Journal of the American College of Cardiology Vol. 62, No. 22, 2013� 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.08.1616

STATE-OF-THE-ART PAPER

International Expert Consensus Statement

Percutaneous Transluminal Renal Denervation for theTreatment of Resistant Hypertension

Markus P. Schlaich, MD,* Roland E. Schmieder, MD,y George Bakris, MD,zPeter J. Blankestijn, MD, PHD,x Michael Böhm, MD,k Vito M. Campese, MD,{Darrel P. Francis, MB, BCHIR, MA, MD,# Guido Grassi, MD,** Dagmara Hering, MD, PHD,*

Richard Katholi, MD,yy Sverre Kjeldsen, MD,zz Henry Krum, MBBS, PHD,xx Felix Mahfoud, MD,kGiuseppe Mancia, MD,** Franz H. Messerli, MD,kk Krzysztof Narkiewicz, MD, PHD,{{Gianfranco Parati, MD,##*** Krishna J. Rocha-Singh, MD,yy Luis M. Ruilope, MD, PHD,yyyLars C. Rump, MD,zzz Domenic A. Sica, MD,xxx Paul A. Sobotka, MD,kkk Costas Tsioufis, MD,{{{Oliver Vonend, MD,zzz Michael A. Weber, MD,### Bryan Williams, MD,****

Thomas Zeller, MD,yyyy Murray D. Esler, MBBS, PHD*

Melbourne, Australia; Nürnberg, Düsseldorf, Bad Krozingen, and Homburg/Saar, Germany;Chicago and Springfield, Illinois; Utrecht, the Netherlands; Los Angeles, California; London, United Kingdom;Milan, Italy; Oslo, Norway; New York and Brooklyn, New York; Gdansk, Poland; Madrid, Spain;Richmond, Virginia; Columbus, Ohio; and Athens, Greece

C

From the *Baker I

Faculty of Medicin

Australia; yDepart

Erlangen-Nürnber

Chicago, Illinois; xCenter, Utrecht,

Universitätskliniku

Nephrology, Keck

Angeles, California

and Lung Institut

Medica, Milano-B

Multimedica, Sest

Cooperative, Sprin

Oslo, Norway; xx

atheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently beenintroduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions.Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined asstandardized systolic clinic blood pressure �160 mm Hg (or �150 mm Hg in patients with type 2 diabetes) despiteappropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly,these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation.Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance ofmedication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressuremonitoringis mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patientsshould have preserved renal function, with an estimated glomerular filtration rate �45 ml/min/1.73 m2. Optimalperiprocedural management of volume status and medication regimens at specialized and experienced centersequipped with adequate infrastructure to cope with potential procedural complications will minimize potential patientrisks. Long-termsafety andefficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts tomonitortreated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation couldhave beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential usefor such indications should currently be limited to formal research studies of its safety and efficacy. (J AmColl Cardiol2013;62:2031–45) ª 2013 by the American College of Cardiology Foundation

DI Heart & Diabetes Institute/Heart Centre, Alfred Hospital and

e, Nursing and Health Sciences, Monash University, Melbourne,

ment of Medicine 4, Nephrology and Hypertension, University of

g, Nürnberg, Germany; zThe University of Chicago Medicine,

Department of Nephrology and Hypertension, University Medical

the Netherlands; kKlinik für Innere Medizin III, Kardiologie,

m des Saarlandes, Homburg/Saar, Germany; {Division of

School of Medicine, University of Southern California, Los

; the #International Centre for Circulatory Health, National Heart

e, Imperial College London, London, United Kingdom; **Clinica

icocca University and Istituto di Ricerche a Carattere Scientifico

o San Giovanni, Milan, Italy; yyPrairie Education and Research

gfield, Illinois; zzDepartment of Cardiology, University of Oslo,

Monash Centre of Cardiovascular Research & Education in

Therapeutics, Department of Epidemiology & Preventive Medicine, Monash

University, Melbourne, Australia; kkDivision of Cardiology, St. Luke’s Roosevelt

Hospital, Columbia University College of Physicians and Surgeons, New York, New

York; {{Department of Hypertension andDiabetology, Medical University of Gdansk,

Gdansk, Poland; ##Department of Cardiology, Istituto Auxologico Italiano, IRCCS,

Milan, Italy; ***Department of Health Sciences, University of Milano-Bicocca, Milan,

Italy; yyyHypertension Unit, Hospital 12 de Octubre, Madrid, Spain; zzzDepartment

of Nephrology, Heinrich-Heine University, Düsseldorf, Germany; xxxDivision of

Nephrology, Department of Medicine and Pharmacology, Virginia Commonwealth

University, Richmond, Virginia; kkkThe Ohio State University, Columbus, Ohio;

the {{{University of Athens, First Cardiology Clinic, Hippocratio Hospital,

Athens, Greece; ###SUNY Downstate College of Medicine, Brooklyn, New York;

****Institute of Cardiovascular Sciences, University College London, United Kingdom;

and the yyyyHeart Centre Bad Krozingen, Germany Bad Krozingen, Germany.

This international expert consensus stat

the Global Medical Education Comm

ported by Medtronic. The concept for

solely by members of this education com

group directly compensated for their i

ment or its writing, editing, or submiss

journal for review or its actual submis

Committee members were reimbursed

for their time in other committee activit

report. This report has not been end

society, and no such endorsement was

Health andMedical Research Council

fees and research support from Med

Boehringer Ingelheim. Dr. Schmiede

Medtronic Ardian. Dr. Bakris has re

support (direct funding to The Univers

a consultant for Takeda, Abbott, CVR

and Drug Administration, REATA, M

the National Kidney Foundation and

editor-in-chief of the American JourUpToDate.Dr. Blankestijn has receive

and St. Jude Medical. Dr. Böhm has

Medtronic, Cordis, and Biosense We

Medtronic. Dr. Grassi has received gra

scientific meetings from Medtronic.

fellowship from the Foundation for P

Abbreviationsand Acronyms

ABPM = ambulatory blood

pressure monitoring

AF = atrial fibrillation

BP = blood pressure

eGFR = estimated

glomerular filtration rate

MSNA = muscle

sympathetic nerve activity

NE = norepinephrine

PVI = pulmonary vein

isolation

RDN = renal denervation

RF = radiofrequency

Schlaich et al. JACC Vol. 62, No. 22, 2013Expert Consensus Statement: Transluminal Radial Denervation for Resistant Hypertension December 3, 2013:2031–45

2032

Scope of the ExpertConsensus Statement

Resistant hypertension is a com-mon and growing yet neglectedclinical problem. General practi-tioners and specialist physiciansare frequently faced with the chal-lenging task of managing thesepatients. A novel interventionaltreatment approach based on tran-sluminal radiofrequency (RF) ab-lation of renal nerves has recentlybeen introduced into clinical med-icine in Australia, Europe, andother countries and has sparkedsubstantial interest from affected

patients, treating and referring practitioners and physicians,interventionalists, and health care providers. In view of thelimited clinical trial data available, it appeared timely andimportant to summarize the views of an international panel toprovide some guidance with regard to the indications, methods,and safety of transluminal renal nerve ablation. The recom-mendations in this statement are based on the interpretation ofclinical trial data available to date and are intended to facilitatea better understanding of the safety, effectiveness, and limitationsof this technology, with a particular focus on appropriate patientselection.

There is a lack of data on the exact prevalence of resistanthypertension, which is commonly defined as blood pressure(BP) higher than target levels despite the use of 3 antihy-pertensive agents in adequate doses from different classes,including a diuretic agent (1). Evidence from the NationalHealth and Nutrition Examination Survey and from large

ementwas the direct work product ofmembers of

ittee on Renal Denervation, convened and sup-

this position paper was conceived and promoted

mittee; at no time were members of the writing

nvolvement in the manuscript concept develop-

ion. Medtronic was not involved in the choice of

sion and response to the editors. The Writing

for travel expenses and provided fair market value

ies unrelated to thewriting and submission of this

orsed by any international or national medical

sought. Dr. Schlaich is supported by National

research fellowships; and has received consulting

tronic Ardian, Abbott, Novartis, Servier, and

r has received lecture and consulting fees from

ceived investigator-initiated grant and research

ity of Chicago) from Forest Labs and Takeda; is

x, Johnson & Johnson, Eli Lilly, the U.S. Food

edtronic, and Relapsya; serves on the boards of

the American Society of Hypertension; and is

nal of Nephrology and hypertension editor for

d consultancy and speaker’s fees fromMedtronic

received fees for lectures and consultancy from

bster. Dr. Francis has received honoraria from

nts for lectures and presentations at international

Dr. Hering has been supported by a research

olish Science (KOLUMB/2010-1). Dr. Katholi

randomized clinical trials indicates that 20% to 30% ofpatients with hypertension require 3 or more antihyperten-sive agents to achieve BP targets. Recent data from theNational Health and Nutrition Examination Survey indicatethat 12.8% of the antihypertensive drug–treated populationfulfilled the criteria of resistant hypertension (2). Data froma large Spanish registry suggested that resistant hypertensionis present in 12% of the treated hypertensive population,but among them, more than one-third have normal ambu-latory BP (3). Data from 205,750 patients with incidenthypertension revealed that 1.9% developed resistant hyper-tension within a median of 1.5 years from initial treatment(0.7 cases per 100 person-years of follow-up) (4). Failure toreach target BP levels despite therapeutic intervention leavespatients at high risk for major cardiovascular events (4,5).

Sympathetic nervous system and BP control. Thesympathetic nervous system plays an important role incirculatory and metabolic control and is a major contributorto the development of hypertension (6,7), mediated viasodium and water retention, increased renin release, andalterations of renal blood flow. Accordingly, direct targetingof the sympathetic nervous system is a logical therapeuticapproach for the treatment of hypertension.

Specific role of renal nerves for hypertension andcardiovascular outcomes. The kidneys have a dense af-ferent sensory and efferent sympathetic innervation. Renalsensory afferent nerve activity directly influences sympatheticoutflow to the kidneys and other highly innervated organsinvolved in cardiovascular control (8,9) (Fig. 1). Afferentand efferent sympathetic nerves can interact to modulatesympathetic activity (10). Abrogation of renal sensory afferentnerves reduces both BP and organ-specific damage causedby chronic sympathetic overactivity in various experimental

provides consulting services to Medtronic. Dr. Kjeldsen has consulted and lectured for

Bayer, Medtronic, Boehringer Ingelheim, Takeda, AZ, Leo, Nycomed, sanofi-aventis,

and Sankyo. Dr. Krum is an investigator in studies sponsored by Medtronic and has

received honoraria and lecture fees. Dr. Mahfoud is supported by Deutsche Hoch-

druckliga andDeutsche Forschungsgemeinschaft; and has received fees for lectures and

consultancy from Medtronic Ardian, Cordis, St. Jude, and Covidien. Dr. Mancia has

received consulting and lecture fees from Medtronic. Dr. Messerli has received

consulting and lecture fees from Medtronic. Dr. Narkiewicz has received honoraria

(boardmembership, consultancy, and payment for lectures) fromMedtronic. Dr. Parati

has received consulting and lecture fees from Medtronic. Dr. Rocha-Singh is

a consultant for Medtronic Ardian. Dr. Ruilope has served as adviser and speaker for

Medtronic Ardian. Dr. Rump has received speaker’s honoraria and travel support from

Medtronic Ardian. Dr. Sobotka is a former employee of Medtronic Ardian. Dr.

Tsioufis has received research grants and lecture and consulting fees from St. Jude

Medical; and travel support from Medtronic. Dr. Vonend has received speaker’s

honoraria and travel support from Medtronic Ardian. Dr. Weber provides consulting

services to Medtronic and Boston Scientific. Dr. Williams is a National Institute for

Health Research senior investigator; and a member of the Global Scientific Steering

Committee for Renal Denervation of Medtronic. Dr. Zeller has received fees for

lectures and consultancy from Medtronic Ardian. Dr. Esler is supported by National

Health andMedical ResearchCouncil research fellowships; and has received consulting

fees and research support fromMedtronic Ardian and KonaMedical. All other authors

have reported that they have no relationships relevant to the contents of this paper to

disclose.

Manuscript received June 2, 2013; revised manuscript received August 17, 2013,

accepted August 17, 2013.

Figure 1 Effects of Afferent Renal Nerve Signaling

Various triggers, such as renal injury and ischemia, can stimulate afferent signaling from the kidney to central integrative nuclei, with the consequence of exaggerated efferent

sympathetic outflow to target organs, including the heart, the vasculature, the kidneys, and other organs involved in both cardiovascular and metabolic control, as illustrated.

Renal denervation, by targeting both efferent and afferent nerves as can be achieved by catheter-based application of radiofrequency energy, may be useful to effectively

interrupt this vicious cycle. OSA ¼ obstructive sleep apnea; pCO2 ¼ partial pressure of carbon dioxide; RAAS ¼ renin-angiotensin-aldosterone system.

JACC Vol. 62, No. 22, 2013 Schlaich et al.December 3, 2013:2031–45 Expert Consensus Statement: Transluminal Radial Denervation for Resistant Hypertension

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models (11,12). Although afferent activity cannot be quan-tified in humans, there is strong evidence that it modulatesthe level of central sympathetic outflow. Assessment of re-gional overflow of norepinephrine (NE) from the kidneys toplasma has demonstrated that renal NE spillover rates canbe markedly elevated in patients with essential hypertension(13) and are associated with hypertensive end-organ damagesuch as left ventricular hypertrophy (14).

Catheter-Based Renal Nerve Ablation

Method. Against this background, a novel catheter-basedapproach to selectively denervate the human kidneys wasrecently introduced (15). In this approach, renal nerveablation is achieved percutaneously via the lumen of therenal artery using RF energy. Other treatment modalities,such as ultrasound, cryoablation, and perivascular delivery ofneurotoxins, are currently being investigated and brieflyreviewed in the Online Appendix. Although most intra-luminal approaches share many of the principal features, theapproach for RF ablation used in the clinical trials currentlyavailable is described here.

Access to the renal artery is typically gained using a 6-F to9-F sheath introduced into the femoral artery. A renal arteryangiogram is obtained to assess anatomic suitability and toexclude significant renal artery stenosis or other relevantrenal artery pathology. Each renal artery should have adiameter of �4 mm and a length of �20 mm to allowadequate application of RF energy and a sufficient numberof RF ablation treatments (�4). Smaller dimensions mayinterfere with the application of RF energy because of lower

blood flow and reduced cooling effects and may predisposeto vascular spasm. Local application of vasodilators such asnitroglycerin may be useful to prevent or revert spasm ofrenal arteries.

To identify abnormal vascular anatomies that may inter-fere with the ablation procedure, renal vascular imagingshould be carried out before renal denervation (RDN). Anaortogram obtained before selective renal angiography at thetime of intervention is helpful to identify the presence ofmultiple renal arteries.

The treatment catheter is introduced through a 6-Fto 9-F guiding catheter into the renal artery and placeddistally before the first branch of the renal artery underfluoroscopic guidance to ensure close and stable contact withthe vessel wall. Discrete low-energy RF ablations are thenapplied from distally to proximally within each renalartery (Fig. 2). RF ablation in areas with atheroscleroticplaques should be avoided. The duration of the procedure istypically 30 to 60 min. Minor vascular irregularities likelyrepresenting intimal edema can often be observed directlyafter the procedure at the treatment sites. These are typicallynot flow limiting and commonly resolve by the end of theprocedure.Periprocedural and post-procedural management. PAIN

MANAGEMENT. The ablation procedure is typically accom-panied by diffuse, visceral, nonradiating abdominal pain,which does not persist beyond the RF energy applicationand should be managed using intravenous analgesic andanxiolytic or sedative medications. Vital signs, includingBP, heart rate, and oxygen saturation, should be monitoredduring the procedure.

Figure 2Schematic Illustration of the PercutaneousCatheter-Based Approach to FunctionallyDenervate the Human Kidney

Similar to routine angiography, access to the renal artery is obtained through

a sheath in the femoral artery. The treatment catheter is then introduced into the

renal artery through a guiding catheter, and discrete radiofrequency (RF) ablation

treatments lasting 2 min each are applied along the renal artery, as illustrated. At

least 4 ablations are performed in each artery, which are separated both longi-

tudinally (by at least 5 mm) and rotationally to achieve circumferential coverage of

the renal artery. Catheter tip temperature and impedance are constantly monitored

during ablation and RF energy delivery is regulated according to a pre-determined

algorithm.

Schlaich et al. JACC Vol. 62, No. 22, 2013Expert Consensus Statement: Transluminal Radial Denervation for Resistant Hypertension December 3, 2013:2031–45

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SYSTEMIC ANTICOAGULATION AND ANTIPLATELET THERAPY.

Before the procedure, appropriate systemic anticoagulationshould be attained and verified by activated clotting time, witha target of 200 to 250 s. Recent data from a porcine model (16)and from human studies using optical coherence tomography(17) demonstrate the possible occurrence of endothelial-intimal edema and thrombus formation. Periprocedural anti-platelet therapy may therefore be advisable in patientsundergoing RDN. Although this has not been investigated inclinical trials, the use of 250 mg of acetylsalicylic acid duringthe procedure and 75 to 100 mg/day for up to 4 weeks afterRDN has been suggested (18).

ASSESSMENT OF EFFICACY. It is important to note that BPrarely changes directly after the procedure. It often takesseveral weeks to months for BP reductions to occur. Patientsshould be informed accordingly to avoid unrealistic expec-tations. Currently, there is no reliable clinical parameteravailable that would allow the prediction of the BP responsein an individual patient or to assess the degree of RDNachieved. The exact mechanisms by which RDN results ina BP reduction are not yet fully established but seem toinclude a reduction in sympathetic activation, total periph-eral resistance, renin release, and alterations of water andsodium handling.

There is currently no readily available variable to monitorthe efficacy of the procedure itself. Conceptually, assessment

of muscle sympathetic nerve activity (MSNA) would bea good candidate variable for this purpose, but the method isnot suitable for everyday clinical practice. Nevertheless, ina report on a single patient, a progressive reduction inMSNA was obtained over time and paralleled by a reductionin BP (19). Data from a larger cohort of 25 patients withresistant hypertension confirm a significant reduction inMSNA after RDN (20).

Theoretically, a lack of effect on BP could be explained by1 or more of these 3 factors: 1) a procedure failure, that is,that the procedure did not result in sufficient ablation ofnerves to provoke a BP-lowering response; 2) a pathophysi-ology failure, that is, that overactivity of renal nerves wasnot a significant contributor to the elevated BP in a givenpatient; and 3) despite the procedure being technicallysuccessful, the cardiovascular system is unable to respondwith a lowering of BP, for instance because of arteries thatare too stiff or calcified to dilate. Thus far, it is impossible toclearly distinguish among these possibilities.Clinical studies. Clinical data are currently available from 2trials assessing the safety and efficacy of RDN (15,21). Bothof these studies were carried out in patients whowere resistant to conventional pharmacologic treatment asdefined by the failure to achieve systolic BP <160 mm Hg(or <150 mm Hg in patients with diabetes) despite ad-equate doses of at least 3 antihypertensive drugs fromdifferent classes, typically including a diuretic agent (1).

THE SYMPLICITY HTN-1 TRIAL. The initial trial (SymplicityHTN-1 [Renal Sympathetic Denervation in Patients WithTreatment-Resistance Hypertension]) was designed asan observational first-in-human evaluation of the safetyand BP-lowering efficacy of selective RDN (15). A total of45 consecutive patients (mean age 58 � 9 years) with a meanBP of 177/101 � 20/15 mm Hg were included. Patientswere on a mean of 4.7 � 1.5 antihypertensive drugs. Theprocedure was associated with significant reduction in bothsystolic and diastolic office BPs at 1, 3, 6, 9, and 12 months,with mean decreases in office BP of �14/�10 � 4/3, �21/�10 � 7/4, �22/�11 � 10/5, �24/�11 � 9/5, and �27/�17 � 16/11 mm Hg, respectively. To assess physiologicalresponses to RDN, radiotracer dilution methodologies wereapplied to assess the overflow of NE from the kidneys intothe circulation before and after the procedure. Analyses from10 patients revealed a substantial reduction in mean NEspillover of 47% (95% confidence interval: 28% to 65%) at1 month after bilateral denervation.

THE SYMPLICITY HTN-2 TRIAL. After this first-in-human proof-of-concept and safety study, a randomized controlled clinical trial(Symplicity HTN-2) was initiated that included a total of 106patients from 24 centers in Australia and Europe (21). Patientswere randomized in a 1:1 ratio to renal ablation treatment (n ¼52) or a control group (n¼ 54). Both groups had similar baselinecharacteristics and antihypertensive regimen with the exceptionof estimated glomerular filtration rate (eGFR), which was lowerin the active treatment group (77 vs. 86 ml/min, p ¼ 0.013).

JACC Vol. 62, No. 22, 2013 Schlaich et al.December 3, 2013:2031–45 Expert Consensus Statement: Transluminal Radial Denervation for Resistant Hypertension

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The difference in the primary endpoint of seated officeBP between the RDN group and the control group was 33/11 mm Hg (p < 0.001 for both systolic and diastolic BP),resulting in a mean BP of 147/84 mm Hg in the RDN groupat 6 months (from 178/96 mm Hg at baseline, p < 0.001),while no change in BP was observed in the controlgroup (178/97 mm Hg at baseline and 179/96 mm Hgat 6 months, p ¼ 0.77) (Fig. 3). Home BP recordingsconfirmed the observed office BP changes, with reductionsby 20 � 17 mm Hg systolic and 12 � 11 mm Hg diastolicin the RDN group. In contrast, systolic (2 � 13 mm Hg)and diastolic (0 � 7 mm Hg) home BP did not changesignificantly in the control group. The absolute differencebetween the groups was 22/12 mm Hg (p < 0.001).Ambulatory BP measurements were available from only20 patients in the treatment group and 25 patients inthe control group. Ambulatory systolic BP was reducedby �11 � 15 mm Hg (p ¼ 0.006) and ambulatory diastolicBP by �7 � 11 mm Hg (p ¼ 0.014) at 6 months post-procedurally in the RDN group, whereas no changes wereobserved in the control group (systolic BP:�3� 19 mmHg;diastolic BP: �1 � 12 mm Hg). RDN resulted in controlof BP, defined as systolic BP <140 mm Hg, in 39% ofpatients, whereas only 3% of patients in the control groupachieved BP control. Twenty percent of the patientswho underwent RDN had reductions in drug treatmentbefore the 6-month follow-up visit, whereas antihy-pertensive drug treatment was reduced in only 6% patients

Figure 3 Changes in Office DBP and SBP in the RDN Group and the

*p < 0.0001, yp ¼ 0.002, zp ¼ 0.005. Reprinted with permission from Esler et al. (21)

denervation; SBP ¼ systolic blood pressure; Symplicity HTN ¼ Renal Sympathetic Dener

in the control group (p ¼ 0.04). Eight percent of patientsin the RDN group and 12% of patients in the controlgroup had increases in drug treatment before the 6-monthfollow-up visit (p ¼ 0.74).

Recently published data on longer-term follow-up, in-cluding 6-month crossover results, indicate that 12 monthsafter the procedure, the mean decrease in office systolicBP in the initial RDN group was similar to the 6-monthdecrease. The mean systolic BP of the crossover group6 months after the procedure was also significantly lowered(from 190.0 � 19.6 to 166.3 � 24.7 mm Hg, a changeof �23.7 � 27.5 mm Hg; p < 0.001) (22).

THE SYMPLICITY HTN-3 TRIAL. Following the unblindedevidence from Symplicity HTN-1 and Symplicity HTN-2,to eliminate the possibility that patient awareness ofthe procedure or subconscious observer bias might becontributing, a larger multicenter, prospective, single-blind,randomized controlled study of the safety and effectivenessof RDN in subjects with uncontrolled hypertension iscurrently ongoing in the United States, the SymplicityHTN-3 trial. The inclusion criteria are very similar to thoseof Symplicity HTN-2, with even more stringent medicationrequirements, as described in detail elsewhere (23). Atotal of 530 patients with resistant hypertension willbe randomized in a 2:1 ratio to undergo either RDN ora sham procedure. Additionally, all subjects will undergoambulatory blood pressure monitoring (ABPM). Results

Control Group in the Symplicity HTN-2 Trial

. ANOVA ¼ analysis of variance; DBP ¼ diastolic blood pressure; RDN ¼ renal

vation in Patients With Treatment-Resistant Hypertension.

Schlaich et al. JACC Vol. 62, No. 22, 2013Expert Consensus Statement: Transluminal Radial Denervation for Resistant Hypertension December 3, 2013:2031–45

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are expected to be available in early 2014 and will providevaluable information with reduced scope for behavioralbias.

REAL-WORLD EXPERIENCE. An increasing number of reportson smaller case series are available. A recent report publishedin abstract form summarizes the experience from 8 Euro-pean centers (24). Office and ambulatory BP measurementswere extracted from the medical files of 73 patients withresistant hypertension before and 6 months after RDN.Office systolic and diastolic BP decreased by 18.7 � 2.7/7.5� 1.7 mm Hg (p < 0.001), while ambulatory systolic anddiastolic BP decreased by 6.7 � 2.1/4.2 � 1.3 mm Hg(p ¼ 0.002). The proportion of patients with reductions insystolic office BP of >10 mm Hg was 64%.

The relevance of drug adherence has been highlightedby a small observational study (25). To be eligible forRDN, patients required an ambulatory daytime systolic BP>135 mm Hg after witnessed intake of their antihyperten-sive drugs. When these criteria were applied, only 6 of18 patients were still eligible for RDN. This study docu-ments the insidious nature of pharmaceutical nonadherenceand reinforces the need for chronic hypertension therapiesthat respect patient choice not to adhere to long-termpolypharmacy.

Another recent report summarizes data from 346uncontrolled hypertensive patients from 10 centers inEurope and Australia (26). Patients were separated accord-ing to daytime ABPM into 303 with true-resistant hyper-tension (office systolic BP 172.2 � 22 mm Hg, 24-h systolic

Figure 4Changes in Office DBP and SBP and ABP in Patients WithThose With Pseudoresistant Hypertension

Reprinted with permission from Mahfoud et al. (26). ABP ¼ ambulatory blood pressure; D

BP 154 � 16.2 mm Hg) and 43 with pseudoresistanthypertension (office systolic BP 161.2 � 20.3 mm Hg, 24-hsystolic BP 121.1 � 19.6 mm Hg). At 3-month, 6-month,and 12-month follow-up, office SBP was reduced by 21.5,23.7, and 27.3 mm Hg and office diastolic BP by 8.9, 9.5,and 11.7 mm Hg (n ¼ 245, 236, and 90, p < 0.001 for all),respectively. In patients with true treatment resistance,significant reductions in 24-h systolic BP (�10.1, �10.2,and�11.7 mmHg, p< 0.001) and diastolic BP (�4.8,�4.9,and �7.4 mm Hg, p < 0.001) were evident at 3, 6, and12 months, respectively. Although office BP was reduced toa similar extent in patients with pseudoresistant hyper-tension, no effect onBP as assessed byABPMwas observed inthis cohort (Fig. 4).

More recently, the effects of RDN on BP in patients withmoderately resistant hypertension (i.e., office BP �140/90 mm Hg despite the use of at least 3 antihypertensivedrugs, including a diuretic agent, in adequate doses) weredescribed (27). In this study, a total of 54 patients with officeBP �140/90 and <160/100 mm Hg and confirmed diag-noses of resistant hypertension by 24-h ABPM (BP �130/80 mm Hg) underwent RDN. At 6 months afterthe procedure, office BP was reduced by �13/7 mm Hg(systolic: 151 � 6 vs. 138 � 21 mm Hg, p < 0.001; dia-stolic: 83 � 10 vs. 75 � 11 mmHg, p < 0.001). AmbulatoryBP measurements were available from 36 patients andrevealed a reduction in mean 24-h BP of 14/7 mm Hg.In 51% of patients, office BP was controlled to <140/90mm Hg after RDN.

True Treatment-Resistant Hypertension and

BP ¼ diastolic blood pressure; SBP ¼ systolic blood pressure.

Figure 5Mean Systolic and Diastolic BP Changes FromBaseline After Renal Denervation With Up to2 Years of Follow-Up in the Symplicity HTN-1 Trial

Reprinted with permission from Symplicity HTN-1 Investigators (31). BP ¼ blood

pressure.

JACC Vol. 62, No. 22, 2013 Schlaich et al.December 3, 2013:2031–45 Expert Consensus Statement: Transluminal Radial Denervation for Resistant Hypertension

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Another smaller study in a similar cohort of 20 patientswith office systolic BPs of 140 to 160 mm Hg despite �3antihypertensive medications who underwent RDN revealedBP reductions of a similar magnitude of 13.1� 13.6 mmHgsystolic and 5.0 � 8.3 mm Hg diastolic office BP at6 months (28). Compared with baseline, the mean ambula-tory systolic and diastolic 24-h BPs were reduced by 11.3 �8.6 and 4.1� 7.3mmHg at 6months, respectively. Althoughthese preliminary data are encouraging, other studies suggestthat patients with milder resistant hypertension do notshow consistent decreases in BP at 3 or 6 months afterRDN (29).

In this context, it is noteworthy that the reduction in meanBP on ABPM after RDN was generally less pronounced thanthe reduction in office BP. This is not surprising and a well-known phenomenon observed in many other BP-loweringtrials. However, the magnitude of the difference betweenoffice and ambulatory BP changes appears to be somewhatmore pronounced than that observed in BP-lowering trialsusing pharmacological approaches, as recently discussed indetail (30) (Online Fig. 1).

LONGER-TERM EFFICACY. The long-term durability of theprocedure remains an important question. A recent analysisof patients treated with catheter-based RDN in a non-randomized and uncontrolled fashion (total n ¼ 153)demonstrated reductions in mean office BP of 23/11, 26/14, and 32/14 mm Hg at 12-month, 18-month, and24-month follow-up (31), respectively (Fig. 5). Very re-cently, data on an expanded group of patients from thatcohort including 59 patients who had been followed throughto 2 years and 24 patients through to 3 years after RDNhave been presented and demonstrated that the mean BPchange after RDN was �33/15 mm Hg at 2 years and �33/19 mm Hg at 3 years, with increasing rates of BP responsedefined as a reduction of systolic BP of >10 mm Hg overtime. These data indicate that RDN results in significantand durable reductions of systolic BP in patients withtreatment-resistant hypertension and suggest that evenpatients with minimal initial reductions in BP may havesignificant reductions later on, a finding that needs to betaken into account should a repeated RDN procedure everbe considered. Further and longer studies are required toascertain the durability of RDN.

SAFETY. In Symplicity HTN-1, vascular safety analysis con-sisting of renal angiography at 14 to 30 days after the pro-cedure and magnetic resonance angiography at 6 months afterthe procedure revealed no instances of renal artery aneurysmor stenosis or other long-term adverse events. Using the first-generation RF catheter, 1 renal artery dissection occurred in1 patient before energy delivery, which required stentingand resolved without further adverse consequences. Renalfunction was not compromised. The impact on eGFR wasneutral with �1.4 ml/min (95% confidence interval: �4.6 to1.7 ml/min) at 3 months and �2.8 ml/min (95% confidenceinterval: �6.4 to 0.8 ml/min) at 12 months. In the extended

Symplicity HTN-1 cohort (n ¼ 153), a total of 3 groinpseudoaneurysms occurred. One patient required stenting ofa renal artery ostial stenosis that was present at baseline buthad grown by 6 months. Of note, no RF energy had beendelivered in this location.

In Symplicity HTN-2, periprocedural events requiringtreatment were rare and consisted of 1 femoral arterypseudoaneurysm, 1 post-procedural decrease in BP resultingin a reduction in antihypertensive drugs, 1 urinary tractinfection, 1 extended hospital admission for assessment ofparaesthesia, and 1 case of back pain that was treated withanalgesics and resolved after 1 month. Seven of 52 patients(13%) who underwent RDN had transient intraproceduralbradycardia requiring atropine. Renal function, as assessedby serum creatinine, eGFR, and cystatin C levels, wereunchanged from baseline in both groups at 6 months. Six-month renal vascular imaging identified 1 patient withpossible progression of an underlying atherosclerotic lesion,which required no therapy.

Two recently published case reports describe the devel-opment and progression of a renal artery stenosis (32,33)and a potential link with the RDN procedure. Long-termfollow-up of treated patients with repeat imaging of therenal arteries will be required to adequately address thisissue.

In addition toBP lowering, RDNhas been shown to reduceheart rate (34) (Fig. 6) and to reduce BP during exercisewithout compromising chronotropic competence (35).

Additional Potential Beneficial Effects ofRenal Denervation

A series of studies have reported on the effects of RDN onaspects other than BP reduction. The majority of thesestudies were observational and uncontrolled and comprised

Figure 6Changes in HR According to HR Tertiles at Baseline in136 Patients With Resistant Hypertension WhoUnderwent Renal Denervation

Values are mean � SEM. The p values are for comparisons with baseline.

Reprinted with permission from Ukena et al. (34). ANOVA ¼ analysis of variance;

HR ¼ heart rate.

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small study cohorts with only short-term follow-up. Theytherefore need to be interpreted with appropriate caution.Clearly, larger, adequately designed studies are necessary,and many are currently being undertaken to confirm or rejectthese initial findings. Nevertheless, pathophysiologicconsiderations suggest that some of these initial findingsmay have potential clinical relevance.Glucose metabolism. Hypertension is frequently associ-ated with metabolic alterations. Sympathetic activation hasbeen identified as an important contributor to this detri-mental clinical scenario (36). Sympathoinhibition wouldtherefore be expected to improve glycemic control (37). Ina subcohort of the Symplicity HTN-2 trial, patients fromboth the RDN (n ¼ 37) and control groups (n ¼ 13)underwent detailed assessment of glucose metabolism.Levels of fasting glucose, insulin, C-peptide, glycosylatedhemoglobin, and calculated insulin sensitivity (homeostasismodel assessment of insulin resistance) improved signifi-cantly after 3 months. Mean 2-h glucose levels during oralglucose tolerance tests were also reduced significantly by27 mg/dl (p ¼ 0.012), while there were no significantchanges in BP or in any of the metabolic markers in thecontrol group (38) (Fig. 7).

Left ventricular hypertrophy. Additional factors that maytranslate into better outcomes after RDN include improve-ments in cardiac baroreflex sensitivity and a reduction in leftventricular mass (19). These initial findings from a singlecase report have now been confirmed in a larger cohort of 46patients with resistant hypertension for which they under-went RDN (39). RDN was not only associated withsubstantial reductions in systolic and diastolic BP (�22.5/

�7.2 mm Hg at 1 month and �27.8/�8.8 mm Hg at 6months, p < 0.001 at each time point) but also significantlyreduced mean interventricular septal thickness and LV massindex at 1 and 6 months, respectively (Fig. 8). Diastolicfunction was also improved, as assessed by mitral valvelateral E/E ratio, which decreased after RDN from 9.9 � 4.0to 7.9 � 2.2 at 1 month and 7.4 � 2.7 at 6 months (p <0.001), indicating reduction of left ventricular filling pres-sures. No such changes were observed in a matched group of18 control patients. These data may indicate that the effectsof RDN go beyond that of merely reducing BP and maycontribute to regression of hypertensive end-organ damage.Atrial fibrillation. Both animal and human studies suggestthat the autonomic nervous system plays an important rolein the initiation and maintenance of atrial fibrillation (AF).A recent study by Pokushalov et al. (40) reported that RDNreduced AF recurrence when combined with pulmonary veinisolation (PVI). In this study, 27 patients with hypertensionwith histories of symptomatic paroxysmal or persistent AFwere enrolled, 14 of whom underwent PVI only and 13 ofwhom were treated with PVI and RDN. At 12-monthfollow-up, patients in the PVI plus RDN group experi-enced significant reductions in systolic (from 181 � 7 to 156� 5 mm Hg, p < 0.001) and diastolic (from 97 � 6 to 87 �4 mm Hg, p < 0.001) BP and had a substantially lower rateof recurrence of AF. Nine of the 13 patients (69%) treatedwith PVI plus RDN were free of AF, whereas this was thecase in only 4 of the 14 patients (29%) in the PVI-onlygroup (p ¼ 0.033). Although optimized BP control mightplay a considerable role in decreasing the development ofrecurrence of AF, this study raises the possibility thatreducing sympathetic drive with RDN may reduce the rateof AF recurrence in patients with resistant hypertension.However, in a recent letter to the editor, several concernswere raised pertaining to the design of the study, insufficientdescription of methods, and inconsistencies with datareporting and statistics (41). Further studies are needed toassess the therapeutic potential of RDN in the setting of AF.Heart failure. Heart failure is commonly characterized bysubstantial neurohormonal activation directed particularly tothe heart and kidneys, providing a theoretical basis for thepotential usefulness of targeting renal nerves with RDN inthis context. A small pilot study including 7 patients withchronic mild to moderate systolic heart failure (mean ejec-tion fraction 43 � 15%) did not raise any procedural orsafety concerns (42), particularly no major decrease in BPdespite low baseline levels and no change in renal function,and demonstrated a mild improvement in 6-min walkingdistance, while ejection fraction and other cardiac structuraland functional changes were not changed significantly after6 months. Larger clinical trials are ongoing to delineate thepotential role of RDN in heart failure.Chronic and end-stage kidney disease. Sympatheticactivation is a hallmark of chronic kidney disease butgenerally neglected as a therapeutic target (43). Given therelevance of both renal efferent and afferent nerves in this

Figure 7 Changes in Fasting Glucose, Fasting Insulin, C-Peptide, and HOMA-IR

Change (�SEM) in fasting glucose (A), fasting insulin (B), C-peptide (C), and homeostasis model assessment-insulin resistance (D) at 1 and 3 months after renal denervation

compared with baseline. Reproduced with permission from Mahfoud et al. (38). ANOVA ¼ analysis of variance; HOMA-IR ¼ homeostasis model of assessment of insulin

resistance.

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condition (11,12), these patients may derive specific benefitfrom an intervention targeting the renal nerves (44). Arecent proof-of-concept study in 15 patients with resistanthypertension (mean BP 174 � 22/91 � 16 mm Hg despitethe use of 5.6 � 1.3 antihypertensive drugs) and moderate tosevere chronic kidney disease (mean eGFR 31.2 � 8.9 ml/min/1.73 m2) in whom office and ambulatory BP andserum biochemistry were obtained before and at 1-month,3-month, 6-month, and 12-month follow-up after RDNrevealed a favorable safety profile with no compromise oftreated arteries evident on angiographic evaluation andpreserved renal function up to 12-months follow-up (45).Office systolic and diastolic BP decreased by �32 � 18/�15 � 12 mm Hg at 6-month follow-up (p < 0.001).Nighttime ambulatory BP was significantly reduced(p < 0.05), resulting in restoration of a more physiologicdipping pattern (45). Although renal hemodynamic statushas not been assessed in this chronic kidney disease cohort,recent data from a larger cohort of 100 patients with resistanthypertension and eGFRs >45 ml/min/1.73 m2 demon-strated that RDN reduced the renal resistive indexat 3-month and 6-month follow-up (46). Although meancystatin C, eGFR, and urinary albumin excretion remainedunchanged after RDN, the number of patients with micro-albuminuria or macroalbuminuria decreased (46). Whetherthese potentially beneficial changes in renal hemodynamicstatus may translate into improved renal outcomes in patientswith resistant hypertension and various stages of chronickidney disease needs to be determined.

Sympathetic tone is substantially enhanced in patients withend-stage renal disease and may play a role in the high rate ofcardiovascular events in these patients (47). Nephrectomy ofthe native nonfunctioning kidney in patients with or withoutkidney transplantation resulted in a reduction ofMSNA (48).A preliminary proof-of-concept study of RDN was per-formed in 12 patients with end-stage renal disease anduncontrolled hypertension (49). Standardized BP measure-ments were obtained in all patients on dialysis-free daysat baseline and follow-up. The mean office BP was 170.8/89.2 mm Hg despite the use of a mean of 3.8 � 1.4 antihy-pertensive drugs. Three of 12 patients could not undergoRDN because of atrophic renal arteries. Compared withbaseline, office systolic BP was reduced (from 166 � 16.0 to148 � 11, 150 � 14, and 138 � 17 mm Hg, respectively),whereas there was no change in the 3 nontreated patients.Measures of renal NE spillover and MSNA were availablein 2 patients before and after RDN, and these markers weresubstantially reduced by RDN. These initial results in-dicate that there is high sympathetic drive in end-stage renaldisease, and it can be reduced by RDN, resulting in a signif-icant BP reduction. Whether this translates into improvedoutcomes in these high-risk patients requires confirmationin appropriately designed, larger population studies.

Patient Selection

On the basis of the available data from clinical studies,only those patients who have severe treatment-resistant

Figure 8Changes in LVH After Bilateral RD in 46 Patients With Resistant Hypertension Compared With 18 Control PatientsWho Did Not Undergo Renal Denervation

Comparison of LVMI (A), IVSTd (B) and reduction of LVMI (C) between the RDN and control group, and individual changes in LVMI in patients who did undergo RD (D) at various

time points. Reprinted with permission from Brandt et al. (39). LVH ¼ left ventricular hypertrophy; LVMI ¼ left ventricular mass index; IVSTd ¼ end-diastolic interventricular

septum thickness; RD ¼ renal denervation.

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hypertension, defined as office systolic BP �160 mm Hg(�150 mm Hg in patients with type 2 diabetes) despitetreatment with �3 antihypertensive drugs of different types,including one diuretic agent, at adequate doses shouldundergo renal nerve ablation (Fig. 9). Elevated BP should beconfirmed by 24-h ABPM, because up to one-third ofpatients with treatment-resistant hypertension have normalBP outside the office (50). Every effort should have beenmade to identify and reverse contributing lifestyle factorsand discontinue or minimize the use of substances that canincrease BP. Secondary causes of hypertension should havebeen re-evaluated and excluded, as previously summarized(51) (Table 1). Careful attention should have been paid toexclude nonadherence to drug therapy as an important andoften neglected cause of treatment resistance (52). Theimportance of systematic screening to assess eligibility forRDN was highlighted in a recent study demonstrating that2 of 3 patients with suspected resistant hypertension werefound to be ineligible if the aforementioned criteria wereapplied, primarily because of previously undiagnosedsecondary hypertension, white coat hypertension, or BPlower than currently recommended thresholds (53).

In the Symplicity HTN-1 and Symplicity HTN-2studies, patients were excluded if renal function wasreduced to an eGFR <45 ml/min/1.73 m2. Contrast mediaare administered during the procedure. Patients withmarkedly reduced glomerular filtration rates may be

particularly vulnerable to acquiring acute renal failure. Thecholesterol embolus syndrome is a potential risk if there isrenal atherosclerosis (54). Even in dialysis patients, loss ofresidual renal function and diuresis may have a negativeimpact on quality of life and prognosis. Currently, RDN inpatients with advanced chronic kidney disease (glomerularfiltration rate <45 ml/min/1.73 m2) is therefore recom-mended only in clinical trials.Background therapy. Whether only patients who havetried aldosterone antagonists should be eligible for renalnerve ablation is controversial. Systolic BP reductions up to25 mm Hg have been reported after administering spi-ronolactone as a fourth antihypertensive agent (55,56), but notall patients respond to such an extent. A randomizedcontrolled trial suggested that the incremental effect on officesystolic BP was only 6.5 mm Hg (57). Long-term treatmentwith spironolactone is hampered by side effects such asgynecomastia, while eplerenone currently has the drawback ofrelatively high cost. Furthermore, there is a risk for hyper-kalemia with aldosterone antagonists, which requires moni-toring. Although the incidence of hyperkalemia maynumerically be low, patients with treatment-resistant hyper-tension in general receive already 1 or 2 agents blocking therenin-angiotensin system and may already have reduced renalfunction (eGFR <60 ml/min/1.73 m2), both factors thatincrease the incidence of hyperkalemia. Spironolactoneincreases potassium levels, especially in white subjects (58,59),

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and its widespread initiation after publication of theRandomized Aldactone Evaluation Study was accompaniedby an increase in hospitalizations for hyperkalemia (60),although this has been put in perspective by others (59).Moreover, if unexpected circumstances occur that compro-mise renal function, such as the administration of nonsteroidalanti-inflammatory drugs or volume loss with diarrhea, the rateof hyperkalemia may increase further. Thus, an individualizedapproach balancing the pros and cons of lifelong administrationof aldosterone antagonists is preferential.

There is no sufficient clinical research experience of renalnerve ablation in the setting of hemodynamically or anatomi-cally significant renal artery abnormalities (e.g., stenosis orfibromuscular dysplasia), previous renal artery interventionsincluding previous renal stent procedures, unstable clinicalconditions (e.g., acute cardiovascular events), or in children orpatients with preeclampsia. These should, therefore, currentlybe considered contraindications in routine clinical practice.General requirements for sites involved in RDNprocedures. In patients with difficult-to-control BP,secondary forms of hypertension should be suspected andexcluded. RDN is not the first-line therapy for such patients.A detailed screening program should be completed toexclude curable forms of secondary hypertension. Specializedcenters are typically best equipped to perform thoroughdiagnostic investigations and provide the expertise and in-frastructure for appropriate patient management and selec-tion, procedure implementation, management of potentialcomplications, and the essential follow-up.

Although the clinical experience with RDN is mounting,with more than 6,000 treated patients worldwide, it cannot

Figure 9 Patient Assessment to Determine Eligibility for RDN

The flowchart describes the recommended pathway to assess eligibility for renal denervat

a series of diagnostic tests to confirm true treatment resistance. Furthermore, reversing of

RDN is considered. Throughout this process, communication between hypertension spec

patient’s care is essential. ABPM ¼ ambulatory blood pressure monitoring; BP ¼ blood p

filtration rate; MRA ¼ magnetic resonance angiography; OSA ¼ obstructive sleep apnea;

yet be rated as a standard procedure in resistant hyperten-sion. It should be offered only to selected patients inwhom the present danger from hypertensive complicationssuch as death, myocardial infarction, and stroke exceedthe potential for long-term harm from the procedure,for which the 36 months of follow-up of patients inclinical trials may not yet be sufficient to be definitivelyexcluded.Patient follow-up. Regular follow-up visits after RDN arenecessary to assess short-term and long-term safety andefficacy and to adjust patients’ BP medications if required.Given the known limitations of conventional clinic BPreadings, additional measures such as systematic homeBP monitoring (61) and ABPM should be implementedas part of the follow-up of treated patients. The firstscheduled follow-up should occur within the first 4 weeksafter the procedure and then at 3, 6, and 12 months, withsubsequent yearly visits. In addition to BP measurements,assessment of renal function (serum creatinine, eGFR,electrolytes) is mandatory. Repeat renal artery imaging at6 months or later after RDN is recommended to excludeany post-procedural structural alterations, particularly if BPhas not dropped or has even increased. Depending on pre-existing comorbidities, repeat electrocardiography, echo-cardiography, assessment of glucose metabolism (fastingglucose, insulin, glycosylated hemoglobin, oral glucosetolerance test), measurement of urinary albumin and creat-inine ratios and protein excretion, assessment of markers ofarterial stiffness, and other tests can provide additionalinformation on the therapeutic effects of RDN but are notmandatory.

ion (RDN). Patients who present with presumed treatment resistance should undergo

contributing factors and optimization of pharmacotherapy should be attempted before

ialists, interventional cardiologists, and other health care providers involved in the

ressure; CTA ¼ computed tomographic angiography; eGFR ¼ estimated glomerular

SBP ¼ systolic blood pressure; US ¼ ultrasound.

Table 1 Clinical Features and Diagnostics of Secondary Causes of Hypertension

Secondary Cause Clinical Features Screening TestAdditional/

Confirmatory Test

Renal vasculardisease

� ARAS� Rapid deterioration of renal

function (especially afteradministration ofRAS-modulating agents)

� Onset of hypertensionafter age 50 yrs

� Flash pulmonary edema� Length difference �1.5 cm

between the kidneys� FMD

� Early-onset hypertension(particularly in young women)

� Renal duplexultrasonography

� MRI� CT� DSA

Renal parenchymaldisease

� Clinical history (including)� Recurring UTI� Analgesic abuse� Familial diseases

� Anemia� Fluid overload

� eGFR� Urine dipstick

(e.g., erythrocytes,leukocytes,proteinuria)

� Urine albumin/creatinine ratio

� Renal ultrasonography� Kidney biopsy

(in reasonable cases)

Primaryhyperaldosteronism

� Muscle weakness� Hypokalemia (occasional)� Incidentaloma

� Aldosterone-reninratio (at best understandardizedconditions)

� Oral sodium loading� Saline infusion� Fludrocortisone

suppression test� Captopril challenge� CT� Adrenal vein sampling

OSA � Daytime hypersomnia� Frequent nocturnal arousals� Morning asthenia with or

without headache� Severe snoring

� Specificquestionnaires

� Polygraphy(ambulant)

� Polysomnography(sleep center)

Drug-inducedhypertension

� Detailed medical history(including OTC medicines)

Pheochromocytoma � Hypertension(paroxysmal or sustained)

� Headache� Sweating� Palpitations� Fasting hyperglycemia� Incidentaloma� Genetic predisposition

� Urinary fractionatedmetanephrines

� Plasma-freemetanephrines

� CT� MRI� 123I-labeled MIBG

scintigraphy� Genetic screening

Cushing’ssyndrome

� Classical physical findings� Central obesity� Moon face� Buffalo hump� Red striae� Hirsutism

� Glucose intolerance/diabetes� Menstrual irregularities

� 24-h urinarycortisol excretion

� Dexamethasonesuppression test

� Exclusion ofexogenousglucocorticoidintake

� MRI� CT� CRH testing

Coarctationof the aorta

� Headache� Hypertension in the upper

extremities with lower extremitypressure

� Discrepancies between bilateralbrachial blood pressure

� Congenital heart disease

� Chest radiography� Echocardiography

� MRI

Reprinted with permission from Ott et al. (51).ARAS ¼ atherosclerotic renal artery stenosis; CRH ¼ corticotropin-releasing hormone; CT ¼ computed tomography; DSA ¼ digital subtraction

angiography; eGFR ¼ estimated glomerular filtration rate; FMD ¼ fibromuscular dysplasia; MIBG ¼ metaiodobenzylguanidine; MRI ¼ magneticresonance imaging; OSA ¼ obstructive sleep apnea; OTC ¼ over-the-counter; RAS ¼ renin-angiotensin system.

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Study Limitations

The studies carried out so far have been restricted to patientswith severe and treatment-resistant hypertension withsystolic BP >160 mm Hg. These results cannot be simplyextrapolated to less severe forms or secondary forms ofhypertension.

Although uncontrolled, follow-up data are available beyond3 years by now, this may not yet be sufficient to ascertain thelong-term durability of the effect. Indeed, renal and hearttransplantation models indicate that renal nerves have thepotential to regrow anatomically after injury, raising thepossibility of finite time limits in the physiologic effects of theprocedure. However, on the basis of previous data, it appearsunlikely that the human kidney achieves functional reinner-vation (62), and the physiologic importance of anatomicregrowth of efferent nerve fibers in sustaining BP remainsunproved. If functional reinnervation occurred, perhapsmirrored by BP elevations, the issue of repeat renal nerveablation would have to be explored.

Theoretical concerns relate to the altered responsivenessto certain stimuli in the absence of sufficient renal sympa-thetic innervation. The renal nerves are only 1 componentof the complex mechanisms that make up baroreceptorfunction. For instance, the direct effects of the baroreceptorarch on peripheral vascular resistance are unaffected. Theexperience from kidney transplantation in humans, inthe process of which sympathetic nerves of the kidneysare severed, is perhaps the most persuasive evidence todemonstrate that the denervated kidney is capable ofmaintaining electrolyte and volume homeostasis, suggestingthat selective ablation of renal nerves is unlikely to result inadverse consequences.

Follow-up imaging of renal arteries 6 months after RDNdid not reveal evidence of major vascular damage. Publisheddata reporting on 2-year follow-up in a cohort of 153 patientstreated with RDN did not report major vascular abnormali-ties. However, imaging studies of the renal vasculature werenot part of the routine investigation at 1-year and 2-yearfollow-up.

Currently, there are no clinical trial data available toindicate the effects of RDN on cardiovascular outcomes.

Several technical aspects also require attention. Theseinclude the management of patients with dual renal arteriesand accessory arteries that may not be accessible for renalnerve ablation, as well as the role of RDN in patients withrenal artery stenosis, a condition that is characterized notonly by activation of the renin-angiotensin system but alsoby heightened sympathetic drive (63).

As indicated earlier, only a limited number of ambulatoryBP measurements were extractable from study-controlledpatients. In the Symplicity HTN-2 trial, only 20 patientsin the RDN group and 25 patients in the control group hadevaluable measurements (>70% successful readings) (21).The difference in reduction of systolic BP after 6 monthswas less pronounced, with only 8 mm Hg between the RDN

and control groups. Whether this is a manifestation ofinadvertently biased measurement of BP by physicians awareof treatment allocation or a reflection of a larger effect on thealerting response is currently unknown. Ambulatory BP datafrom the Symplicity HTN-3 trial will provide importantinsights.

Finally, there is only limited information to what extentthe RDN procedure is able to interfere with afferentsensory nerve traffic and efferent sympathetic renal innerva-tion. Elaborate microneurographic measurements (MSNA)are currently the only way to quantify sympathetic nerveactivity. Further studies need to be conducted to address thisissue.

Conclusions

Evidence from the available clinical trials indicate thatcatheter-based RF ablation of renal nerves improve BPcontrol in patients with resistant hypertension, with a safetyprofile to 3 years that seems acceptable for the degree andreliability of BP improvement. The effects of RDN appearto be mediated via interference with both efferent sympa-thetic and afferent sensory nerves and may extend beyondBP control.

RDN should currently be considered only in patientswhose BP cannot be controlled by a combination of lifestylemodification and pharmacologic therapy that is tailoredaccording to current guidelines.

It is not known whether RDN may be useful in less severeforms of hypertension or in other conditions characterizedby heightened renal sympathetic nerve activity, such as heartfailure, metabolic syndrome, heart arrhythmias such asAF, chronic and end-stage renal disease, and others. It istherefore not recommended to perform RDN in thesepatient cohorts outside of appropriately designed clinicaltrials.

Information on the long-term safety and efficacy of theRDN procedure is being collected in national and interna-tional registries.

Many uncertainties remain. One is the longer term, whenthe risk for cardiovascular events grows, as does the oppor-tunity to benefit from event prevention; and meanwhile, thepotential for currently unrecognized complications mightgrow along with the natural accumulation of unrelatedadverse events. A second is the suitability for patients outsidethe idealized group of patients who tend to volunteer forrandomized controlled trials. A third is how to balance thedesirability of BP control, individual patients’ desire to feelconfident that their BP is controlled, their reluctance to takevery large numbers of tablets, their reluctance to undergoirreversible and invasive procedures, and the cost of theprocedure versus the cost and consequences of letting BPcontinue uncontrolled. While addressing these issues, anaccurate assessment of daily life BP control is an essentialrequirement, and systematic use of home BP monitoringand/or ABPM is thus mandatory. Clinicians must consider

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all of these in the context of individual patients to give advicein a suitable perspective.

Reprint requests and correspondence: Prof. Markus Schlaich,Neurovascular Hypertension & Kidney Disease Laboratory, BakerIDI Heart & Diabetes Institute, PO Box 6492, St Kilda RoadCentral, Melbourne, Victoria 8008, Australia. E-mail: markus.schlaich@bakeridi.edu.au.

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Key Words: renal denervation - resistant hypertension - sympathetic.

APPENDIX

For supplementary material and a figure and a table, please see the onlineversion of this article.