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thetic nerve signalling to key organs. Beyond the already
expected BP-lowering effect after renal afferent bre disruption, data reported by Lopes etal. provide a persuasive explanation about how a catheter-based RDN approach may have
caused the halt [55] or even improvement in renal function
[56] that was noticed in patients with hypertension and CKD,
as well as the reduction in albuminuria [55, 56], an independent risk factor for cardiovascular events [57] and a predictor
for the progression of CKD [58]. These data point out potential underpinning mechanisms through which RDN can mitigate the renal and cardiovascular risk in affected patients.
Fig. 9.1 Schematic of Possible Connections Amongst Different Neural
Structures. There are multiple pathways to connect renal sympathetic
nerves with the stellate ganglion. Both preganglionic and postganglionic sympathetic bers may innervate the renal artery, according to the
representation of possible connections among different nerve structures
[46, 48–54, 101–103]
mately 10% of renal sympathetic neurons in cats originated
from the thoracic chain ganglia (stellate through T13) [48].
In view of the described connections between these two
structures, RDN may directly result in retrograde cell death
in the stellate ganglion. Furthermore, the application of uorescent dyes in the renal nerves results in uorescent labeling
of the sympathetic cell bodies in paravertebral and prevertebral ganglia [49–51].
Since the sympathetic preganglionic neurons that project
to the stellate ganglion are dispersed in spinal cord segments
T1-T10 [52], they have ample opportunities to interrelate
with the preganglionic cells that link indirectly with sympathetic nerve bers surrounding the renal arteries. However,
there are some other pathways that may contribute to the
trans-synaptic degeneration [46], such as the ganglion cells
of renal afferent nerves in the thoracic and lumbar spine dorsal root ganglia, which connect to the posterior and lateral
hypothalamic nuclei, and the locus ceruleus in the brain stem
[53, 54]. All these types of connections suggest one cause of
persistent effects of RDN may be remodeling of the critical
brainstem areas and the stellate ganglia.
Moreover, Lopes et al. recently reported that chemical
afferent renal denervation (ARD) decreased BP, RSNA and
reactive oxygen species (ROS) in both kidneys, as well as
normalised renal function, proteinuria and activation of
intrarenal renin-angiotensin system (RAS) in renovascular
hypertension. This data demonstrates that afferent renal
nerves are crucial for the maintenance of BP and renal sympathetic hyperactivation, as well as renal function, in the
renovascular hypertension model [2]. Afferent renal nerve
ablation leads to the mitigation of sympathetic signals arising from the kidneys to the brain, which per se lowers central
sympathetic outow ultimately reducing the efferent sympa-
The Potential Role ofInammatory Pathways
Some studies propose that renal inammation may be
directly triggered by amplied renal sympathetic nerve
activity, as there is much evidence that inammation of the
vasculature, brain, and kidneys contributes to chronic
increases in BP [59–61]. Recently, a study reported that
angiotensin II (AngII)-induced hypertension in mice is
blunted by RDN and that this is paralleled by reduced renal
inammation independently of the BP [62]. Since specic
ablation of renal afferent nerves had no effect on the pathogenesis of hypertension in this study, it was concluded that
the antihypertensive effect of RDN was due to ablation of
efferent renal sympathetic nerve-mediated renal inammation [62]. Similarly, Banek et al. also reported that RDN
attenuates hypertension and renal inammation in the rat
deoxycorticosterone acetate (DOCA)-salt model of hypertension [63]. Importantly, they also observed that resting
afferent renal nerve discharge is elevated in DOCA-salt rats
and hypothesized that this is caused by an increase in certain
inammatory cytokines in the kidney [63]. Another nding
was that afferent-specic renal nerve ablation attenuated the
development of hypertension in this model to the same
degree as total RDN [63]. The authors concluded that even
though renal inammation may have its onset in efferent
renal sympathetic nerves, hypertension was driven by augmented afferent renal nerve trafc, probably secondary to
renal inammation [63]. A subsequent study from the same
group demonstrated that afferent-specic renal nerve ablation also decreased arterial pressure in the established phase
of DOCA-salt hypertension to the same degree as total RDN
[64]. However, neither method of ablation reversed renal
inammation in the established phase of this model suggesting additional drivers of inammation.
Even though there is a shortage of clinical studies directly
measuring renal inammation after RDN, there are several
studies in which peripheral inammation was evaluated.
Kampmann and colleagues reported similar cardiovascular
and inammatory responses in hypertensive humans that
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underwent catheter-based RDN, where all measured circulating inammatory cytokines (TNF-α, IL-6, and IL-1β)
remained unaffected 6months post-treatment, despite a signicant decrease in arterial pressure [65]. In contrast to these
results, a clinical report from Zaldivia and colleagues [66]
described a reduction in circulating inammatory cytokines
(MCP-1, IL-1β, TNF-α, and IL-12) several months after
catheter-based RDN in hypertensive subjects. Further clinical and preclinical investigations are necessary to elucidate
the anti-inammatory effect of RDN.
Clinical Evidence
In patients with CKD, renal function decline was attenuated
in patients treated with moxonidine, a drug known to
decrease sympathetic activity, compared with those treated
with nitrendipine, a dihydropyridine calcium channel
blocker. As BP was only slightly affected, this nding points
to a BP-independent effect of moxonidine [67]. Denervation
of the renal efferent nerves and renal afferent nerves in animal models of CKD has been shown to attenuate hypertension and thus prevent further deterioration of kidney function
[53, 68–70]. Hering et al. reported that RDN in resistant
hypertensive patients caused substantial BP fall and rapid
decrease in the ring properties of single sympathetic vasoconstrictor bers, which was more pronounced than multiunit MSNA inhibition [71]. The disruption of sympathetic
hyperactivity and the interruption of the renin-angiotensinaldosterone system feedback loop may partially benet this
population. In different stages of CKD, the presence of
micro- and macro-albuminuria is not only an independent
risk factor for cardiovascular events [57, 72], but also predicts progression of CKD [58]. Along these lines, a study
reported that following RDN, the magnitude of albuminuria
as well as the prevalence of micro- and macroalbuminuria
was reduced in treatment-resistant hypertensive patients
[55]. Ott etal. analyzed the change of the renal function over
time before and after RDN amongst patients with CKD and
treatment resistant hypertension. Their ndings suggested
that RDN decreases BP and slows or even halts the decline of
renal function in treatment-resistant hypertensive patients
with CKD stages 3 and 4 [73]. Hering et al. reported that
stage 3–4 CKD patients had a sustained reduction in ofce
BP post-RDN [28]. Another important observation from this
pilot study was the absence of further deterioration of renal
function in this patient cohort. Short- and mid-term follow up of renal function assessed by plasma and urine testing, as
99m
well as
aggravation of renal impairment. Autoregulation of the kidney did not appear to be adversely affected, as indicated by
preserved renal function despite substantial BP reduction
(Fig.9.2) [28]. Kiuchi etal. presented a series of CKD resis-
Tc-MAG-3 scanning, demonstrated no evidence of
tant hypertensive patients who were followed up for 2years
after RDN.Their results indicate that RDN (stages 2–4) provided a signicant reduction in BP and was associated with a
long-term increase in glomerular ltration rate and a signicant decrease in albumin excretion in patients with resistant
hypertension and CKD [74] (Fig.9.3). While this preliminary data is encouraging, these merits further investigation in
a larger population.
Delacroix et al. also demonstrated that RDN resulted in
22% improvement in eGFR at 6 months post-procedure.
Moreover, although not statistically signicant, there was an
8% improvement in plasma creatinine with a drop in plasma
aldosterone levels in patients with higher baseline values and
Fig. 9.2 Individual changes in renal function post to renal denervation.
Individual changes in creatinine-based estimated glomerular ltration
rate (GFR) before renal denervation (pre-RDN); at 1week (W); and at
1-, 3-, 6-, and 12-month (M) follow-up (FU) [28]
Fig. 9.3 Renal denervation effects in the long-term. Estimated glomerular ltration rate (eGFR) at baseline and at months 1, 3, 6, 12, 18,
and 24 after renal denervation. Values are presented as mean±standard
deviation. *P<0.0001 vs. corresponding baseline values. At months 18
and 24, patients who required chronic renal replacement therapy (n=3)
were assigned an eGFR value of 0 [74]
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a 16% increase in urine creatinine [26]. While it is challenging to interpret these results owing to the limited numbers,
this data suggests that the improvement in total blood ow per
cardiac cycle post-RDN is probably not due to local vascular
resistance but rather due to a more effective and efcient kidney resulting from decreased BP that potentially resets the
renal equilibrium. Furthermore, a decreased heart rate possibly permits longer transition times for blood ow through the
kidneys enabling longer and better ltration. Similarly, this
could well be attributed to expansion of venous capacitance
that likely occurs with reductions in sympathetic nervous system activity leading to greater intravascular volume and loading of the ventricle. In another recent study, Schlaich etal.
demonstrated that end-stage renal disease (ESRD) individuals with poorly controlled hypertension who received RDN
experienced a sustained systolic BP reduction and a signicant decrease in MSNA over 12-months, supporting the
safety of RDN in these patients [29].
For RDN to become an established treatment of hypertensive CKD, it is most important that renal function is not
adversely affected. Based on the data above, to examine
whether renal nerve function returned in the long-term,
Singh etal. examined vascular contraction to nerve stimulation in renal arteries and determined nerve regrowth by
assessing renal TH (tyrosine hydroxylase), CGRP (calcitonin gene-related peptide), and norepinephrine levels in kidneys at 30 months after RDN. RDN normalized BP in
hypertensive CKD sheep such that BP was similar to that of
the normotensive sheep with intact nerves. Glomerular ltration rate decreased by ~22% in CKD sheep with intact nerves
but increased ~26% in hypertensive CKD-RDN sheep by
30months. At 30months, urinary albumin was ~127% and
left ventricular mass was ~41% greater in CKD sheep with
intact nerves than control. However, urinary albumin was
~60% less and left ventricular mass was ~40% less in the
CKD sheep that underwent RDN compared with their intact
counterparts. At 30months in CKD-RDN sheep, neurovascular contraction (~56%), the renal proportion of TH (~50%),
CGRP (~67%), and norepinephrine content (~49%) were all
less compared to CKD-intact animals; all these variables
were similar between normotensive-intact and normotensiveRDN groups. RDN provoked a sustained reduction in BP
and enhancements in renal function. Regrowth of renal
nerves and the return of function were observed in hypertensive CKD-RDN sheep, but levels were only partially restored
[75]. These ndings suggest that RDN reduces BP in the
long-term and is renoprotective and cardioprotective in
CKD. In line with clinical studies, these ndings demonstrate that RDN may improve renal function in the long-term
in CKD and be considered as an exciting potential approach
for treating kidney diseases (Fig.9.4).
Preservation of renal function is an essential therapeutic
target as it will delay the onset of ESRD and the need for
renal replacement therapy with substantial benets regarding
the patient quality of life and healthcare costs. Given that
chronic sympathetic activation leads to the progression of
CKD [22, 76, 77] the increase in GFR and RBF is likelyto be
driven by a reduction in sympathetic ouow after
RDN.Another possibility is that sympathetically mediated
vasoconstriction of renal vascular beds over time may be
reduced in the CKD sheep following denervation resulting in
an overall decrease in renal vascular resistance (RVR). This
may be associated with improvements in nitric oxide bioavailability and reduction in oxidative stress-known drivers
of CKD in this model [78].
It is important to note that there are potential alternative
explanations, i.e. the increase in GFR may be indicative of
single nephron hyperltration, which in turn due to glomerular hypertension, may herald an accelerated decline in GFR
in the future. However, this hyperltration if associated with
glomerular hypertrophy or the observed increase in RBF
after RDN and potentially altering the point of glomerular
ultraltration equilibrium, may not cause further glomerular
damage [79]. Indeed, the reduction in albuminuria observed
with RDN in CKD suggests that the improved GFR does not
negatively inuence the integrity of the glomerular basement
membrane. Nevertheless, further investigations into the
exact mechanisms via which RDN improves GFR are
warranted.
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Fig. 9.4 Renal Function in Response to Hemorrhage. Glomerular ltration rate (GFR), renal blood ow (RBF) and renal vascular resistance
(RVR) before and during 120min following end of hemorrhage at 11
and 30months after either sham (intact) or renal denervation (RDN). (a,
Outlook andImplications
c, e) MAP, HR, PRA in control sheep; and (b, d, f) CKD sheep.
Arrowhead indicates end of hemorrhage. CKD indicates chronic kidney
disease. *P<0.05 comparing RDN with intact at 11months; #P<0.05
comparing RDN with intact at 30months [104]
122 studies, a reduction in ofce systolic BP of 10mm Hg
was related to a reduction in cardiovascular events by 20%,
Reduction in target organ damage by pharmacological treatment is closely linked to the decrease in time-averaged BP
achieved. In a meta-analysis including 613,815 patients from
overall mortality by 13%, coronary artery disease by 17%,
strokes by 27% and heart failure by 28%, respectively [80].
In the Heart Outcomes Prevention Evaluation (HOPE-3)
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study, patients with baseline ofce systolic BP more than
143.5mm Hg had a reduction of systolic BP by −5.8/−3.0mm
Hg in response to pharmacologic therapy associated with a
28% lower incidence of cardiovascular events compared
with the placebo group [81]. A meta- analysis of 147 randomized trials comprising 464.000 patients demonstrated that a
reduction in 10mm Hg systolic and 5mm Hg diastolic ofce
BP was related to a decrease of coronary heart disease and
stroke events by roughly 22 and 41%, respectively, depending on the age of the patient [82].
Even though not proven by a prospective outcome trials it
can perhaps be inferred that a 10mm Hg decrease in ofce
systolic BP achieved in RDN trials in which the average age
of the population was ~65 years old, if maintained longterm, would be associated with a reduction in cardiovascular
events by ~25%, especially heart failure and stroke.
The rst demonstration of the role of the sympathetic nervous system in circulatory regulation, in particular the function of the kidney, was provided by Carl Ludwig [83]. His
ideas were further developed by J.Rose Bradford, showing
that stimulation of renal nerves elevated BP [84]. This led to
rst surgical attempts to reduce blood pressure by surgical
interventions to interrupt the sympathetic innervation. One
of them was de-capsulation of the kidneys in 1936 with a
subsequent reduction in BP [85]. Resection of renal nerves
was done for pain relief in hydronephrosis [86]. Furthermore,
sympathetic splanchnicectomy resulted in a signicant BP
reduction with a remarkable reduction of death rate depending on cardiovascular comorbidities [87, 88]. This treatment
was performed in more than 1200 cases in the United States
until 1953 [89]. However, these procedures were accompanied by high mortality and severe side effects and rehospitalization due to orthostatic hypotension, syncopes,
erectile dysfunction, and incontinence [90]. Nevertheless,
the explanation of mechanisms how the sympathetic nervous
activation stimulates BP elevation [91] led to the development of more selective interventional techniques to reduce
BP like renal sympathetic denervation decades later [92].
Catheter-based renal denervation (RDN) is a safe and
minimally invasive treatment option for patients with uncontrolled hypertension and has been shown to reduce renal and
central sympathetic activity [93, 94] with clinically relevant
BP reduction demonstrated in several clinical trials
[95–100].
With important additional trials now underway for several
RDN devices, such as SPYRAL HTN ON-MED
EXPANSION, it is perhaps pertinent for the hypertension
community to develop strategies on exactly how to best allocate the limited resources to ensure the availability of RDN
for those individuals who are likely to benet most.
RDN has provided a signicant BP lowering effect in
patients with hypertension and CKD. More importantly,
RDN seems to associate with no harmful impact on kidneys.
In some studies, it had a long-term increase in eGFR and
decreased albumin excretion, thereby improving the disease
status in patients with early-stage CKD.Although encouraging, this data is preliminary and must be validated in larger
populations. In our view, expanded indications such as CKD,
arrhythmias, heart failure, sleep apnea, and pain syndromes
seem to be a potential target for RDN owing to the sympathetic pathophysiological background involved in these
conditions.
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Obstructive Sleep Apnea, Resistant
https://t.me/medicina_free
Hypertension andRenal Denervation
AdamWitkowski andJacekKądziela
10
Epidemiology ofObstructive Sleep Apnea
The prevalence of sleep apnea (OSA) in the general population varies from 5 to 10% [1]. In the general population and
in patients with cardiovascular disease, OSA is 2–3 times
more common in men than in women and in older than
younger individuals [2]. In hypertensive subjects, the diagnosis of OSA is based on polysomnography and conrmed
when the apnea-hypopnea index (AHI) exceeds 15 events/h
[3]. OSA is the most common disease associated with resistant hypertension. According to aforementioned denition, it
is diagnosed in 64% of patients [3]. In hypertensive patients,
OSA is associated with obesity. However, in patients with
heart failure and stroke, a direct relationship between body
mass index and OSA severity has not been proven [4–6].
OSA is considered an independent risk factor for cardiovascular events, including ischemic heart disease, heart failure, stroke and death [7]. Several mechanisms, such as
inammation, oxidative stress, and endothelial dysfunction
underlie the association between OSA and cardiovascular
disease [8, 9]. Continuous positive airway pressure (CPAP)
is the treatment of choice for severe OSA and may ameliorate its consequences [2, 10].
Patophysiology ofObstructive Sleep Apnea
OSA is characterized by recurrent episodes of complete or
partial upper airway obstruction during sleep [11]. OSA
occurs when sleep-related inhibition of respiratory drive to
the upper airway dilator muscles is superimposed on a previously narrowed airway [2]. The upper airway may be narrowed due to macroglossia, tonsillar hypertrophy or increased
fatty deposits in surrounding neck tissues. In addition, peripharyngeal uid retention and its rostral nocturnal shift
A. Witkowski (*) · J. Kądziela
Department of Interventional Cardiology and Angiology,
National Institiute of Cardiology, Warsaw, Poland
e-mail: witkowski@hbz.pl; jkadziela@ikard.pl
while sleeping has been postulated as a reason for increasing
peripahryngeal tissue mass. Recumbent position provokes
neck veins distension and edema of surrounding soft tissue
that increases the upper airway resistance and facilitates its
obstruction. In different scenarios (heart failure, chronic kidney disease, hypertension, obesity) intensive sodium and
water retention may be dietary [12], neurogenic- resulting
from increased sympathetic activity leading to renin release
[13], or humoral - as a consequence of activation of the
renin-angiotensin-aldosterone axis [14]. It has been demonstrated that, in response to the application of lower body
positive pressure, neck circumference increases and the pharyngeal cross-sectional area decreases giving higher pharyngeal resistance and collapsibility [15, 16]. Simultaneously,
leg uid volume is reduced, conrming that changes of upper
airway resistance are secondary to the uid shift towards the
peripharyngeal area. In a study including non-obese healthy
subject, a direct relationship between the volume of the nocturnal uid shift and the change of neck circumference and
severity of OSA was reported [17]. Moreover, in patients
with chronic venous insufciency, the use of compression
stockings diminished daytime uid accumulation in the legs
and overnight uid shift and, by consequence, reduced AHI
by 35% [18]. Further evidence that nocturnal rostral uid
shift can cause OSA was provided by two studies, demonstrating that uid removal using overnight peritoneal dialysis
in patients with chronic renal failure increased pharyngeal
upper airway diameter and alleviated OSA severity as compared to the removal of the same amount of uid with continuous 24-h dialysis [19, 20]. Similar improvement was
conrmed by the conversion of hemodialysis from a daytime
to an overnight procedure [21].
Another potential mechanism linking OSA and uid
retention is hyperaldosteronism that is very common in subjects with resistant hypertension. Aldosterone-mediated
chronic uid retention may inuence OSA severity in
patients with resistant hypertension. In one study treatment
with a mineralocorticoid receptor antagonist substantially
reduced the severity of OSA [14].
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_10
107
108
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A. Witkowski and J. Kądziela
Relationship Between Hypertension
andObstructive Sleep Apnea
It is known that intermittent hypoxia or experimentally
induced OSA can cause persistent daytime hypertension in
rats and dogs [22, 23]. In one study, it was demonstrated that
subjects with an AHI ≥15 had almost three-fold greater likelihood of developing hypertension than those with an AHI of
zero [24], however some other studies did not conrm this
relationship [25, 26]. Nevertheless, the remarkable nding
that OSA is by far the most common disease associated with
drug resistant hypertension and that its treatment may lower
blood pressure suggest that OSA plays a provocative role in
hypertension pathogenesis [27].
Sympathetic Neural Mechanisms inResistant
Hypertension andObstructive Sleep Apnea
Increased sympathetic activity, consistently evident in OSA
patients, likely plays a key role in the development of resistant hypertension. Autonomic and hemodynamic responses
to obstructive sleep apnea are very complex and include the
effects of apnea, hypoxia, hypercapnia, the Mueller maneuver (inspiration against a closed glottis), and arousal [28].
Hypoxia and hypercapnia both cause an increase in sympathetic activity and this increase is especially marked during
apnea [29–32]. The role of sympathetic activation in OSA
patients was further elucidated in a study by Somers etal.
[33] Patients with OSA had high sympathetic activity when
awake, with further increment in blood pressure and sympathetic activity during sleep. These increases are attenuated by
treatment with CPAP indicating that OSA induces sympathetic activation and facilitates blood pressure rises during
sleep. Sympathetic overactivation in OSA patients also acts
to increase the heart rate [34], and can worsen the prognosis
of patients with cardiovascular diseases, specically by causing cardiac ß-adrenoreceptor desensitization, arrhythmias,
myocyte injury and necrosis and peripheral vasoconstriction
[35]. It may also promote renal sodium retention, both
directly and through stimulation of the renin-angiotensinaldosterone axis.
tion of the autonomic nervous system. In another study, RDN
caused an elevation of urine volume and sodium excretion in
rats with acute total obstructive apnea [37]. This suggests that
the increase in renal sympathetic nerve activity during apnea
episodes prevents the elevation of renal excretory function in
non-denervated animals. It supports the hypothesis that renal
sympathetic nerves play an important role in sodium homeostasis, with renal nerve activation enhancing sodium retention
and that suppression of the sympathetic activity by RDN may
counteract or diminish this effect.
Human Experience
The potential impact of renal sympathetic denervation (RDN)
on sleep apnea was reported in two human studies [38, 39].
The rst study included 10 patients with resistant hypertension
(dened as systolic ofce blood pressure greater than 160mm
Hg despite the treatment with 3 or more antihypertensive
drugs including diuretic) and sleep apnea [38]. OSA was diagnosed in 8 patients and mixed sleep apnea (obstructive and
central) in two. There were 5 patients with mild sleep apnea
(AHI 5 to 15 events/h) and 5 patients with moderate-to-severe
apnea (AHI > 15 events/h). Two patients were treated with
CPAP before RDN and maintained during the follow-up
period. All patients underwent catheter- based radiofrequency
RDN (Symplicity, Medtronic, Minneapolis, MN, USA). The
median reduction of systolic blood pressure was 22mm Hg
(p<0.01) and 34mm Hg (p<0.01) at 3 and 6months after
RDN, respectively (Fig.10.1), with no differences between
Renal Denervation inResistant Hypertension
andObstructive Sleep Apnea
Animal Studies
In an experimental study by Linz et al. renal denervation
(RDN) but not treatment with ß-blocker inhibited postapneic
blood pressure rises in pigs [36]. RDN also had an antiarrhythmic effect, reducing atrial brillation inducibility by modula-
Fig. 10.1 Median systolic and diastolic BP changes after renal sympathetic denervation procedure at 3 and at 6months of follow-up. Error
bars represent interquartile range (Figure reused with permission from
the 1st edition of the book)
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