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JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 5, NO. 3, 2012
© 2012 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 1936-8798/$36.00
DOI: 10.1016/j.jcin.2011.12.011
STATE-OF-THE-ART PAPER
Renal Denervation for Hypertension
Stefan C. Bertog, MD,*† Paul A. Sobotka, MD,‡§ Horst Sievert, MD*
Frankfurt, Germany; Minneapolis, Minnesota; and Columbus, Ohio
JACC: CARDIOVASCULAR
INTERVENTIONS CME
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CME Objective for This Article: After reading
this article, the reader should understand the anatomy and physiology of the renal sympathetic nervous system and its role in blood pressure regulation,
as well as the results of seminal experience with renal
sympathetic denervation in animal models and humans. In addition, the reader will be up-to-date
with recent experience using catheter-based renal
denervation to treat essential hypertension and the
potential use of this concept in conditions other
than hypertension.
CME Editor Disclosure: JACC: Cardiovascular
Interventions CME Editor Habib Samady, MB,
ChB, FACC, has research grants from the Wallace
H. Coulter Foundation, Volcano Corp., St. Jude
Medical, Forrest Pharmaceuticals Inc., and Pfizer Inc.
Author Disclosure: Dr. Bertog has reported that
he has no relationships relevant to the contents of
this paper to disclose. Dr. Sobotka was chief medical
officer of Ardian Inc. and is now an employee of
Medtronic Inc. Prof. Sievert has received study
honoraries, travel expenses, and consulting fees from
Medtronic Inc.
Medium of Participation: Print (article only);
online (article and quiz).
CME Term of Approval:
Issue Date: March 2012
Expiration Date: February 28, 2013
From the *Cardiovascular Center Frankfurt, Frankfurt, Germany; †Department of Cardiology, Veterans Affairs Medical Center,
Minneapolis, Minnesota; ‡Medtronic Inc., Minneapolis, Minnesota; and the §Ohio State University, Columbus, Ohio. Dr. Bertog
has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Sobotka was chief medical officer
of Ardian Inc. and is now an employee of Medtronic Inc. Prof. Sievert has received study honoraries, travel expenses, and
consulting fees from Medtronic Inc.
Manuscript received September 21, 2011; revised manuscript received November 28, 2011, accepted December 8, 2011.
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Renal Denervation for Hypertension
Systemic hypertension is a major burden to the individual and society. Its association with major adverse cardiac and cerebral events and favorable effects of antihypertensive therapy are undisputed. However, despite multidrug therapy,
blood pressures are frequently suboptimally controlled. Moreover, adverse drug effects often interfere with patients’ lifestyles and affect compliance. Therefore, alternative treatment strategies have been explored. Most recently, attention has
been redirected to the sympathetic nervous system (SNS) in the pathogenesis of hypertension. In addition, interruption
of the renal SNS in humans with resistant hypertension has been studied with promising results. The following review
provides an overview of the anatomy and physiology of the renal SNS, the rational for manipulating the SNS, and the
results of therapeutic renal sympathetic denervation. (J Am Coll Cardiol Intv 2012;5:249 –58) © 2012 by the American College
of Cardiology Foundation
The profound effect of systemic hypertension on the individual and society and beneficial effects of antihypertensive
therapy are no longer questioned. However, frequently,
despite treatment, blood pressures remain suboptimally
controlled. This, in addition to unwanted side effects of
antihypertensive medications, has stimulated exploration of
alternative treatment modalities. Most recently, attention
has been redirected to the renal sympathetic nervous
system (SNS) in the pathogenesis of systemic hypertension and to its successful interruption with catheter-based
radiofrequency application.
The important role of the SNS in hypertension has been
explored by measurement of its activity in hypertensive
subjects as well as by examination of blood pressure changes
after manipulation of sympathetic activity.
Though not universal, higher levels of catecholamines are
found in hypertensive individuals (1) and in those with
borderline hypertension (2). Likewise, an increase in renal
(3), cardiac (3–5) and skeletal muscle SNS activity (2,5) has
been described in hypertensive patients. In patients with
severe hypertension, a direct relationship between blood
pressure and sympathetic activity has been reported (6).
Perhaps the most striking evidence in support of a
dominant role of the SNS in human blood pressure control
is the effect of surgical sympathectomy (more or less
extensive removal of sympathetic ganglia depending on the
technique used). Though it has never been compared with
no therapy or medical therapy in a controlled or randomized
fashion, a profound improvement in blood pressure control
was demonstrated in most studies (7,8). In addition, a
reduction in cardiac size (8,9), improvement in renal function (8 –10) and lower incidences of headaches (10), precordial pain (10), and cerebrovascular (10) events were
reported. Moreover, several studies suggested a reduction in
mortality compared to an uncontrolled group of medically
treated patients (11–13). These beneficial effects were counterbalanced by significant operative morbidity and mortality
and unwanted side effects that, together with the advent of
more effective antihypertensive medications, led to abandonment of this procedure in the early 1970s. Nonetheless,
the experience lends undisputable support to the important
role of the SNS in blood pressure control and confirms that
a favorable blood pressure response can be achieved by a
reduction in sympathetic tone.
Focusing now on the more targeted disruption of the
renal SNS, most experience stems from observations made
in patients with renal insufficiency undergoing nephrectomy
or renal transplantation and animal models of renal sympathectomy.
The impact of the renal SNS on blood pressure control is
well recognized in patients with kidney disease. Overactivity
of the SNS has been demonstrated in patients with endstage renal disease requiring dialysis, with normalization
after bilateral nephrectomy (14). Even if uremic toxins are
removed after kidney transplantation, sympathetic overactivity persists in patients whose native diseased kidneys are
not removed (15), lending support to the notion that the
diseased kidneys account for the increased sympathetic
activity. Removal of a diseased kidney (e.g., for pyelonephritis or congenital hypoplasia) in patients with hypertension can lead to blood pressure normalization (16 –18).
Likewise, bilateral nephrectomy of native kidneys in patients with end-stage renal disease and kidney transplants
has been shown to improve or normalize blood pressures
(19,20). Though renin levels in patients with end-stage
renal disease are frequently elevated and thus overactivity of
the renin-angiotensin system may contribute to hypertension, there is ample evidence that overactivity of the afferent
sympathetic nervous signals is at least as important as renin
release is in the genesis and maintenance of hypertension, as
well as in the improvement after nephrectomy. For example,
it has been shown that beta-blocker therapy in kidney
transplant patients is only effective in patients whose native
kidneys have not been removed (21). Further, inhibition of
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the renin-angiotensin system has a modest effect on muscle
sympathetic nervous activity and blood pressure control in
patients with end-stage kidney disease, yet, administration
of the central sympatholytic agent, clonidine, has a substantial blood pressure–lowering effect (22). It is not clear what
triggers the increased activity of renal afferent sympathetic
nerves. However, renal ischemia may be the cause or at least
a contributor. To this effect, in patients with ischemia
caused by renal artery stenosis, normalization of muscle
sympathetic activity has been demonstrated after renal
artery angioplasty (23). Similarly, blood pressure normalization after unilateral nephrectomy in patients with renal
artery stenosis has been reported (24).
A complete summary of animal data relevant to the topic
of renal denervation surpasses the limits of this review.
However, 3 animal experiments merit discussion. In spontaneously hypertensive rats whose renal sympathetic activity
is increased, the development of hypertension is delayed and
the severity is attenuated by prior bilateral renal sympathetic
denervation (25). In animals undergoing bilateral nephrectomy and autoreimplantation of their kidneys, any sympathetic influences to and from the kidney are disrupted. This
has been shown to result in significant diuresis (26). Though
the mechanism and long-term effects have been disputed, a
readjustment of the pressure natriuresis response is plausible. Lastly, in dogs, stimulation of renal sympathetic nerves
causes hypertension (27). Of note, this does not appear to be
related solely to a reduction in renal blood flow, as this
parameter changes little with chronic renal sympathetic
stimulation (27).
In conclusion, human experience and animal experiments
unequivocally support not only an important role of the
SNS in blood pressure regulation, but also a beneficial blood
pressure response to the interruption of the renal SNS.
Anatomy and Physiology of the
Renal SNS
The renal SNS affects blood pressure by 2 pathways (Fig. 1).
It supplies the kidneys by a rich network of efferent,
exclusively noradrenergic, sympathetic fibers located in the
adventitia of the renal arteries and returns signals to the
central nervous system via afferent sympathetic fibers likewise located in the adventitia.
Autonomic centers in the medulla oblongata and midbrain receive and integrate afferent signals from end organ
sensors and baroreceptors as well as from the hypothalamus,
cortex, and limbic system and transmit efferent signals to
sympathetic pre-ganglionic neurons in the intermediolateral
column of the spinal cord. Fibers from neurons in the
intermediolateral column (T10 to T12, L1 to L2) extend via
splanchnic nerves to post-ganglionic neurons located in
pre-vertebral ganglia. Post-ganglionic neurons reach the
kidney via the adventitia of the renal arteries. Efferent
Bertog et al.
Renal Denervation for Hypertension
251
sympathetic fibers supply every aspect of the kidney, including the renal tubular cells (28), juxtaglomerular apparatus
(29), and vasculature (30,31). Stimulation of efferent fibers
causes activation of the adluminal basolateral Na/K adenosine triphosphatases (32), thereby promoting sodium and
water retention, renin secretion via the juxtaglomerular
apparatus (33), and vasoconstriction of renal arterioles.
Hence, the efferent renal SNS will raise the goal blood
pressure by a direct effect on the kidney promoting salt and
water retention. Further, renin release stimulates the production of angiotensin II and thereby mineralocorticoids,
mediating vasoconstriction and sodium and water retention,
respectively. There appears to be a graded response depending on the intensity of the sympathetic signal, such that with
low frequency stimulation renin secretion is first affected,
followed by tubular sodium reabsorption and renal vascular
tone at higher frequencies (34).
In addition, and often underappreciated, the kidney
transmits signals via afferent sympathetic fibers, the cell
bodies of which are located in the dorsal root ganglia, to
neurons of the posterior gray column of the ipsilateral spinal
cord (35,36), from where signals are further relayed to
autonomic centers in the central nervous system as well as to
the contralateral kidney. The afferent fiber endings are
found in all parts of the kidney;
Abbreviation
the richest network, however, is
and Acronym
located in the renal pelvis. Signals are transmitted by 2 families
SNS ⴝ sympathetic nervous
system
of receptors, the mechanosensitive receptors that relay information regarding hydrostatic renal pelvic pressure, as well as
renal arterial and venous pressure, and chemosensitive
receptors activated by renal ischemia and changes in the
chemical milieu of the renal interstitium (37). Afferent
sympathetic dorsal root neurons transmit signals to the
central nervous system. By their communication with
sympathetic centers in the central nervous system, afferent sympathetic signals assume a major role in the
regulation of overall sympathetic tone. This is elegantly
demonstrated in an animal model whose kidneys have
been injured by phenol injection. Blood pressure rises
after phenol injections are prevented by prior dorsal
rhizotomy (selective afferent sympathetic fiber interruption by transection of the dorsal roots) (38). Similarly, in
rats with renal insufficiency, hypertension can be prevented by dorsal rhizotomy (39).
Thus, the SNS has a profound effect on the kidney’s
ability to regulate the goal blood pressure, and, vice versa,
the kidney has an important effect on the overall sympathetic tone. In addition, afferent fibers communicate with
the contralateral kidney, thereby allowing maintenance of
sodium and water balance despite unilateral disturbances
of salt and water excretion (40). For example, a unilateral
increase in hydrostatic pressure (e.g., because of ureteral
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Figure 1. The Renal SNS
NTS ⫽ solitary tract nucleus; PVN ⫽ paraventricular nucleus; RVLM ⫽ rostral ventrolateral medulla.
obstruction and hydronephrosis), via an increase in afferent
sympathetic activity transmitted to the efferent fibers of the
contralateral kidney, reduces the efferent renal sympathetic
activity and, thereby, results in diuresis and natriuresis in the
contralateral kidney (renorenal reflex) (40).
When examining the role of the SNS in the genesis of
hypertension, it is important to recognize that it is not activated
in an all-on or all-off fashion. Instead, the sympathetic activity
to certain organs only (e.g., the kidney or heart) (41) can be
increased and thus have an impact on blood pressure control in
the absence of a substantial activation of sympathetic fibers to
other organs. This, in addition to differences in catecholamine
metabolism, may explain variability in blood catecholamine
levels in hypertensive patients. Two methods have allowed a
more refined assessment of the SNS activity in humans:
microneurography (42) and norepinephrine spillover (43,44).
Microneurography measures the SNS activity in skeletal muscles. It can be used as a surrogate for overall sympathetic drive.
Norepinephrine spillover can be used to measure organ-specific
as well as overall SNS activity.
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Results of Percutaneous
Sympathetic Denervation in Humans
Our better understanding of the interplay between the
kidney and SNS elucidates the importance of the SNS in
blood pressure control and the pathogenesis of hypertension. In addition, the desirable results of sympathetic
denervation in animal models and in patients who have
undergone nephrectomies, together with the recognition of
the favorable location of the sympathetic fibers and their
exquisite sensitivity to radiofrequency, have resulted in the
development of catheter-based radiofrequency ablation of
the renal sympathetic nervous fibers.
In a human feasibility, safety, and efficacy trial (Symplicity-1
[Catheter-based renal sympathetic denervation for resistant
hypertension: a multicentre safety and proof-of-principle
cohort study]), 45 patients with drug-resistant hypertension
underwent bilateral application of radiofrequency to the
renal arteries (45). After renal artery angiography, anticoagulation and administration of opioid analgesics for control
of diffuse abdominal pain that invariably occurs during this
procedure, via 8-F femoral artery access, an 8-F guide
catheter was positioned in the renal arteries, allowing
delivery of a radiofrequency catheter (Fig. 2) into the renal
arteries and circumferential application of radiofrequency
energy (Fig. 3). The catheter tip is steerable via a hand
control and is connected to a console (Fig. 4). Delivery of
radiofrequency energy was monitored with a temperature
and impedance sensor at the tip of the catheter such that
unwanted tissue injury related to overheating was avoided.
Two procedure-related complications occurred: 1 renal
artery dissection related to catheter manipulation, which
was treated successfully with renal artery stenting; and 1
femoral artery pseudoaneurysm. A significant blood pressure
reduction at 1-month follow-up of 14 and 10 mm Hg
(systolic and diastolic, respectively) was followed by a
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253
sustained response with a pronounced systolic and diastolic
blood pressure reduction of 27 and 17 mm Hg, respectively,
at 12 months. Antihypertensive medication was adjusted in
13 patients at follow-up with a reduction in the number of
antihypertensive medications in 9 patients and an increase
in 4. Importantly, a significant blood pressure reduction
remained even after excluding those 4 patients from the
analysis whose antihypertensive medications were intensified. In 13% of patients, no favorable blood pressure
response occurred. In 10 patients who underwent renal
norepinephrine spillover measurements, a significant reduction in renal norepinephrine spillover was shown, confirming the intended reduction in sympathetic drive to the
kidney. In addition, total body norepinephrine spillover
decreased significantly, lending support to the hypothesis
that, by a reduction in afferent renal sympathetic signaling,
the overall sympathetic tone can be reduced. In 1 patient,
renal norepinephrine spillover, total body norepinephrine
spillover, the plasma renin level, and muscle sympathetic
activity decreased after renal denervation (46). In addition,
the cardiac muscle mass assessed by cardiac magnetic
resonance imaging decreased by 15 g. Registry data, including patients from Symplicity-1 who have completed 24months follow-up (n ⫽ 18), demonstrate a sustained blood
pressure reduction (33/14 mm Hg) (47).
More recently, in the Symplicity HTN-2 (Renal Sympathetic Denervation in Patients with Treatment-Resistant
Hypertension) trial, 106 patients with resistant hypertension were randomized to catheter-based therapy in addition
to conventional antihypertensive medications, versus antihypertensive medications only, in a 1-to-1 fashion (48). The
transcatheter techniques were similar to the previously
described study. The primary endpoint was systolic blood
pressure at 6-month follow-up. There was a significant
difference in blood pressure changes from baseline between
Figure 2. Fluoroscopic Images of Catheter Positions in the Renal Artery
(Left) Radiofrequency catheter positioned in the right renal artery. (Right) Contrast injection into the right renal artery.
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Figure 3. Radiofrequency Catheter Positioning in the Renal Artery
Radiofrequency catheter positioning in the renal artery aiming at circumferential application of radiofrequency spaced apart by approximately 5 mm.
Reprinted, with permission, from Medtronic Ardian, Mountainview, California.
patients treated with catheter-based renal sympathectomy
(reductions of 32/12 ⫾ 23/11 mm Hg) and those treated
medically (0/1 ⫾ 21/10 mm Hg), with a mean blood
pressure difference of 33/11 mm Hg between the groups at
6 months. A systolic blood pressure improvement of at least 10
mm Hg was observed in 84% of patients in the interventional
group and in 35% in the medically treated control group. On
24-h ambulatory blood pressure monitoring, a significant
blood pressure reduction was seen in patients who underwent
renal sympathectomy (11/7 ⫾ 15/11 mm Hg), whereas the
blood pressure was unchanged in patients with medically
managed hypertension only. Importantly, the blood pressure
reduction measured by 24-h ambulatory monitoring was less
pronounced than that reported during office visits. One patient
developed a pseudoaneurysm at the femoral access site treated
successfully with ultrasound-guided manual compression.
Seven patients developed transient bradycardia requiring atropine administration. The renal function and urine-albumincreatinine ratios remained unchanged at follow-up in both
groups.
Limitations to Human Experience With
Catheter-Based Renal Sympathetic Denervation
Figure 4. Symplicity Catheter System
The steerable radiofrequency catheter is shown and the console that provides feedback to the operator regarding impedance and radiofrequency
energy delivery as well as duration of energy application. Reprinted, with
permission, from Medtronic Ardian, Mountainview, California.
The results of Symplicity-1 and Symplicity HTN-2 are
very encouraging; however, several limitations deserve
discussion.
Symplicity-1 was a proof-of-principle study that did not
include a control group and operators and investigators were
unblinded. Therefore, though the blood pressure remained
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unchanged in 5 patients who were excluded from the study,
a placebo effect and observer bias cannot be excluded.
Second, patients with accessory renal arteries were excluded.
Hence, it cannot be assumed that renal denervation in the
main renal arteries will translate into a similar beneficial
effect in patients who have accessory renal arteries. Third,
screening for secondary hypertension was limited. Fourth,
13% of patients were nonresponders. The reason for the
absence of a blood pressure response in these patients
remains unclear, as renal or overall sympathetic activity was
not consistently measured before or after renal denervation
in these patients.
In Symplicity HTN-2, though the design was a randomized controlled trial, the investigators who performed blood
pressure measurements were not blinded to the treatment
mode. In addition, sham procedures were not performed in
the control group. Hence, once again, a placebo effect and
observer bias cannot be entirely ruled out.
Given well-described pulmonary vein stenoses after radiofrequency pulmonary vein isolation to treat atrial fibrillation, concerns have been raised regarding the possibility of
renal artery stenosis caused by application of radiofrequency
to the renal arteries. However, the intensity of radiofrequency energy is several magnitudes lower than that used for
pulmonary vein isolation. In Symplicity-1, in 18 patients
who underwent renal angiography 2 to 4 weeks after the
procedure and in 14 patients who underwent renal artery
magnetic resonance imaging, no renal artery stenosis was
seen. Of note, in 1 registry patient, progression of a mild
renal artery stenosis to a hemodynamically significant lesion
remote from the site of radiofrequency application requiring
renal artery stenting was reported (47). Similarly, in Symplicity HTN-2, in 43 of 49 patients who underwent renal
sympathectomy, renal artery imaging at 6-month follow-up
did not show any significant renal artery stenosis or aneurysmal deformation. Nevertheless, despite the absence of
treatment-related renal artery stenoses in both studies, a risk
of renal artery stenosis in longer-term follow-up cannot be
excluded at this point.
In both Symplicity trials, only patients with renal arteries
with an anatomy favorable to catheter-based therapy (minimal length of 20 mm allowing an adequate landing zone
and minimal diameter of 4 mm) were included. A higher
procedural risk in patients with more unfavorable anatomy
is possible.
Patients with more than mild renal insufficiency were
excluded even though sympathetic overactivity is typically
pronounced in the setting of renal insufficiency. In these
patients, though a favorable effect on blood pressure control
is anticipated, definitive statements regarding the benefit
and safety of renal denervation cannot be made.
The office blood pressure response in Symplicity HTN-2
was more pronounced than the ambulatory blood pressure
response. This may be related to a more pronounced
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Renal Denervation for Hypertension
255
activation of the SNS with office blood pressure measurements than during ambulatory blood pressure monitoring
and hence more marked effect after renal denervation.
Finally, similar to sympathetic reinnervation described
after heart transplantation (49), sympathetic reinnervation
to the kidney is conceivable and may abolish or attenuate a
long-term effect. However, regrowth of sympathetic nerve
fibers to the kidneys has not been shown in humans (50).
Moreover, given the absence of angina in patients with
transplant vasculopathy after heart transplantation, afferent
sympathetic reinnervation is less likely. In addition, in those
patients enrolled in Symplicity-1 and additional patients
who underwent renal sympathetic denervation, 2-year
follow-up demonstrated a pronounced lasting blood pressure reduction (47).
Future Perspectives
The importance of the renal SNS activity in hypertension
and its modulation are well established. Several aspects
deserve further exploration.
First, it has become apparent that this procedure does not
cause universal blood pressure lowering. The reason for the
response variability remains to be determined. One potential cause may be incomplete denervation. It is also possible
that renal sympathetic activity has a subordinate role in the
genesis and maintenance of hypertension in subsets of
hypertensive patients with normal renal sympathetic tone.
The renal sympathetic tone is not uniformly increased.
Instead, there appears to be variability in renal efferent
sympathetic nerve activity in hypertensive patients. For
example, in patients older than 60 years, though skeletal
muscle sympathetic activity is increased, renal norepinephrine spillover is frequently normal (3), whereas in patients
with the metabolic syndrome, renal and overall sympathetic
overactivity is frequently very pronounced (51,52). Thus, it
would be very important to identify parameters that may
predict the response to renal denervation and help in patient
selection.
Second, the SNS activity appears to be of most importance in the earlier stages of hypertension. Early modification of SNS activity in these patients may bring a curative
treatment for essential hypertension within reach. Thus,
trials, including patients with milder forms of hypertension
are warranted. Exploration of the impact of renal denervation in patients with secondary forms of hypertension, such
as primary hyperaldosteronism that cannot be treated with
surgical intervention should also be considered.
Third, obesity and insulin resistance are frequent companions of hypertension. Sympathetic overactivity has been
observed with obesity, insulin resistance, and the metabolic
syndrome, and improvements in glucose metabolism and
insulin resistance have been reported after renal sympathetic
denervation (53–55). A compromised skeletal muscle mi-
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Bertog et al.
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crocirculation has been suggested to be present in patients
with hypertension (56). Sympathetic denervation may enhance skeletal muscle blood flow mediated by a reduction in
adrenergic alpha-1 receptor stimulation, increased skeletal
muscle-capillary density, and a change in muscle fiber types
(57), thereby potentially improving glucose uptake in the
skeletal muscle. In addition, a decrease in glucagon secretion
and gluconeogenesis and reduced activity of the reninangiotensin system may contribute to the beneficial effects
of renal denervation on glucose metabolism and insulin
resistance. Although our current understanding of the
preceding findings is far from complete, given the high
incidence of cardiovascular events in patients with insulin
resistance and impaired glucose metabolism and the favorable impact of reduced sympathetic drive, lower event rates
after renal denervation are conceivable. Studies to this effect
evaluating the impact of sympathetic denervation on diabetes control and cardiovascular events are ongoing. In addition, further exploration of the impact of renal sympathectomy on the development of diabetic nephropathy is
warranted as increases in glomerular filtration of up to 25%
to 50% have been described early in the course of (type 1)
diabetes, perhaps contributing to the development of glomerulosclerosis and diabetic nephropathy (58,59), and prevention of glomerular hyperfiltration has been reported after
renal sympathetic denervation in an animal model (60).
Similarly, moxonidine, a central sympathetic inhibitor has
been associated with a reduction in microalbuminuria in
patients with (type 1) diabetes (61). Further supporting a
potentially protective effect on renal function beyond that
expected due to blood pressure reduction, the natural
decline in estimated glomerular filtration rate expected
depending on blood pressure at any given time was smaller
than predicted at early follow-up, even after taking the
blood pressure reduction into account, after renal denervation in 153 hypertensive patients (including those enrolled
in Symplicity-1) (47). However, in a small number of
patients who completed later (up to 24 months) follow-up,
the reduction in estimated glomerular filtration rate was
more pronounced than that observed in a study examining
the effect of ramipril, telmisartan, or both on renal function
(62). Given these findings, further studies of the long-term
impact on renal hemodynamics and function, particularly
comparing renal denervation in a controlled fashion to
conventional medical therapy, are warranted before a final
statement regarding either a protective, neutral, or harmful
effect can be made.
Fourth, the impact of renal denervation on the renorenal
reflex particularly in conditions affecting only 1 kidney is
not clear. For example, whether during urinary obstruction of 1 kidney a compensatory diuresis of the contralateral kidney can be expected in the same magnitude as
would occur in the absence of renal denervation remains
to be determined.
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Fifth, the autonomic nervous system affects nearly every
part of the body. Given the myriad effects of an overactive
SNS beyond blood pressure control, many of which are
detrimental, renal denervation in some conditions associated with sympathetic overactivity require further investigation. For example, in light of increased SNS activity in
patients with systolic heart failure (63), its association with
increased mortality (64) and the well-established benefits of
beta adrenoreceptor blockade (65) and modification of the
renin-angiotensin system (66), the concept of renal denervation to reduce overall sympathetic drive in heart failure is
intriguing. Along this line, a reduction in left ventricular
filling pressures and improved left ventricular systolic function following renal denervation has been shown in animal
models of heart failure (67). Similarly, a potential benefit in
patients with hepatorenal syndrome characterized by SNS
overactivity (68) is possible. Lastly, an increased sympathetic drive has been described in patients with sleep apnea,
together with a favorable impact on the apnea-hypopnea
index after catheter-based renal sympathetic denervation
(53). Hypothetically, this may be related to a reduction in
fluid shifts to the neck with recumbent positioning after
renal denervation based on the observation that a greater
fluid shift from the lower extremities to the neck occurs in
patients with uncontrolled versus well-controlled hypertension (69). The reported improvements in sleep apnea with
aldosterone antagonists further supports a potential deleterious effect of excessive nocturnal rostral fluid shifts
(70). Studies examining the mechanism and impact of
sympathetic denervation in patients with sleep apnea are
ongoing.
Finally, it should be mentioned that catheter-based renal
denervation is not the only device-based therapy available
aiming to reduce the sympathetic nervous tone. Similar to
renal sympathetic denervation, baroreceptor stimulation
reduces the overall SNS activity and has been shown to
lower blood pressure in a safety and feasibility trial (71).
Recently, the results of a phase III trial comparing baroreceptor stimulation to conventional medical therapy in patients with resistant hypertension were published demonstrating a significant blood pressure reduction (72).
However, it failed to meet 1 of the 2 primary efficacy
endpoints (blood pressure responder rate at 6 months) likely
related to an underestimation of blood pressure improvements
in the control group. Importantly, as expected with the
implantation of any foreign body, some adverse events occurred (4.8% nerve injury with residual deficit and 2.6% wound
complications). Further studies will determine this concept’s
role in hypertension treatment.
Conclusions
We have entered an exciting era with the ability to modulate
the SNS and achieve an improvement in blood pressure
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control with percutaneous renal denervation and potentially
beneficial effects on a plethora of other conditions associated
with sympathetic overactivity. Renal denervation has become routine in some countries. Nevertheless, we should
maintain our quest to further improve our understanding of
the SNS in the pathogenesis of hypertension and some
other disorders. Lastly, the SNS and mechanisms governing
blood pressure control are complex and, though the procedure has demonstrated a good safety record, some longterm consequences may not be foreseeable. Therefore,
systematic follow-up of patients who underwent renal sympathetic denervation is warranted. Only carefully planned
trials further elucidating the physiology and examining the
clinical effects of renal denervation on multiple levels will
allow safe adoption of a promising concept and technology for
patients with a variety of conditions other than hypertension.
Reprint requests and correspondence: Dr. Horst Sievert, Cardiovascular Center Frankfurt, Seckbacher Landstrasse 65, 60389
Frankfurt, Germany. E-mail: [email protected].
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Key Words: hypertension 䡲 renal denervation 䡲 sympathetic nervous system.
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