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American Journal of Kidney Diseases

Renal Denervation: A Review

  • Jimena Rey
    Affiliations
    Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid, Madrid, Spain

    Internal Medicine Department, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
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  • Raymond R. Townsend
    Correspondence
    Address for Correspondence: Raymond R. Townsend, MD, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, 122 Founders Building, Philadelphia, PA 19104.
    Affiliations
    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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      Uncontrolled hypertension persists as an important health issue despite the availability of many medications and nondrug therapies that lower blood pressure. Increasingly, nonadherence to medication is found in approximately 2 of every 5 patients with uncontrolled hypertension. In the search for interventions that lower blood pressure that do not rely on adherence to a regimen requiring daily ingestion of medication or repeated physical activity, device-based methods that denervate the renal arteries have emerged as a potential complement to standard antihypertensive treatments. At least 3 different approaches to renal artery denervation are under active investigation, including the use of radiofrequency energy, ultrasound, or the injection of neurolytic agents into the renal perivascular tissue. In this review, we cover what is currently known about the mechanisms of antihypertensive effects of renal denervation, summarize the efficacy and safety of renal denervation using recent controlled trial publications in a number of hypertensive populations, and conclude with some thoughts about challenges in the field, including the optimization of patient selection for the procedure and what the reader can expect in the near future in this rapidly developing field.

      Index Words

      Background

      The original Veterans Administration Cooperative Trials
      Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg.
      ,
      Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg.
      established the value of detecting and treating increased blood pressure (BP) and formed the basis of the first Joint National Committee report on the detection and management of hypertension.
      Anonymous. Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. A cooperative study.
      These milestone studies were enabled by the availability of oral antihypertensive agents. Before the Veterans Administration (now Veterans Affairs) studies demonstrated the feasibility of management of essential hypertension, it was largely not undertaken in clinical practice. It was only when hypertension entered an accelerated phase, typically with the emergence of heart, brain, or kidney problems, that interventions were considered. Among these interventions, there were several surgical approaches, including sympathetic denervation (“Smithwick procedure”)
      • Grimson K.S.
      • Orgain E.S.
      Results of treatment of patients with hypertension by total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy.
      and bilateral adrenalectomy.
      • Wolferth C.C.
      • Fitts W.T.
      • Jeffers W.A.
      • Sellers A.M.
      The place of adrenalectomy in the treatment of severe arterial hypertension.
      Surgical morbidity and mortality limited the widespread acceptance of these techniques. In addition, there was early work undertaken to lower BP using device-based therapies such as carotid baroreceptor stimulation.
      • Rothfeld E.L.
      • Parsonnet V.
      • Raman K.V.
      • Zucker I.R.
      • Tiu R.
      The effect of carotid sinus nerve stimulation on cardiovascular dynamics in man.
      However, signal spread and infections reduced the appeal of this approach. Another strategy emerged with extremely stringent diets that practically eliminated sodium intake using a diet of rice, fruit, and distilled water,
      • Kempner W.
      Treatment of hypertensive vascular disease with rice diet.
      but these suffered from a lack of long-term sustainability. These limitations of these approaches contributed to the search for safe and tolerable medications.
      As antihypertensive pharmacology blossomed in the 1970s through the 1990s, with attendant investigations supporting these new agent classes, the growing portfolio of clinical trials led to multiple revisions of the Joint National Committee reports. These focused on medication therapy as the cornerstone of antihypertensive intervention. Although the Joint National Committee reports acknowledged the benefits of concurrent lifestyle modifications (less salt, less weight, less alcohol, more exercise) that were useful when successfully achieved, clinical experience has shown them to often be difficult to maintain.
      Despite widely available antihypertensive agents, drug-resistant hypertension (no matter how defined) remains a difficult issue in clinical hypertension care.
      • Carey R.M.
      • Calhoun D.A.
      • Bakris G.L.
      • et al.
      Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association.
      The frequency of office BP measurements exceeding current guideline-directed BP goals has been reported to range from as low as 2% (Daugherty et al
      • Daugherty S.L.
      • Powers J.D.
      • Magid D.J.
      • et al.
      Incidence and prognosis of resistant hypertension in hypertensive patients.
      ) to >20% (Egan et al
      • Egan B.M.
      • Zhao Y.
      • Axon R.N.
      • Brzezinski W.A.
      • Ferdinand K.C.
      Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008.
      ). With the decrease in new antihypertensive medication classes available in the clinic (there have been no additions since 2007
      • Oh B.H.
      • Mitchell J.
      • Herron J.R.
      • Chung J.
      • Khan M.
      • Keefe D.L.
      Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension.
      ), the search for more effective ways to manage drug-resistant hypertension was diverted into revisiting device-based approaches. The success of early renal denervation (RDN) trials fueled this initiative.
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
      • et al.
      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      ,
      • Esler M.D.
      • Krum H.
      • Sobotka P.A.
      • Schlaich M.P.
      • Schmieder R.E.
      • Bohm M.
      Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomised controlled trial.
      In this review, we will discuss the current state of this field, with an emphasis on studies undertaken in patients with kidney disease.

      Mechanisms of Denervation

      Currently, 3 approaches that use a percutaneous access route to the kidney artery are in development in the United States. These approaches use radiofrequency ablation (RFA), ultrasound, or a neurotoxin injected through the wall of the kidney artery into the perivascular space.
      RFA uses a catheter to position electrodes (typically 4 spaced approximately 6 mm apart in a spiral sequence) that generate heat using medium-frequency alternating current. The heat generated seems well tolerated by the kidney arterial wall, but is toxic to the nerves surrounding the kidney artery that are in the heat energy field. The energy field ranges as far as 7 mm from the kidney artery lumen.
      Ultrasound approaches deliver a series of ultrasound-emitting sources (again typically 4) that are typically mounted on a catheter with an inflatable balloon system that allows irrigation of the portion of the catheter in contact with the kidney arterial wall with a solution that maintains a cooler temperature in the kidney artery lumen than in the perivascular space.
      The third approach introduces a smaller catheter with 3 tiny concentrically placed microneedles embedded in it. When the catheter is properly positioned, the microneedles are extended, penetrating the kidney artery wall into the perivascular space, and a small amount of liquid neurotoxin (typically a total of 0.6 mL of absolute ethanol) is injected through the 3 needles simultaneously.
      Denervation effects are thought to result from interruption of renal sympathetic nerves. Progressively intense stimulation of the renal sympathetic nerves results in an increase in renin release at low stimulation levels, a reduction in sodium excretion at intermediate levels, and an increase in renal vascular resistance at the highest levels.
      • DiBona G.F.
      • Esler M.
      Translational medicine: the antihypertensive effect of renal denervation.

      Developments in Renal Artery Anatomy

      When RDN studies were first undertaken in humans, the empirical approach was to denervate only within the main renal artery before branching based on the reasoning that the nerves governing BP-related signals to and from the kidney were largely accessible by this approach.
      • Kandzari D.E.
      • Bhatt D.L.
      • Sobotka P.A.
      • et al.
      Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 trial.
      Among the many reconsiderations undertaken after the failure of the SYMPLICITY HTN-3 study,
      • Bhatt D.L.
      • Kandzari D.E.
      • O’Neill W.W.
      • et al.
      A controlled trial of renal denervation for resistant hypertension.
      more attention was paid to the actual human neural anatomy. Summarized briefly, some nerves that innervate the kidney do extend from the sympathetic ganglia near the origins of the renal artery from the aorta and travel on the surface of the kidney artery. However, some of these nerves from periaortic ganglia touch down on the renal artery surface and then divert away from the kidney artery before entering the kidney. Moreover, some nerves that innervate the kidney join the renal arterial vessels after the first bifurcation of the main kidney artery and are not among those in the perivascular space of the renal artery before the bifurcation. Further information is available in a recent summary of the current understanding of renal perivascular neural anatomy.
      • Garcia-Touchard A.
      • Maranillo E.
      • Mompeo B.
      • Sanudo J.R.
      Microdissection of the human renal nervous system: implications for performing renal denervation procedures.
      Given the fundamental differences among the RDN approaches—the ultrasound and neurolytic approaches are currently directed to the main renal artery, whereas RFA now treats the main artery and the early branches—rigorous head-to-head comparisons are needed to understand if these anatomic issues are critical to clinical benefit.
      Additionally, little is known about renal sympathetic nerve regrowth after denervation in humans. Although renal nerves appear to regrow in denervated rodents, tissue levels of norepinephrine do not recover to predenervation levels,
      • Rodionova K.
      • Fiedler C.
      • Guenther F.
      • et al.
      Complex reinnervation pattern after unilateral renal denervation in rats.
      and beneficial effects of RDN on a model of heart failure are not lessened with nerve regrowth.
      • Chen P.
      • Guo Z.
      • Chen Y.
      • et al.
      The influence of inhibiting renal neural regeneration on the efficacy of renal denervation to chronic heart failure.
      If renal sympathetic nerves regrow in humans, there is no evidence of functional recovery within the first 3 years (the extent of published follow-up intervals in human RDN studies) because the decrease in BP is maintained over time.
      • Mahfoud F.
      • Mancia G.
      • Schmieder R.
      • et al.
      Renal denervation in high-risk patients with hypertension.

      Efficacy of Renal Denervation

      When RDN was first applied to people with hypertension, often in the presence of 5 or more medications with office-measured systolic BPs (SBPs) >160 mm Hg, the subsequent BP reductions were typically in the range of 25-30 mm Hg after approximately 6 months. The early trials lacked a sham control and relied on office BP measurements.
      • Krum H.
      • Schlaich M.
      • Whitbourn R.
      • et al.
      Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.
      ,
      • Esler M.D.
      • Krum H.
      • Sobotka P.A.
      • Schlaich M.P.
      • Schmieder R.E.
      • Bohm M.
      Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomised controlled trial.
      The large, sham-controlled SYMPLICITY HTN-3 study was undertaken in a similar population and observed that, although office SBP measurements were reduced by 14 mm Hg in those who received RFA, those in the sham control group had a reduction of 12 mm Hg. More recent RDN trial designs employed more careful control of nonprotocol medication use (assured by urine and blood screening for antihypertensive medications), a redesigned ablation catheter (when using RFA), a diastolic BP requirement of ≥90 mm Hg in-office, and the use of ambulatory BP monitoring to ensure exclusion of “white-coat effects” (which are common in this population
      • Carey R.M.
      • Calhoun D.A.
      • Bakris G.L.
      • et al.
      Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association.
      ). The results of newer RDN trials show lesser reductions of office and ambulatory SBP in the intervention and sham arms than earlier RDN trials. In addition, assumptions about the nerves in the kidney perivascular space were also revisited, and the technique for the RFA approach now includes the main renal artery and branches with lumen sizes of ≥3 mm, as well as suitable accessory arteries.
      • Bohm M.
      • Townsend R.R.
      • Kario K.
      • et al.
      Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design.
      The ultrasound and injection techniques remain focused on the main renal artery.
      • Mauri L.
      • Kario K.
      • Basile J.
      • et al.
      A multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: the RADIANCE-HTN and REQUIRE clinical study designs.
      ,
      • Mahfoud F.
      • Weber M.
      • Schmieder R.E.
      • et al.
      Catheter-based alcohol-mediated renal denervation for the treatment of uncontrolled hypertension: design of two sham-controlled, randomized, blinded trials in the absence (TARGET BP OFF-MED) and presence (TARGET BP I) of antihypertensive medications.
      We will cover efficacy in several domains. These will include uncontrolled hypertension (treated and untreated with medications), resistant hypertension, and denervation in patients with hypertension and chronic kidney disease (CKD), including those receiving hemodialysis.

      Uncontrolled Hypertension

      Figure 1 shows the office systolic and 24-hour ambulatory SBP responses to RDN in various studies. Table 1 conveys further information about the studies in Fig 1. In the absence of antihypertensive medication (RADIANCE-HTN SOLO,
      • Azizi 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.
      SPYRAL HTN-OFF MED
      • Bohm M.
      • Kario K.
      • Kandzari D.E.
      • et al.
      Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.
      ), RDN produces an average of 9-11 mm Hg of office SBP reduction and 5-7 mm Hg of ambulatory SBP reduction. In the presence of antihypertensive medication (RADIANCE-HTN TRIO,
      • Azizi M.
      • Sanghvi K.
      • Saxena M.
      • et al.
      Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.
      SPYRAL HTN-ON MED Pilot
      • Kandzari 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.
      ), RDN produces an average of 9 mm Hg of office SBP reduction and 9 mm Hg of ambulatory SBP reduction. These results are predicated on office SBPs of 150-180 mm Hg, office diastolic BPs >90 mm Hg, and ambulatory SBPs >135 mm Hg over 24 hours at baseline.
      Figure thumbnail gr1
      Figure 1Office and ambulatory systolic blood pressure (SBP) changes. Tornado plots of changes in office and ambulatory SBP following sham or active intervention in double-masked randomized sham-controlled trials of renal denervation in patients with uncontrolled hypertension in the period following the SYMPLICITY HTN-3 study. Trial names are indicated on the left side of each panel.
      Table 1Completed Trials of Renal Denervation
      • Azizi 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.
      • Bohm M.
      • Kario K.
      • Kandzari D.E.
      • et al.
      Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.
      • Azizi M.
      • Sanghvi K.
      • Saxena M.
      • et al.
      Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.
      • Kandzari 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.
      ,
      • Ott C.
      • Mahfoud F.
      • Schmid A.
      • et al.
      Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.
      • Kiuchi M.G.
      • Chen S.
      Improvement of renal function after renal sympathetic denervation in CKD patients with controlled vs. uncontrolled hypertension.
      • Hering D.
      • Marusic P.
      • Duval J.
      • et al.
      Effect of renal denervation on kidney function in patients with chronic kidney disease.
      • Ott C.
      • Schmid A.
      • Ditting T.
      • Veelken R.
      • Uder M.
      • Schmieder R.E.
      Effects of renal denervation on blood pressure in hypertensive patients with end-stage renal disease: a single centre experience.
      StudyMethodNActive:ShamInclusionPrimary OutcomeResults
      Trials excluding patients with reduced eGFR
      Defined variously as eGFR<40-45mL/min/1.73m2.
      SPYRAL HTN-OFF MED Pivotal
      • Bohm M.
      • Kario K.
      • Kandzari D.E.
      • et al.
      Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.
      RFA3311:1Office BP 150-179/≥90 mm Hg on no BP meds24-h ABPM SBP at 3 moRDN: ↓5 mm Hg; sham: ↓1 mm Hg
      RADIANCE-HTN SOLO
      • Azizi 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.
      US1461:1Office BP 140-180/90-110 mm Hg on no BP medsDaytime ABPM SBP at 2 moRDN: ↓7 mm Hg; sham: ↓2 mm Hg
      SPYRAL HTN-ON MED Pilot
      • Kandzari 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.
      RFA801:1Office BP 150-179/≥90 mm Hg on 1-3 stable BP meds24-h ABPM SBP at 6 moRDN: ↓9 mm Hg; sham: ↓2 mm Hg
      RADIANCE-HTN TRIO
      • Azizi M.
      • Sanghvi K.
      • Saxena M.
      • et al.
      Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.
      US1361:1Office BP ≥140/≥90 mm Hg on 3 stable BP medsDaytime ABPM SBP at 2 moRDN: ↓8 mm Hg; sham: ↓3 mm Hg
      Studies in patients with CKD
      Ott et al
      • Ott C.
      • Mahfoud F.
      • Schmid A.
      • et al.
      Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.
      RFA27No shamCKD 3-4 with resistant HTN (ESH/ESC definition)NephroprotectioneGFR slope improved at 1 y post intervention
      Kiuchi and Chen
      • Kiuchi M.G.
      • Chen S.
      Improvement of renal function after renal sympathetic denervation in CKD patients with controlled vs. uncontrolled hypertension.
      RFA108No shamCKD with or without controlled HTNNephroprotectionCKD with uncontrolled HTN had better eGFR outcome vs CKD with controlled HTN at 6 mo
      Hering et al
      • Hering D.
      • Marusic P.
      • Duval J.
      • et al.
      Effect of renal denervation on kidney function in patients with chronic kidney disease.
      RFA46No shameGFR ≤60 mL/min/1.73 m2NephroprotectioneGFR stabilized over 12-24 mo follow-up
      Ott et al
      • Ott C.
      • Schmid A.
      • Ditting T.
      • Veelken R.
      • Uder M.
      • Schmieder R.E.
      Effects of renal denervation on blood pressure in hypertensive patients with end-stage renal disease: a single centre experience.
      RFA6No shamHD and 24 h ABPM ≥135/85 mm Hg on 3 medsΔ24-h ABPM24-h ABPM: ↓20/15 mm Hg at 6 mo
      Abbreviations: ABPM, ambulatory blood pressure measurement; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESH/ESC, European Society of Hypertension/European Society of Cardiology; HD, hemodialysis; HTN, hypertension; RDN, renal denervation; RFA, radiofrequency ablation; SBP, systolic blood pressure; US, ultrasound.
      a Defined variously as eGFR <40-45 mL/min/1.73 m2.

      CKD

      CKD affects 10% of the world’s population
      • Bello A.K.
      • Levin A.
      • Tonelli M.
      • et al.
      Assessment of global kidney health care status.
      and is within the top 10 noncommunicable diseases contributing to disability and premature death.
      GBD 2016 Causes of Death Collaborators
      Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016.
      Although numerous factors contribute to hypertension in CKD,
      • Schalekamp M.A.
      • Man in’t Veld A.J.
      • Wenting G.J.
      The second Sir George Pickering memorial lecture. What regulates whole body autoregulation? Clinical observations.
      ,
      • Townsend R.R.
      • Taler S.J.
      Management of hypertension in chronic kidney disease.
      sustained activation of the sympathetic nervous system is crucial in the pathogenesis and maintenance of hypertension and in CKD progression.
      • Converse Jr., R.L.
      • Jacobsen T.L.
      • Toto R.D.
      • et al.
      Sympathetic overactivity in patients with chronic renal failure.
      Therefore, it seems to be a potential strong pathophysiological rationale for RDN in the CKD population.
      • Xia M.
      • Liu T.
      • Chen D.
      • Huang Y.
      Efficacy and safety of renal denervation for hypertension in patients with chronic kidney disease: a meta-analysis.
      Because of safety concerns in regard to iodinated contrast agent use, reduced estimated glomerular filtration rate (eGFR; <45 mL/min/1.73 m2) is an exclusion criterion in the pivotal RDN trials.
      • Schmieder R.E.
      Renal denervation: where do we stand and what is the relevance to the nephrologist?.
      Even though there are few data available regarding the safety of RDN in patients with CKD, no safety signal has surfaced in any of the sham-controlled trial registries and meta-analyses that included patients with CKD stages 3a and 3b.
      • Xia M.
      • Liu T.
      • Chen D.
      • Huang Y.
      Efficacy and safety of renal denervation for hypertension in patients with chronic kidney disease: a meta-analysis.
      ,
      • Mahfoud F.
      • Bohm M.
      • Schmieder R.
      • et al.
      Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry.
      Data from the Global SYMPLICITY Registry suggests similar BP-lowering efficacy by RDN in patients with CKD compared with patients with normal kidney function.
      • Mahfoud F.
      • Bohm M.
      • Schmieder R.
      • et al.
      Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry.
      Further, a meta-analysis of 48 study cohorts detected no statistically different change in eGFR over an average 9 months of follow-up.
      • Sanders M.F.
      • Reitsma J.B.
      • Morpey M.
      • et al.
      Renal safety of catheter-based renal denervation: systematic review and meta-analysis.
      A recent meta-analysis of 11 single-center nonrandomized, uncontrolled studies including 238 patients has been published.
      • Xia M.
      • Liu T.
      • Chen D.
      • Huang Y.
      Efficacy and safety of renal denervation for hypertension in patients with chronic kidney disease: a meta-analysis.
      Its aim was to evaluate the efficacy and safety of RDN for patients with hypertension and CKD. It showed a post-RDN decrease of office BP and 24-hour ambulatory BP monitoring, including office SBP and office diastolic BP. eGFR values at 1, 3, 6, 12, and 24 months after RDN were not significantly different from those determined before the procedure (P > 0.05). Four trials included in this meta-analysis
      • Schlaich M.P.
      • Bart B.
      • Hering D.
      • et al.
      Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease.
      • Kiuchi M.G.
      • Chen S.
      Effectiveness of renal sympathetic denervation in renal function and blood pressure in CKD and non-CKD patients with controlled vs. uncontrolled hypertension.
      • Prasad B.
      • Berry W.
      • Goyal K.
      • Dehghani P.
      • Townsend R.R.
      Central blood pressure and pulse wave velocity changes post renal denervation in patients with stages 3 and 4 chronic kidney disease: The Regina RDN Study.
      • Scalise F.
      • Sole A.
      • Singh G.
      • et al.
      Renal denervation in patients with end-stage renal disease and resistant hypertension on long-term haemodialysis.
      had reported data on antihypertensive medications before and after RDN and showed a significant decrease in these drugs after RDN (P < 0.001). RDN did not heighten the risk of rapid decline in kidney function or other major adverse events.
      • Xia M.
      • Liu T.
      • Chen D.
      • Huang Y.
      Efficacy and safety of renal denervation for hypertension in patients with chronic kidney disease: a meta-analysis.
      Some small studies have analyzed whether RDN could exert nephroprotective effects (Table 1). Ott et al reported results of an observational study of 27 patients with CKD stages 3/4 and resistant hypertension.
      • Ott C.
      • Mahfoud F.
      • Schmid A.
      • et al.
      Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.
      All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic). eGFR was monitored for as long as 3 years before and 1 year after RDN. The annual eGFR change before RDN was −4.8 mL/min/1.73 m2. Following the procedure, the significant reduction in BP was accompanied by a halt in eGFR decrease, with an average annual change in eGFR of +1.5 mL/min/1.73 m2.
      • Ott C.
      • Mahfoud F.
      • Schmid A.
      • et al.
      Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.
      Similar results were reported by Kikuchi and Chen.
      • Kiuchi M.G.
      • Chen S.
      Improvement of renal function after renal sympathetic denervation in CKD patients with controlled vs. uncontrolled hypertension.
      In a longer observational study of 46 patients with CKD (baseline eGFR ≤60 mL/min/1.73 m2), Hering et al reported on eGFR from 60 months before denervation and then at 3, 6, 12, and 24 months after RDN.
      • Hering D.
      • Marusic P.
      • Duval J.
      • et al.
      Effect of renal denervation on kidney function in patients with chronic kidney disease.
      Compared with baseline, RDN was associated with improved eGFR at 3 months (+3.73 ± 1.64 mL/min/1.73 m2; P = 0.02), with no further significant changes at 6 (+2.54 ± 1.66 mL/min/1.73 m2; P = 0.13), 12 (+1.78 ± 1.64 mL/min/1.73 m2; P = 0.28), or 24 (−0.24 ± 2.24 mL/min/1.73 m2; P = 0.91) months after RDN.
      Little evidence is available for RDN in patients with kidney failure who are receiving maintenance hemodialysis. Ott et al conducted a pilot study to show the effects of RDN in this population.
      • Ott C.
      • Schmid A.
      • Ditting T.
      • Veelken R.
      • Uder M.
      • Schmieder R.E.
      Effects of renal denervation on blood pressure in hypertensive patients with end-stage renal disease: a single centre experience.
      Ambulatory BP was significantly reduced over 6 months, and there was no change in hemodialysis parameters during follow-up. More recently, Scalise et al published results comparing drug therapy versus RDN in 24 patients who had been receiving hemodialysis for approximately 6 years and had resistant hypertension despite an average of 5.4 BP-lowering medications.
      • Scalise F.
      • Sole A.
      • Singh G.
      • et al.
      Renal denervation in patients with end-stage renal disease and resistant hypertension on long-term haemodialysis.
      RDN was associated with a significant BP-lowering effect. The reduction persisted over a 1-year follow-up, and there were no significant periprocedural complications.
      The small CKD populations included in the available studies makes it difficult to infer conclusions as a result of a general absence of sham controls (Table 1). However, there is an ongoing sham-controlled trial, the RDN-CKD study (ClinicalTrials.gov identifier NCT04264403). This prospective, double-blind, sham-controlled, multicenter feasibility study seeks to determine if RDN effectively reduces 24-hour ambulatory SBP in 80 patients with CKD stage 3a or 3b.

      Diabetes

      The percentages of enrolled patients with diabetes vary among pivotal RDN trials. In the SYMPLICITY HTN-3 trial, 47% of the participants in the intervention group were diabetic, compared with 40% of those receiving the sham procedure
      • Bhatt D.L.
      • Kandzari D.E.
      • O’Neill W.W.
      • et al.
      A controlled trial of renal denervation for resistant hypertension.
      ; these respective values were 4% versus 5% in SPYRAL HTN-OFF MED,
      • Bohm M.
      • Kario K.
      • Kandzari D.E.
      • et al.
      Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.
      13% versus 19% in SPYRAL HTN-ON MED,
      • Kandzari 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.
      3% versus 7% in RADIANCE-HTN SOLO,
      • Azizi 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.
      and 30% versus 25% in RADIANCE-HTN TRIO.
      • Azizi M.
      • Sanghvi K.
      • Saxena M.
      • et al.
      Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.
      In the subgroup analyses of the SYMPLICITY HTN-3 trial, the difference in the changes in office SBP was −4.53 (95% CI, −11.51 to 2.46) mm Hg in the diabetic population (P = 0.20), compared with −3.46 mm Hg (95% CI, −9.55 to 2.62) in the nondiabetic population (P = 0.26).
      • Bhatt D.L.
      • Kandzari D.E.
      • O’Neill W.W.
      • et al.
      A controlled trial of renal denervation for resistant hypertension.
      Figure 2 shows SBP changes 6 months after RDN in the Global SYMPLICITY Registry.
      • Mahfoud F.
      • Mancia G.
      • Schmieder R.
      • et al.
      Renal denervation in high-risk patients with hypertension.
      Figure thumbnail gr2
      Figure 2Office systolic blood pressure (SBP) reductions at 6 months compared with baseline in 766 patients with diabetes mellitus (DM) and 364 with chronic kidney disease (CKD; defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2). Data are adapted from the 6-month time point reported in the Global SYMPLICITY Registry.
      • Mahfoud F.
      • Mancia G.
      • Schmieder R.
      • et al.
      Renal denervation in high-risk patients with hypertension.
      This is a real-world registry of patients who underwent renal denervation with radiofrequency ablation. Ambulatory blood pressure (BP) monitoring was not required for inclusion in the registry and was performed in only a modest number of registry participants, so these data are not shown. Note: The office SBP changes here are not directly comparable to those obtained in rigorous clinical trials shown in .
      Beyond improved BP control, some RDN research indicates a decrease in fasting glucose level and an increase in insulin sensitivity,
      • Mahfoud F.
      • Schlaich M.
      • Kindermann I.
      • et al.
      Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study.
      ,
      • Witkowski A.
      • Prejbisz A.
      • Florczak E.
      • et al.
      Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea.
      likely as a result of attenuation of sympathetic nervous system activity.
      • Pan T.
      • Guo J.H.
      • Teng G.J.
      Renal denervation: a potential novel treatment for type 2 diabetes mellitus?.
      However, in the DREAMS Study, RDN did not lead to a significant improvement of insulin sensitivity within 12 months of treatment.
      • Verloop W.L.
      • Spiering W.
      • Vink E.E.
      • et al.
      Denervation of the renal arteries in metabolic syndrome: the DREAMS-study.
      All these studies were completed by 2015. The systematic review of Pan et al
      • Pan T.
      • Guo J.H.
      • Teng G.J.
      Renal denervation: a potential novel treatment for type 2 diabetes mellitus?.
      concluded that, as a result of the contradictory results, more clinical trials are needed before any definite conclusion can be drawn. Some clinical trials are ongoing in an effort to determine if RDN has some role in glycemic control in diabetes. Since 2018, Gao-Jun et al have been recruiting patients for a clinical trial whose aim is to measure changes in glucose metabolism from baseline at 6 months and 2 years after RDN (ClinicalTrials.gov identifier NCT03418415).

      Costs

      RDN procedures are not approved for clinical use in the United States, but there is one cost-effectiveness study undertaken by Australian investigators in which the cost of the RDN procedure was estimated to be €6,573 (approximately $9,530 Australian or $7,300 US).
      • Chowdhury E.K.
      • Reid C.M.
      • Zomer E.
      • Kelly D.J.
      • Liew D.
      Cost-effectiveness of renal denervation therapy for treatment-resistant hypertension: a best case scenario.

      Clinical Predictors of BP Response to RDN

      As shown in Figure 3, most randomized, controlled studies of RDN in uncontrolled hypertension observed that approximately 2 of every 3 patients have a ≥5-mm Hg SBP reduction over 24 hours.
      • Townsend R.R.
      • Sobotka P.A.
      Catheter-based renal denervation for hypertension.
      The identification of predictors that identify patients who are more or less likely to show a response has remained a significant challenge to this field. As shown in the center of Figure 4, the most significant predictor of denervation efficacy to date has been SBP at the time of intervention, with higher SBP levels associated with a greater SBP reduction, a phenomenon often cited as Wilder’s law.
      • Wilder J.
      Basimetric approach (law of initial value) to biological rhythms.
      A number of other candidate predictors have been proposed. These typically fall into 2 categories: those that likely reflect greater underlying sympathetic activity and those that reflect a stiffer arterial vasculature. Because the RDN procedure is thought to reduce BP through downregulation of sympathetic activity,
      • Schlaich M.P.
      • Sobotka P.A.
      • Krum H.
      • Lambert E.
      • Esler M.D.
      Renal sympathetic-nerve ablation for uncontrolled hypertension.
      this makes sense. On the contrary, arterial stiffness is often associated with an increase in the ratio of collagen to elastin in large vessels, and patients with indicators of arterial stiffness such as isolated systolic hypertension
      • Safar H.
      • Chahwakilian A.
      • Boudali Y.
      • Debray-Meignan S.
      • Safar M.
      • Blacher J.
      Arterial stiffness, isolated systolic hypertension, and cardiovascular risk in the elderly.
      may be less responsive because of a “fixed” element of inelasticity (ie, more collagen) in the vessel wall. Such reasoning was used in recent study designs that used an inclusion criterion of diastolic BP ≥90 mm Hg in the office. Clinical markers of arterial stiffness include higher pulse wave velocity in the aorta and greater wave reflection resulting in a proportionately higher central artery systolic pressure. Although these studies are suggestive, they are usually small in number and await confirmation in larger and more diverse hypertensive populations.
      Figure thumbnail gr3
      Figure 3Renal denervation responders. Donut graphs of participants who did or did not experience a ≥5-mm Hg reduction in 24-hour ambulatory systolic blood pressure (SBP) in double-blinded randomized controlled trials of renal denervation. Within each circle, the number of patients in the denervation arm in that trial is shown.
      Figure thumbnail gr4
      Figure 4Predictors of renal denervation (RDN) response. The only established predictor of blood pressure (BP) reduction after RDN is BP level before intervention (top middle).
      • Fink G.D.
      • Phelps J.T.
      Can we predict the blood pressure response to renal denervation?.
      Situations in which sympathetic activity may be increased such as sleep apnea,
      • Kario K.
      • Bhatt D.L.
      • Kandzari D.E.
      • et al.
      Impact of renal denervation on patients with obstructive sleep apnea and resistant hypertension – insights from the SYMPLICITY HTN-3 Trial.
      higher heart rate,
      • Bohm M.
      • Tsioufis K.
      • Kandzari D.E.
      • et al.
      Effect of heart rate on the outcome of renal denervation in patients with uncontrolled hypertension.
      higher plasma renin activity,
      • Mahfoud F.
      • Townsend R.R.
      • Kandzari D.E.
      • et al.
      Changes in plasma renin activity after renal artery sympathetic denervation.
      and increased nocturnal BP (and more variable nocturnal BP)
      • Gosse P.
      • Cremer A.
      • Pereira H.
      • et al.
      Twenty-four-hour blood pressure monitoring to predict and assess impact of renal denervation: the DENERHTN Study (Renal Denervation for Hypertension).
      may also be useful in predicting RDN response. Situations in which arterial stiffness is less prevalent,
      • Fengler K.
      • Rommel K.P.
      • Hoellriegel R.
      • et al.
      Pulse wave velocity predicts response to renal denervation in isolated systolic hypertension.
      there is greater pulse wave reflection (PWV; ie, higher central aortic BPs),
      • Ott C.
      • Schmid A.
      • Toennes S.W.
      • et al.
      Central pulse pressure predicts BP reduction after renal denervation in patients with treatment-resistant hypertension.
      or there is less evidence of aortic calcification by imaging
      • Courand P.Y.
      • Pereira H.
      • Del Giudice C.
      • et al.
      Abdominal aortic calcifications influences the systemic and renal hemodynamic response to renal denervation in the DENERHTN (Renal Denervation for Hypertension) Trial.
      also seem to be predictive of BP reduction following RDN.

      Patient Acceptability of RDN

      No matter how effective a therapy is, if patients are unwilling to try it, any therapeutic benefit will remain hypothetical. Investigations into patient preference information for competing treatments have become more common and are encouraged by regulatory agencies like the US Food and Drug Administration, particularly when a device-based intervention is involved.
      • Webber C.M.
      • Chen A.L.
      • Gebben D.J.
      • Saha A.
      • Tarver M.E.
      Measuring patient preferences at the FDA Center for Devices and Radiological Health: reflections and projections.
      A recent international study of patient preference information conducted in the United States and Europe enrolled more than 2,700 patients and more than 1,900 physicians. The investigators made several interesting observations. Among the patients surveyed, those with unmedicated hypertension were more likely to opt for RDN compared with those taking medication, and this finding was not linked to the degree of increased BP. Also, patients who had medication side effects were also willing to consider RDN. Physicians, on the contrary, were more likely to consider RDN when BP was higher or when more medications were needed. Overall, approximately 40% of the patients and physicians surveyed would consider RDN as an option instead of new or additional medication. A United States–based 400-person patient preference information study presented in November 2021 at the Transcatheter Therapeutics Conference
      • Kandzari D.E.
      • Weber M.A.
      • Poulos C.
      • Cohen S.A.
      • Jones D.
      • Pathak A.
      Patient preferences for interventional and pharmaceutical treatments among U.S. adults with uncontrolled hypertension.
      should provide more insight in this area when published.

      Safety of RDN

      Given that RDN is an invasive procedure, it is incumbent on those who are developing these technologies to ensure that the risk-benefit ratio is not skewed toward risk. Risk in RDN is divided into the periprocedural period (the time of the actual denervation and the ensuing 30 days) and the postprocedural risk, which is often the second through the sixth month following the procedure. Most RDN studies continue to assess patient status for 3 years after denervation. Fortunately, the risk profile in both periods demonstrates a low incidence of adverse events, as shown in Table 2. The incidence of renal artery stenosis requiring an intervention has been studied in greatest detail in the RFA population, including those treated outside the clinical trial setting. We noted a 0.2%-per-year incidence of renal artery stenosis requiring intervention in more than 5,000 patients followed for 2 years.
      • Townsend R.R.
      • Walton A.
      • Hettrick D.A.
      • et al.
      Review and meta-analysis of renal artery damage following percutaneous renal denervation with radiofrequency renal artery ablation.
      Most cases of interval renal artery stenosis requiring intervention occur within the first 6 months after RDN. Importantly, kidney function appears to be unperturbed by denervation, even when denervation is undertaken in those with decreased kidney function (CKD stages 3b and 4).
      • Xia M.
      • Liu T.
      • Chen D.
      • Huang Y.
      Efficacy and safety of renal denervation for hypertension in patients with chronic kidney disease: a meta-analysis.
      Table 2Adverse Events Associated With Renal Denervation
      • Azizi 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.
      • Bohm M.
      • Kario K.
      • Kandzari D.E.
      • et al.
      Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.
      • Azizi M.
      • Sanghvi K.
      • Saxena M.
      • et al.
      Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.
      • Kandzari 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.
      EventRADIANCE-HTN SOLO (n = 64)
      • Azizi 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.
      SPYRAL HTN-OFF MED (n = 166)
      • Bohm M.
      • Kario K.
      • Kandzari D.E.
      • et al.
      Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.
      SPYRAL HTN-ON MED (n = 38)
      • Kandzari 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.
      RADIANCE-HTN TRIO (n = 69)
      • Azizi M.
      • Sanghvi K.
      • Saxena M.
      • et al.
      Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.
      Periprocedural (denervation day and≤30 d after)
      Death0001 (1%)
      Acute kidney injury0000
      Embolic event0000
      Femoral vascular injury0001 (1%)
      Renal artery stenosis0000
      Pain >2 d post procedure8 (11%)NRNR12 (17%)
      Hypertensive emergency0000
      HF hospitalization0000
      Postprocedural (1-6 mo after denervation)
      New RAS (>50%)0000
      Scr doubling0001 (1%)
      Hypertensive emergency01 (1%)00
      Heart failure hospitalization0000
      Stroke, TIA0000
      AMI0001 (1%)
      Coronary intervention0000
      Renal angioplasty/stent0000
      New orthostasis0000
      Abbreviations: AMI, acute myocardial infarction; NR, not reported; RAS, renal artery stenosis; Scr, serum creatinine; TIA, transient ischemic attack.

      RDN for Conditions Other Than Hypertension

      RDN studies have been conducted in conditions in which denervation may have benefit separate from any reduction in BP, including heart failure,
      • Kresoja K.P.
      • Rommel K.P.
      • Fengler K.
      • et al.
      Renal sympathetic denervation in patients with heart failure with preserved ejection fraction.
      arrhythmias,

      Nantha Kumar N, Nyatsuro K, Ahmad S, et al. Systematic review of renal denervation for the management of cardiac arrhythmias. Clin Res Cardiol. Published online November 8, 2021. doi:10.1007/s00392-021-01950-8

      and metabolic syndromes.
      • Carnagarin R.
      • Lambert G.W.
      • Kiuchi M.G.
      • et al.
      Effects of sympathetic modulation in metabolic disease.
      Another possible application is the kidney-related discomfort in patients with polycystic kidney disease, which, in a small subset of severe cases, requires opioids and profoundly affects quality of life. Although the pathophysiology of this pain is complex, RDN has been described in case reports as having a beneficial effect.
      • Lugo-Gavidia L.M.
      • Nolde J.M.
      • Kiuchi M.G.
      • et al.
      Interventional approaches for loin pain hematuria syndrome and kidney-related pain syndromes.
      Notably, the benefits of RDN in these other contexts can be discerned on a time scale faster than seen in the treatment of hypertension, which takes months to produce an effect. Coverage of these topics has appeared recently.
      • Blankestijn P.J.
      • Meijvis S.C.
      Renal denervation: time to refine the focus of research.

      Upcoming Trials

      The RDN portfolio includes several pending trials, as shown in Table 3. Primary completion of the SPYRAL HTN-ON MED pivotal trial (ClinicalTrials.gov identifier NCT02439775), sponsored by Medtronic, is expected in October 2022. The SPYRAL AFFIRM trial (NCT05198674), also sponsored by Medtronic, initiated in February 2022. Primary completion of the RADIANCE II trial in stage 2 hypertension (NCT03614260), sponsored by ReCor, is anticipated in July 2022. Primary completion of the TARGET BP I trial (NCT02910414), sponsored by Ablative Solutions, is anticipated in December 2022.
      Table 3Listing of Ongoing Denervation Studies
      Study/RegistrySponsorMethodTarget EnrollmentActive:ShamPrimary OutcomeExpected CompletionGeographic Region
      SPYRAL HTN-ON MED PivotalMedtronicRFA3402:1Δ24-h ABPM SBP at 6 mo10/2022Global
      RADIANCE IIReCorUltrasound2251:1ΔDaytime ABPM SBP at 2 mo7/2022Europe, USA
      TARGET BP OFF-MEDAblative SolutionsAbsolute ethanol injection901:1ΔABPM SBP at 2 mo3/2023Europe
      TARGET BP IAblative SolutionsAbsolute ethanol injection3001:1ΔABPM SBP at 3 mo12/2022USA
      CKD-RDNUniversity of ErlangenUltrasound801:1Δ24-h ABPM SBP at 6 mo1/2023Germany
      GSR DEFINE RegistryMedtronicRFA5,000All ActiveObservation10/2027Global
      Global Paradise System RegistryReCorUltrasound3,000All ActiveObservation12/2031Global
      Abbreviations: ABPM, ambulatory blood pressure measurement; CKD, chronic kidney disease; RDN, renal denervation; RFA, radiofrequency ablation; SBP, systolic blood pressure.
      The 3,000-person Global SYMPLICITY Registry will be expanded to include an additional 2,000 people receiving RFA in what will be known as the GSR DEFINE registry (NCT01534299); as of April 2022, it was listed as recruiting. ReCor has announced a Global Paradise System Registry (NCT05027685) to follow people treated with the ultrasound approach to denervation; this study is also listed as recruiting. Both registries are thought to represent “real-world” follow-up, as neither collects information as strictly as a protocol-driven randomized clinical trial. However, both registries will have repeated office BP measurements, some repeated ambulatory BP monitoring data, and measures of safety like kidney function estimates, along with a record of interval cardiovascular events, typically at yearly intervals.

      Summary

      RDN, regardless of approach, remains a research-only procedure in the United States. The BP-lowering efficacy of RDN appears similar to those of many single-agent antihypertensive medications. The safety profile of RDN, an invasive procedure, has remained at an acceptable level to date. In the absence of unanticipated findings in the pending trials, we anticipate that RDN could one day be an added to the antihypertensive toolbox.

      Article Information

      Authors’ Full Names and Academic Degrees

      Jimena Rey MD, and Raymond R. Townsend, MD.

      Support

      None.

      Financial Disclosure

      Dr Townsend is a consultant to Medtronic for global RDN study design and oversight, receives royalties from UpToDate, and is a member of the data and safety monitoring board for AXIO. Dr Rey declares that she has no relevant financial interests.

      Peer Review

      Received November 23, 2021, in response to an invitation from the journal. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor, who served as Acting Editor-in-Chief. Accepted in revised form March 14, 2022. The involvement of an Acting Editor-in-Chief was to comply with AJKD’s procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.

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