Renal Sympathetic Nerve Ablation

Number: 0847

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses radiofrequency ablation of the renal sympathetic nerve.

  1. Experimental, Investigational, or Unproven

    Aetna considers microwave, radiofrequency, or ultrasound ablation of the renal sympathetic nerve experimental, investigational, or unproven for the treatment of the following indications (not an all-inclusive list) because of insufficient evidence in the peer-reviewed literature:

    1. Acute myocardial infarction
    2. Cardiac arrhythmias
    3. Chronic kidney-related pain
    4. Chronic renal failure
    5. Heart failure
    6. Hypertension
    7. Obstructive sleep apnea
    8. Ventricular tachycardia.

    Aetna considers transurethral renal pelvic denervation using radiofrequency ablation experimental, investigational, or unproven for the treatment of hypertension and all other indications because of insufficient evidence in the peer-reviewed literature.

  2. Related Policies


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes not covered for indications listed in the CPB :

no specific code
0338T - 0339T Transcatheter renal sympathetic denervation, percutaneous approach including arterial puncture, selective catheter placement(s) renal artery(ies), fluoroscopy, contrast injection(s), intraprocedural roadmapping and radiological supervision and interpretation, including pressure gradient measurements, flush aortogram and diagnostic renal angiography when performed
0935T Cystourethroscopy with renal pelvic sympathetic denervation, radiofrequency ablation, retrograde ureteral approach, including insertion of guide wire, selective placement of ureteral sheath(s) and multiple conformable electrodes, contrast injection(s), and fluoroscopy, bilateral

ICD-10 codes not covered for indications listed in the CPB (not all inclusive) :

G47.33 Obstructive sleep apnea (adult) (pediatric)
G89.29 Other chronic pain [kidney-related]
I10 - I16.9 Hypertensive disease
I21.01 - I21.4 ST elevation (STEMI) and non-ST elevation NSTEMI myocardial infarction
I47.0 - I47.9 Paroxysmal tachycardia
I48.0 - I48.92 Atrial fibrillation and flutter
I49.01 - I49.9 Other cardiac arrhythmias
N18.1 - N18.9 Chronic kidney disease
N23 Unspecified renal colic [chronic kidney-related pain]

Background

Radiofrequency Ablation for the Treatment of Hypertension

Hypertension is an independent risk factor for cardiovascular disease.  Treatment frequently includes administration of three or more drugs. Resistant hypertension is defined as blood pressure which remains above target levels despite use of the maximum tolerated dose of antihypertensive medications, consisting of at least three different classes of drugs, including a diuretic. Radiofrequency (RF) ablation of sympathetic nerve fibers around renal arteries has been proposed as a non-pharmacologic treatment to reduce blood pressure in drug resistant hypertension (Simonyi et al, 2013).

Selective renal sympathetic denervation interrupts the influence of the sympathetic nervous system on the kidney and systemic hemodynamics.  The sympathetic innervation of the kidney is implicated in the pathogenesis of hypertension through effects on renin secretion, increased plasma renin activity that leads to sodium and water retention, and reduction of renal blood flow.  Renal sympathetic ablation is a minimally invasive procedure utilizing a RF catheter inserted through the femoral artery and selectively engaging the renal artery (Papademitriou et al, 2011).

Krum et al (2009) performed a proof-of-principle trial of therapeutic renal sympathetic denervation in patients with resistant hypertension (i.e., systolic blood pressure greater than or equal to 160 mm Hg on 3 or more anti-hypertensive medications, including a diuretic) to assess safety and blood-pressure reduction effectiveness.  The investigators enrolled 50 patients at 5 Australian and European centers; 5 patients were excluded for anatomical reasons (primarily due to dual renal artery systems).  Patients received percutaneous RF catheter-based treatment between June 2007 and November 2008, with subsequent follow-up to 1 year.  The effectiveness of renal sympathetic denervation with renal noradrenaline spillover was assessed in a subgroup of patients.  Primary endpoints were office blood pressure and safety data before the procedure and at 1, 3, 6, 9, and 12 months after the procedure.  Renal angiography was done before, immediately after, and 14 to 30 days after procedure, and magnetic resonance angiogram was assessed 6 months after procedure.  Blood-pressure lowering effectiveness  was analyzed using repeated measures ANOVA.  In treated patients, baseline mean office blood pressure was 177/101 mm Hg (SD 20/15), (mean of 4.7 anti-hypertensive medications); estimated glomerular filtration rate was 81 ml/min/1.73m(2) (SD 23); and mean reduction in renal noradrenaline spillover was 47 % (95 % confidence interval [CI]: 28 % to 65 %).  Office blood pressures after procedure were reduced by -14/-10, -21/-10, -22/-11, -24/-11, and -27/-17 mm Hg at 1, 3, 6, 9, and 12 months, respectively.  In the 5 non-treated patients, mean rise in office blood pressure was +3/-2, +2/+3, +14/+9, and +26/+17 mm Hg at 1, 3, 6, and 9 months, respectively.  One intra-procedural renal artery dissection occurred before RF energy delivery, without further sequelae.  There were no other renovascular complications.  The authors concluded that catheter-based renal denervation causes substantial and sustained blood-pressure reduction, without serious adverse events, in patients with resistant hypertension.  They also stated that prospective randomized clinical trials are needed to investigate the usefulness of this procedure in the management of this condition.

A prioritizing summary of the Australia and New Zealand Horizon Scanning Network on renal sympathetic denervation for the treatment of resistant hypertension concluded that based on the low level of available evidence, it would appear that renal denervation may be a viable option for the treatment of resistant hypertension (Mundy & Hiller, 2010). Blood pressure was significantly lower after renal denervation than that measured at baseline; however, it is unclear whether this decrease is considered clinically significant. Final 12-month follow-up data were only reported for a small portion of the enrolled patients (22%) and in addition, six of the 45 patients were considered non-responders with non-significant reductions in blood pressure. The summary concluded that well conducted randomized controlled trial is needed to adequately investigate whether renal denervation is capable of producing a sustained lowering of blood pressure in hypertensive patients resistant to medication (Mundy & Hiller, 2010).

Voskuil et al (2011) described their first experience with a percutaneous treatment modality using renal artery RF ablation.  Selected patients were resistant to at least 3 types of anti-hypertensive medical therapy (office systolic blood pressure greater than or equal to 160 mm Hg; n = 9) or who did not tolerate medication (n = 2).  Between July and November 2010, a total of 11 patients received percutaneous RF treatment and were followed for 1 month after treatment.  Urine and blood samples were taken to evaluate the effects on renal function and neuro-humeral factors.  No peri-procedural complications or adverse events during follow-up were noted.  A reduction of mean office blood pressure was observed from 203/109 +/- 32/19 mmHg at baseline to 178/97 +/- 28/21 mm Hg at 1 month follow-up (mean difference 25 +/- 12 mm Hg, p < 0.01).  The investigators also noted a significant decrease in aldosterone level (391 +/- 210 pmol/L versus 250 +/- 142 pmol/L; p = 0.03), but there was no decrease in plasma renin activity (190 +/- 134 fmol/L/s versus 195 +/- 163 fmol/L/s; p = 0.43).  No change in renal function was noted.  The authors concluded that catheter-based renal denervation seems an attractive novel minimally invasive treatment option in patients with resistant hypertension, with a low-risk of serious adverse events. 

Mahfoud et al (2011) summarized the expert consensus and recommendations of the working group "Herz und Niere" of the German Society of Cardiology (DGK), the German Society of Nephrology (DGfN) and the German Hypertension League (DHL) on renal denervation for anti-hypertensive treatment.  Renal denervation was defined as a new, interventional approach to selectively dennervate renal afferent and efferent sympathetic fibers.  The authors noted that renal denervation has been demonstrated to reduce office systolic and diastolic blood pressure in patients with resistant hypertension, defined as systolic office blood pressure greater than or equal to 160 mm Hg and greater than or equal to 150 mm Hg in patients with diabetes type 2, which should currently be used as blood pressure thresholds for undergoing the procedure.  Exclusion of secondary hypertension causes and optimized anti-hypertensive drug treatment was described as mandatory in every patient with resistant hypertension. They also specified that 24-hour blood pressure measurements should be performed in order to exclude pseudo-resistance.  Preserved renal function was an inclusion criterion in the Symplicity studies. Therefore, renal denervation should be only considered in patients with a glomerular filtration rate greater than 45 ml/min.  Adequate center qualification in both treatment of hypertension and interventional expertise are essential to ensure correct patient selection and procedural safety.  The authors stated that long-term follow-up after renal denervation and participation in the German Renal Denervation (GREAT) Registry are recommended to assess safety and efficacy after renal denervation over time.

Lobodzinski (2011) reviewed renal denervation system technology for treatment of drug resistant hypertension.  These researchers described "an investigational device that is currently tested in an on-going clinical trial.  The denervation device uses the RF thermal ablation catheter attached to the RF generator.  The RF catheter is inserted into the renal artery and positioned in the vicinity of the efferent and afferent parasympathetic innervations.  Renal denervation is a minimally invasive, localized procedure and the procedural and recovery times are very short.  The entire procedure lasts about 40 minutes.  In early clinical trials, the systolic blood pressure in 87 % of patients who underwent the denervation procedure resulted in an average blood pressure drop of greater than 10 mm Hg.  The procedure has no systematic side effects, and appears to be beneficial in the management of hypertension in patients refractory to pharmacological therapy."

Patel and White (2012) stated that renal artery intervention to treat hypertension is one of the frontiers of ongoing research in combating this epidemic.  The investigators discussed recent data regarding renal artery angioplasty with stenting (PTRS) and catheter-based renal sympathetic denervation.  They noted that despite progress in this field, large, multi-center, randomized trials that compare these treatment modalities with medical therapy for hypertension are lacking.

Tam et al (2013) stated that resistant hypertension, defined as the failure to achieve target blood pressure despite concurrent use of 3 anti-hypertensive agents of different classes, is estimated to affect 20 to 30 % of hypertensive patients.  These patients are vulnerable to cardiovascular, cerebrovascular and renal complications.  There is ample evidence that sympathetic nervous system hyperactivity contributes to the initiation, maintenance, and progression of hypertension.  The renal sympathetic nervous system, in particular, has been identified as a major culprit for the development and progression of hypertension, heart failure and chronic kidney disease in both preclinical and human studies.  Traditional surgical sympathectomy proposed in the 1940s was halted due to unacceptable operative risk and the emergence of anti-hypertensive medications.  The authors report that recently, catheter-based renal sympathetic denervation by RF ablation has shown encouraging intermediate-term results with minimal complications in patients with resistant hypertension. 

A May, 2012 National Institute for Health and Clinical Excellence guideline stated that "current evidence on percutaneous transluminal RF sympathetic denervation of the renal artery for resistant hypertension is from limited numbers of patients, but there is evidence of efficacy in the short and medium term. There is inadequate evidence on efficacy in the long term; this is particularly important for a procedure aimed at treating resistant hypertension. The limited evidence suggests a low incidence of serious periprocedural complications, but there is inadequate evidence on long-term safety. Therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research (NICE, 2012)."

Esler et al (2012) noted that renal sympathetic nerve activation contributes to the pathogenesis of hypertension. Symplicity HTN-2, a multicenter, randomized trial, demonstrated that catheter-based renal denervation produced significant blood pressure lowering in treatment-resistant patients 6 months after the procedure compared with controls, which were medication-only patients. The authors presented longer-term follow-up, including 6-month crossover results, is now presented. Eligible patients were on ≥ 3 antihypertensive drugs and had a baseline systolic blood pressure ≥160 mm Hg (≥ 150 mm Hg for type 2 diabetics). After the 6-month primary end point was met, renal denervation in control patients was permitted. Patients randomized to immediate renal denervation (n = 47) were evaluated one year post-procedure and crossover patients were evaluated 6 months post-procedure. At 12 months after the procedure, the mean fall in office systolic blood pressure in the initial renal denervation group (-28.1 mm Hg; 95 % confidence interval, -35.4 to -20.7; p < 0.001) was similar to the 6-month fall (-31.7 mm Hg; 95 % confidence interval, -38.3 to -25.0; p = 0.16 versus 6-month change). The mean systolic blood pressure of the crossover group 6 months after the procedure was significantly lowered (from 190.0 ± 19.6 to 166.3 ± 24.7 mm Hg; change, -23.7 ± 27.5; p < 0.001). In the crossover group, there was 1 renal artery dissection during guide catheter insertion, before denervation, corrected by renal artery stenting, and 1 hypotensive episode, which resolved with medication adjustment. Control patients who crossed over to renal denervation with the Symplicity system had a significant drop in blood pressure similar to that observed in patients receiving immediate denervation. The authors concluded that renal denervation provided safe and sustained reduction of blood pressure to 1 year.

Geisler et al (2012) conducted a study to assess cost-effectiveness and long-term clinical benefits of renal denervation in resistant hypertensive patients. The authors noted that in the Symplicity HTN-2 randomized controlled trial, catheter-based renal denervation (RDN) lowered systolic blood pressure by 32 ± 23 mm Hg from 178 ± 18 mm Hg at baseline. A state-transition model was used to predict the effect of RDN and standard of care on 10-year and lifetime probabilities of stroke, myocardial infarction, all coronary heart disease, heart failure, end-stage renal disease, and median survival. The investigators adopted a societal perspective and estimated an incremental cost-effectiveness ratio in U.S. dollars per quality-adjusted life-year, both discounted at 3% per year. Robustness and uncertainty were evaluated using deterministic and probabilistic sensitivity analyses. Renal denervation substantially reduced event probabilities (10-year/lifetime relative risks: stroke 0.70/0.83; myocardial infarction 0.68/0.85; all coronary heart disease 0.78/0.90; heart failure 0.79/0.92; end-stage renal disease 0.72/0.81). Median survival was 18.4 years for RDN versus 17.1 years for standard of care. The discounted lifetime incremental cost-effectiveness ratio was $3,071 per quality-adjusted life-year. The investigators acknowledged that findings were relatively insensitive to variations in input parameters except for systolic blood pressure reduction, baseline systolic blood pressure, and effect duration. The 95 % credible interval for incremental cost-effectiveness ratio was cost-saving to $31,460 per quality-adjusted life-year. The model suggests that catheter-based renal denervation, over a wide range of assumptions, is a cost-effective strategy for resistant hypertension that might result in lower cardiovascular morbidity and mortality.

The Symplicity HTN-3 Trial is currently in progress. Early clinical evaluation with catheter-based, selective renal sympathetic denervation in patients with resistant hypertension has mechanistically correlated sympathetic efferent denervation with decreased renal norepinephrine spillover and renin activity, increased renal plasma flow, and has demonstrated clinically significant, sustained reductions in blood pressure. The SYMPLICITY HTN-3 Trial is a pivotal study designed as a prospective, randomized, masked procedure, single-blind trial evaluating the safety and effectiveness of catheter-based bilateral renal denervation for the treatment of uncontrolled hypertension despite compliance with at least 3 antihypertensive medications of different classes (at least one of which is a diuretic) at maximal tolerable doses. The primary effectiveness endpoint is defined as the change in office-based systolic blood pressure from baseline to 6 months (Kandzari et al, 2012).

In a pilot study, Ott et al (2013) examined the effect of RDN in patients with treatment-resistant hypertension (TRH) according to the established definition (Joint National Committee VII and European Society of Hypertension/European Society of Cardiology guidelines), i.e., office blood pressure (BP) greater than or equal to 140/90 mm Hg (with at least 3 anti-hypertensive drugs, including a diuretic, in adequate doses) and confirmed by 24-hour ambulatory BP monitoring (ABPM).  In this study, there were 54 patients with moderate TRH (office BP greater than or equal to 140/90 mm Hg and less than 160/100 mm Hg and diagnosis confirmed by 24-hour ABPM of greater than or equal to 130/80 mm Hg) who underwent catheter-based RDN using the Symplicity catheter (Medtronic Inc., Mountain View, CA).  Patients were treated with 5.1 ± 1.4 anti-hypertensive drugs on average.  Office BP was significantly reduced by 13/7 mm Hg 6 months after RDN (systolic: 151 ± 6 mm Hg versus 138 ± 21 mm Hg, p < 0.001; diastolic: 83 ± 11 mm Hg versus 75 ± 11 mm Hg, p < 0.001).  In patients (n = 36) who underwent ABPM 6 months after treatment, there was a reduction in average 24-hour ABPM by 14/7 mm Hg (systolic: 150 ± 16 mm Hg versus 136 ± 16 mm Hg, p < 0.001; diastolic: 83 ± 10 mm Hg versus 76 ± 10 mm Hg, p < 0.001).  In 51 % of patients, office BP was controlled below 140/90 mm Hg after RDN.  In addition, heart rate decreased from 67 ± 11 to 63 ± 10 beats/min (p = 0.006).  The authors concluded that these findings indicated that RDN may reduce office and 24-hour ambulatory BP substantially in patients with moderate TRH.  The main drawbacks of this study were the lack of a control group and the relatively small sample size.  These researchers stated that there is a need for a large-scale, prospective, randomized, multi-center, controlled trial in this group of TRH patients to precisely define the therapeutic role of RDN in moderate TRH.

Fadl Elmula et al (2014) examined the BP-lowering effect of RDN versus clinically adjusted drug treatment in true TRH after excluding patients with confounding poor drug adherence.  Patients with apparent TRH (n = 65) were referred for RDN, and those with secondary and spurious hypertension (n = 26) were excluded.  Treatment-resistant hypertension was defined as office systolic BP (SBP) greater than 140 mm Hg, despite maximally tolerated doses of greater than or equal to 3 anti-hypertensive drugs including a diuretic.  In addition, ambulatory daytime SBP greater than 135 mm Hg after witnessed intake of anti-hypertensive drugs was required, after which 20 patients had normalized BP and were excluded.  Patients with true TRH were randomized and underwent RDN (n = 9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n = 10).  The study was stopped early for ethical reasons because RDN had uncertain BP-lowering effect.  Office SBP and diastolic BP in the drug-adjusted group changed from 160 ± 14/88 ± 13 mm Hg (± SD) at baseline to 132 ± 10/77 ± 8 mm Hg at 6 months (p < 0.0005 and p = 0.02, SBP and diastolic BP, respectively) and in the RDN group from 156 ± 13/91 ± 15 to 148 ± 7/89 ± 8 mm Hg (p = 0.42 and p = 0.48, SBP and diastolic BP, respectively).  Systolic BP and diastolic BP were significantly lower in the drug-adjusted group at 6 months (p = 0.002 and p = 0.004, respectively), and absolute changes in SBP were larger in the drug-adjusted group (p = 0.008).  Ambulatory BPs changed in parallel to office BPs.  The authors concluded that these findings suggested that adjusted drug treatment has superior BP-lowering effects compared with RDN in patients with true TRH.

Bhatt et al (2014) stated that prior unblinded studies have suggested that catheter-based RDN reduces blood pressure in patients with resistant hypertension.  These investigators designed a prospective, single-blind, randomized, sham-controlled trial.  Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo RDN or a sham procedure.  Before randomization, patients were receiving a stable anti-hypertensive regimen involving maximally tolerated doses of at least 3 drugs, including a diuretic.  The primary efficacy end-point was the change in office SBP at 6 months; a secondary efficacy end-point was the change in mean 24-hour ambulatory SBP.  The primary safety end-point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70 % at 6 months.  A total of 535 patients underwent randomization.  The mean (± SD) change in SBP at 6 months was -14.13 ± 23.93 mm Hg in the denervation group as compared with -11.74 ± 25.94 mm Hg in the sham-procedure group (p < 0.001 for both comparisons of the change from baseline), for a difference of -2.39 mm Hg (95 % CI: -6.89 to 2.12; p = 0.26 for superiority with a margin of 5 mm Hg).  The change in 24-hour ambulatory SBP was -6.75 ± 15.11 mm Hg in the denervation group and -4.79 ± 17.25 mm Hg in the sham-procedure group, for a difference of -1.96 mm Hg (95 % CI: -4.97 to 1.06; p = 0.98 for superiority with a margin of 2 mm Hg).  There were no significant differences in safety between the 2 groups.  The authors concluded that this blinded trial did not show a significant reduction of SBP in patients with resistant hypertension 6 months after RDN as compared with a sham control.

Bakris et al (2014) noted that prior studies of catheter-based RDN have not systematically performed ambulatory blood pressure monitoring (ABPM) to assess the efficacy of the procedure.  SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) was a prospective, blinded, randomized, sham-controlled trial.  The current analysis detailed the effect of RDN or a sham procedure on ABPM measurements 6 months post-randomization.  Patients with resistant hypertension were randomized 2:1 to renal denervation or sham control.  Patients were on a stable anti-hypertensive regimen including maximally tolerated doses of at least 3 drugs including a diuretic before randomization.  The powered secondary efficacy end-point was a change in mean 24-h ambulatory SBP.  Non-dipper to dipper (nighttime BP 10 % to 20 % lower than daytime BP) conversion was calculated at 6 months.  The 24-hour ambulatory SBP changed -6.8 ± 15.1 mm Hg in the RDN group and -4.8 ± 17.3 mm Hg in the sham group: difference of -2.0 mm Hg (95 % CI: -5.0 to 1.1; p = 0.98 with a 2 mm Hg superiority margin).  The daytime ambulatory SBP change difference between groups was -1.1 (95 % CI: -4.3 to 2.2; p = 0.52).  The nocturnal ambulatory SBP change difference between groups was -3.3 (95 CI: -6.7 to 0.1; p = 0.06).  The percent of non-dippers converted to dippers was 21.2 % in the RDN group and 15.0 % in the sham group (95 % CI: -3.8 % to 16.2 %; p = 0.30).  Change in 24-hour heart rate was -1.4 ± 7.4 in the RDN group and -1.3 ± 7.3 in the sham group; (95 % CI: -1.5 to 1.4; p = 0.94).  The authors concluded that this trial did not demonstrate a benefit of RDN on reduction in ambulatory BP in either the 24-hour or day and night periods compared with sham.

On January 9, 2014, Medtronic, Inc. announced that its U.S. pivotal trial in RDN for TRH, SYMPLICITY HTN-3, failed to meet its primary efficacy end-point.  Medtronic intends to formulate a panel of independent advisors made up of physicians and researchers who will be asked to make recommendations about the future of the global hypertension clinical trial program, as well as provide advice on continued physician and patient access to the Symplicity technology in countries with regulatory approvals.  Pending this panel review, the company intends to:

  • Suspend enrollment in the 3 countries where renal denervation hypertension trials are being conducted for regulatory approvals (SYMPLICITY HTN-4 in the U.S., HTN-Japan and HTN-India).
  • Begin informing clinical trial sites and investigators, global regulatory bodies, and customers of these findings and decisions.
  • Continue to ensure patient access to the Symplicity technology at the discretion of their physicians in markets where it is approved.
  • Continue the Global SYMPLICITY post-market surveillance registry and renal denervation studies evaluating other non-hypertension indications.

Ukena et al (2012) stated that sympathetic activity plays an important role in the pathogenesis of ventricular tachyarrhythmia.  Catheter-based RDN is a novel treatment option for patients with resistant hypertension, proved to reduce local and whole-body sympathetic activity.  Two patients with chronic heart failure (CHF) (non-obstructive hypertrophic and dilated cardiomyopathy, New York Heart Association [NYHA] III) suffering from therapy-resistant electrical storm underwent therapeutic RDN.  In both patients, RDN was conducted with agreement of the local ethics committee and after obtaining informed consent.  The patient with hypertrophic cardiomyopathy had recurrent monomorphic ventricular tachycardia (VT) despite extensive anti-arrhythmic therapy, following repeated endocardial and epicardial electrophysiological ablation attempts to destroy an arrhythmogenic intra-mural focus in the left ventricle.  The second patient, with dilated non-ischemic cardiomyopathy, suffered from recurrent episodes of polymorphic VT and ventricular fibrillation.  The patient declined catheter ablation of these tachycardias.  In both patients, RDN was performed without procedure-related complications.  Following RDN, ventricular tachyarrhythmias were significantly reduced in both patients.  Blood pressure and clinical status remained stable during the procedure and follow-up in these patients with CHF.  The authors concluded that these findings suggested that RDN is feasible even in cardiac unstable patients.  Moreover, they stated that randomized controlled trials (RCTs) are urgently needed to study the effects of RD in patients with electrical storm and CHF.

Tsioufis (2013) reported that a small study presented at ACC 2013 has shown that RDN, besides reducing resistant hypertension, produces a favorable effect on atrial and ventricular arrhythmias.  In the study, the researchers treated 14 patients with resistant hypertension who underwent ABPM and Holter monitoring at baseline and 1 month after RDN.  For the procedure, the investigators used the EnligHTN ablation catheter (St Jude Medical).  Patients with grade II and above of the Lown-Wolf classification were considered to have complex ventricular arrhythmias while the presence of greater than or equal to 3 consecutive premature supraventricular contractions was defined as paroxysmal atrial fibrillation.  These researchers found that after 1 month, office and 24-hour BP was significantly reduced by 38/14.1 mmHg, p < 0.001/0.003 and 18/9.5 mmHg, p < 0.001/0.001, respectively.  Office heart rate was reduced by 7 beats per minute (bpm), (p = 0.046), ambulatory heart rate by 5.5 bpm, and average 24-hour heart rate by 6.7 bpm (p = 0.022).  The researchers also found that complex ventricular arrhythmias were present in 5 out of the 14 patients (1 with non-sustained VT and 4 with ventricular couplets) at baseline but persisted only in 2 of them 1 month after RDN (2 patients with ventricular couplets).  The number of premature ventricular contractions was significantly decreased after RDN (from 2.23/hour to 0.39/hour, p = 0.019).  Episodes of paroxysmal atrial fibrillation were detected in 5 of 14 subjects at baseline and in 2 of those patients 1 month after RDN.  The total number of premature supraventricular contractions was also significantly decreased after RDN from 1.62/hour to 0.72/hour (p = 0.039), the authors found.  There was no relationship between the observed difference in premature supraventricular and ventricular contractions after RDN and the drop in office and 24-hour BP.

Hoffman et al (2013) presented a case of ventricular storm (VS) in a patient with acute ST-elevation myocardial infarction (STEMI).  After initial successful thrombus extraction and percutaneous coronary intervention (PCI) of the proximal left anterior descending (LAD) coronary artery, a 63-year old male patient showed recurrent monomorphic VT and ventricular fibrillation (VF) episodes refractory to anti-arrhythmic drug therapy.  After initial successful VT ablation, fast VT and VF episodes remained an evident problem despite maximum anti-arrhythmic drug therapy.  Due to an increasing instability, RDN was performed.  Implantable cardioverter defibrillator interrogation and 24-hour Holter monitoring excluded recurrent episodes of VT or VF at a 6-month follow-up after discharge.  The authors concluded that this case high-lighted that RDN was effective and safely performed in a hemodynamically unstable patient with VS after STEMI and adjunct catheter ablation.  They stated that RDN may open a new avenue for an adjunctive interventional bailout treatment of such highly challenging patients.

Remo et al (2014) reported the largest case series to-date using RDN as adjunctive therapy for refractory VT in patients with underlying cardiomyopathy.  A total of 4 patients with cardiomyopathy (2 non-ischemic, 2 ischemic) with recurrent VT despite maximized anti-arrhythmic therapy and prior endocardial (n = 2) or endocardial/epicardial (n = 2) ablation underwent RDN ± repeat VT ablation.  Renal denervation was performed spirally along each main renal artery with either a non-irrigated (6 W at 50°C for 60 seconds) or an open irrigated ablation catheter (10 to 12 W for 30 to 60 seconds).  Renal arteriography was performed before and after RDN.  Renal denervation was well-tolerated acutely and demonstrated no clinically significant complications during follow-up of 8.8 ± 2.6 months (range of 5.0 to 11.0 months).  No hemodynamic deterioration or worsening of renal function was observed.  The number of VT episodes was decreased from 11.0 ± 4.2 (5.0 to 14.0) during the month before ablation to 0.3 ± 0.1 (0.2 to 0.4) per month after ablation.  All VT episodes occurred in the first 4 months after ablation (2.6 ± 1.5 months).  The responses to RDN were similar for ischemic and non-ischemic patients.  The authors concluded that this case series provided promising preliminary data on the safety and effectiveness of RDN as an adjunctive therapy in the treatment of patients with cardiomyopathy and VT resistant to standard interventions.

There is an ongoing clinical trial, "RESCUE-VT" (REnal SympathetiC Denervation to sUpprEss Ventricular Tachyarrhythmias); this study is currently recruiting participants (Last verified June 2016).

Shantha and Pancholy (2015) noted that recent evidence associates sympathetic tone with severity of obstructive sleep apnea (OSA).  Renal sympathetic denervation, by decreasing sympathetic tone, has the potential to decrease OSA severity.  Small observational studies that assessed this hypothesis lacked precision.  In a meta-analysis, these investigators attempted to pool available data from studies that have assessed the effect of RDN on OSA severity in patients with OSA.  Medline, Embase, Cochrane central, Ovid, Cinahl, web of science, and conference abstracts were searched for eligible citations by 2 independent reviewers using key words "renal denervation", "hypertension", and "obstructive sleep apnea".  From a total of 2,863 identified citations, using meta-analysis of observational studies in epidemiology method, 5 studies were assessed eligible and included in the meta-analysis.  All 5 studies followed an observational study design, involved patients with OSA and hypertension, and reported an apnea-hypopnea index (AHI) 6 months post-RDN; 4 were "before and after" studies and 1 compared continuous positive airway pressure with RDN.  In the pooled analysis, involving 49 patients, RDN was associated with a significant reduction in mean AHI [weighted mean difference -9.61 (95 % CI: -15.43 to -3.79, p = 0.001)] 6 months post-RDN. One study also reported improvement in oxygen desaturation index and Epworth sleepiness scale score 6 months post-RDN.  The authors concluded that RDN is associated with significant improvement in OSA severity.  Moreover, they stated that these findings need validation in RCTs that evaluate the effect of RDN in patients with OSA, which can potentially broaden the clinical applicability of RDN.

Chen and Upadhyay (2017) stated that early clinical studies primarily in Australia and Europe established renal denervation as a well-tolerated and feasible procedure that resulted in a sustained reduction in BP among individuals with severe resistant HTN.  A recent RCT in the U.S. using a sham procedure in the control arm, however, did not show a significant additional benefit in BP lowering from renal denervation.  This review summarized and critically examined the evidence for renal denervation in HTN management and identifies areas for future research.  The authors concluded that renal denervation is a potentially promising treatment option for drug-resistant uncontrolled HTN; future efforts should focus on refining the denervation technology and identifying individuals who are most likely to benefit from the denervation procedure.

Townsend et al (2017) noted that previous randomised renal denervation studies did not show consistent effectiveness in reducing blood pressure (BP).  In a randomised, international, single-blind, sham-controlled, multi-center, proof-of-concept (POC) study, these researchers examined the effect of renal denervation on BP in the absence of anti-hypertensive medications.  Patients were enrolled at 21 centers in the U.S., Europe, Japan, and Australia.  Eligible patients were drug-naive or discontinued their anti-hypertensive medications.  Patients with an office systolic BP (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic BP (DBP) of 90 mm Hg or greater, and a mean 24-hour ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at 2nd screening underwent renal angiography and were randomly assigned to renal denervation or sham control.  Patients, care-givers, and those assessing BP were blinded to randomization assignments.  The primary endpoint, change in 24-hour BP at 3 months, was compared between groups.  Drug surveillance was carried out to ensure patient compliance with absence of anti-hypertensive medication.  The primary analysis was performed in the intention-to-treat (ITT) population.  Safety events were assessed at 3 months.  Between June 25, 2015, and January 30, 2017, a total of 353 patients were screened; 80 patients were randomly assigned to renal denervation (n = 38) or sham control (n = 42) and followed-up for 3 months.  Office and 24-hour ambulatory BP decreased significantly from baseline to 3 months in the renal denervation group: 24-hour SBP -5.5 mm Hg (95 % CI: -9.1 to -2.0; p = 0.0031), 24-hour DBP -4·8 mm Hg (-7.0 to -2.6; p < 0.0001), office SBP -10.0 mm Hg (-15.1 to -4.9; p = 0.0004), and office DBP -5.3 mm Hg (-7.8 to -2.7; p = 0.0002).  No significant changes were observed in the sham-control group: 24-hour SBP -0.5 mm Hg (95 % CI: -3.9 to 2.9; p = 0.7644), 24-hour DBP -0.4 mm Hg (-2.2 to 1.4; p = 0.6448), office SBP -2.3 mm Hg (-6.1 to 1.6; p = 0.2381), and office DBP -0.3 mm Hg (-2.9 to 2.2; p = 0.8052).  The mean difference between the groups favored renal denervation for 3-month change in both office and 24-hour BP from baseline: 24-hour SBP -5.0 mm Hg (95 % CI: -9.9 to -0.2; p = 0.0414), 24-hour DBP -4.4 mm Hg (-7.2 to -1.6; p = 0.0024), office SBP -7.7 mm Hg (-14.0 to -1.5; p = 0.0155), and office DBP -4.9 mm Hg (-8.5 to -1.4; p = 0.0077).  Baseline-adjusted analyses showed similar findings.  There were no major adverse events (AEs) in either group.  The authors concluded that results from SPYRAL HTN-OFF MED provided biological proof-of-principle for the BP-lowering effectiveness of renal denervation.  This was a proof-of-concept study and was funded by Medtronic.

In a commentary on the afore-mentioned study by Townsend et al (2017), Jalil and White (2018) stated that “Townsend et al have successfully carried out an important device study in hypertension that has provided evidence regarding the effectiveness of renal denervation that yields an important platform for the next step of evaluating the efficacy and safety of this catheter in a larger randomized sham-control trial in drug-treatment resistant hypertension.  Future phase 3 or pivotal studies could use more than 1 design to gain approval by regulatory bodies, but should incorporate sham-control with skilled operators, improved patient selection, and standardization of anti-hypertensive regimens with quantitative screening for antihypertensive drug levels to avoid potential confounding of drug non-adherence”.

In an international, randomised, single-blind, sham-control, POC trial, Kandzari et al (2018) examined the safety and BP response after renal denervation or sham control in patients with uncontrolled hypertension on anti-hypertensive medications with drug adherence testing.  Patients with uncontrolled hypertension (aged 20 to 80 years) were enrolled at 25 centers in the U.S., Germany, Japan, UK, Australia, Austria, and Greece.  Eligible patients had an office SBP of between 150 mm Hg and 180 mm Hg and a DBP of 90 mm Hg or higher; a 24 hour ambulatory SBP of between 140 mm Hg and 170 mm Hg at 2nd screening; and were on 1 to 3 anti-hypertensive drugs with stable doses for at least 6 weeks.  Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control.  Patients, care-givers, and those assessing BP were masked to randomization assignments.  The primary effectiveness endpoint was BP change from baseline (measured at screening visit two), based on ambulatory BP measurements assessed at 6 months, as compared between treatment groups.  Drug surveillance was used to assess medication adherence.  The primary analysis was carried out in the ITT population.  Safety events were assessed through 6 months as per major AEs; and follow-up is ongoing.  Between July 22, 2015, and June 14, 2017, a total of 467 patients were screened and enrolled.  This analysis presented results for the first 80 patients randomly assigned to renal denervation (n = 38) and sham control (n = 42).  Office and 24-hour ambulatory BP decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24-hour SBP -7.0 mm Hg, 95 % CI: -12.0 to -2.1; p = 0.0059, 24-hour DBP -4.3 mm Hg, -7.8 to -0·8; p = 0.0174, office SBP -6.6 mm Hg, -12.4 to -0.9; p = 0.0250, and office DBP -4.2 mm Hg, -7.7 to -0.7; p = 0.0190).  The change in BP was significantly greater at 6 months in the renal denervation group than the sham-control group for office SBP (difference -6.8 mm Hg, 95 % CI: -12.5 to -1.1; p = 0.0205), 24-hour SBP (difference -7.4 mm Hg, -12.5 to -2.3; p = 0.0051), office DBP (difference -3.5 mm Hg, -7.0 to -0.0; p = 0.0478), and 24-hour DBP (difference -4.1 mm Hg, -7.8 to -0.4; p = 0.0292).  Evaluation of hourly changes in 24-hour SBP and DBP showed BP reduction throughout 24 hours for the renal denervation group; 3-month BP reductions were not significantly different between groups.  Medication adherence was about 60 % and varied for individual patients throughout the study.  No major AEs were recorded in either group.  The authors concluded that renal denervation in the main renal arteries and branches significantly reduced BP compared with sham control with no major safety events.  Incomplete medication adherence was common (about 50 % were not adherent to their prescribed anti-hypertensive medication regimen).  These investigators stated that the findings of this study and that of Townsend et al (2017) encouraged further study with this method of renal denervation for persistent hypertension despite the prescription of medical therapy and inform the design and conduct of subsequent trials.

The authors stated that this study had several drawbacks.  As an exploratory, POC study, this trial did not pre-specify a hypothesis for differences in BP measurements at any particular time interval.  If the analyses were pre-specified, however, assuming a treatment difference of 7 ± 11 mm Hg between renal denervation and sham control groups, and 2-sided alpha level of 0.05, a sample size of 80 patients (40 per cohort) would provide 80 % statistical power to reject the null hypothesis of no treatment difference between groups.  Instead, the investigational plan included prospectively planned interim analyses to examine if an adequate treatment effect with acceptable reduction in BP variability in the control cohort could be achieved; thus, informing further study.  To this purpose, a particular limitation -- and challenge for future studies -- relates to the prevalence of medical non-adherence despite patient education and awareness of drug testing.  Although absence of detectable drug at a single time-point implied more frequent non-adherence, it was not predictable for a single patient at interval assessments, and increasing recognition of this potential confounder as common among both pharmaceutical and device trials raises the question whether such assays should be imposed as common practice in hypertension trials.  In part related to this issue, these findings were suggestive of effect in both adherent and non-adherent populations; but could not confirm the benefit of renal denervation among patients with higher drug adherence given the small sample size.  Nevertheless, the prevalence of both number of medications and adherence were similar in both groups, and critically, as previously stated, ambulatory BP measurements were obtained only following witnessed pill ingestion in all patients.  For the same reasons related to size of the study population, the safety of renal denervation involving main artery and branch treatment could not be confirmed; however, the absence of safety events through 6 months in this trial was consistent with none observed at 3 months applying the same procedural method in the SPYRAL HTN-OFF MED trial.  Furthermore, as in previous studies of renal denervation, there was no measure of effective renal nerve ablation; however, the number of ablations per patient and procedural technique were similar to those observed in the SPYRAL HTN-OFFMED trial that showed similar and significant reductions in 24-hour BP at 3 months using the same procedural method and technology.  Additionally, the inclusion criteria in the protocol for number of required anti-hypertensive medications was revised during enrollment to allow patients to be on up to 3 medications, instead of exactly 3, to facilitate enrollment.  These researchers did not examine sodium intake or impose any restrictions on dietary or lifestyle habits (e.g., smoking), and these factors could have influenced BP measurements.  Lastly, the results observed with this therapy and in this specific population may not be generalizable to more varied clinical populations and alternative interventional therapies for hypertension or medication classes not represented in this trial.

Mahfoud et al (2019) stated that several studies and registries have reported sustained reductions in BP after renal denervation.  The long-term safety and effectiveness following renal denervation in real-world patients with uncontrolled hypertension, however, remains unknown.  In a prospective, open-label registry, these investigators examined the long-term safety and effectiveness of renal denervation, including its effects on renal function.  This study was carried out at 196 active sites worldwide in hypertensive patients receiving renal denervation treatment.  Among 2,237 patients enrolled and treated with the SYMPLICITY Flex catheter, 1,742 were eligible for follow-up at 3 years.  Baseline office and 24-hour ambulatory SBP were 166 ± 25 and 154 ± 18 mmHg, respectively.  SBP reduction after renal denervation was sustained over 3 years, including decreases in both office (-16.5 ± 28.6 mmHg, p < 0.001) and 24-hour ambulatory SBP (-8.0 ± 20.0 mmHg; p < 0.001).  A total of 21 % of patients had a baseline estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2.  Between baseline and 3 years, renal function declined by 7.1 ml/min/1.73 m2 in patients without chronic kidney disease (CKD; eGFR greater than or equal to 60 ml/min/1.73 m2; baseline eGFR 87 ± 17 ml/min/1.73 m2) and by 3.7 ml/min/1.73 m2 in patients with CKD (eGFR of less than 60 ml/min/1.73 m2; baseline eGFR 47 ± 11 ml/min/1.73 m2).  No long-term safety concerns were observed following the renal denervation procedure.  The authors concluded that long-term data from the Global SYMPLICITY Registry representing the largest available cohort of hypertensive patients receiving renal denervation in a real-world clinical setting showed both the safety and effectiveness of the procedure with significant and sustained office and ambulatory BP reductions out to 3 years.  The Global SYMPLICITY Registry was funded by Medtronic.

The authors stated that this study had several drawbacks.  As common in registries, not all patients currently enrolled in the Global SYMPLICITY Registry reached 36-month follow-up.  At the time of this report, 3-year follow-up data was available for 50 % of the enrolled population.  It remained speculative whether patients with good or poor response to renal denervation decided to resign from follow-up examinations.  However, when patients with complete follow-up were analyzed using mixed models as a sensitivity analysis, no major differences in the results were observed.  In addition, the Global SYMPLICITY Registry was a single-arm registry and as such did not involve control groups to compare outcomes.  There was no way to rule out a Hawthorne/placebo effect, which could be caused by participation and care during the study.  Comparison of eGFR measurements between patients with versus without medication changes was limited since reported medication changes were not verified with medication adherence testing.  The renal denervation procedures for this analysis were all carried out with the 1st-generation, single-electrode SYMPLICITY Flex RDN catheter system.  This device may make it more difficult to achieve a pattern of 4-quadrant ablations than the current SYMPLICITY Spyral catheter technology, especially within the GSR study design that did not encourage more treatment ablations or allow for treatment in the renal artery side branches or accessories.  The observed safety profile should be regarded as being device-specific; these researchers stated that there is a need for continued long-term follow-up of patients treated with the newer SYMPLICITY Spyral catheter and revised procedural techniques.

Bolignano and Coppolino (2019) stated that hypertension remains a major public health problem and one of the most relevant causes of cardiovascular mortality and morbidity worldwide.  Approximately 10 % of hypertensive individuals are considered as "resistant" as they are unable to attain and maintain optimal BP values despite the concurrent use of 3 anti-hypertensive agents of different classes at optimal doses.  As resistant hypertension conveys a higher risk of adverse outcomes, the search for effective treatments to properly manage this condition has progressively surged as a true health priority.  The renal nerve plexus plays a central role in regulating arterial BP and renal sympathetic over-activity is a major component in the development and progression of hypertension.  On these premises, minimally-invasive catheter-based devices for renal nerve ablation have been developed and tested as an alternative treatment for resistant hypertension; however, clinical study results had been conflicting.  These investigators provided a historical perspective on the scientific evidence forming the foundation of renal never ablation from accrued clinical evidence to possible future applications.  The authors concluded that more research and clinical experience is needed to fully reveal limits and potential indications of this procedure.

Bohm and colleagues (2020) noted that catheter-based renal denervation has significantly reduced blood pressure (BP) in previous studies.  Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) Trial was designed to examine the efficacy of renal denervation in the absence of anti-hypertensive medications.  In this international, prospective, single-blinded, sham-controlled trial, carried out at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the United Kingdom, and the USA, hypertensive patients with office systolic BP (SBP) of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure.  The primary efficacy end-point was baseline-adjusted change in 24-hour SBP and the secondary efficacy end-point was baseline-adjusted change in office SBP from baseline to 3 months after the procedure.  These researchers used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials.  The primary safety and efficacy analyses were performed in the intention-to-treat (ITT) population.  From June 25, 2015 to October 15, 2019, a total of 331 patients were randomly assigned to either renal denervation (n = 166) or a sham procedure (n = 165).  The primary and secondary efficacy end-points were met, with posterior probability of superiority more than 0.999 for both.  The treatment difference between the 2 groups for 24-hour SBP was -3.9 mm Hg (Bayesian 95 % credible interval [CI]: -6.2 to -1.6) and for office SBP the difference was -6.5 mm Hg (-9.6 to -3.5).  No major device-related or procedural-related safety adverse events (AEs) occurred up to 3 months.  The authors concluded that the SPYRAL Pivotal Trial showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower BP in the absence of anti-hypertensive medications.

The authors stated that this study had several drawbacks.  Blood pressure assessment in patients not treated with medications was limited to 3 months to avoid prolonging medication withdrawal.  Because previous trials have shown an increasing treatment effect between 3 months and 6 months, this shorter duration might have resulted in under-estimation of the treatment effect.  Not all patients followed protocol requirements to stay off medications, as assessed by drug and urine testing; although results in the per-protocol cohort were consistent with the ITT results.  An intra-procedural indicator of successful renal denervation is not available for operator feedback.  Patients with a history of heart failure (HF), cerebrovascular accident (CVA) or transient ischemic attack (TIA), or atrial fibrillation (AF) were excluded from the study because these patients require medications such as renin-angiotensin-aldosterone system inhibitors for secondary prevention of hypertension, and it would have been unethical to withhold these medications.  Furthermore, although not all patients had primary efficacy end-point observations available (often related to meeting protocol-specified criteria for resuming medications, and more commonly observed in the sham group), the efficacy analyses were consistent when multiple imputation for missing values was performed.  It should also be noted that this trial was sponsored by Medtronic.

Stavropoulos and associates (2020) stated that despite the availability of a numerous anti-hypertensive agents, hypertension treatment and control rates remain low in many countries.  The role of the SNS has long been recognized, but recent sham control renal denervation studies demonstrated conflicting results.  In a systematic review and meta-analysis, these researchers examined outcomes of sham-controlled studies utilizing new technologies and procedures; 6 published randomized, sham-controlled studies were included in this meta-analysis.  Of those, 3 trials used the first-generation RF renal denervation device and technique and the other 3 used second-generation devices and techniques.  A total of 981 patients with hypertension were randomized in all 6 trials to undergo renal denervation (n = 585) or sham procedure (n = 396).  Overall, renal denervation resulted in a decrease of 24-hours systolic ABP by 3.62 mm Hg (95 % CI: -5.28 to -1.96; I2 = 0 %), compared to sham procedure (GRADE: low).  Renal denervation also reduced day-time systolic ABP by 5.51 mm Hg (95 % CI: -7.79 to -3.23; I2 = 0 %), compared to sham procedure but not night-time systolic ABP.  Office SBP was reduced by 5.47 mm Hg (95 % CI -8.10 to -2.84; I2 = 0 %), compared to sham control.  Further analysis demonstrated that second-generation devices were effective in reducing BP, whereas the first-generation devices were not.  The authors concluded that results of this meta‐analysis suggested that renal denervation worked in the short-term and may contribute to better management and control of uncontrolled hypertension.  Nonetheless, the effect was relatively small and most likely diluted by non‐responders.  Moreover, these researchers stated that further, well‐designed studies (larger, adequately powered RCTs) are needed to better-define the role of renal denervation in the treatment of hypertension in the general population.

The authors stated that the drawbacks of this study included the small number of the included RCTs (n = 6), the relatively small sample size (n = 981), the short-term follow‐up period (up to 6 months), and small number of studies.  Furthermore, these investigators did not carry out meta‐regression analyses for the investigation of the observed heterogeneity, due to the small number of included trials.

Liu and colleagues (2020) stated that renal sympathetic denervation (RSD) is a new method for the treatment of refractory hypertension (RH); however, few studies have focused on the effects of RSD on blood flow and the interaction between temperature field and flow field.  These researchers designed a numerical simulation of electromagnetic field, flow field and temperature field coupling by finite element method.  Numerical simulation results were verified by particle image velocimetry (PIV) and in-vitro experiment.  From the simulation results, when the flow velocity increased to 0.05 m/s, the turbulence near the electrode disappeared and flow state became uniform laminar flow.  With the increases of flow velocity (0 m/s to 0.1 m/s), temperature rise of the renal artery, the electrode tip and blood decreased from 13°C, 24°C and 5.4°C to 9.3°C, 9.7°C and 0.2°C, respectively.  From PIV experiment and in-vitro experiment results, when the flow rate increased to 0.5 L/min, it appeared similar phenomenon with the velocity of 0.05 m/s in simulation.  With the increases of flow rate (0 L/min to 0.8 L/min), temperature rise of 3 points decreased from 11.2°C, 20.5°C and 3.6°C to 7.8°C, 8.5°C, and 0.4°C, respectively.  When the blood flow rate exceeded 0.5 L/min, there was no large velocity gradient and reflux area in the flow field, so there would be no hemolysis and thrombosis.  Thus, the temperature field had less influence on the flow field.  With the increase of flow rate, the temperature at all 3 points decreased.  Therefore, the flow field had an effect on the temperature field; however, the central temperature of renal artery could still reach the treatment target in which temperature rose to be more than 6°C.  The authors concluded that he findings of this study preliminarily verified the safety and effectiveness of RSD.

Versaci and co-workers (2020) noted that initial studies on RDN for the treatment of non-controlled arterial hypertension (HTN) via RF ablation of renal arteries demonstrated that RDN is an effective therapeutic strategy to reduce arterial BP.  Nonetheless, the 1st randomized study, SYMPLICITY-HTN-3, failed to demonstrate a clear benefit for RND over the control group.  Technologic evolution, with the introduction of new 2nd generation multi-electrode devices, allowed deep energy delivery along the full circumference of the vessel.  Two recent randomized studies involving patients assuming (SPYRAL HTN-ON MED) or not (SPYRAL HTN-OFF MED) anti-hypertensive pharmacotherapy, demonstrated the safety and efficacy of RDN using 2nd generation systems for RF ablation.  Another recent randomized study demonstrated that RDN with US (RADIANCE-HTN SOLO) of the main renal arteries led to a significant BP reduction compared to the control group.  The authors concluded that the findings of these studies renewed the interest of the scientific community towards attempting to define the appropriate role of RDN in the treatment of RH.  Moreover, these researchers stated that larger trials, with a greater number of recruited patients and longer follow-ups, are needed to better define the role of RDN in controlling arterial BP values and in reducing the number of anti-hypertensive drugs and their adequate dose for long-term control of BP.

Mahfoud et al (2020) noted that renal denervation is under investigation for treatment of uncontrolled hypertension and might represent an attractive treatment for patients with high cardiovascular (CV) risk.  It is important to examine if baseline CV risk affects the effectiveness of renal denervation.  These researchers examined if BP reduction and event rates after renal denervation in patients with various co-morbidities, testing the hypothesis that renal denervation is effective and durable in these high-risk populations.  BP reduction and AEs over 3 years were evaluated for several high-risk subgroups in the GSR (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons through 3 years registry), an international registry of renal denervation in patients with uncontrolled hypertension (n = 2,652).  Comparisons were made for patients aged 65 years or older versus aged under 65 years, with versus without isolated systolic hypertension, with versus without atrial fibrillation (AF), and with versus without diabetes mellitus (DM).  Baseline CV risk was estimated using the American Heart Association (AHA)/American College of Cardiology (ACC) atherosclerosis cardiovascular disease (ASCVD) risk score.  Reduction in 24-hour SBP at 3 years was -8.9 ± 20.1 mm Hg for the overall cohort, and for high-risk subgroups, BP reduction was -10.4 ± 21.0 mm Hg for resistant hypertension, -8.7 ± 17.4 mm Hg in patients aged 65 years or older, -10.2 ± 17.9 mm Hg in patients with DM, -8.6 ± 18.7 mm Hg in isolated systolic hypertension, -10.1 ± 20.3 mm Hg in chronic kidney disease (CKD), and -10.0 ± 19.1 mm Hg in AF (p < 0.0001 compared with baseline for all).  BP reduction in patients with measurements at 6, 12, 24, and 36 months showed similar reductions in office and 24-hour BP for patients with varying baseline ASCVD risk scores, which was sustained to 3 years; and AE rates at 3 years were higher for patients with higher baseline CV risk.  The authors concluded that BP reduction after renal denervation was similar for patients with varying high-risk co-morbidities and across the range of ASCVD risk scores.  The impact of baseline risk on clinical event reduction by renal denervation-induced BP changes could be examined in further studies.  Moreover, these investigators stated that future investigations should examine the effectiveness of renal denervation to prevent major adverse CV events in patients with isolated systolic and other specified forms of hypertension.

The authors stated that this study had several drawbacks.  First, this report included a post-hoc analysis from a large, prospective, single-arm, open-label, real-world registry.  As often observed in registries, not all patients were available for 3-year follow-up, and no control group was available for comparison.  However, the overall large number of patients available and the extended duration of follow-up showed a persistent BP reduction over 3 years.  Second, baseline BP has been reported to be a predictor of BP reduction, and several of the comparison subgroups had different baseline SBP.  However, these differences were appropriately adjusted using ANCOVA, and the benefit in BP reduction was consistent.  Third, CV risk scores could not be re-calculated at follow-up because serum cholesterol measurement was not mandatory.  However, because SBP is a key determinant of risk, one might assume that calculated risk improved in this group.

In an editorial commentary on the study by Mahfoud et al (2020), Textor (2020) stated that effective BP reduction remains the single largest reversible risk to lower CV mortality.  Recent guidelines continue to ratchet down goal BP levels, as reflected by the 2017 American College of Cardiology/American Heart Association guidelines, the European Society of Hypertension guidelines, and others.  These Global SYMPLICITY Registry (GSR) data re-affirmed the potential for renal denervation to achieve sustained, moderate SBP reductions, consistent with the more recent preliminary reports using somewhat different technologies for denervation.  For individuals with treatment-resistant hypertension, some respond with spectacular and meaningful BP reductions that were previously unachievable.  It should be emphasized that although population average changes in SBP were modest, the SD was large (i.e., SBP change overall at 36 months was −16.5 ± 28 mm Hg).  Hence, some individuals experienced SBP reductions of more than 30 to 40 mm Hg after this interval.  Although these were not universally achieved, these data were consistent with occasional patients that have major BP reductions and could reduce anti-hypertensive drug requirements following renal denervation.  How to identify those individuals who are likely to have clinically important benefits remains uncertain -- and could not be inferred directly from these registry data.  The editorialist stated that the outcomes reported here suggested that age, diabetes, isolated systolic hypertension (ISH), CKD, or other demographic data do not reliably demarcate the populations likely to respond to RDN; and identifying the truly optimal candidates for renal denervation remains the unresolved “holy grail” for this technology.

Haribabu and associates (2021) stated that hypertension is one of the most important risk factors for cardiovascular disease, which is the leading cause of mortality.  The World Health Organization (WHO) estimated that in 2019 more than 1.13 billion individuals worldwide were suffering from hypertension.  Despite the advances in new medical therapies, control of hypertension remains suboptimal.  Treatment with RDN was primarily developed to treat RH and is a potential method for treating congestive heart failure, diabetes, and chronic renal failure.  RDN entails passing a catheter into the renal arteries and ablating their sympathetic nerves using RF or US energy.  Despite promising results in initial trials, RDN failed to achieve its efficacy endpoints as a treatment RH; however, the recent series of successful trials showed that RDN is back as a serious therapeutic alternative.  The authors reviewed the current state-of-the-art RDN devices including Symplicity Flex, Symplicity Spyral, Vessix, EnligHTN, Iberis, TIVUS system, and Paradise.  They also provided an in-depth review of future RDN devices that include Cryo-RDN, Golden Leaf Catheter, Synaptic, SyMapCath, ConfidenHT System, and Grizzly Microwave Ablation system.

Zhang et al (2022) examined the effectiveness of RF ablation (RFA) of renal artery sympathetic nerve in the treatment of secondary hypertension.  A total of 8 patients with secondary hypertension were treated with renal denervation (RDN); and were followed-up for 3 to 18 months, of which 5 cases were followed-up for more than 12 months and 8 cases were followed-up for more than 3 months.  A total of 8 patients were treated with RFA via the renal artery catheter.  The parameters such as pre-operative BP, anti-hypertensive drugs, organ function, intra-operative ablation resistance, power, time, and temperature were determined.  The related changes of BP, anti-hypertensive drugs, and visceral function and the occurrence of side effects at 1 week and 1, 3, 6, and 12 months after operation were related to the operation.  The authors concluded that RDN had a significant effect in the treatment of refractory hypertension, with stable post-operative decrease in BP, reduced drug dosage, and less side effects.  This was a small (n = 8) study with no control/comparative group.

Moreover, these researchers stated that there are still many problems that need to be solved with regard to RDN.  First, identify indications -- clear which part of the group for RDN is the primary problem. RDN can effectively reduce the renal sympathetic nerve activity, lower BP, the concept can not only be used in the treatment of refractory hypertension; its indication should be renal sympathetic nerve activity hyperfunction caused by a series of disease.  Second, how to find and evaluate indicators of sympathetic over-activation -- although epinephrine, norepinephrine, dopamine, aldosterone, and other indicators can reflect renal sympathetic activity, reliable indicators with high specificity and sensitivity are still lacking at present, and more studies are needed to further examine appropriate indicators for evaluation.  Third, further improvement of surgical methods -- the structure and shape of renal arteries and sympathetic nerves are different in different individuals; thus, the surgical methods are also different.  These investigators stated that how to investigate a better surgical method and block more sympathetic nerves as much as possible is worth further discussion and research.

Rao and Krishnan (2022) discussed the role of renal sympathetic nerves in the pathophysiology of hypertension; and provided an update on the available evidence regarding the short- and long-term safety and effectiveness of RDN in the treatment of hypertension; and considered its future perspectives.  These investigators noted that RDN is a percutaneous endovascular catheter-based neuromodulation approach that enables ablation of renal sympathetic nerve fibers within the adventitial layer of the renal arteries using RF (most extensively studied), ultrasound (US) energy, or neurolytics (e.g., alcohol).  In the past 10 years, advancements in procedural techniques and well-designed sham-controlled studies employing 24-hour ABPM have shown that RDN has an excellent safety profile and resulted in a modest reduction of BP, in a wide range of hypertensive phenotypes (mild-to-resistant), irrespective of anti-hypertensive medication use and this effect is sustained over a 3-year period.  Superiority of a particular RDN modality has not been yet established.  Despite strong evidence showing the safety and effectiveness of RDN, current data do not support its use as a primary approach in the treatment of hypertension due to its modest treatment effect and concerns regarding its long-term sustainability.  Perhaps the best use of RDN is in hypertensives intolerant to anti-hypertensive medications or as an adjunct to aldosterone antagonists in the management of resistant hypertension.  Patient selection will be critical to show a meaningful benefit of RDN.  The authors concluded that future well-designed studies are needed to determine predictors and measures of response to RDN, long-term effectiveness given question of renal nerve regeneration, comparison of available technologies, safety in patients with advanced kidney disease, and improvement in patient QOL measures.

Mahfoud et al (2022) stated that renal denervation has been shown to lower BP in the presence of anti-hypertensive medications; however, long-term safety and effectiveness data from randomised trials of renal denervation are lacking.  In this pre-specified analysis of the SPYRAL HTN-ON MED study, these researchers compared changes in BP, anti-hypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group.  This study enrolled patients from 25 clinical centers in the U.S., Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office SBP between 150 mm Hg and 180 mm Hg and DBP of 90 mm Hg or higher.  Eligible patients had to have 24-hour ambulatory SBP between 140 mm Hg and less than 170 mm Hg, while taking 1 to 3 anti-hypertensive drugs with stable doses for at least 6 weeks.  Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency (RF) renal denervation or a sham control procedure.  Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross-over after 12-month follow-up completion.  The primary endpoint was the treatment difference in mean 24-hour SBP at 6 months between the renal denervation group and the sham control group.  Statistical analyses were carried out on the ITT population.  Long-term effectiveness was assessed using ambulatory and office BP measurements up to 36 months.  Drug surveillance was used to evaluate medication use.  Safety events were assessed up to 36 months; and an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial.  Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n = 38) or a sham control procedure (n = 42).  Mean ambulatory SBP and DBP were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of anti-hypertensive drugs.  The medication burden at 36 months was 2.13 medications (SD 1.15) in the renal denervation group and 2.55 medications (2.19) in the sham control group (p = 0.26).  A total of 24 (77 %) of 31 patients in the renal denervation group and 25 (93 %) of 27 patients in the sham control group adhered to medication at 36 months.  At 36 months, the ambulatory SBP reduction was -18.7 mm Hg (SD 12.4) for the renal denervation group (n = 30) and -8.6 mm Hg (14.6) for the sham control group (n = 32; adjusted treatment difference -10.0 mm Hg, 95 % CI: -16.6 to -3.3; p = 0.0039).  Treatment differences between the renal denervation group and sham control group at 36 months were -5.9 mm Hg (95 % CI: -10.1 to -1.8; p = 0.0055) for mean ambulatory DBP, -11.0 mm Hg (-19.8 to -2.1; p = 0.016) for morning SBP, and -11.8 mm Hg (-19.0 to -4.7; p = 0.0017) for night-time SBP.  There were no short-term or long-term safety issues associated with renal denervation.  The authors concluded that RF renal denervation compared with sham control produced a clinically meaningful and lasting BP reduction up to 36 months of follow-up, independent of concomitant anti-hypertensive medications and without major safety events.  These investigators stated that renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension.  This study and was funded by Medtronic.

Kandzari et al (2023) stated that renal denervation (RDN) lowers BP in patients with uncontrolled hypertension in the absence of anti-hypertensive medications.  In a prospective, randomized, sham-controlled, patient- and assessor-blinded study, these researchers examined the safety and effectiveness of RDN in the presence of anti-hypertensive medications.  This trial enrolled patients from 56 clinical centers worldwide.  Patients were prescribed 1 to 3 anti-hypertensive medications.  Patients were randomized to RF-RDN or sham control procedure.  The primary effectiveness endpoint was the baseline-adjusted change in mean 24-hour ambulatory SBP at 6 months between groups using a Bayesian trial design and analysis.  The treatment difference in the mean 24-hour ambulatory SBP from baseline to 6 months between the RDN group (n = 206; -6.5 ± 10.7 mm Hg) and sham control group (n = 131; -4.5 ± 10.3 mm Hg) was -1.9 mm Hg (95 % CI: -4.4 to 0.5 mm Hg; p = 0.12).  There was no significant difference between groups in the primary effectiveness analysis with a posterior probability of superiority of 0.51 (Bayesian treatment difference: -0.03 mm Hg [95 % CI: -2.82 to 2.77 mm Hg]).  However, there were changes and increases in medication intensity among sham control patients.  RDN was associated with a reduction in office SBP compared with sham control at 6 months (adjusted treatment difference: -4.9 mm Hg; p = 0.0015).  Night-time BP reductions and win ratio analysis also favored RDN.  There was 1 adverse safety event among 253 assessed patients.  The authors concluded that there was no significant difference between groups in the primary analysis; however, multiple secondary endpoint analyses favored RDN over sham control.  Moreover, these investigators stated that continued long-term follow-up of this population will be important to examine RDN as an adjunctive therapy for the treatment of hypertension.

Barbato et al (2023) noted that since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality studies, including randomized, sham-controlled trials on catheter-based RDN were published, confirming both the BP-lowering safety and effectiveness of RF and US RDN in a broad range of patients with hypertension, including resistant hypertension.  A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice.  This expert group proposed that RDN is an adjunct therapeutic option in uncontrolled resistant hypertension, confirmed by ABPM, despite best efforts at lifestyle and pharmacotherapies.  RDN may also be used in patients who are unable to tolerate anti-hypertensive medications in the long-term.  A shared decision-making process is a key feature and preferably includes a patient who is well-informed on the benefits and limitations of the procedure.  The decision-making process should take the patient's global cardiovascular (CV) risk and/or the presence of hypertension-mediated organ damage or CV complications into account.  Multi-disciplinary hypertension teams involving hypertension experts as well as interventionalists evaluate the indication and facilitate the RDN procedure.  Interventionalists require expertise in renal interventions and specific training in RDN procedures.  Centers performing these procedures require the skills and resources to deal with potential complications.  The authors concluded that further investigation is needed to address open questions and examine the impact of BP-lowering with RDN on clinical outcomes and potential clinical indications beyond hypertension.

Wang et al (2023) stated that RDN is proposed as a durable and patient compliance independent treatment for hypertension; however, 20 % to 30 % non-responder after RDN treatment weakened the therapeutic effect, which may be due to blind ablation.  The renal nerve mapping/selective ablation system developed by SyMap Medical Ltd (Suzhou), China, has the function of mapping renal sympathetic/parasympathetic nerve sites and selectively removing renal sympathetic nerves and is expected to meet the urgent unmet clinical need of targeted RDN.  The "Sympathetic Mapping/Ablation of Renal Nerves Trial" (SMART) is a prospective, randomized, single-blinded, sham procedure-controlled, multi-center trial designed to examine the safety and effectiveness of targeted renal sympathetic denervation in patients with essential and uncontrolled hypertension.  The study is the 1st clinical registry trial using a targeted RDN for the treatment of uncontrolled hypertension; the dual-endpoint design can answer the question of how many anti-hypertensive drugs can be reduced in patients following RDN.

The Society of Cardiovascular Angiography and  Interventions (SCAI)’s position statement on “Renal denervation for hypertension” (Swaminathan et al, 2023) stated that hypertension is the leading cause of death and disability, and the prevalence of uncontrolled hypertension is increasing worldwide.  In addition to inertia for lifestyle interventions, cost, side effects, and the impact of poly-pharmacy on quality-of-life (QOL) limit access and adherence to pharmacotherapy.  Device therapies targeting the renal sympathetic nervous system hold promise as adjuncts to abate or interventions to abolish HTN, depending upon the underlying severity of BP elevation.  In addition renal denervation may have beneficial effects on several conditions beyond hypertension that are likely to be manifestations of sympathetic imbalance including sleep apnea, left ventricular hypertrophy, albuminuria, as well as atrial fibrillation.  The authors concluded that appropriate patient selection, pre-procedure evaluation, careful procedural planning and technique, implementation of strict operator training standards, as well as facility requirements are paramount to programmatic success.

Mohammad et al (2024) examined the clinical outcomes following RDN for hypertensive patients with chronic kidney disease (CKD).  Prospective studies published between January 1, 2010 and November 15, 2022 where systematically identified for RDN outcomes on office and ambulatory BP, eGFR, creatinine, and procedural characteristics from 3 online databases (Medline, PubMed, Embase).  Random effects model to combine risk ratios and mean differences was used.  Where possible, clinical outcomes were pooled and analyzed at 6, 12 and 24 months.  Significance was set at p ≤ 0.05.  A total of 11 prospective trials, with a total of 226 patients with treatment resistant hypertension receiving RDN met the inclusion criteria.  Age ranged from 42.5 ± 13.8 years to 66 ± 9 years.  Main findings of this review included a reduction in office SBP and DBP systolic at 6 months [-19.8 (p < 0.00001)/-15.2 mm Hg (p < 0.00001)] and 12 months [-21.2 (p < 0.00001)/-9.86 mm Hg (p < 0.0005)] follow-up compared to baseline.  This was also observed in systolic and diastolic 24-hour ambulatory BP at 6 months [-9.77 (p = 0.05)/-3.64 mm Hg (p = 0.09)] and 12 months [-13.42 (p = 0.0007)/-6.30 mm Hg (p = 0.001)] follow-up compared to baseline.  The reduction in systolic and diastolic 24-hour ambulatory BP was maintained to 24 months [(-16.30 (p = 0.0002)/-6.84 mm Hg (p = 0.0010)].  Analysis of kidney function through eGFR showed non-significant results at 6 months (+1.60 ml/min/1.73 m2, p = 0.55), 12 (+5.27 ml/min/1.73 m2, p = 0.17), and 24 months (+7.19 ml/min/1.73 m2, p = 0.36) suggesting an interruption in natural CKD progression.  Similar results were observed in analysis of serum creatinine at 6 months (+0.120 mg/dL, p = 0.41), 12 months (+0.100 mg/dL, p = 0.70), and 24 months (+0.07 mg/dL, p = 0.88).  Assessment of procedural complications deemed RDN in a CKD cohort to be safe with an overall complication rate of 4.86 %.  The authors concluded that the results of the pooled analysis suggested an interruption to the progressive decline of renal function that is typically observed in CKD.  Moreover, the safety of RDN in patients with CKD was demonstrated; therefore, RDN may serve as clinically useful for patients with treatment resistant HTN and CKD.  Moreover, these researchers stated that long-term studies with larger cohorts consisting of randomization and shams that employ next-generation ablation catheters are needed to establish the impact on renal metrics that expands beyond eGFR and serum creatinine.   They stated that future trials should also examine the effect of the BP-lowering effects of CKD progression and hence examine if the effect of RDN on eGFR is dependent on BP reduction or if there is a mechanism independent of BP that contributes to the alterations in eGFR.

Wang et al (2024) noted that previous trials of RDN have been designed to examine reduction of BP as the primary effectiveness endpoint using non-selective RDN without intra-operatively verified RDN success.  It is an unmet clinical need to map renal nerves, selectively dennervate renal sympathetic nerves, provide read-outs for the interventionalists and avoid futile RDN. In a prospective, randomized, single-blinded, sham-controlled, multi-center study, these researchers examined the safety and effectiveness of renal nerve mapping/selective RDN (msRDN) in patients with uncontrolled HTN and examined if anti-hypertensive drug burden is reduced while office SBP (OSBP) is controlled to target level (less than 40 mmHg).  The study combined 2 effectiveness endpoints at 6 months as primary outcomes:  The control rate of patients with OSBP of less than 140 mmHg (non-inferior outcome) and change in the composite index of anti-hypertensive drugs (Drug Index) in the treatment versus sham group (superior outcome).  This design avoided confounding from excess drug-taking in the sham group.  Anti-hypertensive drug burden was evaluated by a composite index constructed as: Class N (number of classes of anti-hypertensive drugs) × (sum of doses).  A total of 15 hospitals in China participated in the study, and 220 patients were enrolled in a 1:1 ratio (msRDN versus sham).  The key inclusion criteria included: age (18 to 65 years), history of essential HTN (at least 6 months), heart rate (greater than or equal to 70 bpm), OSBP (greater than or equal to 150 mmHg and less than or equal to 180 mmHg), ambulatory BP monitoring (ABPM, 24-hour SBP of greater than or equal to 130 mmHg or daytime SBP of greater than or equal to 135 mmHg or nighttime SBP of greater than or equal to 120 mmHg), renal artery stenosis (less than 50 %) and renal function (eGFR greater than 45 ml/min/1.73 m2).  The catheter with both stimulation and ablation functions was inserted in the distal renal main artery.  The RDN site (hot spot) was selected if SBP increased (greater than or equal to 5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was carried out at the same site.  At sites where there was decreased SBP (greater than or equal to 5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was carried out.  The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested; then either treated or avoided.  After msRDN, patients had to follow a pre-defined, vigorous drug titration regimen in order to achieve target OSBP (less than 140 mmHg).  Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine.  This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing.  Between July 8, 2016 and February 23, 2022, a total of 611 patients were consented, 220 patients were enrolled in the study who received standardized anti-hypertensive drug treatments (at least 2 drugs) for at least 28 days, presented OSBP f greater than or equal to 150 mmHg and less than or equal to 180 mmHg and met all inclusion and exclusion criteria.  In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively.  Hot, cold and neutral spots was 48.0 %, 27.5 % and 24.4 % of total mapped sites, respectively.  At 6 months, the Control Rate of OSBP was comparable between msRDN and sham group (95.4 % versus 92.8 %, p = 0.429), achieved non-inferiority margin -10 % (2.69 %; 95 % CI: -4.11 % to 9.83 %, p < 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to sham group (4.37 (6.65) versus 7.61 (10.31), p = 0.010) and superior to sham group (-3.25; 95 % CI: -5.56 to -0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP of less than 140 mmHg; 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and sham groups, respectively (p < 0.001 from baseline; p > 0.05 between groups).  Safety profiles were comparable between msRDN and sham groups, showing the safety and effectiveness of renal mapping/selective RDN to treat uncontrolled HTN.  The authors concluded that msRDN therapy achieved the objectives of reducing the drug burden of HTN patients and controlling OSBP  less than 140 mmHg, with only approximately 4 targeted ablations per renal main artery, much lower than in previous trials.  Moreover, these researchers stated that based on these promising results, further investigations are needed to examine the net effects of msRDN on BP in patients without anti-hypertensive drug therapy.

The authors stated that this study had several drawbacks.  First, office SBP of less than 140 mmHg was designed as a primary treatment target because this was a pivotal study in China, and it has to be compliant with Chinese Hypertension Guidelines, which maintains OSBP of less than 140 mmHg as a goal for BP control.  However, these investigators acknowledged that this is a major limitation of the study because the target BP was not the same as that recommended by European Society of Hypertension (ESH), American College of Cardiology (ACC)/American Heart (AHA) guidelines.  Second, BP-lowering effects of anti-hypertensive medications in the drug regimen were different, and Drug Index could not reflect these differences.  In particular, the non-linear relationship between anti-hypertensive medication doses and BP-lowering effects was unable to be captured by the method used in the trial for calculating Drug Index.  However, both msRDN and sham group employed the same methods for Drug Index,; therefore, this may reduce the bias of the calculation and the Index.  Third, modification of diet in renal disease (MDRD) equation was used to calculate eGFR, which is not as accurate as the index based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPIP).  However, MDRD is one of the standards accepted by the regulatory agency (National Medical Products Administration) in China.  Fourth, for some anti-hypertensive drugs, the detection time in urine exceeds 24 hours; therefore, results of urine samples may have bias.  Fifth, compared to other studies, patients enrolled in this study were relatively younger with high HRs; in addition, only 29 female patients were enrolled; thus, it might lead to uncertainty whether this device would lower BP in older, female patients.

On behalf of the American Heart Association Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on the Kidney in Cardiovascular Disease; and Council on Peripheral Vascular Disease, Cluett et al (2024) stated that HTN is a leading risk factor for CV morbidity and mortality.  Despite the widespread availability of both pharmacological and lifestyle therapeutic options, BP control rates are worsening globally.  In fact, only 23 % of individuals with HTN in the U.S. achieve therapeutic objectives.  In 2023, the FDA approved RDN as an adjunctive treatment for patients in whom lifestyle modifications and anti-hypertensive medications do not adequately control BP.  This FDA approval followed the publication of multiple randomized studies using rigorous trial designs, all incorporating renal angiogram as the sham control.  Most but not all of the new generation of trials reached their primary endpoint, showing modest effectiveness of RDN in lowering BP across a spectrum of HTN, from mild-to-truly resistant.  Individual patient responses vary, and further research is needed to identify those who may benefit most.  The initial safety profile appeared favorable, and multiple ongoing studies are examining longer-term safety and effectiveness.  Multi-disciplinary teams that include HTN specialists and adequately trained proceduralists are critical to ensure that referrals are made appropriately with full consideration of the potential risks and benefits.  Incorporating patient preferences and engaging in shared decision-making conversations will aid patients in making the best decisions given their individual circumstances.  The authors concluded that although further research is needed, RDN presents a novel therapeutic strategy for patients with uncontrolled HTN.

Furthermore, an UpToDate review on “Treatment of resistant hypertension” (Brook and Townsend, 2024) lists renal denervation as one of the experimental therapies.  

Treatment of Heart Failure

Booth et al (2015) noted that sympathetic drive, especially to the heart, is elevated in heart failure (HF) and is strongly associated with poor outcome. The mechanisms causing the increased sympathetic drive to the heart remain poorly understood. Catheter-based RDN, which reduces BP and sympathetic drive in hypertensive patients, is a potential treatment in HF. These researchers investigated the short-term effects of catheter-based RDN on BP, heart rate (HR) and cardiac sympathetic nerve activity (CSNA) and on baroreflex function in a conscious, large animal model of HF. Adult Merino ewes were paced into heart failure (ejection fraction<40%) and then instrumented to directly record CSNA. The resting levels and baroreflex control of CSNA and HR were measured before and 24h after bilateral renal (n=6) or sham (n=6) denervation; RDN was performed using the Symplicity Flex Catheter System® (Medtronic) using the same algorithm as in patients. Catheter-based RDN significantly reduced resting diastolic BP (p < 0.01) and mean arterial BP (p < 0.05), but did not change resting HR or CSNA compared with sham denervation. Renal denervation reduced the BP at which CSNA was at 50 % of maximum (BP50; p < 0.005) compared with sham denervation. The authors concluded that in an ovine model of HF, catheter-based RDN did not reduce resting CSNA in the short-term. There was, however, a lack of a reflex increase in CSNA in response to the fall in arterial BP due to a leftward shift in the baroreflex control of CSNA, which may be due to denervation of renal efferent and/or afferent nerves.

Dai and colleagues (2015) examined the feasibility and effects of percutaneous renal sympathetic nerve RF ablation in patients with HF. A total of 20 patients with HF were enrolled, aged from 47 to 75 (63 ± 10) years. They were divided into the standard therapy (n = 10), and renal nerve RF ablation groups (n = 10). There were 15 males and 5 female patients; including 8 ischemic cardiomyopathy, 8 dilated cardiomyopathy, and 8 hypertensive cardiopathy. All of the patients met the criteria of NYHA classes III to IV cardiac function. Patients with diabetes and renal failure were excluded. Percutaneous renal sympathetic nerve RF ablation was performed on the renal artery wall under X-ray guidance. Serum electrolytes, neurohormones, and 24-hour urine volume were recorded 24 hours before and after the operation. Echocardiograms were performed to obtain left ventricular ejection fraction (LVEF) at baseline and 6 months. Symptoms of dyspnea and edema, BP, and HR were also monitored. After renal nerve ablation, 24-hour urine volume was increased, while neurohormone levels were decreased compared with those of pre-operation and standard therapy. No obvious change in HR or BP was recorded. Symptoms of HF were improved in patients after the operation. No complications were recorded in the study. The authors concluded that percutaneous renal sympathetic nerve RF ablation may be a feasible, safe, and effective treatment for the patients with severe congestive HF. These preliminary findings need to be validated by well-designed studies.

Treatment of Cardiac Arrhythmias and Chronic Renal Failure

Thorp and Schlaich (2015) noted that animal and human studies have shown that chronic activation of renal sympathetic nerves is critical in the pathogenesis and perpetuation of treatment-resistant hypertension. Bilateral renal denervation has emerged as a non-pharmacological treatment for resistant hypertension that involves the selective ablation of efferent and afferent renal nerves to lower BP.  However, the most recent and largest RCT failed to confirm the effectiveness of renal denervation over a sham procedure, prompting widespread re-evaluation of the therapy's efficacy.  Disrupting renal afferent sympathetic signaling to the hypothalamus with renal denervation lowers central sympathetic tone, which has the potential to confer additional clinical benefits beyond BP control.  Specifically, there has been substantial interest in the use of renal denervation as either a primary or adjunct therapy in pathological conditions characterized by central sympathetic over-activity (e.g., renal disease, HF and metabolic-associated disorders).  Recent findings from pre-clinical and proof-of-concept studies appeared promising with renal denervation shown to confer cardiovascular and metabolic benefits, largely independent of changes in BP.  These investigators explored the pathological rationale for targeting sympathetic renal nerves for BP control.  They discussed latest developments in renal nerve ablation modalities designed to improve procedural success along with prospective findings on the efficacy of renal denervation to lower BP in treatment-resistant hypertensive patients.  The authors presented preliminary evidence in support of renal denervation as a possible therapeutic option in disease states characterized by central sympathetic over-activity.

Barrett (2015) examined the role played by renal sympathetic nerves in the regulation of cardiovascular function, focusing on changes that occur during the development of hypertension and HF. While elevated levels of renal sympathetic activity (RSA) are a feature of many cardiovascular diseases, the relationship is not straightforward, especially in the case of hypertension.  These researchers noted that before consideration of targeting the renal nerves in the clinical management of cardiovascular diseases it is essential that their role in the development of the disease is established.  In recent years, with the development of new clinical techniques to target the renal nerves specifically, researchers have seen a renewed interest in the role of the renal sympathetic nerves in the development of cardiovascular diseases.  In understanding the potential of renal nerve ablation for the treatment of cardiovascular disease, first the role played by these nerves in cardiovascular regulation must be determined.  Elevated RSA not only has the potential to increase fluid retention but may also act in a feed-forward manner to increase sympathetic activation further, increasing the workload of the heart and the potential for arrhythmias.  Direct recordings of RSA in animal models of hypertension and renal noradrenaline spill-over levels in individual patients with hypertension have illustrated that hypertension is not always accompanied by an increase in RSA.  Elevated RSA is a feature of severe HF, but whether removal of the renal nerves then compromises the ability to maintain cardiac function when faced with a stressor such as sepsis remains unclear.  The authors concluded that understanding when increased renal sympathetic drive is contributing to the progression of cardiovascular diseases such as hypertension and HF would appear to be the key to understanding when renal nerve ablation is likely to be of benefit.

Oparil and Schmieder (2015) stated that hypertension is the most common modifiable risk factor for cardiovascular disease and death; and lowering BP with anti-hypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available therapeutic options, a substantial portion of the hypertensive population has uncontrolled BP.  The unmet need of controlling BP in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its co-morbidities.  These investigators discussed new drugs and interventional treatments that are undergoing pre-clinical or clinical testing for hypertension treatment.  New drug classes (e.g., inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist) are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na(+)/H(+) exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1-7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or pre-clinical development.  The 2 main interventional approaches, trans-catheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment-resistant hypertension in some countries.  The authors stated that renal denervation is also being evaluated for treatment of various co-morbidities (e.g., CHF, cardiac arrhythmias and chronic renal failure).  Novel interventional approaches in early development include carotid body ablation and arterio-venous fistula placement.  They noted that none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.

Also, UpToDate reviews on "Overview of the management of chronic kidney disease in adults" (Rosenberg, 2016), "Arrhythmia management for the primary care clinician" (Levy and Olshansky, 2016), and "Treatment of symptomatic arrhythmias associated with the Wolff-Parkinson-White syndrome" (Di Biase and Walsh, 2016) do not mention renal denervation/renal nerve ablation as a therapeutic option.

Treatment of Acute Myocardial Infarction

Feng and colleagues (2017) evaluated the therapeutic effects of RDN on acute MI in canines and explored its possible mechanisms of action.  A total of 18 healthy mongrel dogs were randomly assigned to either the control group, the MI group or the MI + RDN group.  To assess cardiac function, LVEF, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and fraction shortening (FS) were recorded.  Additionally, hemodynamic parameters such as left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and HR were measured.  Cardiac oxidative stress levels were evaluated based on the expression of p47phox mRNA, malondialdehyde (MDA), anti-superoxide anion free radical (ASAFR) and activity of superoxide dismutase (SOD).  To measure the local activity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS), the levels of tyrosine hydroxylase (TH), angiotensin II (AngII), angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) [Ang(1-7)] and Mas receptor (MasR) in myocardial tissues were recorded.  The expression of TH in renal tissue and serum creatinine were used to assess the effectiveness of the RDN procedure and renal function, respectively.  These researchers found that MI deteriorated heart function and activated cardiac oxidative stress and the local neuro-humoral system, while RDN partially reversed these changes.  Compared with the control group, parameters including LVEDD, LVESD, LVEDP and the levels of ASAFR, MDA, p47phox,ACE2, Ang(1-7), MasR, AngII and TH-positive nerves were increased (all p < 0.05) in myocardial infracted dogs; meanwhile, LVEF, FS, LVSP and SOD expression were decreased (all p < 0.05).  However, after RDN therapy, these changes were significantly improved (p < 0.05), except that there were no significant differences observed in FS or LVSP between the 2 groups (p = 0.092 and 0.931, respectively).  More importantly, the expression of TH, AngII and Ang(1-7) was positively correlated with MDA and negatively correlated with SOD.  Between-group comparisons demonstrated no differences in serum creatinine (p = 0.706).  The authors concluded that RDN attenuated cardiac re-modelling and improved heart function by decreasing the level of cardiac oxidative stress and the local activity of the SNS and RAS in cardiac tissues.  Additionally, the safety of the RDN procedure was established, as no significant decrease in LVSP or rise in serum creatinine was observed in this study.  Moreover, these investigators stated that to confirm the validity of these results, studies both in humans and animals should be undertaken on a larger scale and with a longer observation time.

This study had several drawbacks:
  1. MI was only validated by the pathological specimen and echocardiography, and these researchers did not evaluate the infarct size, which reduced the persuasion to a certain extent,
  2. the number of subjects was not large enough (n = 18), which may have affected the  statistical analysis,
  3. due to lack of a control + RDN group, the effects of the intervention could not be excluded completely, and
  4. the observation time was short (4 weeks).

Treatment of Chronic Kidney-Related Pain

Casale and colleagues (2008) presented their medium-term experience with laparoscopic RDN and nephropexy for autosomal dominant polycystic kidney disease (ADPKD)-related pain in the pediatric patient.  A total of 12 patients aged 8 to 19 years (mean age of 12.4 years) with ADPKD presented with chronic pain refractory to narcotic analgesics were enrolled in this study.  These subjects underwent laparoscopic RDN of 16 kidneys.  Mean operative time was 152 minutes and mean hospital stay was 2.17 days.  All patients were pain-free at discharge and remain pain-free at a mean follow-up of 25.5 months; 3 adolescent patients each had an episode of flank pain.  One was associated with pyelonephritis, another with stones, and the third with trauma and a hematoma.  The authors concluded that laparoscopic RDN and nephropexy is a promising option for pediatric patients with uncontrolled ADPKD-related pain.

Gambaro and co-workers (2013) stated that loin pain hematuria syndrome (LPHS) is a severe renal pain condition of uncertain origin and often resistant to treatment.  Nephrectomy and renal auto-transplantation have occasionally been performed in very severe cases.  Its pathogenesis is controversial.  In this study, a 40-year old hypertensive woman was diagnosed with LPHS after repeated diagnostic imaging procedures had ruled out any renal, abdominal or spinal conditions to justify pain.  Notwithstanding treatment with 3 drugs, she had frequent hypertensive crises during which the loin pain was dramatically exacerbated.  Vascular causes of the pain and hypertension were investigated and excluded.  Her renal function was normal.  The patient was referred to a multi-disciplinary pain clinic, but had no significant improvement in her pain symptoms despite the use of non-steroidal anti-inflammatory drugs (NSAIDs), adjuvant anti-depressants and opioid-like agents.  The pain and the discomfort were so severe that her quality of life (QOL) was very poor, and her social and professional activities were compromised.  Nephrectomy and renal auto-transplantation have occasionally been performed in these cases.  Since visceral pain signals flow through afferent sympathetic fibers, these investigators felt that percutaneous catheter-based RF ablation of the renal sympathetic nerve fibers (recently introduced for the treatment of drug-resistant hypertension) could be valuable for pain relief.  They treated the patient with RF ablation applied only to the right renal artery.  After a 6-month follow-up, the patient was pain-free and normotensive with all drugs withdrawn.  She experienced no hypertensive crises in the meantime.  The authors concluded that this observation suggested that percutaneous sympathetic RF denervation could prove to be an effective mini-invasive strategy for the treatment of chronic renal pain, and LPHS in particular.

de Beus and colleagues (2013) stated that RDN using a catheter delivering RF energy to the renal artery vessel wall has recently emerged as a promising new treatment for difficult-to-treat hypertension.  The beneficial effect of this intervention, attributable to sympathetic nerves interruption, has been coherently demonstrated in both an observational study and a controlled trial.  Of note, according to the available follow-up studies, the hypotensive effect of RDN has been shown to last for up to 2 to 3 years.  The European Society of Hypertension has published a position paper with recommendations for the application of this new technique including the eligibility criteria and issues that need to be addressed in further trials.  Several other conditions associated with sympathetic over-activity as diverse as HF, atrial fibrillation (AF), insulin resistance, sleep apnea and polycystic ovary syndrome have been described as being responsive to RDN and/or are being subjected to further study.  Renal denervation has become a hot topic as illustrated by the large number of ongoing and planned trials of the technique. In this issue, Gambaro et al (2013) described the use of catheter-based RDN for yet another indication, namely pain control in LPHS.  The authors concluded that application of catheter-based RDN should be subjected to a properly conducted clinical trial in order to provide definitive evidence for its effectiveness, or otherwise, in LPHS.

Casteleijn and associates (2014) noted that chronic pain is a common concern in patients with ADPKD.  These investigators reported, to their best knowledge, the first catheter-based RDN procedure in a patient with ADPKD resulting in successful management of chronic pain.  The patient was a 43-year old woman whose chronic pain could not be controlled by pain medication or splanchnic nerve blockade.  Transluminal RF RDN was performed as an experimental therapeutic option with an excellent result, indicating that this procedure should be considered for chronic pain management in ADPKD.

Riccio and colleagues (2014) described a case of RDN in a woman with single-kidney stage 4 chronic kidney disease secondary to ADPKD and uncontrolled treatment-resistant hypertension.  Due to failure of all other therapeutic strategies, including uni-nephrectomy, RDN by RF ablation of the single renal artery was performed.  After the procedure, the patient’s BP declined remarkably, decreasing her need for anti-hypertensive medication.  Moreover, the patient did not experience a significant decline in kidney function.  Furthermore, the authors noted that several studies supported the safety and efficacy of RDN.  However, the existing evidence was limited by small studies and short-term follow-up.  They stated that a large trial, recently completed but not yet published (at the time of writing), as well as ongoing clinical trials, should provide important information regarding the safety and efficacy of RDN for resistant hypertension or other indications.

Casteleijn and co-workers (2017) stated that ADPKD patients can suffer from chronic pain that can be refractory to conventional treatment, resulting in a wish for nephrectomy.  These investigators examined the effect of a multi-disciplinary treatment protocol with sequential nerve blocks on pain relief in ADPKD patients with refractory chronic pain.  As a first-step a diagnostic, temporary celiac plexus block with local anesthetics was performed.  If substantial pain relief was obtained, the assumption was that pain was relayed via the celiac plexus and major splanchnic nerves.  When pain recurred, patients were then scheduled for a major splanchnic nerve block with RF ablation.  In cases with no pain relief, it was assumed that pain was relayed via the aortico-renal plexus, and catheter-based RDN was performed.  A total of 60 patients were referred, of which 44 were eligible.  In 36 patients, the diagnostic celiac plexus block resulted in substantial pain relief with a change in the median visual analog scale (VAS) score pre-post intervention of 50/100.  Of these patients, 23 received a major splanchnic nerve block because pain recurred, with a change in median VAS pre-post block of 53/100.  In 8 patients without pain relief after the diagnostic block, RDN was performed in 5, with a borderline significant change in the median VAS pre-post intervention of 20/100.  After a median follow-up of 12 months, 81.8 % of the patients experienced a sustained improvement in pain intensity, indicating that the treatment protocol was effective in obtaining pain relief in ADPKD patients with refractory chronic pain.

de Jager and colleagues (2018) noted that LPHS and ADPKD are the most important non-urological conditions to cause chronic severe kidney-related pain.  Multi-disciplinary programs and surgical methods have shown inconsistent results with respect to pain reduction.  Percutaneous catheter-based RDN could be a less invasive therapeutic option for these patients.  These researchers examined the change in perceived pain and use of analgesic medication from baseline to 3, 6 and 12 months after RDN.  Patients with LPHS or ADPKD, who experienced kidney-related pain for greater than or equal to 3 months with a VAS score of greater than or equal to 50/100 were included in this trial.  Percutaneous RDN was performed with a single-electrode RF ablation catheter.  Renal denervation was performed in 11 patients (6 with LPHS and 5 with ADPKD).  Perceived pain declined in the whole group by 23 mm (p = 0.012 for the total group).  In patients with LPHS and ADPKD, the median daily defined dosage of analgesic medication decreased from 1.6 [inter-quartile range (IQR) 0.7 to 2.3] and 1.4 (IQR 0.0 to7.4) at baseline to 0.3 (IQR 0.0 to 1.9; p = 0.138) and 0.0 (IQR 0.0 to 0.8; p = 0.285) at 12 months, respectively.  Mean estimated glomerular filtration rate (eGFR) decreased in the whole group by 5.4 ml/min/1.73 m2 at 6 months compared with baseline (p = 0.163).  The authors concluded that these findings suggested that percutaneous catheter-based RDN reduced pain complaints and the use of analgesic medication in patients with LPHS or ADPKD.  Moreover, they stated that these results can serve as the rationale for a larger, preferably randomized (sham) controlled study.

Prasad and associates (2018) stated that LPHS is characterized by severe unilateral or bilateral loin pain that suggests a renal origin but occurs in the absence of identifiable or relevant urinary tract disease.  Hematuria can either be microscopic or macroscopic, but the renal abnormalities responsible for the hematuria are unexplained.  Debilitating pain refractory to conventional pain medications is the main cause of morbidity.  In a single-arm, single-center study, 12 patients between the ages of 21 and 62 years (11 women, 1 man) with LPHS underwent endovascular ablation of the renal nerves between July 2015 and November 2016, using the Vessix renal denervation system.  The primary objective was to achieve 30 % reduction in self-reported pain with the McGill Pain Questionnaire (MPQ) at 6 months.  The secondary objectives were to measure changes in disability (Oswestry Disability Index [ODI]), mood (Geriatric Depression Scale [GDS]), and QOL (EuroQol-5D [EQ-5D] and the MOS 36-Item Short Form Survey [SF-36]) scores from baseline to 6 months post-procedure; 10 of 12 patients at 3 months and 11 of 12 patients at 6 months reported a greater than 30 % reduction in pain based on the MPQ at 3 and 6 months.  These researchers found consistent improvements in MPQ, ODI, GDS, EQ-5D, and SF-36 scores from baseline to 6 months post-procedure.  The authors concluded that RDN was associated with a considerable improvement in pain, disability, QOL, and mood.  These findings suggested that percutaneous catheter-based delivery of RF energy is a safe, rapid therapeutic option that should be considered in all patients with LPHS.

The authors stated that results of this study would no doubt have to be followed-up with a RCT involving a sham group.  Nevertheless, the initial improvement in pain observed in these patients opened up the possibility of conducting further clinical studies of LPHS with RDN as the treatment modality.  Also, long-term clinical studies are needed to fully evaluate the beneficial effects of RDN.  The negative results associated with RDN in BP trials, venoplasty in multiple sclerosis, vertebroplasty for wedge compression fractures, use of percutaneous laser myocardial re-vascularization, cardio-inhibitory syncope with implantation of a pacemaker, and intra-articular injection of anti-inflammatory medications should temper one’s enthusiasm regarding the apparently positive results to be proved only to have a sham impact.

Microwave Denervation of the Renal Sympathetic Nerve

Balaji et al (2024) noted that transcatheter RDN has had inconsistent effectiveness and concerns for durability of denervation.  These investigators examined long-term safety and effectiveness of transcatheter microwave RDN in-vivo in normotensive sheep in comparison to conventional RFA.  Sheep underwent bilateral RDN, receiving 1 to 2 microwave ablations (maximum power of 80 to 120 W for 240 s to 480 s) and 12 to 16 RFA (180 s to 240 s) in the main renal artery in a paired fashion, alternating the side of treatment, euthanized at 2 weeks (acute; n = 15) or 5.5 months (chronic; n =15), and compared with un-denervated controls (n = 4).  Microwave RDN produced substantial circumferential peri-vascular injury compared with RFA at both 2 weeks (area 239.8; IQR: 152.0 to 343.4 mm2 versus 50.1; IQR: 32.0 to 74.6 mm2, p < 0.001; depth 16.4; IQR: 13.9 to 18.9 mm versus 7.5; IQR: 6.0 to 8.9 mm, p < 0.001) and 5.5 months (area 20.0; IQR: 3.4 to 31.8 mm2 versus 5.0 ; IQR: 1.4 to 7.3 mm2, p = 0.025; depth 5.9; IQR: 1.9 to 8.8 mm versus 3.1; IQR: 1.2 to 4.1 mm, p = 0.005) using mixed models.  Renal denervation resulted in significant long-term reductions in viability of renal sympathetic nerves (58.9 % reduction with microwave (p = 0.01) and 45 % reduction with RF (p = 0.017)] and median cortical norepinephrine levels (71 % reduction with microwave (p < 0.001), and 72.9 % reduction with RF (p <0.001)) at 5.5 months compared with un-denervated controls.  The authors concluded that transcatheter microwave RDN produced deep circumferential peri-vascular ablations without significant arterial injury to provide effective and durable RDN at 5.5 months compared with RF RDN.  Moreover, these researchers stated that further dose‐finding studies employing hypertensive models are needed to ascertain the appropriate clinical dosing regimen for microwave RDN in the future.  With the advent of technologies designed to improve the depth and circumferentiality of ablation energy delivery for RDN, it will be important to devise methods to ensure that ablation energy is delivered judiciously to achieve consistent and durable denervation outcomes.

Ultrasound Denervation of the Renal Sympathetic Nerve

Weber et al (2019) stated that initial studies of catheter-based RDN for uncontrolled HTN using RFA in the main renal arteries showed that RDN was effective in lowering office (BP.  However, the 1st randomized sham-controlled trial, SYMPLICITY-HTN-3, did not show significantly lower office or 24-hour ambulatory SBP compared with sham treatment.  Subsequent studies in both animals and humans revealed the potential importance of more distal and branch renal artery RFA, and a 2nd-generation multi-electrode system became available.  These researchers noted that 2 recent randomized sham-controlled studies in patients not taking anti-hypertensive drugs (SPYRAL HTN-OFF MED) or continuing to take drugs (SPYRAL HTN-ON MED) performed RDN with the 2nd-generation RFA system using an ablation protocol that included treatment of the distal renal artery as well as the branch renal arteries.  These studies showed that RDN significantly reduced office and 24-hour ambulatory BP compared with sham treatment.  Another recent randomized sham-controlled trial in patients not receiving medications showed that RDN with catheter-based ultrasound (US) (RADIANCE-HTN SOLO) applied in just the main renal arteries significantly lowered daytime ambulatory and office BP compared with sham treatment.  These trials have renewed clinical and scientific interest in defining the appropriate role of RDN in the treatment of refractory HTN.  Furthermore, other important issues will need to be addressed in the future such as the development of tests to determine the extent of RDN at the time of the procedure and the potential of renal nerve fibers to regain their patency at some later stage following the ablation procedure.

Yap and Balachandran (2021) noted that HTN is a risk factor for coronary artery disease (CAD) and stroke.  Only about 50 % of the patients with HTN are adequately controlled on medical therapy, and approximately 25 % may develop severe or resistant HTN, which is defined as failure to achieve target BP of less than 140/90 mmHg while on full doses of an appropriate 3-drug regimen that includes a diuretic.  Increasingly more attention has been paid to the potential of RDN as treatment for resistant HTN, guided by a better understanding of renal nerve anatomy.  These researchers stated that RDN is undergoing transformation as a technology for the treatment of resistant HTN.  Early studies reported effectiveness in treating resistant HTN patients with significant reduction in office BP.  However, the randomised, sham-controlled trial, Symplicity HTN-3, did not show any significant difference in BP reduction between the RDN and the sham control arm.  Since then, further improvements have been made in developing 2nd generation systems.  Subsequent studies revealed the importance of more distal and branch renal artery ablation, and multi-electrode systems have been employed.  Two randomised sham-controlled trials, the SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED studies showed the effectiveness of RDN with the 2nd-generation RFA system.  These studies showed that RDN significantly reduced office and 24-hour ambulatory BP when compared with sham control treatment.  The RADIANCE-HTN SOLO trial also showed effectiveness using an US-based catheter system for RDN treatment of resistant HTN.  These investigators stated that the findings of these studies have re-invigorated current clinical interest in RDN as treatment for resistant HTN.  There is increasing evidence for RDN as an effective treatment for uncontrolled or resistant HTN.  The RDN procedure has also evolved with time, with an improved practice of delivering a larger number of ablations to distal vessels in addition to main renal arteries.  The authors concluded that the RDN procedure exhibited a low complication rate and may provide an approach that could potentially reduce the morbidity and mortality risks associated with resistant HTN.

Azizi et al (2021) stated that endovascular RND reduces BP in patients with mild-to-moderate HTN; however, its effectiveness in patients with true resistant HTN has not been shown.  In a randomised, single-blind, sham-controlled, multi-center study, these researchers examined the safety and effectiveness of endovascular US-RND in patients with HTN resistant to 3 or more anti-hypertensive medications.  This trial was carried out at 28 tertiary centers in the U.S. and 25 in Europe; participants included patients aged 18 to 75 years with office BP of at least 140/90 mm Hg despite 3 or more anti-hypertensive medications including a diuretic.  Eligible patients were switched to a once-daily, fixed-dose, single-pill combination of a calcium channel blocker (CCB), an angiotensin receptor blocker (ARB), and a thiazide diuretic.  After 4 weeks of standardized therapy, patients with daytime ambulatory BP of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centers) to US-RND or a sham procedure.  Patients and outcome assessors were masked to randomization.  Addition of anti-hypertensive medications was allowed if specified BP thresholds were exceeded.  The primary endpoint was the change in daytime ambulatory SBP at 2 months in the ITT population; safety was also assessed in the ITT population.  Between March 11, 2016, and March 13, 2020, a total of 989 participants were enrolled, and 136 were randomly assigned to RDN (n = 69) or a sham procedure (n = 67).  Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82 %] of 51 in the RDN group versus 47 [82 %] of 57 in the sham procedure group; p = 0.99).  RDN reduced daytime ambulatory SBP more than the sham procedure (-8.0 mm Hg [IQR -16.4 to 0.0] versus -3.0 mm Hg [-10.3 to 1.8]; median between-group difference -4.5 mm Hg [95 % CI: -8.5 to -0.3]; adjusted p = 0.022); the median between-group difference was -5.8 mm Hg (95 % CI: -9.7 to -1.6; adjusted p = 0.0051) among patients with complete ambulatory BP data.  There were no differences in safety outcomes between the 2 groups.  The authors concluded that compared with a sham procedure, US-RDN reduced BP at 2 months in patients with HTN resistant to a standardized triple combination pill.  Moreover, these researchers stated that if the BP- lowering effect and safety of RDN were maintained in the long-term, RDN might be an alternative to the addition of further anti-hypertensive medications in patients with resistant HTN.

Drawz et al (2023) noted that RDN represents a new dimension to the treatment of HTN, with multiple device manufacturers seeking pre-market Food and Drug Administration (FDA) approval currently.  Interest in the safety and effectiveness of the treatment has spurred compelling mechanistic studies into the function of renal nerves and down-stream impacts of denervation.  A trial of the ultrasound Paradise Catheter system (RADIANCE II) found a 6.3 mmHg reduction in SBP relative to sham controls.  A trial of the Symplicity Spyral system (SPYRAL HTN-ON MED) found an insignificant reduction in SBP relative to sham controls.  Individuals were taking anti-hypertensive medications during the study, and researchers noted the sham group experienced a larger medication burden than the RDN group.  Recent pre-clinical studies have examined potential risks of RDN, how sympathetic activity broadly was affected, as well as identifying possible biomarkers to identify individuals where RDN would be more successful.  The authors concluded that studies of RDN continued to find a robust anti-hypertensive effect, especially in studies wherein medications were withdrawn.  These researchers stated that further investigations into mechanisms and indicators for usage of the technique are needed to identify the patient population most likely to benefit from usage of RDN.

Fulton et al (2024) noted that HTN is one of the largest contributors to CV morbidity and mortality in the U.S., and is estimated to affect 47 % of the U.S. population; however, recent estimates suggested that over 40 % continue to have uncontrolled HTN.  In past 10 years, multiple randomized, placebo-controlled studies have shown the safety and effectiveness of RDN as an adjunctive therapy, culminating in the recent approval of 2 devices by the FDA.  These devices employ either RF or US energies to ablate the peri-vascular sympathetic nerves in the renal arteries and have been shown to reduce BP.  The authors stated that there are still multiple issues regarding the future of the technology in its applications and reimbursement landscapes.

Kim and Kwon (2024) stated that resistant HTN is diagnosed in patients whose BP target is unmet despite the use of 3 or more anti-hypertensive medications.  Systemic sympathetic hyper-activation is associated with the development of resistant HTN.  As the kidney is largely pervasive of the sympathetic nervous system, RDN was developed to control BP by attenuating the renal and systemic sympathetic hyper-activity.  Renal denervation is a minimally invasive procedure that employs RF or US energy waves to reduce the activity of the renal artery nerves.  Previous clinical trials have shown conflicting findings regarding the effectiveness of the procedure.  Symplicity HTN-1 and -2 Trials showed effective BP-lowering effect in the RDN group with a good safety profile; however, the Symplicity HTN-3 Trial reported no difference in BP-lowering effect between the RDN and control sham procedure groups.  Some recent studies with sham control as well as meta-analysis demonstrated clinical benefits of RDN.  Other clinical benefits of RDN entailed glucose control, CV protective effect, reduction of OSA, and neuralgia control.  A subset of patients with satisfactory BP control response to the procedure may experience improved glucose control due to the overall reduced sympathetic activity and insulin resistance.  Sympathetic activity control following RDN has cardio-protective effects, especially for those with arrhythmia and left ventricular hypertrophy.  Furthermore, RDN could be helpful in renal origin pain control.  The authors concluded that RDN is a safe, effective, non-invasive procedure with many clinical benefits beyond BP control.  Moreover, these researchers stated that further investigations in the procedure/technique as well as selection of target patients are needed for wider clinical use of RDN in resistant HTN.

In a case report, Shiraki et al (2024) described the use of US-RDN by means of the Paradise System in a patient with HF with preserved ejection fraction.  Initially, the cardiac sympathetic nerve activity of the patient exhibited a late heart/mediastinum (H/M) ratio of 2.00, and a wash-out rate of 66.0 % by cardiac iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy.  Subsequently, the patient underwent trans-femoral US-RDN targeting the left, right upper, and right lower renal arteries.  At the 6 month follow-up, no significant change was observed in 123I-MIBG findings; however, the estimated stressed blood volume (eSBV) decreased from 1,722 to 1,029 ml/70 kg.  At 18 months, 123I-MIBG findings improved, with the late H/M ratio reaching 2.76 and the wash-out rate decreasing to 43.1 %.  The authors concluded that this case report highlighted the potential of US-RDN in lowering eSBV within 6 months and subsequently improving cardiac sympathetic nerve activity at the 18 month follow-up.  Moreover, these researchers stated that the precise mechanism by which RDN improved cardiac sympathetic nerve activity remains unclear, and further research is needed to elucidate these underlying mechanisms.

Transurethral Renal Pelvic Denervation Using Radiofrequency Ablation

Herring et al (2022) noted that endovascular renal denervation lowers BP.  In an open-label, single-arm, feasibility study, these researchers examined an alternative approach to renal denervation using RF energy delivered across the renal pelvis utilizing the natural orifice of the urethra and the ureters.  This trial enrolled patients with uncontrolled hypertension despite anti-hypertensive pharmacotherapies.  The primary effectiveness endpoint was the change in ambulatory day-time SBP 2 months after renal pelvic denervation.  The 18 patients (mean age of 56 ± 12 years) enrolled were taking an average of 2.7 anti-hypertensive drugs daily.  Renal pelvic denervation reduced mean daytime SBP by 19.4 mm Hg (95 % CI: -24.9 to -14.0, p < 0.001) from its baseline of 148.4 ± 8.7 mm Hg.  Mean night-time (-21.4 mm Hg [95 % CI: -29.5 to -13.3]) and 24-hour (-20.3 mm Hg [95 % CI: -26.2 to -14.5]) SBP each fell significantly (p < 0.001) as did the corresponding DBPs (p < 0.001).  Office SBP decreased from 156.5 ± 12.3 mm Hg by 22.4 mm Hg (95 % CI: -31.5 to -13.3, p < 0.001) by 2 months.  Office SBP decreased over time (p = 0.001 by linear trend test) starting by day 1 with a decrease of 8.3 mm Hg (95 % CI: -16.9 to 0.3, p = 0.057).  There were no serious AEs; mild transitory back pain followed the procedure.  Serum creatinine decreased by 0.08 mg/dL (p = 0.02) and eGFR increased by 7.2 ml/min/1.73 m2 (p = 0.03) 2 months after ablation procedure.  The authors concluded that based on these initial findings, a well-powered, randomized, sham-controlled trial of renal pelvic denervation to more fully establish its safety and effectiveness is now justified in patients with uncontrolled hypertension despite drug therapy.

Mufarrih et al (2024) stated that despite optimal medical therapy, the BP of a significant proportion of hypertensive patients remains uncontrolled.  Catheter-based RDN has been proposed as a potential intervention for uncontrolled hypertension.  These investigators carried out an updated meta-analysis to examine the safety and effectiveness of RDN in patients with uncontrolled hypertension, with emphasis on the differential effect of RDN in patients on and off anti-hypertensive medications.  Online data-bases were searched to identify randomized clinical trials comparing safety and effectiveness of RDN versus control in patients with uncontrolled hypertension.  Subgroup analyses were carried out for sham-controlled trials and studies that used RDN devices that have gained or are currently seeking FDA approval.  A total of 15 studies with 2581 patients (RDN, 1,723; sham, 858) were included.  In patients off anti-hypertensive medications undergoing RDN, a significant reduction in 24-hour ambulatory SBP (-3.70 [95 % CI: -5.41 to -2.00] mm Hg), office SBP (-4.76 [95 % CI: -7.57 to -1.94] mm Hg), and home SBP (-3.28 [95 % CI: -5.96 to -0.61] mm Hg) was noted.  In patients on anti-hypertensive medications, a significant reduction was observed in 24-hour ambulatory SBP (-2.23 [95 % CI: -3.56 to -0.90] mm Hg), office SBP (-6.39 [95 % CI: -11.49 to -1.30]), home SBP (-6.08 [95 % CI: -11.54 to -0.61] mm Hg), day-time SBP (-2.62 [95 % CI: -4.14 to -1.11]), and night-time SBP (-2.70 [95 % CI: -5.13 to -0.27]), as well as 24-hour ambulatory DBP (-1.16 [95 % CI: -1.96 to -0.35]), office DBP (-3.17 [95 % CI: -5.54 to -0.80]), and day-time DBP (-1.47 [95 % CI: -2.50 to -0.27]).  The authors concluded that RDN significantly reduced BP in patients with uncontrolled hypertension, in patients on and off anti-hypertensive medications, with a favorable safety profile.  Moreover, these researchers stated that larger RCTs and post-market registries with extended follow‐up are needed to establish the long‐term safety and effectiveness of RDN.  Furthermore, this updated review did not mention transurethral renal pelvic denervation using radiofrequency ablation as an option  for the treatment of uncontrolled hypertension.


References

The above policy is based on the following references:

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