patients who underwent bilateral RSD, Brandt and colleagues showed the procedure could reduce left ventricular mass, improve diastolic function and other cardiac functional parameters [Brandt et al. 2012]. Given these cardiac implications, of potential concern could be RSD’s ability to negatively impact necessary physiological responses under stressful situations, for example, exercise, or so-called chronotropic competence. Ukena and colleagues undertook cardiopulmonary assessment at baseline and at 3 months following RSD and demonstrated reduced BP during exercise but no compromise of chronotropic competence [Ukena et al. 2011]. Therefore, RSD may have a role in cardiac health; however, current claims require validation through more research.

The wider potential effects of RSD were recently studied by Witkowski and colleagues and BP, sleep apnoea and glycaemic control were all analysed [Witkowski et al. 2011]. At 6-month follow up of 10 patients after RSD, BP was reduced, in keeping with previously reported data (median −34/−13 mmHg), but interestingly, decreases were also seen in haemoglobin A1C levels and apnoea–hypopnoea index. This study only demonstrates proof-of-concept data and the reasons for the change in sleep apnoea are not fully understood. However, the observed effect on glucose metabolism has also been studied by others, including Mahfoud and colleagues, who demonstrated improved glucose metabolism and insulin sensitivity in patients who underwent RSD [Mahfoud et al. 2011]. Overall, these expanded applications of RSD represent exciting opportunities for further research.

Conclusion

RSD using RF energy represents the new frontier in a long history of hypertension management. Current data derived from the Symplicity trials are promising, but many unanswered questions remain. Future larger scale, improved study designs, for example, Symplicity HTN-3, may help clarify current ambiguities.

Innovation is necessary to reduce the global bur den of hypertension and multiple renal denervation devices are being developed to address this need. As research progresses, the link between the sympathetic nervous system, the kidney and other diseases may become clearer, thus expanding the clinical applicability of renal denervation.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

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Renal denervation for treatment-resistant hypertension

Abstract

Keywords

Introduction

Historical perspective: from 2600 BC to catheter-based renal sympathetic denervation

Rationale of renal sympathetic denervation

Renal sympathetic denervation: the evidence

Proof-of-principle trial

Primary outcomes

Secondary outcomes

Symplicity HTN-1

Symplicity HTN-2

Procedural safety data

Uncertainty and limitations of clinical knowledge

Renal vessel damage

Ambulatory versus office-based blood pressure measurement

Nonresponders

Durability of treatment effect and possible reinnervation

Renal function: a cause for concern?

Symplicity HTN-3

Devices

Medtronic Symplicity renal denervation system

ReCor Medical Paradise

Covidien’s OneShot renal denervation device

St Jude Medical EnligHTN

Vessix Vascular V2 System

The future of renal denervation?

Broader applications of renal sympathetic denervation

Conclusion

Footnotes

Funding

Conflict of interest statement

References