Emerging evidence on renal denervation for the treatment of hypertension
Authors: Christina M. Wyatt, Stephen C. Textor
Journal: Kidney International (2018)

The sympathetic nervous system plays a central role in the regulation of blood pressure and the pathogenesis of hypertension. In the first half of the 20th century, surgical sympathectomy was shown to reduce systolic blood pressure by more than 40 mm Hg in approximately one-half of treated patients with severe symptomatic hypertension.1Peet M.M. Woods W.W. Braden S. The surgical treatment of hypertension. Results in 350 consecutive cases treated by bilateral supradiaphragmatic splanchnicectomy and lower dorsal sympathetic ganglionectomy. Clinical lecture at New York session.JAMA. 1940; 115: 1875-1885Crossref Scopus (16) Google Scholar This approach was abandoned because of intraoperative and long-term morbidity and the increased availability of effective antihypertensive medications. Experimental studies establishing multiple afferent and efferent connections between the kidney and central nervous system have provided a rationale to undertake denervation of the renal nerves to modulate systemic blood pressures.2Wyss J.M. The role of the sympathetic nervous system in hypertension.Curr Opin Nephrol Hypertens. 1993; 2: 265-273Crossref PubMed Scopus (49) Google Scholar, 3Kopp U.C. Role of renal sensory nerves in physiological and pathophysiological conditions.Am J Physiol Regul Integr Comp Physiol. 2015; 308: R79-R95Crossref PubMed Scopus (103) Google Scholar Initial proof-of-concept trials and the SYMPLICITY HTN-2 trial in 2010 suggested that catheter-based renal denervation may be safe and effective to reduce office systolic blood pressure in individuals with resistant hypertension4Symplicity HTN-2 InvestigatorsRenal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial.Lancet. 2010; 376: 1903-1909Abstract Full Text Full Text PDF PubMed Scopus (1869) Google Scholar; however, these studies were limited by the lack of a sham control arm and by the reliance primarily on office blood pressure measurements. Subsequent trials confirmed the safety of catheter-based renal denervation, but failed to show a consistent benefit on blood pressure outcomes.5Fadl Emula F.E.M. Feng Y.M. Jacobs L. et al.Sham or no sham control: that is the question in trials of renal denervation for resistant hypertension. A systematic meta-analysis.Blood Press. 2017; 26: 195-203Crossref PubMed Scopus (28) Google Scholar These efforts have been hampered by documented medication non-adherence6Azizi M. Pereira H. Hamdidouche I. et al.Adherence to antihypertensive treatment and the blood pressure-lowering effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) trial.Circulation. 2016; 134: 847-857Crossref PubMed Scopus (116) Google Scholar and by the lack of methods to confirm the extent of renal denervation. Recently, 3 additional trials have extended the data available and suggested a modest benefit of percutaneous approaches to renal denervation in the treatment of hypertension compared with sham controls. These trials based outcomes on ambulatory blood pressure monitoring, and provided data both for patients with and without ongoing drug treatment, with efforts to evaluate medication adherence when relevant.7Townsend R.R. Mahfoud F. Kandzari D.E. et al.SPYRAL HTN-OFF MED trial investigatorsCatheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, sham-controlled, proof-of-concept trial.Lancet. 2017; 390: 2160-2170Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 8Kandzari D.E. Bohm M. Mahfoud F. et al.Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN ON-MED proof-of-concept randomised trial.Lancet. 2018; 391: 2346-2355Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 9Azizi M. Schmieder R.E. Mahfoud F. et al.Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.Lancet. 2018; 391: 2335-2345Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar Notably, all 3 trials excluded individuals with stage 3b or higher chronic kidney disease (CKD). Two of these trials were proof-of-concept trials that evaluated a new approach to catheter-based renal denervation using radiofrequency ablation in individuals with elevated blood pressure both in the absence of medical therapy (SPYRAL HTN-OFF MED) and in the context of stable antihypertensive therapy (SPYRAL HTN-ON MED).7Townsend R.R. Mahfoud F. Kandzari D.E. et al.SPYRAL HTN-OFF MED trial investigatorsCatheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, sham-controlled, proof-of-concept trial.Lancet. 2017; 390: 2160-2170Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 8Kandzari D.E. Bohm M. Mahfoud F. et al.Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN ON-MED proof-of-concept randomised trial.Lancet. 2018; 391: 2346-2355Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar Eligible participants had office systolic blood pressure measurements between 150 and 179 mm Hg, office diastolic blood pressure measurements greater than 90 mm Hg, and mean 24-hour systolic blood pressure measurements between 140 and 169 mm Hg either on no antihypertensive medications (SPYRAL HTN-OFF MED) or on a stable antihypertensive regimen including up to 3 medications (SPYRAL HTN-ON MED). Eighty participants in each trial were randomized to a renal angiogram followed by catheter-based renal denervation versus a renal angiogram alone. Participants, treating providers, and other study personnel involved in follow-up visits were blinded to treatment assignment.7Townsend R.R. Mahfoud F. Kandzari D.E. et al.SPYRAL HTN-OFF MED trial investigatorsCatheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, sham-controlled, proof-of-concept trial.Lancet. 2017; 390: 2160-2170Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 8Kandzari D.E. Bohm M. Mahfoud F. et al.Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN ON-MED proof-of-concept randomised trial.Lancet. 2018; 391: 2346-2355Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar The RADIANCE-HTN SOLO trial evaluated an alternative approach to renal denervation based on endovascular ultrasound and thermal ablation in the absence of antihypertensive medications; a parallel trial is in progress to evaluate this technology in participants on stable 3-drug regimens.9Azizi M. Schmieder R.E. Mahfoud F. et al.Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.Lancet. 2018; 391: 2335-2345Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar Eligible participants were on 2 or fewer antihypertensive medications at the initial screening, and had daytime ambulatory blood pressure measurements of at least 135/85 mm Hg and less than 170/105 mm Hg 4 weeks after withdrawing antihypertensive medications. Randomized participants also had suitable vascular anatomy as determined by CT or a magnetic resonance angiogram. After randomization, participants underwent a renal angiogram for confirmation of suitable vascular anatomy, followed by renal denervation in participants randomized to the intervention arm and no further intervention in participants randomized to the sham control arm. Participants and their treating providers again were blinded to treatment assignment.9Azizi M. Schmieder R.E. Mahfoud F. et al.Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.Lancet. 2018; 391: 2335-2345Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar Results of all 3 trials were generally consistent, insofar as there was a greater reduction in ambulatory blood pressure levels from baseline to follow-up in the renal denervation group compared with the sham control group in the primary intention-to-treat analysis. In SPYRAL HTN-OFF MED, the mean difference in 24-hour systolic and diastolic blood pressure reduction at 3 months was 5.0 mm Hg and 4.4 mm Hg, respectively. In SPYRAL HTN-ON MED, the mean difference in 24-hour ambulatory systolic and diastolic blood pressure measurements at 6 months was 7.0 mm Hg and 4.3 mm Hg, respectively. In RADIANCE-HTN SOLO, the mean difference in daytime ambulatory systolic (the primary outcome) and diastolic blood pressure measurements at 2 months was 6.3 mm Hg and 2.6 mm Hg, respectively. Why the studies selected different time points to assess the primary outcome, and why the results differed across time points, is not clear. Generally, similar results were reported for office blood pressure measurements and in per-protocol analyses. No major adverse events were reported in any of the trials; 1 participant randomized to renal denervation in RADIANCE-HTN subsequently underwent renal artery stenting for a pre-existing lesion.7Townsend R.R. Mahfoud F. Kandzari D.E. et al.SPYRAL HTN-OFF MED trial investigatorsCatheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomized, sham-controlled, proof-of-concept trial.Lancet. 2017; 390: 2160-2170Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 8Kandzari D.E. Bohm M. Mahfoud F. et al.Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN ON-MED proof-of-concept randomised trial.Lancet. 2018; 391: 2346-2355Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 9Azizi M. Schmieder R.E. Mahfoud F. et al.Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.Lancet. 2018; 391: 2335-2345Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar Although these recent sham-controlled trials provide further proof of concept that supports a reduction in blood pressure after percutaneous catheter-based renal denervation, the effect on blood pressure was relatively modest. In addition, no data were provided to establish the extent and durability of actual renal denervation. Whether patients and providers would consider a reduction in ambulatory systolic blood pressure measurements of 5 to 7 mm Hg sufficient to justify an invasive procedure, and whether this approach would be cost effective over the long term, should be the subject of future studies. The potential added benefit of renal denervation may be greater in individuals with resistant hypertension or who are unable to remain adherent to medical therapy. Some clinicians have argued that such patients may have limited options for further medical therapy. SPYRAL HTN-ON MED initially sought to enroll participants with uncontrolled hypertension on a regimen of 3 antihypertensive drugs, but ultimately reduced this requirement. Overall, only one-half of the randomized participants were prescribed 3 agents at baseline, and adherence with antihypertensive therapy as assessed by detectable plasma drug level using tandem high-performance liquid chromatography and mass spectroscopy was only approximately 60%.8Kandzari D.E. Bohm M. Mahfoud F. et al.Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN ON-MED proof-of-concept randomised trial.Lancet. 2018; 391: 2346-2355Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar RADIANCE-HTN TRIO is anticipated to provide more insight into the efficacy of renal denervation in individuals whose hypertension is not optimally controlled despite the use of 3 antihypertensive agents.9Azizi M. Schmieder R.E. Mahfoud F. et al.Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.Lancet. 2018; 391: 2335-2345Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar The potential efficacy and safety of renal denervation in individuals with advanced CKD was not addressed in these studies, which excluded individuals with stage 3b or higher CKD. Taken together, these results support further studies of catheter-based renal denervation to become a more widely used antihypertensive clinical tool. All the authors declared no competing interests.