|Year : 2016 | Volume
| Issue : 2 | Page : 45-49
Renal denervation therapy for hypertension: Current and future perspectives
Mohd Aslam Khan1, C Raghu2
1 Department of Cardiology, Omni Hospitals, Hyderabad, Telangana, India
2 Department of Cardiology, Prime Hospitals, Hyderabad, Telangana, India
|Date of Web Publication||6-Jun-2016|
Mohd Aslam Khan
Department of Cardiology, Omni Hospitals, Opposite PVT Market, Dilsukhnagar, Hyderabad - 500 035, Telangana
Source of Support: None, Conflict of Interest: None
Hypertension (HTN) is the most common chronic cardiovascular disease with increasing prevalence and morbidity in India as well as worldwide. Despite the availability of different effective subgroups of antihypertensive drugs, few patients may not respond and causes significant morbidity. Resistant HTN is defined as blood pressure above target goals in patients using three different antihypertensive drugs in maximum tolerated doses, including a diuretic. Prevalence of resistant HTN varies from 8% to 18% of all hypertensives. Increased sympathetic nervous system activity has been identified as one potential cause for resistant HTN. Catheter-based renal denervation (RDN) has been studied in different subgroups of patients for the treatment of resistant HTN. Clinical data for usefulness of RDN till date show mixed results, and overall indications for procedure are unclear. Different observational studies and randomized, controlled trials (Symplicity HTN-2, Prague-15, RSD-LEIPZIG, and DENERHTN) support both safety and efficacy of procedure, whereas some smaller studies and large Symplicity HTN-3 trial failed to show the superiority of RDN when compared to medical therapy alone. The aim of the present review is to provide an overview of RDN therapy in the treatment of HTN and current status of this procedure in management of such patients.
Keywords: Catheter-based renal denervation, resistant hypertension, Symplicity
|How to cite this article:|
Khan MA, Raghu C. Renal denervation therapy for hypertension: Current and future perspectives. Heart India 2016;4:45-9
| Introduction|| |
Hypertension (HTN) is a highly prevalent and most frequent chronic cardiovascular disease in India as well as worldwide.  Long-term prognosis suggests that up to 50% of the adult population will suffer from HTN using the standard guideline definition.  Prevalence of resistant HTN varies from approximately 8% to 18% of all patients. Resistant HTN has been defined as - uncontrolled blood pressure (BP) (>140/90 mmHg; >130-139/80-85 mmHg in patients with diabetes mellitus; >130/80 mmHg in chronic kidney disease with proteinuria) despite the use of at least three antihypertensive drugs of different classes, including a diuretic, at maximum recommended or tolerated dosages. ,, Pseudoresistance is often encountered due to poor adherence, white-coat HTN, or inadequate drug combination. This should be differentiated from true resistance based on adequate history.  Secondary causes of resistant HTN should be excluded by systemic evaluation of these patients as they may occur in 20% of these. , There is ample evidence that sympathetic nervous system contributes to the development and progression of almost all phenotypes of HTN, therefore this has become the target for new therapeutic strategies. ,
Therefore, we reviewed the current status of renal denervation (RDN) therapy as a modality for resistant HTN.
| Pathophysiology of renal sympathetic nervous system|| |
Increased sympathetic nervous activity has been attributed to various cardiovascular diseases such as HTN, heart failure, chronic kidney disease, metabolic syndrome, and diabetes mellitus. , Sympathetic nervous system provides the kidneys with efferent (thoraco-lumbar outflow) fibers and receives information for the central nervous system via afferent fibers by mechano- and chemo-receptors. Efferent fibers innervate the renal vasculature, tubular part of nephron, and juxtaglomerular renin-containing granular cells.  Efferent stimulation leads to tubular sodium retention, reduced renal blood flow, and renin release by juxtaglomerular apparatus. These effects influence short- and long-term BP regulation. 
| Renal denervation|| |
It is catheter-based, radiofrequency or ultrasound-based method to directly target the renal sympathetic nerves. In the current clinical practice, seven CE-certified RDN-catheters are available (Medtronic® Symplicity Flex, Spyral, St. Jude® EnligHTN, Vessix® The V2, Terumo® Iberis, Cardiosonic® TIVUS, and Recor® Paradise). New devices such as microneedle delivery of guanethidine or ethanol to target renal sympathetic nerves are also under investigation (e.g., Mercator Medsystems® Bullfrog infusion catheter).
After obtaining the vascular access (femoral or radial), catheter is inserted percutaneously and positioned to the distal segment of renal artery under fluoroscopy using guiding catheter (renal double curve or internal mammary catheter). Renal sympathetic nerves are more abundant in the anterior area of arterial ostium.  The arterial wall is focally heated up to a maximum of 70°C by means of high frequency or ultrasound energy. Focal heating destroys the renal sympathetic nerves located in adventitia. Heparin is given to achieve an activated clotting time of >250 s during the procedure. Common complications include renal artery edema/spasm which disappears within few hours. Rarely, renal artery perforation may occur.
Recently, external body delivery of focused ultrasound energy to the renal arteries has been used to accomplish renal sympathetic denervation. The Kona Medical sound surround system is a noninvasive treatment that delivers externally focused ultrasound to the renal nerves using Doppler-based ultrasound image guidance. This approach has shown promising results in early trials and animal studies; however, this approach is still in experimental stage. 
| Analysis of different trials|| |
The Symplicity HTN-1 (n = 150) was the first multicenter, proof-of concept and safety study for patients with resistant arterial HTN (mean age: 57 years) undergoing catheter-based RDN. Patients in the Symplicity HTN-1 study were heavily medicated, taking an average of five antihypertensive drugs, and were still poorly controlled (office BP 175/98 mmHg). The primary endpoint was peri-procedural and safety of the treatment (n = 45) after 1 and 12 months published in 2009 at the lancet after 4 weeks, a significant reduction of systolic and diastolic office BP by 14 and 10 mmHg has been described, which increased to 27 and 17 mmHg (P = 0.026) after 12 months. The recently presented 36-month long-term follow-up indicates a sustained BP-lowering effect of 32 and 14 mmHg (P < 0.01, n = 88), making a significant functional regrowth or re-innervation of the kidneys unlikely. A drop of 10 mmHg and more in systolic BP (response to treatment) were seen in 93% at the final report after 3 years. One new renal artery stenosis requiring stenting and three deaths unrelated to RDN occurred during the 3-year follow-up. As secondary endpoint, a reduction of renal norepinephrine spillover was significantly reduced by 47% (n = 10), providing direct evidence for the inhibition of sympathetic activation. 
Subsequently, the multicenter, prospective, randomized simplicity HTN-2 trial was conducted. Patients who had a baseline systolic BP of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo RDN with previous treatment or to maintain previous treatment alone (control group) at 24 participating centers. About 106 (56%) of 190 patients screened for eligibility were randomly allocated to RDN (n = 52) or control (n = 54) groups between June 2009 and January 2010. About 49 (94%) of 52 patients who underwent RDN and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based BP measurements in the RDN group reduced by 32/12 mmHg (standard deviation 23/11, baseline of 178/96 mmHg, P < ·0001), whereas they did not differ from baseline in the control group (change of 1/0 mmHg [21/10], baseline of 178/97 mmHg, P = ·77 systolic and P = ·83 diastolic). Between-group differences in BP at 6 months were 33/11 mmHg (P < ·0001). At 6 months, 41 (84%) of 49 patients who underwent RDN had a reduction in systolic BP of 10 mmHg or more, compared with 18 (35%) of 51 controls (P < ·0001). No serious procedure-related or device-related complications were noted and occurrence of adverse events did not differ between groups; one patient who had RDN had possible progression of an underlying atherosclerotic lesion, but required no treatment. 
A number of observational studies as well as national and international registries confirmed the results of the first-in-man trials. However, the randomized, blinded, sham-controlled Symplicity HTN-3 trial failed to demonstrate the superiority of RDN as compared to a sham procedure in reducing BP after 6 months.  At 6 months follow-up, the average decrease in office and ambulatory systolic BP in the RDN group was 14 and 7 mmHg, as compared to a fall of 12 and 5 mmHg in the control group, respectively. Neither office nor ambulatory differences in BP met the prespecified criteria for statistically significant superiority. Several possible explanations, such as inadequate patient selection, low operator experience, and inadequate technical performance of the procedure have been discussed extensively. , In line, Kandzari et al. showed a subgroup analysis of Symplicity HTN-3 that higher number of ablations and quadrantic ablation in all four quadrants of the arterial wall cross-sections were associated with significant greater ambulatory BP reduction compared to sham control group [Figure 1]. 
|Figure 1: (a and b) Systolic blood pressure change at Symplicity hypertension-3 study at 6 months according to ablation pattern|
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Few data are available with regard to the effectiveness of renal sympathetic denervation in patients with resistant HTN, yet only mildly elevated BP. In recently published randomized RSD- LEIPZIG trial which included 71 patients with resistant hypertension and slightly elevated BP (day-time systolic pressure, 135-149 and diastolic pressure, 90-94 mm Hg on 24-hour ambulatory measurement) were randomized in a 1:1 ratio to either renal sympathetic denervation with the Symplicity Flex Catheter (Medtronic) or an invasive sham procedure. The primary efficacy endpoint was the change in 24-h systolic BP at 6 months between groups in the intention-to-treat population. A total of 71 patients underwent randomization. Baseline daytime systolic BP was 144.4 ± 4.8 mmHg in patients assigned to denervation and 143.0 ± 4.7 mmHg in patients randomized to the sham procedure. The mean change in 24-h systolic BP in the intention-to-treat cohort at 6 months was −7.0 mmHg (95% confidence interval, −10.8-−3.2) for patients undergoing denervation and − 3.5 mmHg (95% confidence interval, −6.7-−0.2) in the sham group (P = 0.15). In the per-protocol population, the change in 24-h systolic BP at 6 months was − 8.3 mmHg (95% confidence interval, −11.7-−5.0) for patients undergoing denervation and − 3.5 mmHg (95% confidence interval, −6.8-−0.2) in the sham group (P = 0.042). In patients with mild resistant HTN, renal sympathetic denervation failed to show a significant reduction in the primary endpoint of 24-h systolic BP at 6 months between groups in the intention-to-treat analysis. 
The The Renal denervation for Hypertension trial (DENERHTN) was a prospective, randomized controlled trial to investigate the effect of single electrode Symplicity catheter-based RDN on BP in 121 patients with uncontrolled HTN. All eligible patients aged 18-75 years received a standardized triple antihypertensive treatment (indapamide 1·5 mg, ramipril 10 mg [or irbesartan 300 mg], and amlodipine 10 mg daily) for 4 weeks to confirm treatment resistance by ambulatory BP monitoring before randomization.  Patients were then randomly assigned (1:1) to receive RDN plus an standardized stepped-care antihypertensive treatment (SSAHT) regimen (RDN group) or the same SSAHT alone (control group). The randomization sequence was generated by computer, and stratified by centers. For SSAHT, after randomization, spironolactone 25 mg/day, bisoprolol 10 mg/day, prazosin 5 mg/day, and rilmenidine 1 mg/day were sequentially added from months two to five in both groups if home BP was more than or equal to 135/85 mmHg. The primary endpoint was the mean change in daytime systolic BP from baseline to 6 months as assessed by ambulatory BP monitoring. The primary endpoint was analyzed blindly. The primary efficacy endpoint was met, with a reduction of mean ambulatory day time systolic BP by 16 mmHg following RDN, as compared to a decreased BP by 10 mmHg in the control group after 6 months. 
Finally, the PRAGUE-15 TRIAL was randomized; multicenter study compared the relative efficacy of RDN versus pharmacotherapy alone in patients with true resistant HTN and assessed the effect of spironolactone addition. A total of 106 patients with true resistant HTN were enrolled in this study: Fifty-two patients were randomized to RDN and 54 patients to the spironolactone addition, with baseline systolic BP of 159 ± 17 and 155 ± 17 mmHg and average number of drugs 5.1 and 5.4, respectively.  Twelve-month results are available in 101 patients. The intention-to-treat analysis found a comparable mean 24-h systolic BP decline of 6.4 mmHg, P = 0.001 in RDN versus 8.2 mmHg, P = 0.002 in the pharmacotherapy group. Per-protocol analysis revealed a significant difference of 24-h systolic BP decline between complete RDN (6.3 mmHg, P = 0.004) and the subgroup where spironolactone was added, and this continued within the 12 months (15 mmHg, P = 0.003). Renal artery computed tomography angiograms before and after 1 year post-RDN did not reveal any relevant changes. This study shows that over a period of 12 months, RDN is safe, with no serious side effects and no major changes in the renal arteries. RDN in the settings of true resistant HTN with confirmed compliance is not superior to intensified pharmacological treatment. Spironolactone addition (if tolerated) seems to be more effective in BP reduction.
| Future perspective|| |
RDN therapy is usually used as a last option in patients with resistant HTN. These patients are characterized by a high prevalence of target organ damage, including renal fibrosis and vascular stiffness, which are difficult to reverse whatever methods are used. To improve the efficacy of RDN, the procedure needs to be targeted upon a population with high probability of BP response.  This is complicated by the complex pathophysiology of HTN, lack of clinically applicable, reliable, easy, and reproducible measures of increased sympathetic activity that could be used to guide treatment decisions, and the absence of preprocedural useful predictors of the long-term BP response following RDN.
However, there is clear evidence indicating that younger patients tend to have greater sympathetic nervous system activation than older patients with HTN [Figure 2].  Second, the arterial wall in younger patients might be more responsive to RDN-induced changes in sympathetic tone, since vascular remodeling might be still in a reversible state. Isolated systolic HTN (ISH), defined as office systolic BP ≥ 140 mmHg and diastolic BP < 90 mmHg, is the predominant hypertensive subtype in elderly patients. ISH is characterized by an increased aortic stiffness, increased pressure wave reflections, and low pulse pressure amplification. Data indicate that ISH is associated with limited response to RDN, as it could be expected from drug trials. Accordingly, increased central pulse pressure indicates aortic stiffness and is related to worse BP response after RDN.  Clearly, there is a need for more research on this topic and there are still nonidentifiable predictors of BP response following RDN therapy.
|Figure 2: Sympathetic nerve activities according to age in patients with hypertension|
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Newer trials and studies are on the way, in same line, another multicenter, prospective, single-blind, randomized, placebo-controlled REDUCE-HTN: REINFORCE study is enrolling patients in the US, who are not on medication, and will focus primarily on mean reduction in average 24 h ambulatory systolic BP at 8 weeks postrandomization. Other multicenter, prospective, single-blind, randomized, sham-controlled SPYRAL HTN-OFF MED (NCT 02439749) and SPYRAL HTN-ON MED (NCT02439775) studies will start enrolling approximately 100 patients with moderate-to-severe HTN. These studies will be conducted in around twenty different centers in the US, Europe, Japan, and Australia. The former study will evaluate the effect of RDN on BP in patients not receiving any antihypertensive medication, while latter study in patients with uncontrolled BP despite the intake of three commonly used antihypertensive drugs.
| Conclusions|| |
In patient subgroup with treatment-resistant HTN, catheter-based RDN offers a safe and effective treatment modality to reduce BP and sympathetic activity over at least 36 months. However, further clinical trials and knowledge of reliable predictors of BP response after RDN are required. Even after failed successful results of Symplicity HTN-3 trial, still there is a hope for resurgence of RDN therapy, and further research and clinical trials are awaited in this field.
Financial support and sponsorship
PubMed journals are referred for this study.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr., et al.
Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.
Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the healthy people 2010 blood pressure control goals. Hypertension 2006;47:345-51.
Judd E, Calhoun DA. Apparent and true resistant hypertension: Definition, prevalence and outcomes. J Hum Hypertens 2014;28:463-8.
Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al.
2007 Guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the European society of hypertension (ESH) and of the European society of cardiology (ESC). J Hypertens 2007;25:1105-87.
Mahfoud F, Himmel F, Ukena C, Schunkert H, Böhm M, Weil J. Treatment strategies for resistant arterial hypertension. Dtsch Arztebl Int 2011;108:725-31.
Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: Achievements and perspectives. Hypertension 2009;54:690-7.
Sobotka PA, Mahfoud F, Schlaich MP, Hoppe UC, Böhm M, Krum H. Sympatho-renal axis in chronic disease. Clin Res Cardiol 2011;100:1049-57.
Parati G, Esler M. The human sympathetic nervous system: Its relevance in hypertension and heart failure. Eur Heart J 2012;33:1058-66.
DiBona GF. Sympathetic nervous system and hypertension. Hypertension 2013;61:556-60.
Sakakura K, Ladich E, Cheng Q, Otsuka F, Yahagi K, Fowler DR, et al.
Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol 2014;64:635-43.
Ormiston J, Anderson T, Brinton TJ, Dawood O, Gertner M, Kay P, et al
. Non-invasive renal denervation using externally delivered focused ultrasound: Early experience using Doppler based imaging tracking and targeting for treatment. J Am Coll Cardiol 2014;64 11 Suppl: B121.
Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al.
Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275-81.
Mahfoud F, Cremers B, Janker J, Link B, Vonend O, Ukena C, et al.
Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. Hypertension 2012;60:419-24.
Bhatt DL, Kandzari DE, O′Neill WW, D′Agostino R, Flack JM, Katzen BT, et al.
A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-401.
Pathak A, Ewen S, Fajadet J, Honton B, Mahfoud F, Marco J, et al.
From symplicity HTN-3 to the renal denervation global registry: Where do we stand and where should we go? EuroIntervention 2014;10:21-3.
Mahfoud F, Lüscher TF. Renal denervation: Symply trapped by complexity? Eur Heart J 2015;36:199-202.
Kandzari DE, Bhatt DL, Brar S, Devireddy CM, Esler M, Fahy M, et al.
Predictors of blood pressure response in the symplicity HTN-3 trial. Eur Heart J 2015;36:219-27.
Desch S, Okon T, Heinemann D, Kulle K, Röhnert K, Sonnabend M, et al.
Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension 2015;65:1202-8.
Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, et al.
Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): A multicentre, open-label, randomised controlled trial. Lancet 2015;385:1957-65.
Rosa J, Widimský P, Toušek P, Petrák O, Curila K, Waldauf P, et al.
Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: Six-month results from the Prague-15 study. Hypertension 2015;65:407-13.
Mahfoud F, Böhm M, Azizi M, Pathak A, Durand Zaleski I, Ewen S, et al.
Proceedings from the European clinical consensus conference for renal denervation: Considerations on future clinical trial design. Eur Heart J 2015;36:2219-27.
Esler M, Jennings G, Korner P, Willett I, Dudley F, Hasking G, et al.
Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension 1988;11:3-20.
Mackenzie IS, McEniery CM, Dhakam Z, Brown MJ, Cockcroft JR, Wilkinson IB. Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension 2009;54:409-13.
[Figure 1], [Figure 2]