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J. Doublet et al.
tion as a > 10 mmHg decrease in 24-h systolic BP at
6months. Based on this denition, in the denervation group,
the response rate was 35%.
In the RADIANCE HTN SOLO study targeting non-
resistant hypertension, in the absence of antihypertensive
therapy and based of ABPM recording, 49 of 74 patients
(66%) experienced a decrease >5 mmHg in mean diurnal
systolic BP at 2months in the renal denervation group, compared to 24 of 72 patients (33%) in the control group [6].
Finally, in the RADIOSOUND study the response was
dened as a>5mmHg reduction in daytime systolic BP at
3months [7]. An “extreme” response was dened as a reduction in daytime systolic BP>20mmHg at 3months. Sixty- six
percent of patients were responders in the radiofrequency
renal artery trunk denervation group, 73% in the radiofre-
quency renal artery trunk and branch denervation group, and
67% in the ultrasound denervation group. “Extreme”
responders were found in 8%, 14% and 29% of patients in
the latter groups.
The percentage of responders is, therefore, variable
depending on the denition. The use of ABPM is more
important due to its better reproducibility and therefore
should be used to assess the BP response after
denervation.
Overall, an acceptable denition of response is a decrease
of daytime systolic BP >5–10mmHg. Using this denition,
the response rate is about 60% taking several studies into
consideration (Table21.1). This response rate and magnitude
of BP reduction corresponds more or less to the effects
observed in antihypertensive drug trials.
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Percentage of
responders
58.3% at
6months
Denition of
responders
Decrease
>10mmHg
(SBP
Results (decrease in
mmHg)
RDN=−14,1mmHg
p=0.26
Primary
judgement
criteria
SBP
consultation at
6months
consultation)
41.7% at
6months
Decrease
>20mmHg
(24-h average
RDN=−15.8mmHg
p=0.03
Daytime
average SBP
(ABPM) at
SBP in ABPM)
6months
35% at
6months
Decrease
>10mmHg
(24-h average
RDN=−8.8mmHg
p=0.87
24-hour
average SBP
(ABPM) at
SBP in ABPM)
6months
xx xx
RDN=−5.5mmHg
p<0.05
24-hour
average SBP
(ABPM) at
xx xx
RDN=−9.0mmHg
3months
24-hour
p<0.05
average SBP
(ABPM) at
6months
66% at
2months
Decrease
>5mmHg
(daytime
RDN=−8,5mmHg
p<0.05
average SBP
(ABPM) at
RF main renal
artery: 66% at
average SBP in
ABPM)
Decrease
>5mmHg
Total
cohort=−9.5mmHg
2months
Daytime
average SBP
3months
RF main and
side renal
arteries: 73%
(daytime
average SBP in
ABPM)
(ABPM) at
3months
211
at 3months
Ultrasound:
67% at
3months
RF catheter
unipolar
Description of the
population
(denervation group) Technology
Age=57.9years
BMI=34.2
Renal
Tensional
phenotype
hypertension
under 3
Number of
inclusions
535 Systolic
Randomized controlled
trial with Sham
procedure
RF catheter
unipolar
insufciency=9.3%
Type 2 diabetes=47%
Myocardial
infarction=8.8%
Age=55.2
BMI=30.7
treatments
(ABPM) to
106 HTA resistant
Randomized controlled
trial, renal denervation
RF catheter
GFR=88ml/
mn/1.73m^2
Type 2 diabetes=17%
MACE=30.2%
Age=56
standardized
triple therapy
106 HTA resistant to
against standard
pharmacological
strategy
Randomized controlled
unipolar
BMI=31.2
GFR=90ml/
mn/1.73m^2
Type 2 diabetes=22%
triple therapy
trial, renal denervation
against standard
pharmacological
strategy
RF catheter
multi
electrode
Coronary artery
disease=6%
Age=52.4
BMI=31.6
Type 2 diabetes=4%
Coronary artery
diastolic
hypertension
without
80 Systolo-
Randomized controlled
trial with sham
procedure
RF catheter
multi
electrode
disease=0%
Age=53.9
BMI=31.4
Type 2 diabetes=13%
Coronary artery
disease=3%
treatment
diastolic
hypertension
with 1 to 3
treatments
80 Systolo-
Controlled trial with
sham procedure
Ultrasound Daytime
Age=54
BMI=29.9
Type 2 diabetes=3%
diastolic
hypertension
146 Systolo-
Controlled trial with
sham procedure
ultrasound
and RF
GFR=84.7ml/
min/1.73m^2
Age=63.5
BMI=31.6
without
treatment
hypertension
120 Systolic
Randomized controlled
trial, 2 RF denervation
catheter multi
electrode
Diabetes=46%
GFR=77.4ml/
min/1.73m^2
Coronary artery
disease=36%
under treatment
arms and 1 ultrasound
arm
Study (year) Methodology
Symplicity HTN
Table 21.1 Description of the main clinical trials and response rates
3 (2014)
DENER HTN
(2015)
PRAGUE-15
(2015)
SPYRAL OFF
MED (2017)
SPYRAL ON
MED (2018)
RADIANCE
HTN-SOLO
(2018)
RADIOSOUND
(2019)
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J. Doublet et al.
Clinical Predictors ofResponse
There are few articles suggesting clinical features that may
predict a better response to renal denervation. We will not
discuss here the technical characteristics of the renal denervation procedure which may determine blood pressure
response.
Secondary analysis of the SIMPLICITY 3 trial revealed
some factors predictive of denervation response in multivariate analysis [3]. Systolic BP at baseline >180 mmHg and
mineralocorticoid receptor antagonist (MRA) prescription
was associated with a good response to denervation. In contrast, the initial prescription of vasodilators was predictive of
poor response. Based on ABPM data, the initial prescription
of MRA and a GFR> 60 ml/min/m^2 were predictive of a
response to denervation. The initial prescription of MRA is
thought to be related to a better response to denervation for
several reasons according to the authors. First, patients on
MRA may have had more severe HTN. Second, MRAs
inhibit the sympathetic nervous system, which may potentiate the action of renal denervation [8].
The Global SYMPLICITY Registry is a large registry for
renal denervation procedures [9]. It includes 2237 patients
denervated using Medtronic catheters (SYMPLICITY Flex
and SIMPLICITY SPYRAL single-electrode). The authors
found a signicant reduction in average 24H systolic BP at
3years. Patients with a better response had higher systolic
BP at baseline. In addition, the BP response was poorer in
patients treated with alpha blockers or vasodilators. In this
registry the impact of denervation in certain subgroups with
co-morbidities has been studied [10]. Age>65years, diabetes mellitus and atrial brillation were not associated with a
poorer response to renal denervation. Similarly, patients with
a higher cardiovascular risk score (ASCVD) had a similar
response to denervation compared to patients with a lower
risk score. Patients with isolated systolic hypertension also
experienced a signicant reduction in 24 h systolic BP at
3years.
It should be noted that, after combining data from
Symplicity HTN 3 and the global registry, while some
patients with isolated systolic hypertension experienced a
meaningful blood pressure reduction, overall the response
to renal denervation in patients with isolated systolic hypertension was less pronounced than in patients with combined systolic and diastolic hypertension. For example, at
6-month follow-up, the reduction in 24h ambulatory systolic blood pressure was 9 mmHg in patients with combined hypertension versus 6mmHg in patients with isolated
systolic hypertension. In this analysis, the strongest predictors of ofce blood pressure at 6 months was combined
hypertension, use of aldosterone antagonists and absence
of vasodilators.
In summary, these results from various clinical studies do
not allow identication of clinical factors predictive of
response to denervation within the limits of a very homogeneous and small overall sample size. In the current state of
knowledge, the use of renal denervation can, therefore, be
proposed for any type of hypertension provided the renal
artery anatomy is suitable, even in the presence of signicant
cardiovascular co-morbidities or isolated systolic hypertension recognizing that a blood pressure reduction is more
likely the higher the baseline systolic blood pressure and in
patients with combined hypertension. The latter notion is
likely the reason why randomized trials of second and third
generation devices have included almost exclusively patients
with combined hypertension.
Focus ontheTherapeutic Target:
Sympathetic Tone
The development of renal denervation is based on the results
and principle of thoracolumbar sympathectomy [1]. This
intervention, therefore, seeks to modulate and inhibit the
sympathetic activity responsible in part for the rise in blood
pressure. Two clinical markers of sympathetic tone were
studied: blood pressure variability and heart rate (HR).
Blood Pressure Variability
Secondary analysis of the DENER HTN study found some
arguments supporting the hypothesis that the identication
of an increased sympathetic tone would be of interest in predicting the response to denervation [11]. On ABPM at
6months, and by dening response as a reduction in 24-hour
systolic BP of >20mmHg, two predictive parameters were
identied. Nighttime systolic BP at baseline and its variability appear to be predictive of a signicant response to renal
denervation. Conversely, these two variables are not associated with a BP drop in the control group. Thus, these two
parameters allow classication of patients as responders or
non-responders in 70% of cases in the renal denervation
group. Thus, the night-time systolic BP cut-off value of
136mmHg was predictive of a response to renal denervation
with a sensitivity of 75% and a specicity of 54%. Similarly,
the deviation of night-time systolic BP found a 12mmHg
cut-off value predictive of response with a sensitivity of 55%
and a specicity of 83%. Night-time systolic BP and its variability may reect a more prominent role of the sympathetic
nervous system in the pathogenesis of hypertension in an
individual.
Secondary analysis of the RADIANCE SOLO study’s
ABPM data will be released shortly. The thresholds for
21 Patient Selection forRenal Denervation
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213
night-time systolic BP and its variability previously dened
in the DENER HTN population were applied to the
RADIANCE SOLO study population. The ability of these
parameters in predicting BP response at 2months following
denervation was evaluated [12]. As previously mentioned,
several types of response were dened. The rst was the
“clinical” response (24-hour systolic BP<130mmHg), the
second was the “signicant” response (24-hour systolic BP
decrease>10 mmHg) and the last type was the “extreme”
response (24-hour systolic BP decrease >16.5 mmHg).
Night-time systolic BP and its variability, particularly when
combined, provided good specicity (>90 per cent regardless of the denition) but low sensitivity (9.1–30% depending on the denition) for predicting responders. This analysis
suggests the potential role of night-time systolic BP and its
variability in predicting renal denervation BP response in
hypertensive patients [12].
Heart Rate
The PRAGUE 15 study found a decrease in HR in the renal
denervation group [5]. In addition, day-time systolic BP
and day-time HR were associated with a good response to
renal denervation. These ndings support the hypothesis
that HR is related to denervation response, particularly
through denervation-mediated reduction in sympathetic
activity.
Secondary analysis of the SPYRAL HTN-OFF MED
study found comparable results [13]. A higher baseline HR
was associated with a more pronounced BP drop after renal
denervation. In addition, patients with 24-h HR>73.5bpm
at baseline had a signicant decrease in 24-h systolic BP,
and mean 24-hour HR in the renal denervation group compared to the control group. No signicant difference was
found in patients with mean HR < 73.5 at baseline. In
another analysis, in patients who had a baseline ofce heart
rate of ≥70/min the 24hour ABPM reduction was 6.2mm
Hg compared to 0.1mmHg for those whose heart rate was
<70/min (interaction p-value of 0.008) [14]. This suggests
that patients with adrenergic hypertonicity (higher HR)
would be likely to be more responsive to renal
denervation.
In the secondary analysis of the RADIANCE SOLO
study, the latter value of 73.5bpm was studied as a predictive
factor [15]. For the single criterion of mean heart
rate ≥ 73.5 bpm alone, sensitivity and specicity were
approximately 50%, which do not allow responders discrimination regardless of denition. The evolution of BP compared to baseline at 2months was also compared in the renal
denervation and control groups according to the 24-hour
mean heart rate criteria < or≥ 73.5bpm. The decrease in
day-time systolic BP after renal denervation was greater in
patients with a mean 24-hour heart rate ≥ 73.5bpm compared to those with a mean 24-h <73.5bpm. Nevertheless,
similar ndings were found in the control group.
Diastolic Blood Pressure
In RADIANCE-HTN SOLO, patients who were not taking
any antihypertensive medications at the time of denervation
were randomized to denervation versus sham. A post-hoc
analysis identied diastolic blood pressure and use of antihypertensive medications (at the time of screening) as predictors of response after renal denervation using ultrasound
technology [15]. It is also worth mentioning that there was
a trend toward predictive value of orthostatic hypertension.
A higher diastolic pressure may be a reection of a higher
baseline peripheral arterial resistance and sympathetic tone
[16]. In fact, it has been demonstrated that higher muscle
sympathetic nerve activity (MSNA), a surrogate for a
higher sympathetic tone, correlates with mean blood pressure (which is driven primarily by the diastolic blood pressure [17]).
Arterial Stiness
There is some retrospective data to support that HTN in
patients with stiff arteries is less likely to respond to renal
denervation. More recently, Fengler et al. published the
results of their prospective study of arterial stiffness in 80
patients planned to undergo renal denervation [18]. Arterial
stiffness was assessed by invasive pulse wave velocity
(IPWV) and magnetic resonance imaging based parameters
prior to the procedure. A cut-off of 14.4m/s for IPWV was
used to separate patients with and without stiff arteries. In
patients with stiff arteries (IPWV >14.4m/s), 3months after
denervation the 24hour systolic ABPM reduction was signicantly less pronounced (~6mmHg) compared to patients
whose arteries were less stiff (~14 mmHg) (p < 0.001).
Furthermore, logarithmic ascending aortic distensibility and
baseline systolic BP independently predicted blood pressure
response.
In Practice: Patient Selection
Conrmation ofHTN andExclusion
ofSecondary Causes
First of all: common sense!! HTN must be conrmed by performing home BP or ABPM.Next, secondary cause of HTN
must be ruled out. A systematic hormonal assessment is
therefore mandatory in order to eliminate primary hyperal-
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J. Doublet et al.
dosteronism requiring a specic treatment. Computed
tomography, Duplex ultrasound or magnetic resonance
tomography of the renal arteries is performed to exclude
renovascular HTN and to evaluate anatomical suitability. It is
also important to perform a complete dietary evaluation,
looking for excessive sodium intake and sleep study to assess
for untreated obstructive sleep apnea. Finally, in the context
of resistant arterial hypertension, the evaluation of drug compliance is helpful. This can be assessed by the urinary pharmacological evaluation.
Which Blood pressure Phenotype?
Today, there is little data to select patients on this criterion.
Studies show a comparable BP response in both resistant and
mild hypertension. The registry shows signicant clinical
responses for systolic hypertension whereas randomized
clinical trials selected systolo-diastolic hypertension.
Moreover, it has been shown that patients with isolated systolic hypertension (Mahfoud Symplicity HTN 3) were less
likely to benet from renal denervation compared to those
with combined hypertension. Finally, the homogeneity of the
selected populations and the small sample of patients should
make it necessary to continue the clinical studies especially
in young subjects and poorly represented women. The observation of marked blood pressure variability, particularly during nighttime period, is very specic of a good response to
renal denervation regardless of the blood pressure phenotype. However, this criterion is not sensitive enough and
therefore should not exclude other patients. Furthermore,
while baseline heart rate and diastolic hypertension may
have predictive value in the response rate and may help to
educate a patient who is being considered for denervation
regarding the likelihood of success but should not be used as
sole criteria to include or exclude patients for the procedure.
In conclusion, renal denervation should now be considered for patients after a complete blood pressure check-up.
In cases of resistant hypertension, even in the presence of
co-morbidities, this procedure can be offered. Similarly, in
cases of mild to moderate hypertension, particularly when
associated with therapeutic non-compliance, this technique
can be performed. If the subject is well selected, a signicant
blood pressure response (>5mmHg over 24H) is achieved in
60% of cases, which is more or less the response rate
expected with other classes of anti-hypertensive treatment
(Fig.21.1).
Suspicion of HTN
1st step: Confirmation of
HTN by ABPM or HBPM
Step 2: Screen for secondary
HTN and rule out
incompatible anatomy
Renal denervation with
expected response in 60%
subjects: >5mmHg of PAS
over 24H
Fig. 21.1 Algorithm proposal for the realization of renal denervation
References
1. Parkes WE. Thoracolumbar sympathectomy in hypertension. Br
Heart J. 1958;20:249–52.
2. Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial
of renal denervation for resistant hypertension. N Engl J Med.
2014;370:1393–401.
3. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J.
2015;36:219–27.
4. Azizi M, Sapoval M, Gosse P, etal. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre,
open-label, randomised controlled trial. Lancet. 2015;385:1957–65.
5. Rosa J, Widimsky P, Tousek P, etal. Randomized comparison of
renal denervation versus intensied pharmacotherapy including
spironolactone in true-resistant hypertension: six-month results
from the Prague-15 study. Hypertension. 2015;65:407–13.
6. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN
SOLO): a multicentre, international, single-blind, randomised,
sham- controlled trial. Lancet. 2018;391:2335–45.
7. Fengler K, Rommel KP, Blazek S, et al. A three-arm randomized trial of different renal denervation devices and techniques
in patients with resistant hypertension (RADIOSOUND-HTN).
Circulation. 2019;139:590–600.
8. Wray DW, Supiano MA. Impact of aldosterone receptor blockade
compared with thiazide therapy on sympathetic nervous system
function in geriatric hypertension. Hypertension. 2010;55:1217–23.
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9. Mahfoud F, Bohm M, Schmieder R, etal. Effects of renal denervation on kidney function and long-term outcomes: 3-year follow- up from the Global SYMPLICITY registry. Eur Heart J.
2019;40:3474–82.
10. Mahfoud F, Mancia G, Schmieder R, et al. Renal denervation in high-risk patients with hypertension. J Am Coll Cardiol.
2020;75:2879–88.
11. Gosse P, Cremer A, Pereira H, etal. Twenty-four-hour blood pressure monitoring to predict and assess impact of renal denervation: the DENERHTN study (renal denervation for hypertension).
Hypertension. 2017;69:494–500.
12. Gosse P, Cremer A, Kirtane AJ, etal. Ambulatory blood pressure
monitoring to predict response to renal denervation: a post hoc
analysis of the RADIANCE-HTN SOLO study. Hypertension.
2021;77:529–36.
13. Bohm M, Mahfoud F, Townsend RR, etal. Ambulatory heart rate
reduction after catheter-based renal denervation in hypertensive
patients not receiving anti-hypertensive medications: data from
SPYRAL HTN-OFF MED, a randomized, sham-controlled, proofof- concept trial. Eur Heart J. 2019;40:743–51.
14. Bohm M, Tsious K, Kandzari DE, etal. Effect of heart rate on the
outcome of renal denervation in patients with uncontrolled hypertension. J Am Coll Cardiol. 2021;78:1028–38.
15. Saxena M, Schmieder RE, Kirtane AJ, etal. Predictors of blood pressure response to ultrasound renal denervation in the RADIANCEHTN SOLO study. J Hum Hypertens. 2021;
16. Guyenet PG.The sympathetic control of blood pressure. Nat Rev
Neurosci. 2006;7:335–46.
17. Narkiewicz K, Winnicki M, Schroeder K, et al. Relationship
between muscle sympathetic nerve activity and diurnal blood pressure prole. Hypertension. 2002;39:168–72.
18. Fengler K, Rommel KP, Kriese W, etal. Assessment of arterial stiffness to predict blood pressure response to renal sympathetic denervation. EuroIntervention. 2022;
Testing forSecondary Hypertension
https://t.me/medicina_free
andDifficult toControl Patients
OmarAzzam, MárcioGalindoKiuchi, RevathyCarnagarin,
andMarkusP.Schlaich
22
Denition andEpidemiology
Secondary hypertension refers to all forms of hypertension
that have an identiable and potentially reversible cause. It is
estimated to make up 5–10% of cases of hypertension overall, with variation in proportional representation and patterns
of aetiology by age group. It is also subject to referral bias,
with detection rates unsurprisingly higher in hypertension
referral centres than in other settings [1–3]. As an example of
the inuence of age on the prevalence of several types of
secondary hypertension, a retrospective analysis of patients
(n=148) less than 40years of age admitted to a single hypertension centre in Toulouse, where the prevalence of secondary hypertension was close to 33%, primary aldosteronism
and bromuscular dysplasia were the commonest secondary
causes, accounting for 11.5% and 5.4% of the total cohort,
respectively [4]. While identication and directed treatment
of secondary causes in younger hypertensive cohorts is
mostly associated with achievement of BP targets and reduction in risk of hypertension-mediated organ damage
(HMOD), this is not equally achievable in older age counterparts. This is perhaps, at least in part, driven by the higher
prevalence of residual primary hypertension and the prolonged exposure to elevated BP in more advanced age
cohorts [5].
O. Azzam · M. G. Kiuchi · R. Carnagarin
Dobney Hypertension Centre, Medical School - Royal Perth
Hospital Unit, University of Western Australia,
Perth, WA, Australia
e-mail: omar.azzam@health.wa.gov.au; marcio.galindokiuchi@
uwa.edu.au; revathy.carnagarin@uwa.edu.au
M. P. Schlaich (*)
Dobney Hypertension Centre, Medical School- Royal Perth
Hospital Unit, University of Western Australia,
Perth, WA, Australia
Departments of Cardiology and Nephrology, Royal Perth Hospital,
Perth, WA, Australia
Neurovascular Hypertension & Kidney Disease Laboratory, Baker
Heart and Diabetes Institute, Melbourne, VIC, Australia
e-mail: markus.schlaich@uwa.edu.au
Secondary hypertension is also frequent in patients with
difcult to control, or more specically, treatment-resistant
hypertension. Resistant hypertension is dened as BP
above- treatment goal BP despite concurrent use of three
antihypertensive drug classes, commonly including a longacting calcium channel blocker, a blocker of the reninangiotensin system, and a diuretic, each at optimal or
maximally tolerated doses. Resistant hypertension also
incorporates patients in whom BP targets are achieved on
≥4 antihypertensive medications [6]. Patients with resistant
hypertension are much more likely to have secondary
hypertension than their non-resistant counterparts, as was
strikingly demonstrable by the exclusion of 50% (709 out
of 1416) of resistant hypertension screened for enrolment
in the renal denervation for resistant hypertension
(DENERHTN) trial [7].
The prevalence of true resistant hypertension is not
known, due to a multitude of confounding factors which
include poor medication adherence, inadequate treatments
regimens, and missing out-of-ofce BP measurements. They
are therefore collectively referred to as ‘apparent resistant
hypertension’ [8]. Among treated adults with hypertension,
prevalence of apparent treatment-resistant hypertension varies by population selection and region [9–11]. In a study of
>400,000 patients, compared with non-resistant hypertension, patients with resistant hypertension were found to be at
32% increased risk of developing end-stage kidney disease,
24% increased risk of coronary artery disease, 46% increased
heart failure, 14% increased risk of stroke, and 6% increased
risk of death [12]. It is therefore imperative that resistant
hypertension is properly identied as this would enable targeted cost-effective screening for secondary causes in a population that signicantly stands to benet from denitive
interventions.
© 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_22
217
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O. Azzam et al.
Forms ofSecondary Hypertension
There are several established causes of secondary hypertension as summarized in Table 22.1. Theses can be broadly
divided into endocrine, vascular, renal, sleep-disordered
breathing, and iatrogenic causes. The most common causes
of secondary hypertension vary by age group, with renal
parenchymal disease and coarctation of the aorta accounting
for the bulk of causes in children and adolescents, while
endocrine disorders and, for instance, obstructive sleep
apnoea more prevalently feature in the younger to middleaged adult cohort, and atherosclerotic renal artery disease
more so in older adults.
In the evaluation of a patient with suspected secondary
hypertension, identication of clinical and biochemical clues
consistent with known disease processes, and an understanding of their prevalence by age demographic, might identify
patients who would benet from screening for secondary
hypertension, and guide the choice of conrmatory investigations with greatest yield. As an example, the following
clues point to the likelihood of renovascular hypertension,
and constitute class 1 (Level of Evidence: B) recommendations for performing diagnostic studies [13]:
1. Onset of accelerated, malignant, or grade 3 hypertension
(blood pressure ≥180mm Hg systolic and/or 110mm Hg
diastolic) after the age of 55years, suggestive of atherosclerotic disease
Table 22.1 Causes of secondary hypertension
Renovascular hypertension
Atherosclerotic
Fibromuscular dysplasia
Endocrine
Primary aldosteronism
Cushing’s syndrome
Pheochromocytoma/paraganglioma (PPGL)
Hypothyroidism/Thyrotoxicosis
Hyperparathyroidism
Apparent Mineralocorticoid Excess
Familial hyperaldosteronism type 1 and type 2
Renal
Glomerulonephritis
Chronic kidney disease
Liddle’s syndrome
Gordon’s syndrome
Obstructive sleep apnea
Coarctation of the aorta
Iatrogenic
Hormonal (glucocorticoids, non-steroidal anti-inammatory drugs,
contraceptive pills etc)
Cancer therapies (e.g., tyrosine kinase inhibitors, VEGF blockade)
Calcineurin inhibitors (cyclosporine and tacrolimus)
Illicit substances
Amphetamines, cocaine etc.
VEGF vascular endothelial growth factor
2. Early onset hypertension, especially in females, suggestive of bromuscular dysplasia
3. Unexplained acute and sustained rise in creatinine after
commencement of an angiotensin-converting enzyme
(ACE) inhibitor, angiotensin II receptor blocker (ARB),
or direct renin inhibitor.
4- Severe hypertension in a patient with known atheroscle-
rotic disease at other sites
5- Severe hypertension in a patient with an atrophic kidney
or kidney size asymmetry
6- Sudden, unexplained, recurrent episodes of ash pulmo-
nary oedema (more common in bilateral renal artery
stenosis)
7- Severe hypertension and sudden or unexplained heart
failure and impaired renal function
8- Abdominal systolic-diastolic bruit that lateralises to one
side; a modestly sensitive but highly specic nding [14]
Features suggestive of other causes of secondary hypertension will be mentioned in their respective following
sections.
Renovascular Hypertension (RVH)
Renovascular hypertension (RVH) is a common type of secondary hypertension that is dened as hypertension in the
setting of renal artery stenotic or occlusive disease that lowers renal perfusion pressure to a level that activates the reninangiotensin- aldosterone system. While prevalence is low in
mild-moderate hypertension, it may be as high as 38% in
white patients with severe hypertension in the US [15]. The
overwhelming majority (90%) are caused by atherosclerotic
disease, referred to atherosclerotic renovascular hypertension (ATS-RVH), with remainder predominantly caused by
bromuscular dysplasia (FMD-RVH) [16]. While ATS-RVH
is the dominant form in older patients (>55 years), FMDRVH is the prevailing form of RVH in patients of younger
age and early onset hypertension [17]. Guidelines and consensus statements across several invested societies (American
College of Cardiology/American Heart Association, the
European Society of Cardiology, and Society of
Cardiovascular Angiography and Interventions) strongly
advocate screening for RAS if features of secondary hypertension are present, alternative causes are unlikely, and a corrective procedure would be planned if a signicant lesion
was found [13, 18].
Patients with hypertension often have concurrent established atherosclerotic disease, including of the renal arterial
bed. There is a possibility of a bidirectional relationship
between the two disease states in an individual patient. It is
understandably often challenging to conclude that a renal
artery stenotic lesion contributes to the pathogenesis of
22 Testing forSecondary Hypertension andDicult toControl Patients
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hypertension (i.e., renovascular hypertension). Certainty of
such is perhaps only possible retrospectively if revascularization achieves improvement or resolution of hypertension
[19]. Their nding does not necessarily warrant an intervention given the lack of evidence for clear cut benet with
interventional approaches, and the procedural risks [20].
Notwithstanding, the incidental nding of a renal artery
lesion may predate the development of hypertension, and
therefore warrants surveillance once detected, alongside
monitoring for new (incident) secondary hypertension which
is potentially reversible in this context [21].
Moreover, there is a high prevalence of (>50% luminal)
atherosclerotic renal artery disease in patients with abdominal aortic aneurysm, aorto-occlusive disease, or lowerextremity occlusive diseases who are often comorbid by
hypertension [22]. Previously utilised tests such as Captopril
renal renography and plasma renin activity are no longer utilised in screening or renal artery stenosis. Instead, screening
is largely reliant on non-invasive forms of imaging which
include duplex ultrasonography, computed tomography, and
magnetic resonance imaging.
Fibromuscular Dysplasia
FMD is classied by angiographic appearances into the following two phenotypes:
1. Multifocal FMD, accounting for >80% of cases, and has
a classical appearance described as “string of beads”, due
to alternating bromuscular webs and aneurysmal dilatation. This form is usually histologically associated with
medial broplasia.
2. Focal FMD, accounts for roughly 10% of cases, and
assumes a concentric, smooth, band-like focal or tubular
stenosis. Unlike the multifocal form, this is usually associated with intimal broplasia [23].
As patients with FMD-RVH tend to be younger, there is conceivably much to gain from accurate and timely diagnosis
and classication. Most patients with multifocal FMD
achieve adequate BP control with pharmacotherapy alone,
using an average of 2 antihypertensive agents, and therefore
risks from revascularization may outweigh benets. Patients
with focal FMD on the other hand, are more likely to have
difcult-to-treat hypertension and ischaemic nephropathy
complications. Hypertension cure rates after revascularization vary widely between studies, averaging around 36%
based on a large meta-analysis by Trinquart etal., more commonly in the focal FMD subgroup [24] (Table22.2).
Catheter-based digital subtraction angiography (DSA)
remains the ‘gold standard’ for accurate assessment of renal
FMD.The nding of a pressure gradient threshold of 10% of
Table 22.2 Clinical signs of renal artery bromuscular dysplasia
Early onset hypertension (<30years old), especially in women
Accelerated, malignant, or grade 3 (>180/110mm Hg) hypertension
Resistant hypertension
Unilateral small kidney without causative urological abnormality
Abdominal bruit in the absence of atherosclerotic disease or risk
factors for atherosclerotic disease
Suspected renal artery dissection/ infarction
Presence of FMD in at least one other vascular territory
FMD bromuscular dysplasia. Adapted with slight modication from
Gornik etal. [17]
the mean (aortic) pressure, or a trans-lesional gradient of
>20 mm Hg, can be used to decide whether the lesion is
hemodynamically signicant and guide the decision to proceed with angioplasty, although this is essentially an extrapolation from experience with atherosclerotic renal artery
stenosis [17, 25]. Non-invasive testing by means of
Computed tomographic angiography (CTA) is the study
of choice when clinical suspicion of FMD as a cause of secondary hypertension arises. Magnetic resonance angiography (MRA) offers an alternative where CTA is
contraindicated. CTA provides better spatial resolution and
offers superior sensitivity in detecting renal FMD than MRA,
hence it is preferable for screening if the index of suspicion
is high. The risk of a false negative with both modalities
remains signicant, especially in the case of distal / intrarenal portions of the renal artery [26].
Duplex ultrasound, while non-invasive, more affordable, and devoid of radiation exposure, has several limitations as it is time consuming, affected by patient’s body
habitus, and is highly operator dependent. It is therefore only
cautiously recommended as a screening test for exclusion of
renal FMD in specialized centres with extensive experience
in evaluation FMD [17]. While peak velocity of >200cm/sec
is commonly considered to reect a stenosis of >60%, and a
peak velocity>300cm/sec considered to represent a hemodynamically signicant threshold, estimations of degree of
stenosis by Duplex is fraught with inaccuracy and therefore
should perhaps not be relied on in diagnosing, or indeed surveillance of, renal FMD [27].
Atherosclerotic Renovascular Hypertension
(ATS-RVH)
Unlike FMD, atherosclerotic renal artery stenosis more commonly affects aorto-ostial and the proximal sections of the
main renal arteries (Fig.22.1). This form of renal artery stenosis is most commonly observed in more advanced age
groups (>55–65years) and is often part of systemic atherosclerosis involving several vascular beds [28]. Unilateral disease constitutes somewhere between 53% and 80% in
revascularisation randomised controlled trials, meaning that
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Fig. 22.1 Aortogram illustrating relatively high-grade, bilateral atherosclerotic lesions located at the ostia of the renal arteries in a 63-yearold man. [Adapted from Textor SC. Progressive hypertension in a
patient with “incidental” renal artery stenosis. Hypertension.
2002;40(5):595–600 [21], with permission. Hypertension]
a signicant proportion of patients have bilateral disease
[29–31].
Catheter-based DSA, as with FMD-RVH, remains the
‘gold-standard’ for diagnosis and quantitative assessment of
renal artery stenosis due to atherosclerotic disease. In
addition to excellent depiction of vascular anatomy through
direct injection of contrast medium into the renal artery, it
enables the measurement of pressure gradients across stenotic lesions, which correlates with severity of the lesion and
predicts successful intervention [25, 32]. Non-invasive diagnostic techniques which use angiographic and haemodynamic measures of lesion severity do not correlate well. The
negative results of the largest randomised controlled trials
comparing revascularisation with medical therapy alone are
believed to be at least in part inuenced by inaccurate and
non-standardized radiological assessments used in the selection of trial participants [29, 30].
Duplex ultrasound is the most widely used initial screening modality. It provides a valuable non-invasive and relatively inexpensive means of screening for renal artery
stenosis. In spite of these advantages, it has several limitations relating to procedural challenges (time-consuming,
patient habitus) and diagnostic accuracy. It provides an indirect method of detecting and estimating the severity of stenotic lesion(s), which has propensity to overestimate severity,
and therefore lead to ‘overdiagnosis’. This might at least
partly explain the historical disappointment from results of
renovascular angioplasty for renovascular hypertension,
wherein some patients enrolled had less severe disease and
therefore were less likely to benet from revascularisation
[33]. The additional measurement of renal resistive index
([peak systolic velocity- end-diastolic velocity] divided by
peak systolic velocity) will identify patients with renal artery
stenosis who may benet from revascularisation. In a pro-
O. Azzam et al.
spective study of 131 patients with luminal narrowing >50%,
a resistive index >80% reliably identies patients with renalartery stenosis in whom angioplasty or surgery will not
improve renal function, BP, or kidney survival [34]. This
likely reect the correlation between elevated resistive index
and established arteriosclerotic renal disease [35]. The utility
of an 80% cut off in predicting renal outcomes was replicated by a subsequent study which examined patients who
underwent open or percutaneous intervention for ATSRVH. There was also a strong, independent relationship
between pre-operative resistive index with mortality, but not
with blood pressure response [36]. However, it must be
remembered that this parameter is highly operator dependent, and inuenced by patient factors such as obesity.
Computed tomographic angiography (CTA) is the
most reliable form of non-invasive testing for the diagnosis
RAS. It has a sensitivity of 97%, and specicity of 96%
when assessed in small groups of patients, and therefore if
negative, affords the attending clinician a degree of condence to forgo the need for invasive catheter-based evaluation [37].
Magnetic resonance angiography (MRA) with
gadolinium- enhancement is highly sensitive in detecting
RAS of the proximal/ main renal arteries [38]. It’s main limitation however is the risk of gadolinium related nephrogenic
systemic brosis in patients with moderate-severe renal
impairment, a prominently featured comorbidity in this population cohort. Use of gadolinium, especially a group 1 agent
(gadodiamide), is probably best avoided in patients with an
eGFR <30mL/min/1.73m2 [39, 40].
Primary Aldosteronism (PA)
Primary aldosteronism (PA), initially described by Conn in
1955, refers to a syndrome of autonomous production of
aldosterone by the adrenal cortex, associated classically with
a triad of hypertension, hypokalaemia, and metabolic alkalosis [41]. The biochemical hallmark of PA is an elevated
plasma aldosterone concentration (PAC) and an associated
suppressed plasma renin concentration/activity (PRC /
PRA). Its prevalence in the hypertensive population varies
widely from 2–34% depending on population selection [42–
46]. In contrast to initial description by Conn, the majority of
cases of PA are associated with normokalaemic status, and
therefore have the potential to evade diagnosis if not actively
screened for in cases where a high index of suspicion exists
[47]. Since its early description, the syndrome has been
broadly classied into 2 forms: (1) aldosterone-producing
adenomas (APAs), and (2) bilateral adrenal hyperplasia
(BAH), also known as idiopathic hyperaldosteronism which
accounts for ≅ 60% of cases of PA.APAs is generally associated with higher levels of Aldosterone, more severe hyper-
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