Hypertension

Journal Article

ORIGINAL ARTICLE

Catheter-Based Renal Denervation: 9-Year

Follow-Up Data on Safety and Blood
Pressure Reduction in Patients With Resistant
Hypertension
Gianni Sesa-Ashton , Janis M. Nolde , Ida Muente , Revathy Carnagarin , Rebecca Lee, Vaughan Macefield ,
Tye Dawood, Yusuke Sata, Elisabeth A. Lambert, Gavin W. Lambert , Antony Walton, Marcio G. Kiuchi , Murray D. Esler ,
Markus P. Schlaich

BACKGROUND: Recent sham-controlled randomized clinical trials have confirmed the safety and efficacy of catheter-based
renal denervation (RDN). Long-term safety and efficacy data beyond 3 years are scarce. Here, we report on outcomes after
RDN in a cohort of patients with resistant hypertension with an average of ≈9-year follow-up (FU).

METHODS: We recruited patients with resistant hypertension who were previously enrolled in various RDN trials applying
radiofrequency energy for blood pressure (BP) lowering. All participants had baseline assessments before RDN and repeat
assessment at long-term FU including medical history, automated office and ambulatory BP measurement, and routine blood
and urine tests. We analyzed changes between baseline and long-term FU.

RESULTS: A total of 66 participants (mean±SD, 70.0±10.3 years; 76.3% men) completed long-term FU investigations with a mean
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of 8.8±1.2 years post-procedure. Compared with baseline, ambulatory systolic BP was reduced by −12.1±21.6 (from 145.2 to
133.1) mm Hg (P<0.0001) and diastolic BP by −8.8±12.8 (from 81.2 to 72.7) mm Hg (P<0.0001). Mean heart rate remained
unchanged. At long-term FU, participants were on one less antihypertensive medication compared with baseline (P=0.0052).
Renal function assessed by eGFR fell within the expected age-associated rate of decline from 71.1 to 61.2 mL/min per 1.73 m2.
Time above target was reduced significantly from 75.0±25.9% at baseline to 47.3±30.3% at long-term FU (P<0.0001).

CONCLUSIONS: RDN results in a significant and robust reduction in both office and ambulatory systolic and diastolic BP at
≈9-year FU after catheter-based RDN on less medication and without evidence of adverse consequences on renal function.
(Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853.)

Key Words: blood pressure ◼ catheters ◼ humans ◼ hypertension ◼ sympathetic nervous system

R
enal denervation (RDN) has consistently been
shown in recent years as a viable and effective
nonpharmacological treatment for resistant and
uncontrolled hypertension in the presence or absence of
concomitant antihypertensive therapy.1–4 The procedure
aims to reduce sympathetic overactivity to the kidneys—
a major driver of the hypertensive state5,6—through the
ablation of renal nerves.
Activation of renal sympathetic nerves causes a
host of prohypertensive effects namely renin secre-
tion, increased water and sodium reuptake, and vaso-
constriction.7 These factors increase blood volume and
thus blood pressure (BP) and drive further renal injury
promoting greater renal afferent firing to the central ner-
vous system.8 RDN, through the ablation of the renal
nerves, aims to sever the connection between a centrally

Correspondence to: Markus P. Schlaich, The University of Western Australia, Level 3, MRF Bldg, Rear 50 Murray St, Perth WA 6000, Australia. Email markus.schlaich@
uwa.edu.au
ORCID iD for Markus P. Schlaich: 0000-0002-1765-0195
For Sources of Funding and Disclosures, see page XXX.
© 2023 American Heart Association, Inc.
Hypertension is available at www.ahajournals.org/journal/hyp

Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853 April 2023   1

 Sesa-Ashton et al
NOVELTY AND RELEVANCE
Original Article
What Is New?
This study represents the longest follow-up of renal
denervation patients with gold standard ambulatory blood
pressure measurement to date along with metrics of
renal function.
What Is Relevant?
This work has shown a sustained blood pressure–lower-
ing effect of renal denervation despite a reduction in anti-
hypertensive medication use. Moreover, renal function is
Nonstandard Abbreviations and Acronyms
ABPM ambulatory blood pressure monitoring
BP blood pressure
CKD chronic kidney disease
DDD daily defined doses
FU follow-up
RDN renal denervation
SBP systolic blood pressure
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overactive sympathetic nervous system and the kidneys,
thereby reducing BP. Moreover, given that this ablation
targets both afferent and efferent nerve fibers,9 RDN
may also disrupt afferent firing thereby lowering global
sympathetic activity.
The incidence of hypertension is rising globally.10
Resistant hypertension affects around 10% to 12% of all
patients with confirmed hypertension and is associated
with a significantly greater risk of cardiovascular disease
events.11 Novel means of BP reduction and control in
this patient cohort is, therefore, warranted and needed.
Moreover, antihypertensive drug intolerances are com-
mon barriers to better BP control12 exacerbated by nota-
ble medication nonadherence13 and patient preferences
against lifelong pharmacotherapy14
Recent clinical trials, including long-term results
from the SYMPLICITY HTN-3 trial,3 have consistently
shown the safety and efficacy of RDN against sham
procedures with clinically meaningful reductions in
BP.2,4 However, initial trials and second-generation
investigations have not continued patient follow-up
(FU) beyond 3 years postinterventionally. Although
the safety profile is very favorable, long-term impacts
on renal function are yet to be elucidated. Similarly,
whether the hemodynamic benefits of RDN persist
beyond this period remains unanswered. Given that
BP management and control is a long-term undertak-
ing, assessing persistence of BP-lowering effects over
2   April 2023 Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853
Long-Term Follow-Up After Renal Denervation
maintained in patients both with and without preexisting
renal disease.
Clinical/Pathophysiological Implications?
The findings presented indicate that blood pressure–low-
ering effects of renal denervation are robust and sustained
out to ≈9 years without adverse renal consequences. Criti-
cally, this work alongside a greater number of sham-con-
trolled clinical trials is indicating renal denervation is a safe
and effective approach to achieve sustained blood pres-
sure lowering in patients with resistant hypertension.
prolonged periods of time is critical to demonstrate
sustained clinical benefit.
Our study aimed to investigate the long-term impact
of catheter-based RDN, beyond 3 years postoperatively,
on safety and BP control. This report serves as the first
investigation of its kind to interrogate the efficacy of
RDN in a real-world scenario.
METHODS
Data Availability
The data collected for this work will be available from the cor-
responding author upon reasonable request.
Participants
After HREC approval was granted, we aimed to contact all 163
patients on record to explore their willingness to participate in
long-term FU assessment. Figure 1 summarizes the recruit-
ment process and patient journey.
We recruited 66 participants (77.3% men) who were enrolled
in previous RDN trials during 2009 to 2014 at the Baker Heart
and Diabetes Institute/Alfred Hospital, Melbourne, Australia.
Mean age at FU was 70.0±10.3 years, and mean time since
RDN was 8.8 years (±1.2). All participants had ablations per-
formed using the Symplicity Flex Catheter System (Medtronic)
while participating in approved and registered clinical trials
exploring the safety and utility of catheter-based RDN (https://
www.clinicaltrials.gov; unique identifier: NCT00888433,
NCT0048380, and NCT01865253) trials completed between
2009 and 2014. All participants provided informed, written
consent adhering to the Declaration of Helsinki.
BP Measurements and Pathology Testing
Consenting participants could either participate in person
(n=44) or as a phone FU (n=22). Alongside ambulatory
BP monitoring (ABPM), participants completed a 24-hour
urine collection together with a fasted blood sample for full
blood count, urea, electrolytes, creatinine for renal function
assessment (eGFR), and spot urine testing for urinary albu-
min-creatinine ratio, which were completed at each study
visit in their original trial.
 Sesa-Ashton et al Long-Term Follow-Up After Renal Denervation

Table. Patient Characteristics at Baseline (Before Renal Denervation) and at Long-Term FU

Characteristics Baseline Long-term FU P value

Original Article
Age, y 60.7±9.9 69.6±9.9 <0.0001
Men, n (%) 49 (74.2) 49 (74.2) >0.99
Body mass index, kg/m2 31.9±6.5 32.14±6.2 >0.9
Office systolic BP, mm Hg 151.5±22.1 138.8±21.0 <0.01
Office diastolic BP, mm Hg 79.40±16.0 75.91±14.6 >0.3
ABPM SBP, mm Hg 145.2±17.3 133.1±18.3 <0.0001
ABPM DBP, mm Hg 81.2±12.2 72.7±10.4 <0.0001
ABPM heart rate, bpm 66.3±10.5 67.6±10.7 >0.5
Serum Na+, mmol/L 139.6±3.1 140.1±2.5 >0.3
Serum K+, mmol/L 4.0±0.4 4.0±0.5 >0.3
eGFR, mL/min per 1.73 m2 71.1±16.7 61.2±21.1 <0.0001
No. of antihypertensive drug classes, n 4.23±1.7 3.6±1.5 <0.001
Defined daily dose of antihypertensive medications, n 5.0±2.8 4.1±2.1 <0.005
ABPM indicates ambulatory blood pressure monitoring; BP, blood pressure; DBP, diastolic blood pressure; FU, follow-up; and SBP,
systolic blood pressure.

Given a notable number of participants with chronic kid-
ney disease (CKD) with an eGFR ≤6 mL/min per 1.73 m2 at
baseline, participants were stratified by their baseline eGFR
into CKD and non-CKD groups for analyses surrounding renal
function. The body mass index was calculated from measure-
ment of weight and height for all participants.
Ambulatory BP Monitoring
ABPM (Spacelabs 90207 or 90217 monitor; Spacelabs Medical,
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automatically computed by ABPM recording software (Spacelabs,
WA). Time above target was computed for each time point where
a participant had an ABPM recording for a full sleep-wake cycle.
Statistical Analysis
All statistical analyses were completed in GraphPad Prism for
Mac (version 9.4.1; GraphPad Software, CA). Comparisons solely
between average values between baseline and LTFU were com-
pared using paired t tests or Wilcoxon rank-sum test depending

Inc, Redmond, WA) was completed in 61 of 66 participants, with
5 refusing to wear an ABPM, to interrogate changes in overall BP
at long-term FU. Participants were fitted on-site or self-fitted with
detailed instructions. Participants were advised to complete 26
hours of ABPM, including a full sleep-wake cycle. ABPM continu-
ously monitored systolic BP (SBP), mean, and diastolic BP and
heart rate every 15 minutes during the day (6 AM to 10 PM) and
30 minutes during the night (10 PM to 6 AM).
on normality measured by the D’Agostino-Pearson test. Where
proportions of participants were compared between baseline and
LTFU, χ2 analyses were utilized. In instances where data were com-
pared over original trial participation including long-term FU, mixed-
effects analyses with multiple comparisons were used to determine
significance as opposed to ANOVA to account for missing data.
Where data were non-normal, the Kruskal-Wallis test was used.

Medication Regimen and Daily Defined Doses RESULTS

The complete current antihypertensive regimen was recorded
for each participant at FU including dosages and medica-
tion timing and compared with recorded antihypertensive
regimen at baseline. Drugs were divided into 1 of 10 classes:
β-blockers, α-blockers, calcium channel blockers, angiotensin-
II receptor antagonists, ACE inhibitors, methyldopa, moxoni-
dine, loop diuretics, thiazide diuretics, spironolactone, and other
(for off-label antihypertensive indications). Daily defined doses
(DDDs) were computed by taking a ratio of the total dose of
medication taken per day over the World Health Organization
designated defined daily dose. DDDs were calculated for each
patient and for each drug at their original trial baseline and at
long-term FU using the World Health Organization standard-
ized approaches.15 The total number of participants prescribed
any medication within a drug class was also computed.
Data from 66 patients could be obtained for these analy-
ses from 163 identified potential participants. Forty-three
patients were lost to FU, 42 patients declined participa-
tion, 2 were later diagnosed with secondary hypertension
following their original trial involvement, and 14 patients
were found to be deceased (Figure 1). Patients declined
for several reasons, largely due to concerns about
increasing their risk of exposure to COVID-19 as well
as work and familial commitments. For participants who
could not be contacted, their listed primary care physi-
cian was approached—in many of these cases, 26 of 43,
the patient had not been in contact with that clinic for
several years and their status was unknown.

Time Above Target BP Changes at Long-Term FU

Time above target, the percentage of a 24-hour ABPM record- At baseline, average ABPM SBP and diastolic BP
ing a patient spends above target BP (>135/85 mm Hg), was were 145.2 and 81.2 mm Hg, respectively, compared

Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853 April 2023   3

 Sesa-Ashton et al
Original Article
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Figure 1. CONSORT diagram of participant disposition.
ABPM indicates ambulatory blood pressure monitoring; and U&E, urea, electrolytes, creatinine.
with 133.1 and 72.7 mm Hg at long-term FU (Fig-
ure 2). This resulted in a reduction of 12.1 mm Hg
systolic ([95% CI, 17.78–6.32] P<0.0001) and reduc-
tion of 8.8 mm Hg diastolic ([95% CI, 12.12–5.478]
P<0.0001) between baseline and long-term FU. Both
daytime and nighttime SBP was significantly reduced.
Daytime SBP fell by 12.8 mm Hg (P<0.001) with com-
parable reductions in nighttime SBP at long-term FU
of 11.5 mm Hg (P<0.001; Figure 3). Twenty-four-hour
heart rate remained constant, increasing slightly from
65.0 to 67.0 bpm (P=0.238) as did awake (P=0.406)
and asleep heart rate (P=0.388). Fifty-five percent of
the cohort had an SBP reduction >5 mm Hg at FU. A
waterfall plot highlights the distribution of individual BP
changes (Figure 4)
Consequently, time above target BP threshold was
significantly lowered. Before RDN, participants aver-
aged 75.0±25.9% of time during their ABPM recording
above target (≥135 mm Hg SBP for daytime and ≥120
mm Hg for nighttime). Time above target gradually and
4   April 2023
Long-Term Follow-Up After Renal Denervation
continually decreased across visits falling to 47.3±30.3%
at long-term FU (P<0.0001).
A reduction in SBP was evident when considering
the full 24-hour ABPM recordings between baseline
and long-term FU (P<0.0001). The circadian pat-
tern of BP remained largely consistent between the
time points. While SBP dipping did not significantly
change among the entire cohort (n=57; P=0.74), dip-
ping profile improved notably in those participants who
were nondippers at baseline. Characterized by a fall in
nightly SBP of <10%, nondippers experienced a more
pronounced nocturnal BP fall at long-term FU (n=31;
P=0.0086). Percentage SBP fall increased from
−1.5±5.7% to −6.5±9.3%, gravitating to the desired
value of >10%.
There were pronounced changes in the proportion of
participants across the various grades of hypertension
between time points. We found that 62.7% of partici-
pants were at high-normal or normal BP, with 15 partici-
pants achieving optimal BP below 120 mm Hg systolic
Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853
 Sesa-Ashton et al
compared with just two at baseline. Beyond this, grade
1 hypertension remained the greatest proportion overall
both at baseline and LTFU albeit with marked reductions
in the number of participants with grade 2 hypertension.
There were no grade 3 hypertensives at long-term FU.
These shifts toward lower grade of hypertension were
found to be significant (P=0.0054).
BP Changes in Selected High-Risk Subgroups
Our findings demonstrated consistent BP-lowering
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effects across several subgroups characterized by high
CV risk including those with CKD, diabetes, or isolated
systolic hypertension. BP reductions were consistent in
participants with and without baseline CKD (P=0.1059)
and diabetes (P=0.2809). Moreover, we saw no dif-
ference in long-term BP outcomes in participants with
isolated systolic hypertension compared with those with
combined hypertension at baseline (P=0.4390).
Changes in Medication Use
The substantial BP lowering demonstrated at LTFU
could have been due to increased medication and DDD.
Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853
Long-Term Follow-Up After Renal Denervation
Original Article
Figure 2. xxx.
Baseline and long-term follow-up systolic
(A) and diastolic (B) blood pressure
(BP) as measured by ambulatory blood
pressure monitoring. Data are presented
as a Tukey plot, median±interquartile
range. n=61. ****P<0.0001.
It was, therefore, important to analyze the changes in
medication usage and DDD between baseline and LTFU.
Compared with baseline, there was a reduction in DDD
of 0.922 from 5.0±2.8 DDD of antihypertensive drugs at
baseline to 4.1±2.1 doses at long-term FU (P=0.0045).
The reduced antihypertensive load was largely brought
about by reduced use of sympatholytic medications with
a statistically significant reduction in DDD of β-blockers
(P=0.023; paired Wilcoxon rank). All other antihypertensive
drug classes showed nonsignificant changes (P>0.05).
Moreover, χ2 analyses indicated a significant reduction
in the total number of β-blocker prescriptions (P=0.042)
between long-term FU and baseline, as well as moxonidine
(P=0.042). The use of guideline-directed drug classes for
resistant hypertension did not change between time points
with calcium channel blockers, angiotensin-II receptor
blockers, and diuretics remaining constant in DDDs.
Renal Safety—Preservation of eGFR and
Creatinine Clearance
We observed a preservation of renal function following
RDN particularly in participants with previously diag-
nosed CKD. Participants with an eGFR <60 mL/min
Figure 3. Hourly average ambulatory
blood pressure monitoring (ABPM)–
derived systolic blood pressure
(SBP) between baseline (orange) and
long-term follow-up (blue) across a
full sleep-wake cycle presented as
mean±SEM.
Mixed-effects analysis indicated significant
treatment effect (P<0.0001), n=61.
April 2023   5
 Sesa-Ashton et al
Original Article
per 1.73 m2 at baseline (CKD stage 3a or below, n=18)
showed no significant difference in eGFR at baseline
compared with long-term FU (P=0.32; paired t test).
Likewise, when considering their 36 months of trial
participation in addition to long-term FU, no significant
treatment effect was evident (P=0.13; mixed-effects
analysis, n=18). However, a mean reduction of 9 mL/
min per 1.73 m2 was apparent at LTFU from baseline
(Figure 5).
A reduction of 8.9 mL/min per 1.73 m2 occurred in
participants without baseline CKD (eGFR, >60 mL/
min per 1.73 m2) between baseline and FU (P=0.0002;
Wilcoxon test) in line with acceptable age-associated
declines of 1 to 2 mL/min per year. When considering
past measurements, no significant treatment effect was
apparent (P=0.19; Kruskall-Wallis test). Twenty-four-
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hour urinary creatinine clearance remained stable across
baseline until long-term FU in both CKD and non-CKD
participants (P<0.05). Likewise, urinary albumin-creat-
inine ratio did not significantly differ between baseline
and LTFU in either group (P>0.1).
Long-Term Outcomes—Major Adverse
Cardiovascular Events and Causes of Death
Among the 66 participants in our long-term FU, a total of
4 nonfatal major adverse cardiovascular events occurred
6   April 2023 Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853
Long-Term Follow-Up After Renal Denervation
Figure 4. Waterfall plot of systolic
blood pressure (SBP) reduction
between baseline and long-term
follow-up measured by ambulatory
blood pressure monitoring (ABPM).
Participant response ordered from the
greatest increase in SBP to the greatest
decrease in SBP.
with 3 nonfatal strokes and 1 nonfatal myocardial infarc-
tion between the final study visit and long-term FU.
Sixty-two participants reported no adverse major cardio-
vascular events; however, 3 additional patients received
coronary artery stents following the discovery of notable
coronary stenosis. One participant noted they had begun
dialysis treatment on a background of significant preex-
isting CKD before RDN.
During our investigation, we were made aware
of 14 deceased potential participants. Following
requests to primary care providers and family mem-
bers, cause of death was established for three: 1
fatal myocardial infarction, 1 death from heart failure
with reduced ejection fraction, and 1 death due to
acute pancreatitis. In 11 cases, cause of death and
precipitating factors could not be established due to
rejected requests for information from the patient’s
treating physicians.
DISCUSSION
At a mean of ≈9 years of FU, we observed a statistically
and clinically significant BP reduction of 12.1 mm Hg
systolic and 8.8 mm Hg diastolic despite a reduction in
antihypertensive medication burden. Moreover, RDN
maintained its strong safety profile in the long term with
no adverse effects on renal function.
Figure 5. eGFR measured at each
study visit over full study involvement
and long-term follow-up between
participants without (closed) and with
(open) chronic kidney disease (eGFR
at baseline <60 mL/min per 1.73 m2).
 Sesa-Ashton et al
To our knowledge, this represents the largest
cohort of patients with long-term FU out to a mean of
≈9 years with both office and ambulatory BP assess-
ment after RDN. Our data, therefore, provide impor-
tant information on both the safety and efficacy of
catheter-based RDN with radiofrequency ablation
and are in line with 3-year FU data from randomized
sham-controlled3,4 and other single-center extended
FU investigations.16
BP across the sleep-wake cycle was significantly
reduced from baseline. While overall BP reduction is
the key pillar in reducing cardiovascular morbidity and
mortality, nighttime BP remains the best predictor of
cardiovascular outcomes.17 As such, our significant
daytime and nighttime BP reduction are important
findings. This is likely to contribute to regression of
hypertension-mediated organ damage and cardio-
vascular risk following RDN. RDN appears to have
a particular benefit in nighttime BP management.18
Antihypertensive medications are typically taken
in the morning, and thus the effect is reduced with
increasing drug metabolism and excretion through-
out the day. RDN, however, once performed, seems
to convey benefit throughout the 24-hour cycle.
Moreover, nighttime dipping has been shown to be
associated with sympathetic tone.19 RDN, through
its sympathoinhibitory action, may well contribute to
restore a more physiologic dipping pattern.
It is important to highlight that the reduction in BP at
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long-term FU was not due to increased medication. In
fact, at long-term FU, when patients were on average
9 years older, BP reduction was sustained despite less
antihypertensive medication. Interestingly, the reduction
in DDDs at long-term FU was largely driven by cessa-
tion of moxonidine and reduction in β-blockers. Given
the proposed mechanism of RDN, it is perhaps unsur-
prising that reducing these drug classes has had little
apparent effect on BP. While at first glance a lack of
difference in 24-hour heart rate between our 2 major
time points may challenge this assertion, the reduction
in β-blocker prescription may have masked a potential
reduction in HR with RDN.
SPRINT and the STEP trial have cemented more
aggressive BP control as paramount in hypertension
care.20 Moreover, the legacy effect—a persistent reduc-
tion in adverse events despite intervention cessation—has
been demonstrated in diabetes21 and hyperlipidemia.22
Establishing the legacy effect in hypertension is more
complex with some trials reporting positive long-term
outcomes23 following trial participation while others have
not.24 Indeed, the SPRINT long-term FU indicated no dif-
ference in cardiovascular or all-cause mortality between
intensive and standard treatment,25 despite substantial
differences at the end of the treatment phase. These find-
ings highlight the need for BP-lowering approaches with
sustained long-term effects on BP in order to achieve
Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853
Long-Term Follow-Up After Renal Denervation
maintained CV risk reduction. This seems to be the case
with RDN—a one-off procedure with proven long-term
Original Article
effects on BP. Indeed, considering the data presented
here, the effect of RDN is persistent across the day-
night cycle up to at least 9 years. Moreover, its benefi-
cial effects are likely to persist independent of potential
patient nonadherence to drug regimens.26
A consistent discussion in the context of efficiency of
RDN has been that renal sympathetic nerves have the
capacity to reinnervate ablated renal arteries in normo-
tensive rodent models27 albeit not to a complete return of
function.28 A similar incomplete return of function in sheep
is also apparent out to 30 months29 and 180 days in pigs.30
Whether this phenomenon occurs in humans, or impacts
RDN outcomes, remains to be seen. Human reinnerva-
tion evidence is limited and largely based upon transplant
studies. What is apparent from human studies, and indeed
this work, is that the BP fall following RDN is persistent.
While anatomic renal reinnervation may occur, it is diffi-
cult to assert whether this has any functional relevance.
Considering the growing evidence that RDN continues to
reduce BP in the long term, this is perhaps unlikely.
The BP response to RDN remains heterogeneous in
nature and is difficult to predict. Baseline BP appears
to be the only notable predictor of RDN success with
greater hypertension stages correlating to greater BP
reductions—the same would appear to be the case, for
the most part, in this cohort at long-term FU. Determin-
ing who has the greatest likelihood of success in RDN
remains difficult, and while the procedure is minimally
invasive and with few apparent side-effects, prior iden-
tification of probable responders will likely improve the
procedure’s cost-effectiveness and its consideration in
public health spending.31
Renal Safety and Major Adverse Cardiovascular
Events
Renal Safety
This study also reinforces a strong safety profile for RDN
with metrics of renal function remaining stable from
baseline. Given the relationship between hypertension
and CKD, as well as their overlapping pathophysiology
with elevated sympathetic activity, RDN may serve as
an important treatment modality in this patient group.
Our data suggest that patients with CKD have improved
eGFR sustained for 36 months postoperatively and
no substantial decline in the long term. We saw similar
trends in creatinine clearance, which in this subgroup
immediately improves at 3 months postoperatively. While
there is an evident fall between the final study visit and
long-term FU, this is largely consistent with age-related
declines of between 1 and 2 mL/min per 1.73 m2 per
year in hypertensives.32
The same trends are observed in participants with-
out preexisting kidney disease. Creatinine clearance and
April 2023   7
 Sesa-Ashton et al
eGFR improve following RDN and fall relative to base-
line at long-term FU, albeit nonsignificantly and within
Original Article
acceptable age-related declines. While values of <1.0
mL/min per 1.73 m2 per year are expected in healthy
aging,33 the rate of eGFR fall increases with advancing
age and is complicated by hypertension among other
comorbidities. As such, we view the observed long-term
fall in eGFR as compatible with age-related decline in
this high-risk patient cohort.
Major Adverse Cardiovascular Events
Within our participant sample, 4 major cardiovascular
events were noted: 3 nonfatal strokes and 1 nonfa-
tal myocardial infarction. While increased risk of major
adverse cardiovascular events is well-established in
resistant hypertensives, risk of stroke appears to be
particularly common.34 It is perhaps noteworthy that
nonfatal cardiovascular events were rare in our cohort
despite advancing age occurring in only 6% of partici-
pants. While we lack controls to directly compare with
in this investigation, Hung et al34 indicated that at ≈9
years of FU within a resistant hypertensive cohort,
major adverse cardiovascular event–free survival rate
had fallen by 15%. More work is needed to quantify the
relative risk reduction in larger sample sizes following
RDN in the long term directly compared with untreated
hypertensives.
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Limitations
Recruitment for this study hinged on potential partici-
pants wanting to be involved, which could be linked to
their success with the procedure. This innately would bias
this investigation toward favorable outcomes for RDN.
Contrastingly, time commitments and poor health could
have also reduced the number of participants with strong
BP-lowering responses recruited as well. Likewise, the
impact of the COVID-19 pandemic on study recruitment
must be acknowledged. Many participants were hesitant
to participate due to concerns for their own health given
their age and comorbidities. This limited their desire to
participate even in phone FU appointments as this would
require them to attend local pathology centers.
While there is a lack of evidence to suggest any
increased risk of cardiovascular or other adverse events
following RDN, accurate data concerning participant
cause of death would be able to further build on knowl-
edge from our active participants. While cardiovascular
disease would be expected largely in those who did not
respond to RDN, a wider understanding of mortality out-
comes would act to bolster these findings.
Conclusions
Here we present to our knowledge the longest FU
data after RDN utilizing ABPM demonstrating clinically
8   April 2023 Hypertension. 2023;80:00–00. DOI: 10.1161/HYPERTENSIONAHA.122.20853
Long-Term Follow-Up After Renal Denervation
meaningful BP reductions among a background of
strong renal safety. Future work should focus on optimiz-
ing means to identify participants with the greatest likeli-
hood of RDN success.
Perspectives
This work demonstrates that RDN causes sustained
reductions in BP out to ≈9 years post-intervention, with-
out evidence for adverse renal effects. These reductions
in BP are maintained across the 24-hour period, as well
as across patients with various comorbidities including
diabetes, CKD, and isolated systolic hypertension. RDN
should be considered as a viable treatment option for
patients with resistant hypertension alongside lifestyle
interventions and antihypertensive pharmacotherapy.
ARTICLE INFORMATION
Received December 26, 2022; accepted January 19, 2023.
Affiliations
Human Neurotransmitter and Neurovascular Hypertension and Kidney Dis-
eases Laboratories (G.S.-A., R.L., Y.S., M.D.E., M.P.S.) and Human Autonomic
Neurophysiology Laboratory (G.S.-A., V.M., T.D.), Baker Heart and Diabetes
Institute, Melbourne, Australia. Dobney Hypertension Centre, Medical School–
Royal Perth Hospital Unit and RPH Research Foundation, The University of
Western Australia (J.M.N., I.M., R.C., M.G.K., M.P.S.). Iverson Health Innovation
Research Institute, Swinburne University of Technology, Melbourne, Australia
(E.A.L., G.W.L.). Department of Cardiology, Alfred Health, Melbourne, Victoria,
Australia (Y.S., A.W., M.D.E.). Departments of Cardiology (M.P.S.) and Nephrology
(M.P.S.), Royal Perth Hospital, Western Australia.
Sources of Funding
This study was supported by Medtronic.
Disclosures
M.P. Schlaich has received support from an NHMRC Research Fellowship and
research support from Medtronic, Abbott, and Servier Australia. He serves on
scientific advisory boards for Abbott, BI, Servier, Novartis, and Medtronic. A. Wal-
ton is a Proctor for Medtronic and Abbott, is on the Medical Advisory Board of
Medtronic, and receives grant support from Medtronic, Abbott, and Edwards. M.D.
Esler and G.W. Lambert have received consulting fees and travel and research
support from Medtronic. The other authors report no conflicts.
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