European Journal of Internal Medicine 117 (2023) 66–77

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original article

Catheter-based renal artery denervation: facts and expectations

Paolo Verdecchia a, *, Claudio Cavallini a, Rocco Sclafani a, Andrea Santucci a,
Francesco Notaristefano a, Gianluca Zingarini a, Giovanni Andrea Colombo b, Fabio Angeli b
a
Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy
b
Department of Medicine and Technological Innovation (DiMIT), University of Insubria, Varese and Department of Medicine and Cardiopulmonary Rehabilitation,
Maugeri Care and Research Institute, IRCCS, Tradate, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Catheter-based renal artery denervation (RAD) is entering a new era. After the disappointing results of
Renal artery denervation SYMPLICITY-HTN 3 trial in year 2014, several technical and methodological advancements led to execution of
Blood pressure important SHAM-controlled randomized trials with promising results. Now, the 2023 ESH Guidelines give RAD a
Hypertension
class of recommendation II with a Level of Evidence B. Currently, catheter-based RAD has two main areas of
SHAM procedure
Atrial fibrillation
application: (a) Hypertensive patients who are still untreated, in whom RAD is a sort of a first-line treatment; (b)
Heart failure Difficult-to-control or true resistant hypertensive patients. Notably, randomized SHAM-controlled trials met their
primary end-point in both these conditions. So far, we do not dispose of established predictors of the antihy­
pertensive response to RAD. Some data suggest that younger patients with systo-diastolic hypertension, absence
of diffuse atherosclerosis and evidence of sympathetic nervous system overactivity experience a better BP
response to the procedure. We reviewed the available data on catheter-based RAD and included an updated
meta-analysis of the results of the available SHAM-controlled trials. Overall, the reduction in 24-h systolic blood
pressure (BP) after RAD exceeded that after SHAM by 4.58 mmHg (95% CI 3.07–6.10) in untreated patients, and
by 3.82 mmHg (95% CI 2.46–5.18) in treated patients, without significant heterogeneity across trials, patient
phenotype (untreated versus treated patients) and technique (radiofrequency versus ultrasound). There were no
important safety signals related to the procedure. Notably, some data suggest that RAD could be an effective
additional approach in patients with atrial fibrillation and other conditions characterized by sympathetic nervous
system overactivity.

1. Introduction The unexpected and disappointing results of SIMPLICITY HTN-3

Some clinical studies published before year 2014 raised consistent
expectations worldwide on a promising role of catheter-based renal ar­
tery denervation (RAD) in the management of patients with elevated
blood pressure (BP) [1,2]. Unfortunately, the randomized
SHAM-controlled trial SIMPLICITY HTN-3, published in year 2014 in the
The New England Journal of Medicine and conducted in 535 patients with
resistant hypertension despite three or more antihypertensive drugs
(office systolic BP >160 mmHg and average 24-h ambulatory BP > 135
mmHg) failed to demonstrate the superiority of RAD over the SHAM
procedure in terms of office systolic BP reduction at 6 months (primary
outcome) [3]. It is well known that the SHAM procedure, developed to
preserve the single-blindness, consists in a ‘real’ catheterization of pa­
tients followed in this case by renal angiography, but not by RAD.
generated concerns about the role of RAD in the treatment of hyper­
tension, summarized in the III B recommendation from the 2018 ESC/
ESH Hypertension Guidelines that the use of this procedure is not rec­
ommended ‘until further evidence regarding safety and efficacy be­
comes available’[4].
Over the subsequent years, several pitfalls of the SIMPLICITY HTN-3
that could have limited or precluded its ability to effectively lower BP
came to light [5,6]. In particular, attention was focused on some
objective procedural limitations (uncomplete circumferential
four-quadrant denervation, energy deliver incompletely provided at the
level of the distal branches where sympathetic nerves are closer to the
arterial wall, limited expertise of some Centers, etc.). Other potential
confounding factors limiting the efficacy of RAD were later identified,
including the impact of patients with isolated systolic hypertension, who

* Corresponding author at: Fondazione Umbra Cuore e Ipertensione-ONLUS, Struttura Complessa di Cardiologia, Ospedale S. Maria della Misericordia, Perugia,
Italy.
E-mail address: verdecchiapaolo@gmail.com (P. Verdecchia).

https://doi.org/10.1016/j.ejim.2023.07.041
Received 20 July 2023; Received in revised form 27 July 2023; Accepted 31 July 2023
Available online 4 August 2023
0953-6205/© 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
P. Verdecchia et al.
substantially fail to respond to the procedure [7,8], the correct selection
of patients with true resistant hypertension with exclusion of those with
pseudo-resistant hypertension, the exclusion of patients with unrecog­
nized secondary hypertension, the avoidance of imbalances in
concomitant drug treatment between the groups, the adherence to
treatment during follow-up, etc.
As a result, the subsequent years witnessed a new generation of
clinical trials conducted with newer and more effective multielectrode
catheters and greater attention to some key methodological and tech­
nical aspects.
We reviewed the accrued evidences on this area and added an
updated meta-analysis of SHAM-controlled trials which tested the
antihypertensive effect of RAD. We used 24-h ambulatory BP (ABP) as
endpoint owing to its superiority over office BP to predict outcome [4,
9]. For this purpose, we conducted a literature search using PubMed,
Scopus, EMBASE, Web of Science, and Google Scholar databases ac­
cording to standard methods [10,11]. The following research terms were
used: “renal denervation, blood pressure, high blood pressure, hyper­
tension, safety, efficacy”.
2. Mechanisms of the antihypertensive effect of RAD
The ‘lumbar sympathectomy’ was a surgical procedure introduced
about 70 years ago in the management of patients with severe hyper­
tension, for whom no effective therapy was available at that time [12].
The procedure consisted in the surgical removal of sympathetic ganglia
at lumbar level, a sort of ‘fully extended’ RAD procedure [12]. The
procedure was not only extremely effective in reducing BP, but were also
able to reduce the associated high mortality [13]. However, it was very
badly tolerated by patients due to severe orthostatic hypotension,
impotence, urinary incontinence and surgical complications [12,13].
Thus, the advent of diuretics and other effective and better tolerated
antihypertensive drugs progressively led to its disappearance.
Currently, we know that catheter-based RAD lowers BP through the
blockade of efferent (brain→kidney) and afferent (kidney→brain)
sympathetic nerves (Fig. 1).
2.1. Inhibition of the efferent activity
The efferent sympathetic activity running from the brain to the
Fig. 1. Mechanisms of the blood pressure lowering effect of renal artery denervation.
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European Journal of Internal Medicine 117 (2023) 66–77
kidney originates in the hypothalamus, the brainstem, the rostral
ventrolateral medulla and the paraventricular nucleus. Indeed, the
surgical demolition of the rostral ventrolateral medulla markedly lowers
BP in animal models [14]. Sympathetic renal nerves originate mostly
from celiac and aortorenal ganglion around the aorta. Renal nerves run
in the adventitia and perivascular adipose tissue around the renal ar­
teries. These nerves are closer to the arterial wall, and hence more
sensitive to RAD, not at proximal level but at a more distal level, closer
to the sub-division of the artery into its polar branches [15]. It is known
that norepinephrine release from the renal nerves causes vasoconstric­
tion of renal arterioles, increased reabsorption of sodium at tubular level
and release of renin from the juxtaglomerular cells [15] and these re­
actions are blocked by RAD [16]. It is debated whether a lesser sodium
tubular reabsorption is, or not, an important mechanism underlying the
BP lowering effect of RAD [17]. On the other hand, an increased sym­
pathetic system activity is frequently found in hypertension [18],
particularly in the presence of obesity [16], where RAD is particularly
effective [16].
2.2. Inhibition of the afferent activity
By blocking the afferent sympathetic nerve activity towards the
brain, RAD is able reduce in the central sympathetic outflow with
important systemic implications on the heart, kidney, vessels, muscles
and adipocytes. A proposed mechanism to explain the reduced central
sympathetic outflow could be the functional remodeling and retrograde
cell death of the stellate ganglion as a result of the reduced neural
afferences from the kidney [19]. The lesion of the stellate ganglion could
contribute to explain some antiarrhythmic effects of RAD [20,21].
Through microneurography it is possible to quantify the reduced sym­
pathetic outflow for effect of RAD [2].
3. Technical details
Table 1, modified from Barbato et al. [22] shows the main technical
details of RAD. In general, the delivery of energy through radio­
frequency or ultrasounds warms up the adipose tissue surrounding the
renal arteries, in which the renal nerves are located. Hence, renal nerves
are destroyed as a result of a heating injury.
P. Verdecchia et al.
Table 1
Technical details of renal artery denervation. Modified from Barbato et al. [22].
• Adequate hydration to prevent contrast nephropathy.
• Anticoagulation through intraprocedural unfractionated heparin (70 U/kg)
targeted to activated coagulation time >250 s. Subsequently, aspirin plus
clopidogrel for 2 months.
• Patients under anticoagulant treatment are managed similarly to those undergoing
other hemodynamic invasive procedures.
• Low sedation and analgesia through morphine 1–3 mg or fentanyl 1–2 mcg/kg
intravenously, midazolam 2–3 mg intravenously. Availability of naloxone and
flumazenil.
• Monitoring of vital parameters during the entire procedure.
• Availability of intravenous drugs for hypertensive crisis or renal artery spasm
(nitroprusside, urapidil, nitroglycerine, phentolamine, verapamil).
• Avoid to deliver energy close to plaques or small arteries.
• Duration of procedure generally from 40 to 60 min.
• Prefer newer multielectrode catheters (Symplicity Spiral©, Symplicity G3©, etc)
which allow simultaneous or sequential delivery of energy to all the 4 quadrants,
with at least 45 s for each energy delivery on arterioles of 3–8 mm diameter (main
renal artery and more distal branches).
• Contraindications to RAD: severe renal failure, acute coronary syndrome or stroke
in the past 6 months, renal artery aneurysm, multiple accessories renal arteries with
the main artery supplying less than 75% of kidney, short (length <20 mm) or small
(diameter <4 mm) renal arteries.
• Use femoral access (6 Fr for Spyral RF and 7 Fr for Paradise US) and treat all
accessible renal arteries with diameter from 3 to 8 mm.
• Ablate the main renal arteries and branches (Radiofrequency). Main renal artery,
2–3 ablations per artery (Ultrasound).
• Ensure appropriate contact between the vessel wall and the electrodes
(Radiofrequency) or the complete occlusion of the artery after balloon inflation
(Ultrasound).
• Make simultaneous ablation on 4 points for at least 45 s (ideally 60 s) with
Radiofrequency. Seven seconds per ablation with Ultrasound.
4. Available clinical trials
Fig. 2 shows the main randomized clinical trials on RAD. The table
does not report the early ‘proof-of-concept’ observational studies, but
only the later major trials in which RAD was compared with a SHAM
procedure (up) or with a standard pharmacological treatment of hy­
pertension without SHAM control (down).
Three trials (Symplicity-HTN-2, [1] DENERHEART [23] and
Fig. 2. Main randomized clinical trials on renal artery denervation.
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European Journal of Internal Medicine 117 (2023) 66–77
RADIOSOUND [24]) were conducted without SHAM control (i.e., renal
artery catheterism without RAD) while all the remaining trials used a
SHAM control group. All SHAM-controlled trials were conducted from
year 2014 onwards, after the publication of the disappointing results of
Symplicity HTN-3 [3].
The acronym of trials which met the primary end-point is shown in
green, whereas that of the trials which did not meet the primary end-
point is shown in red. Furthermore, the trials which used the radio­
frequency technique for RAD are not underscored, while those using the
ultrasound technique are underscored. A further important subdivision
regards the phenotype of patients who underwent RAD: some studies
were conducted in patients who were not receiving antihypertensive
drugs at the time of RAD, while other studies were conducted in treated
patients, either not well controlled or frankly resistant to treatment.
All the 3 trials conducted without SHAM control achieved the pri­
mary end-point [1,23,24]. Among the SHAM-controlled trials, 3 trials in
untreated patients achieved the primary end-point (two trials using the
ultrasound technique and one using the radiofrequency technique)
[25–27], while 2 of the 7 trials conducted in treated patients achieved
the primary end-point (one with ultrasound and one with radio­
frequency technique) [28,29]. Three important trials with SHAM con­
trol group are ongoing.
Table 2 shows the main characteristics of trials which met the pri­
mary end-point. In all trials, the primary end-point was based on
ambulatory BP changes over 2–6 months after the RAD procedure.
Fig. 3 shows the effect of RAD versus SHAM control on the primary
end-point (changes in 24-h systolic BP in some studies, or daytime sys­
tolic BP in other studies) in the trials which met the end-point. Ambu­
latory systolic BP fell generally by 4–6 mmHg more after RAD than after
SHAM. Such difference was comparable in initially untreated patients
[25–27] and in those who were treated [28,29] at the time of RAD.
In the RADIANCE.HTN SOLO, the daytime ambulatory BP at 2
months decreased by 6.3 mmHg more in the RAD group than in the
SHAM control group despite the higher number of patients who assumed
antihypertensive drugs at follow-up in the SHAM group (13 patients,
versus 5 patients in the RAD group) [26]. After exclusion of these patient
in a per-protocol analysis, the daytime ambulatory BP at 2 months
decreased by 8.2 mmHg more in the RAD group than in the SHAM group
P. Verdecchia et al. European Journal of Internal Medicine 117 (2023) 66–77

Table 2 after the eight week (trial closure), the BP reduction of 24-h ambulatory
Randomized trials with SHAM control group which met the primary end-point. BP was higher by about 7.2 mmHg in the group which had been ran­
Trial Main features domized to RAD than in that which had been randomized to the SHAM
procedure [30]. There data has been interpreted as suggestive that prior
Untreated hypertensive
patients RAD could increase the efficacy of antihypertensive drugs in the long
term [30].
RADIANCE-HTN SOLO Patients: 146 untreated patients over the 4 weeks
Ultrasound technique before randomization. Daytime ambulatory BP (h. 5. Meta-analysis of SHAM-controlled studies
(Paradise SystemR, ReCor 07:00–22:00) ≥135/85 mmHg.
Medical) Mean age: 54 years.
Lancet 2018; 391:2335–45 Protocol: Randomized to renal denervation (N = First, we identified the randomized sham-controlled trials of RAD in
74) or SHAM procedure (N = 72) patients with hypertension that reported the average 24-h systolic BP at
Primary end-point: Changes at 2 months in randomization and during follow-up. Then, we calculated the change in
daytime (h. 07:00–22:00) ambulatory systolic BP.
24-h systolic BP from baseline to follow-up in the RAD and SHAM group
SPYRAL HTN-OFF MED Patients: 331 untreated patients over the 3–4
Pivotal weeks before randomization. Clinic BP 150–179/ and the difference (±standard eviction (SD)) between the groups. We
Radiofrequency technique ≥90 mmHg and average 24-hr ambulatory BP pooled the changes in BP using random effects restricted maximum
(Multielectrode Symplicity 140–169 mmHg. likelihood (REML) models. Heterogeneity between trials was assessed
SpiralTM) Mean age: 52 years. using I2 statistics. We included some pre-specified subgroup analyses
Lancet 2020; 395:1444–51 Protocol: Randomized to renal denervation (N =
166) or SHAM procedure (N = 165)
(untreated hypertension vs uncontrolled hypertension; ultrasound vs
Primary end-point: Changes at 3 months in 24-h radiofrequency techniques) and a cumulative meta-analysis to explore
ambulatory systolic BP. the impact of SIMPLICITY HTN-3 on results. We used STATA release 17
RADIANCE II Patients: 224 untreated patients over the 4 weeks (STATA Corp, College Station, TX) for statistical analyses. A two-tailed
Ultrasound technique before randomization. Daytime ambulatory BP (h.
pvalue < 0.05 was considered statistically significant.
(Paradise SystemR, ReCor 07:00–22:00) ≥135/85 mmHg.
Medical) Mean age: 55 years. Overall, RAD significantly reduced 24-h ambulatory systolic BP
JAMA 2023; 329:651–661 Protocol: Randomized to renal denervation (N = when compared with the SHAM procedure (− 3.82 mmHg, 95% CI:
Patients with 150) or SHAM procedure (N = 74) − 5.18 to − 2.46; Fig. 7). There was no significant heterogeneity across
uncontrolled Primary end-point: Changes at 2 months in the trials (I2 = 13.76%). Moreover, the effects of RAD on 24-h systolic BP
hypertension daytime (h. 07:00–22:00) ambulatory systolic BP.
SPYRAL HTN-ON MED
was consistent in untreated vs uncontrolled hypertension (p = 0.26;
Radiofrequency technique Patients: 80 treated patients with 1–3 drugs from Fig. 7) and with the use of radiofrequency versus ultrasound RAD de­
(Multielectrode Symplicity ≥6 weeks, uncontrolled (clinic BP 150–180/≥90 vices (p = 0.96; Fig. 8). Cumulative-meta-analyses showed that
SpiralTM) mmHg, 24-h BP 140–170 mmHg). SIMPLICITY HTN-3 did not exert a significance influence on the overall
Lancet 2022; Mean age: 53 years.
end-point (p = 0.16; Fig. 9), among treated patients with uncontrolled
399:1401–1410 Protocol: Randomized to renal denervation (N =
38) or SHAM procedure (N = 42) hypertension (p = 0.60; Fig. 9), and among trials using radiofrequency
Primary End point: Changes at 6 months in 24-h (p = 0.16; Fig. 9).
ambulatory systolic BP.
RADIANCE-HTN TRIO Patients: 136 treated patients with ≥3 drugs from 6. Safety of renal artery denervation
Ultrasound technique ≥4 weeks, resistant (clinic BP ≥ 140/90 despite
(ParadiseR, ReCor Medical) valsartan 160 mg/die (or olmesartan 40 mg/die) +
Lancet 2021; hydrochlorothiazide 25 mg/die + amlodipine Available SHAM-controlled randomized trials and observational
397:2476–2486 5–10 mg/die, and GFR ≥40 ml/min/1.73 body studies did not show important safety signals related to the procedure.
surface area. Femoral hematoma not needing blood transfusion at the site of trans­
Mean age: 52 years.
cutaneous access occurred in less than 1% of procedures [1,26,31].
Protocol: Randomized to renal denervation (N =
59) or SHAM procedure (N = 67) Other very rare unwanted reactions have been reported, including the
Primary End Point: Changes at 2 months in acute dissection of the renal artery [1], renal artery spasm and thrombus
daytime (h. 07:00–22:00) ambulatory systolic BP. formation [32] and de-novo renal artery stenosis possibly requiring
Abbreviations: BP = blood pressure angioplasty [32–34]. A meta-analysis found a very low incidence of
artery stenosis requiring angioplasty, in the order of 0.2% [35]. There
was no report of death, renal artery perforation or acute renal failure
[26].
during RAD. There was no evidence of long-term deterioration of renal
The SPYRAL HTN-OFF MED Pivotal combined data from a prior pilot
function after the procedure [29,34].
trial of 80 patients to the present trial of 251 to get a total population of
331 patients [27]. Average 24-h systolic BP fell by 3.9 mmHg more in
7. Predictors of blood pressure reduction after renal artery
the RAD group than in the SHAM group at 3 months after the procedure,
denervation
despite a variable proportion of patients of around 5–10% who needed
antihypertensive drug treatment in both groups [27].
Unfortunately, there are no solid data at the moment which may
In the RADIANCE II trial, average daytime ambulatory BP at 2
predict the likelihood of success (i.e., effective long-term BP reduction)
months decreased by 6.3 mmHg more in the RAD group than in the
after the procedure. In general, patients with higher BP before the
SHAM group [25]. In particular, among the 196 patients who did not
procedure experienced a greater BP fall after RAD, but this phenomenon
take antihypertensive drugs at follow-up, the proportion of those well
is not specific because it could reflect a regression-to-the mean, or the so-
controlled (daytime ambulatory BP < 135/85 mmHg at the end of
called Wilder’s principle [36,37].
follow-up) was 18.8% in the RAD group and only 4.8% in the SHAM
There is sparse evidence that women, younger individuals, those
group (p = 0.009) [25].
with syst-diastolic hypertension, tachycardia, increased BP variability,
Fig. 4 shows the main results of the SHAM-controlled trials which did
white ethnicity, obstructive sleep apnea, abdominal obesity, treatment
not met the primary end-point. Fig. 5 shows the unique trial which did
of accessory renal arteries and a less aortic calcifications are better re­
not meet the primary end-point in initially untreated patients. This trial
sponders to RAD in terms of BP reduction [38–40].
was interrupted for apparent futility not having reached the primary
A recent patient-level meta-analysis of three SHAM-controlled trials
end-point at the pre-defined interval of 8 weeks after the procedure
conducted with ultrasound-based RAD [41] found a greater 5.9 mmHg
[30]. However, among the patients who started an open drug treatment
reduction in daytime ambulatory BP at 2 months after the procedure in

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P. Verdecchia et al. European Journal of Internal Medicine 117 (2023) 66–77

Fig. 3. Randomized SHAM-controlled trials on renal artery denervation which met the primary end-point.

Fig. 4. Randomized SHAM-controlled trials on renal artery denervation in patients with uncontrolled hypertension which did not meet the primary end-point.

the RAD group than in the SHAM group [41]. Home BP decreased by 6.8
mmHg more in the RAD group than in the SHAM group [41]. Orthostatic
hypotension, which may reflect an increased sympathetic nervous sys­
tem activity [42], was associated with a significantly greater antihy­
pertensive efficacy of RAD [41].
The Italian Society of Hypertension recently issued a comprehensive
Position Paper on RAD [43]. Table 3 shows that main features of
hypertensive patients more likely to be candidates to the procedure
[43].
8. Persistence of blood pressure reduction
The duration of follow-up in the available randomized trials gener­
ally spanned from 2 to 6 months. However, the Global Symplicity

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P. Verdecchia et al.
Fig. 5. The only randomized SHAM-controlled trial [30] on renal artery denervation, conducted in initially untreated patients, which did not meet the pri­
mary and-point.
Table 3
Characteristics of patients more likely to be candidates to RAD. Modified [43].
1 Essential hypertension uncontrolled by a combination of renin-angiotensin
blockers, calcium channel blockers and diuretics at the maximal
recommended and well tolerated dose.
• Additional features
a Adverse reactions to spironolactone.
b Poor adherence to antihypertensive drug therapy.
c Systo-diastolic hypertension.
d Not extensive atherosclerotic vascular damage.
e High, or very high, cardiovascular risk.
f Patient preference.
2 Grade 1 or 2 systo-diastolic hypertension, either untreated or treated with
only 1-2 drugs.
3 Additional features
a Intolerance to multiple antihypertensive drugs.
b Poor adherence to antihypertensive drug therapy.
c High, or very high, cardiovascular risk.
d Paroxysmal atrial fibrillation and planned catheter ablation.
e Patient preference.
Registry, which provided a long-term uncontrolled observation of pa­
tients who had been exposed to RAD [44], showed that the duration of
antihypertensive effect seems to persist at least for 3 years (Fig. 6) [44].
Conversely, some studies showed that at distance if 11 months after
renal denervation, the anatomical and functional integrity of afferent
and efferent renal nerves tend to return to normal, suggesting reinner­
vation [45,46]. In an extended follow-up of the SIMPLICITY-HTN 3
study, 24-h ambulatory systolic BP at 36 months after the procedure fell
by 15.6 mmHg in the group which had received renal artery denerva­
tion, and increased by 0.3 mmHg who had undergone the SHAM pro­
cedure (p < 0.0001) [47]. Treatment was let free in both groups. The
authors concluded that the effect of renal artery denervation does not
wane over time, but might actually increase [47].
Obviously, more long-term studies are needed to clarify this point.
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European Journal of Internal Medicine 117 (2023) 66–77
9. Position of guidelines
The recent 2023 Guidelines of the European Society of Hypertension
(ESH) [9] provided an extensive discussion of the available evidence on
RAD. The resulting recommendations are reported in Table 4. It is
important to remark that, on the basis of the inclusion and exclusion
criteria of the pivotal randomized trials mentioned above, RAD is rec­
ommended as an option in patients with estimated glomerular filtration
rate >40 ml/min/1.73 m2 [9].
The class of recommendation to RAD is II (i.e., conflicting evidence
or opinion about the benefit) and the Level of Evidence is B (randomized
clinical trials with surrogate measures such as BP, meta-analyses) [9].
10. Characteristics of centers
A recent Position Paper of the Italian Society of Hypertension syn­
thetized the features required to Centers responsible for RAD (Table 5)
[43]. A central point is that catheter-based RAD should be performed in
experienced Centers after a shared decisional process between inter­
ventionalists trained in RAD and experts in the management of hyper­
tension, in order to guarantee the correct selection of patients and the
appropriateness and completeness of the invasive procedure.
11. Conclusions
Some points should be remarked:
1 There are two pivotal areas of application of catheter-based RAD:
a Untreated hypertensive patients, in whom RAD may be considered
as a sort of ‘first step’ of management in addition to lifestyle
measures.
b Treated patients with difficult-to-control hypertension.
Randomized SHAM-controlled trials achieved their primary end-
point in both these conditions [25–29].
P. Verdecchia et al. European Journal of Internal Medicine 117 (2023) 66–77

Fig. 6. Long-term efficacy of renal artery denervation in the Global Symplicity Registry [44].

Fig. 7. Changes in 24-h ambulatory systolic blood pressure from baseline to follow-up, expressed as difference between the RAD group and the SHAM group, in
untreated hypertensive patients (upper panel) and patients with uncontrolled hypertension (lower panel).

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P. Verdecchia et al.
Fig. 8. Changes in 24-h ambulatory systolic blood pressure from baseline to follow-up, expressed as difference between the RAD group and the SHAM group, in
patients exposed to ultrasound denervation (upper panel) and those exposed to radiofrequency denervation (lower panel).
1 The advantage of catheter-based RAD over the SHAM procedure in
terms of BP reduction, although statistically significant and clinically
relevant in some trials [25–29], was quantitatively modest in other
trials [1,48–51]. Hence, in order to maximize the benefits of RAD, it
would be of outmost importance to identify the subjects who are
more likely to respond to the procedure. Unfortunately, we do not
yet dispose of validated predictors of the antihypertensive response
to RAD. Patients with apparently increased sympathetic nervous
system activity and absence of diffuse atherosclerotic disease are
expected to benefit most. For example, RAD appears to be particu­
larly effective in non-diabetic subjects and in women [39].
Conversely, patents with increased pulse pressure, in whom the
elevated levels of systolic BP are mostly due to increased large artery
stiffness than to sympathetic overactivity, are those less likely to
draw benefits from RAD [7,8].
2 It would be important to develop and validate specific tests, which
are currently under investigation [52,53], to verify the completeness
of renal denervation at the end of the invasive procedure. For
example, since both ‘pressor’ and ‘depressor’ nerves run around the
renal arteries, the operator should be able to ablate the ‘pressor’
nerves preferentially to achieve the best results [53]. Since it is not
possible to visualize the spatial location of these different fibers, it
has been suggested that the points whose stimulation elicits an im­
mediate rise in BP might be the preferential location of the ‘pressor’
nerves, and hence the best site for ablation [54].
3 The principal contraindication to RAD is renal artery stenosis
(atherosclerotic or fibromuscular) [22,43]. Albeit rare in unselected
hypertensive patients, it may be present in up to 30% of patients with
more severe hypertension [55]. Renal artery ultrasound may not be
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European Journal of Internal Medicine 117 (2023) 66–77
the ideal technique to exclude renal artery stenosis. Computed to­
mography or magnetic resonance with contrast medium should be
considered in selected cases.
4 In order to consider the procedure ‘effective’ in the single patient,
RAD should induce a sustained reduction of office systolic BP by at
least 10 mmHg, and of 24-h ambulatory BP by 6–7 mmHg, because
such a fall is expected to reduce the risk of major cardiovascular
events significantly [55].
5 Further studies are needed to confirm that the antihypertensive ef­
fect noted in the major randomized trials is maintained in the long
and very-long term [56], as observational data suggest [44].
6 The recently published 2023 ESH Guidelines gave RAD a Class II
recommendation as an additional treatment option in patients with
an estimated glomerular filtration rate >40 ml/min/1.73 m2 who
have uncontrolled BP despite the use of antihypertensive drug
combination therapy, or if drug treatment elicits serious side effects
and poor quality of life (II B recommendation). RAD can be consid­
ered as an additional treatment option in patients with resistant
hypertension if the estimated glomerular filtration rate is >40 ml/
min/1.73 m2 (II B recommendation). A comment could be that since
multiple randomized SHAM-controlled trials proved the benefit of
RAD by meeting the primary end-point both in untreated (3 trials)
[25–27] and difficult-to-control patients (2 trials) [28,29], the pro­
cedure should have gained a Level of Evidence A, regardless of the
Class of Recommendation.
7 Initial data suggest that, independently of its effect on BP, RAD could
be an effective additional approach in patients with atrial fibrillation
[20,21], heart failure [57,58] and other conditions characterized by
increased sympathetic nervous system activity [22,59–63]. For
P. Verdecchia et al. European Journal of Internal Medicine 117 (2023) 66–77

Fig. 9. Cumulative meta-analyses. SYMPLICITY HTN-3 did not modify the cumulated estimate from other trials, which are sorted by year of publication.

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P. Verdecchia et al.
Table 4
Recommendations of the 2023 ESH Guidelines concerning renal artery dener­
vation. Modified [9].
Renal artery denervation can be considered as a treatment option in patients with an
estimated glomerular filtration rate >40 ml/min/1.73 m2 who have uncontrolled
blood pressure despite the use of antihypertensive drug combination therapy, or if
drug treatment elicits serious side effects and poor quality of life (II B).
Renal artery denervation can be considered as an additional treatment option in
patients with resistant hypertension if the estimated glomerular filtration rate is
>40 ml/min/1.73 m2 (II B).
Selection of patients to whom renal artery denervation is offered should be done in a
shared decision-making process after objective and complete patient’s information
(I C).
Renal artery denervation should only be performed in experienced specialized centers
to guarantee appropriate selection of eligible patients and completeness of the
denervation procedure (I C).
Table 5
Characteristics of Centers responsible for renal artery denervation. Modified
[43].
Hypertension centers
1 Excellence Centers certified by the European Society of Hypertension and/or
National Hypertension Society.
2 Out-patient activities specifically devoted to difficult-to-control patients.
3 Medical and nurse staff with specific competence in the Hypertension field.
4 Availability of instruments for 24-h ambulatory blood pressure monitoring and
facilities for biochemical tests devoted to the search of secondary hypertension.
5 Multidisciplinary team, including invasive cardiologists and/or radiologists,
finalized to discuss indications to renal artery denervation.
Interventional centers
1 Certified interventionalists (invasive cardiologists and/or radiologists).
2 More than 20 invasive procedures per year on the renal arteries. More than 5
catheter-based renal denervation procedures per year.
3 Formal agreements with the local Health System for the reimbursement of the
procedure.
example, in the ERADICATE-AF trial RAD added to catheter ablation
increased the proportion of patients free from atrial fibrillation at 12
months when compared with catheter ablation alone [20]. These
promising results in atrial fibrillation have been confirmed in a
meta-analysis of 6 randomized studies [21]. Catheter-based RAD
looks promising also in patients with chronic kidney disease (CKD).
In a single-center observational study, office and ambulatory BP
decreased at 12-month after RAD to a similar extent in patients with
CKD and eGFR < 45 mL/min versus those with higher values of eGFR
[64].
Some ongoing trials, including NCT03503773, NCT02910414 and
NCT02439775, will allow a better understanding of the clinical value of
catheter-based RAD in the management of patients with hypertension
and other cardiovascular disorders. In particular, NCT03503773 and
NCT02910414 are ongoing SHAM-controlled trials designed to test the
efficacy and safety of alcohol-mediated neurolysis obtained through
direct injection of alcohol into the space around the renal nerves [38].
As a final consideration, the role of RAD in the clinical practice
should not be intended as a full replacement, but an adjunct to life-style
measures and appropriate drug treatment, when needed, in individual
patients [65].
Declaration of Competing Interest
None of the authors of this study has financial or other reasons that
could lead to a conflict of interest.
Acknowledgment
Supported in part by the Fondazione Umbra Cuore e Ipertensione,
Perugia, Italy.
75
European Journal of Internal Medicine 117 (2023) 66–77
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