Renal sympathetic denervation in therapy resistant hypertension - pathophysiological aspects and predictors for treatment success

Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheter-interventional renal sympathetic denervation (RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success.     

Non-invasive Renal Denervation: Update on External Ultrasound Approaches

In the last decade, intravenous renal denervation (RDN) has emerged as an alternative to pharmacological treatment in patients with resistant hypertension, but currently involves an invasive and technically challenging procedure. The Surround Sound? system utilises externally delivered ultrasound to achieve RDN using a completely non-invasive, automated real-time tracking system coupled with a therapeutic delivery module thereby addressing these limitations. A brief history, technical overview and summary of preclinical and clinical studies of the KonaMedical Surround Sound? system are presented. A literature search using the terms “renal denervation”, “resistant hypertension” and “external ultrasound” was performed using PubMed, and references retrieved were selected based on relevancy and year of publication (date range 1991–2015). The Surround Sound? system appears to be a promising approach to RDN which eliminates several of the factors currently limiting the intravenous approach. So far, it has demonstrated efficacy for reducing blood pressure in resistant hypertension patients with minimal adverse effects. Several double-blind, sham-controlled clinical trials are currently underway to confirm the validity of these findings.     

Renal Nerve Stimulation as Procedural End Point for Renal Sympathetic Denervation

Purpose of Review

Renal sympathetic denervation (RDN) as treatment option for hypertension has a strong rationale; however, variable effects on blood pressure (BP) have been reported ranging from non-response to marked reductions in BP. The absence of a procedural end point for RDN is one of the potential factors associated with the variable response. Studies have suggested the use of renal nerve stimulation (RNS) to adequately address this issue. This review aims to provide an overview of the clinical and experimental data available regarding the effects of RNS in the setting of RDN.

Recent Findings

Animal studies have shown that high-frequency electrical stimulation of the sympathetic nerves in the adventitia of the renal arteries elicits an increase in BP and leads to an increased norepinephrine spillover as a marker of increased sympathetic activity and these effects of stimulation were attenuated or blunted after RDN. In a human feasibility study using RNS both before and after RDN, similar BP responses were observed. Moreover, in patients with resistant hypertension, RNS-induced changes in BP appeared to be correlated with 24-h BP response after RDN. These data suggest that RNS is a useful tool to identify renal sympathetic nerve fibers in patients with treatment-resistant hypertension undergoing RDN, and to predict the likely effectiveness of RDN treatments.

Summary

In acute procedural settings both in animal and human models, RNS elicits increase in BP and HR before RDN and these effects are blunted after RDN. Up to now, there is preliminary evidence that the RNS-induced BP changes predict 24-h ABPM outcome at follow-up in patients with resistant hypertension. Of note, studies are small sized and results of large trials comparing conventional RDN to RNS-guided RDN are warranted.

     

Current Status of Renal Denervation in Hypertension

Over the past 7 years, prospective cohorts and small randomized controlled studies showed that renal denervation therapy (RDN) in patients with resistant hypertension is safe but associated with variable effects on BP which are not substantially better than medical therapy alone. The failure of the most rigorously designed randomized sham-control study, SYMPLICITY HTN-3, to meet the efficacy endpoints has raised several methodological concerns. However, recently reported studies and ongoing trials with improved procedural characteristics, identification of patients with true treatment-resistant hypertension on appropriate antihypertensive regimens further explore potential benefits of RDN. The scope of this review is to summarize evidence from currently completed studies on RDN and discuss future perspectives of RDN therapy in patients with resistant hypertension.     

ESH position paper: renal denervation - an interventional therapy of resistant hypertension

Experts from the European Society of Hypertension prepared this position paper in order to summarize current evidence, unmet needs and practical recommendations on the application of percutaneous transluminal ablation of renal nerves [renal denervation (RDN)] as a novel therapeutic strategy for the treatment of resistant hypertension. The sympathetic nervous activation to the kidney and the sensory afferent signals to the central nervous system represent the targets of RND. Clinical studies have documented that catheter-based RDN decreases both efferent sympathetic and afferent sensory nerve traffic leading to clinically meaningful systolic and diastolic blood pressure (BP) reductions in patients with resistant hypertension. This position statement intends to facilitate a better understanding of the effectiveness, safety, limitations and issues still to be addressed with RDN.     

Renal denervation for resistant hypertension: no

In recent years, catheter-based radiofrequency denervation of the renal arteries (RDN) has emerged as a potential treatment for resistant hypertension. Though initial non-randomized and randomized small studies demonstrate large reductions in office blood pressure, RDN superiority to conventional treatment is not confirmed either by randomized controlled trials or by large international registries. Increasing evidence supports the hypothesis that a rational pharmacological therapeutic scheme is equally or more effective; this approach, together with an intervention aimed at increasing patient’s compliance with treatment, might solve most of the cases of refractory hypertension. Thus, based on current evidence, renal denervation should not be routinely used to treat resistant hypertension. Though the possibility that RDN might be useful in other subsets of hypertensive patients exists, it has never been proven. Thus, its use should be limited to extreme situations, when all other possible treatments have failed.     

Resistant Hypertension and Renal Denervation Where to Now?

Treatment resistant hypertension (TRH) is a major clinical problem with limited treatment options. Renal denervation (RDN) arose as a safe and very effective treatment for TRH with early studies showing dramatic blood pressure reductions however subsequent studies have not shown such a benefit. This review discusses the pathophysiology of TRH and the results of the published studies in RDN for TRH. The initial symplicity (1 and 2) studies using the Ardian RDN catheter showed that office blood pressures were significantly reduced 6 months following the procedure. However these initial studies were limited by a lack of a true control group and inadequate blinding. Subsequent studies (symplicity 3 and simplicity flex) included patients with elevated blood pressures on 24 hr ambulatory blood pressure monitor as well as office measurements. Furthermore, both included a sham arm where patients were randomized to undergo renal angiography alone or RDN, patients were blinded to whether they were in the treatment or sham arm. These more recent studies showed that in both the control and treatment group while there was a significant BP reduction from baseline there was no difference between the groups. Thus RDN appears to have no benefit in blood pressure reduction in those with TRH. RDN currently should only be used in patients with TRH as part of a properly designed clinical study. Pre clinical data suggests that renal sympathetic overactivity is an issue in younger hypertensive patients and this may be the group in which future studies using RDN should focus.     

经导管去肾交感神经术治疗代谢综合征的现状与展望

作为一种新的治疗顽固性高血压的治疗方法,经导管去肾交感神经术已被证实可以有效降低交感神经活性、去甲肾上腺素溢出以及血压.交感神经激活与代谢综合征关系密切,几个临床试验已经显示经导管去肾交感神经术对于改善葡萄糖代谢和胰岛素敏感性有潜在益处.这项技术能否用于治疗代谢综合征值得进一步研究.     

Renal denervation for resistant hypertension: yes

Sympathetic overactivity may have a role in triggering and maintaining resistant hypertension, and catheter-based renal denervation (RDN) has emerged as a promising treatment in refractory hypertension. Recently, the results of the Symplicity HTN-3, the first randomized, sham-controlled trial, failed to confirm the previously reported BP-lowering effects of RDN, although definitive conclusions cannot be drawn due to a number of study limitations. Consequently, although some centers halted their RDN programs, research continues and both the concept of denervation and treatment strategies are being redefined. A new generation of sham-controlled trials is currently underway with the aim of detecting which patients are expected to achieve the most beneficial effect from RDN. In this article, we examine the current data on RDN and discuss some insights and future opportunities.     

The Effects of Catheter‐Based Radiofrequency Renal Denervation on Renal Function and Renal Artery Structure in Patients With Resistant Hypertension

There are no clinical studies on the effects of catheter‐based radiofrequency renal denervation (RDN) on renal artery structure using 64‐detector computed tomography (CT). A total of 39 patients with resistant hypertension received RDN and 38 patients received drug treatment. Mean systolic pressure and diastolic pressure in the RDN group decreased after 1, 3, 6, and 12 months of procedure (P<.05) and urinary protein level significantly decreased after 6 and 12 months (P<.05). The diameter, length, and sectional area of the renal artery; number of cases of atherosclerosis; and plaque burden of 64‐detector CT renal arteriography did not change at 12 months of follow‐up (P<.05), whereas the plaque burden increased significantly in the control group (P<.05). RDN significantly and persistently reduced blood pressure and decreased urinary protein excretion rate in patients with resistant hypertension and did not exhibit any adverse effect on renal function and renal artery structure.     

Clinical outcomes of laparoscopic‐based renal denervation plus adrenalectomy vs adrenalectomy alone for treating resistant hypertension caused by unilateral aldosterone‐producing adenoma

Previous studies describing renal denervation (RDN) from the intima of the renal artery for the treatment of resistant hypertension have reported variable efficacies, and RDN triggers renal intimal injury and atherosclerosis. This study aimed to evaluate the efficacy and safety of RDN from the adventitia of renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone‐producing adenoma (APA). A total of 60 consecutive patients with resistant hypertension caused by unilateral APA were enrolled in this study. Patients were randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n = 30) or adrenalectomy alone (control group, n = 30) and were followed up for 12 months. The primary efficacy end point was the change in 24‐hours mean ambulatory systolic blood pressure (SBP) from baseline to 12 months. At the 12‐month follow‐up, the mean reduction of 24‐hours average SBP and office SBP in the RDN group was 20.7 ± 15.2 and 37.1 ± 26.0 mm Hg, respectively, which was significantly higher than the mean reduction of 24‐hours average SBP (11.9 ± 11.1 mm Hg, P = .017) and the office SBP (25.9 ± 16.8 mm Hg, P = .035) in the control group. Serum potassium levels returned to normal 12 months post‐procedure. Patients in the RDN group had higher proportion of cured clinical and biochemical outcomes than those in the control group (35.7% vs 17.9% in clinical outcome; 96.4% vs 89.3% in biochemical outcome, respectively). There were no procedural‐, device‐, or treatment‐related safety events during the 12‐month follow‐up period between the groups. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy is more effective than adrenalectomy alone for treating resistant hypertension caused by unilateral APA.     

经导管去肾交感神经术——当前各种技术的优劣比较

作为一种非药物治疗顽固性高血压新技术,经导管去肾交感神经术（renal denervation,RDN）初步已显示出其安全性和有效性.近年来不同治疗方式的RDN专用导管不断发展,基于此现对当前主要的几种经导管RDN技术进行综述.     

Thirty‐six‐month results of laparoscopic‐based renal denervation plus unilateral laparoscopic adrenalectomy for the treatment of patients with resistant hypertension caused by unilateral aldosterone‐producing adenoma

The aim of this study was to explore the long‐term clinical results of Renal denervation (RDN) from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone‐producing adenoma (APA). Sixty patients with resistant hypertension caused by APA who were treated at Henan Provincial People''s Hospital from December 2016 to March 2018 were selected and randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n = 30) or adrenalectomy alone (control group, n = 30). Office blood pressure (BP), antihypertensive medication usage and other laboratory characteristics were followed every 6 months through 36 months. Follow‐up data were available at 36 months for 23 of 30 subjects in the RDN group and for 21 of 30 subjects who were in the control group. At 36 months postprocedure, the reduction in the RDN group was 42.2 ± 21.6 mmHg and that in the control group was 29.8 ± 13.5 mmHg (p = .029 between the groups). During the follow‐up to 36 months postprocedure, no patients in either the RDN group or the control group died due to surgical complications, and the RDN group had no procedural complications, including renal artery dissection, perforation, and renal artery stenosis. There was no change in the mean eGFR of the two groups, and no serious adverse events were reported. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy resulted in sustained lowering of BP at 3 years in a selected population of subjects with resistant hypertension caused by unilateral APA without serious safety concerns.     

Renal Denervation: A Potential Novel Treatment for Type 2 Diabetes Mellitus?

Type 2 diabetes mellitus (T2DM) is a group of metabolic diseases of multiple etiologies. Although great progress has been made, researchers are still working on the pathogenesis of T2DM and how to best use the treatments available. Aside from several novel pharmacological approaches, catheter-based sympathetic renal denervation (RDN) has gained a significant role in resistant hypertension, as well as improvements in glycemic control in T2DM.In this article, we will summarize herein the role sympathetic activation plays in the progression of T2DM and review the recent clinical RDN experience in glucose metabolism.We performed systematic review in online databases, including PubMed, EmBase, and Web of Science, from inception until 2015.Studies were included if a statistical relationship was investigated between RDN and T2DM.The quality of each included study was assessed by Newcastle–Ottawa scale score. To synthesize these studies, a random-effects model or a fixed-effects model was applied as appropriate. Then, we calculated heterogeneity, performed sensitivity analysis, tested publication bias, and did meta-regression analysis. Finally, we identified 4 eligible articles.In most studies, RDN achieved via novel catheter-based approach using radiofrequency energy has gained a significant role in resistant hypertension, as well as improvements in glycemic control in T2DM. But the DREAMS-Study showed that RDN did not change median insulin sensitivity nor systemic sympathetic activity.Firstly, the current published studies lacked a proper control group, along with the sample capacity was small. Also, data obtained in the subgroups of diabetic patients were not separately analyzed and the follow-up period was very short. In addition, a reduction in blood pressure accounts for the improvements in glucose metabolism and insulin resistance cannot be excluded.If the favorable result of better glucose metabolism is confirmed in large-scale, randomized studies, RDN may emerge as a novel therapeutic option for patients with T2DM.     

Is renal denervation still a treatment option in cardiovascular disease?

The role of renal sympathetic denervation (RDN) has been the topic of ongoing debate ever since the impressive initial results. The rationale of RDN is strong and supported by non-clinical studies, which lies in uncoupling the autonomic nervous crosstalk between the kidneys and the central nervous system. Since we know that cardiovascular diseases, such as hypertension, atrial, ventricular arrhythmias and heart failure (HF) are related to sympathetic (over)activity, modulation of the renal nerve activity appears to be a reasonable and attractive therapeutic target in these patients. This review will focus on the existing evidence and potential future perspectives for RDN as treatment option in cardiovascular disease.     

Atrial Remodeling Following Catheter-Based Renal Denervation Occurs in a Blood Pressure– and Heart Rate–Independent Manner

ObjectivesThis study sought to investigate left atrial (LA) remodeling in relation to blood pressure (BP) and heart rate (HR) after renal sympathetic denervation (RDN).BackgroundIn addition to reducing BP and HR in certain patients with hypertension, RDN can decrease left ventricular (LV) mass and ameliorate LV diastolic dysfunction.MethodsBefore and 6 months after RDN, BP, HR, LV mass, left atrial volume index (LAVI), diastolic function (echocardiography), and premature atrial contractions (PAC) (Holter electrocardiogram) were assessed in 66 patients with resistant hypertension.ResultsRDN reduced office BP by 21.6 ± 3.0/10.1 ± 2.0 mm Hg (p < 0.001), and HR by 8.0 ± 1.3 beats/min (p < 0.001). At baseline, LA size correlated with LV mass, diastolic function, and pro-brain natriuretic peptide, but not with BP or HR. Six months after RDN, LAVI was reduced by 4.0 ± 0.7 ml/kg/m² (p < 0.001). LA size decrease was stronger when LAVI at baseline was higher. In contrast, the decrease in LAVI was not dependent on LV mass or diastolic function (E/E′ or E/A) at baseline. Furthermore, LAVI decreased without relation to decrease in systolic BP or HR. Additionally, occurrence of PAC (median of >153 PAC/24 h) was reduced (to 68 PAC/24 h) by RDN, independently of changes in LA size.ConclusionsIn patients with resistant hypertension, LA volume and occurrence of PAC decreased 6 months after RDN. This decrease was independent of BP and HR at baseline or the reduction in BP and HR reached by renal denervation. These data suggest that there is a direct, partly BP-independent effect of RDN on cardiac remodeling and occurrence of premature atrial contractions.     

Catheter-based renal denervation in Chinese patients with chronic kidney disease and uncontrolled hypertension

Sympathetic activation contributes to the progression of hypertension and chronic kidney disease (CKD). Ablation of renal sympathetic nerves lowers blood pressure (BP) and preserves renal function in patients with CKD and uncontrolled hypertension by reducing sympathetic nerve activity. But whether this approach is safe and effective in Chinese patients with CKD is unknown. We performed an observational study of eight patients with CKD stages from 1 to 5, office BP ≥150/90 mmHg, while on at least three antihypertensive drug classes including a diuretic, and diagnosis confirmed by 24 h ambulatory systolic BP measurement ≥135 mmHg. All patients underwent catheter-based renal denervation (RDN) using a newly designed RDN System (Golden Leaf Medtech, Shanghai, China). For up to 6 months after RDN, BP was monitored and renal function was assessed. Mean baseline office BP was 165.0 ± 13.9/97.8 ± 5.5 mmHg, despite treatment with three antihypertensive drugs. Six months after RDN, office BP was reduced by 22.1 ± 12.0 (P = .002)/11.0 ± 8.8 mmHg (P = .012) and average 24 h ambulatory BP by 18 ± 13.7 (P = .01)/9.3 ± 7.7 mmHg (P = .016). After RDN, heart rate and estimated glomerular filtration rate (GFR) had no significant change compared with before RDN. In Chinese patients with CKD, our observational pilot study found that treating hypertension with RDN lowers BP while not affecting renal function. Brief Abstract: We performed RDN in eight Chinese patients with hypertension and CKD. The results showed that RDN lowered blood pressure of these patients significantly and eGFR was stable. No obvious adverse event was observed.     

Catheter-based renal denervation versus intensified medical treatment in patients with resistant hypertension: Rationale and design of a multicenter randomized study—PRAGUE-15

Catheter-based renal denervation (RDN) was considered as a promising method for treatment of resistant hypertension and was increasingly being used worldwide. However, there are equivocal results from only two randomized trials studying the effect of such intervention. Thus, additional data from properly designed long-term comparative trials are needed. The PRAGUE-15 trial is designed as an open, prospective, randomized multicenter trial comparing RDN versus intensified medical treatment in patients with resistant hypertension. Patients randomized to the medical treatment group will receive spironolactone in the absence of contraindications. The primary endpoint will be changes in systolic and diastolic pressure during ambulatory blood pressure monitoring (ABPM) from baseline to 6 months. Herein, we describe the trial design and methodology. The strengths of the trial include ABPM (as the objective endpoint), independent outcomes assessment, and therapeutic use of spironolactone.     

Renal Denervation—Hypes and Hopes

Catheter‐based renal denervation (RDN) is a novel invasive approach in the treatment of resistant hypertension. It is considered a minimally invasive and safe procedure which, as shown by initial experimental and clinical trials, is able not only to reduce blood pressure but also to modify its risk factors by modulation of autonomic nervous system. Recently published results of a randomized Symplicity HTN‐3 trial, which failed to demonstrate RDN‐induced reduction of blood pressure at six months, decreased the initial enthusiasm regarding RDN and raised a question about real efficacy of this procedure. Nevertheless, still there are some other conditions characterized by increased sympathetic tone such as heart failure, atrial fibrillation, or ventricular arrhythmias that may benefit from RDN. Furthermore, novel therapeutical approach toward RDN using adapted electrophysiological or new specially designed electrodes may improve effectiveness of RDN procedure.     

A Japan nationwide web‐based survey of estimation on patients for renal denervation based on blood pressure level and the number of antihypertensives (J‐NEEDs survey)

Catheter‐based renal denervation (RDN) is currently being developed as a new complementary treatment option for hypertension. RDN has not yet received approval in Japan and so the number of possible candidates for RDN in Japan also remains unknown. A total of 10 756 hypertensive patients who regularly visit medical institutions and reported their latest home blood pressure (BP) values were identified from registrants at an online research company. They filled out a survey regarding their prescribed antihypertensives and latest BP values in March 2020 in Japan. The mean age of the patients was 61.3 years old (83.5% male). According to JSH 2019, the prevalence of resistant hypertension (RHT) was estimated to be 1.4% (0.52% having an office BP of 140/90 mm Hg or more while taking three antihypertensives, including diuretics; 0.84% taking four or more antihypertensives regardless of BP level). Assuming the indication for RDN was RHT with morning home systolic BP (HSBP) ≥ 135 mm Hg and office systolic BP (OSBP) ≥ 140 mm Hg, the number of candidates for RDN was estimated to be approximately 340 000 and 372 000, respectively. When hypertensive patients prescribed three or more, two, one, and no antihypertensives were included, the estimated number based on uncontrolled HSBP and OSBP cumulatively increased 2.6, 14.2, 40.6, and 58.0‐fold; 1.8, 8.6, 25.3, and 36.4‐fold, respectively. These findings revealed that a substantial number of hypertensive patients are unable to adequately control their BP level with existing treatments, and new complemental therapies, such as RDN, would alleviate the burden of hypertension in this population.