Effect of renal sympathetic denervation on renal and overall sympathetic output in patients with therapy resistant hypertension

Radiofrequency ablation of the renal sympathetic nerves has emerged as a novel
minimally invasive technique to improve BP control in patients with therapy
resistant hypertension. Recently a randomized controlled trial showed that, in
patients with therapy resistant hypertension, renal sympathetic denervation
(RSD) resulted in a significant reduction in office BP of 32 mmHg after 6
months, compared to an increase of 1 mmHg in controls receiving conventional BP
lowering therapy. Despite the general effectiveness of RSD in lowering BP in
patients with therapy resistant hypertension, the magnitude of the individual
BP lowering response is variable. In the recent Simplicity-2 study, the large
SD of the observed BP lowering effect and the variability in BP outcome
parameters suggest large differences in response to RSD. Moreover, BP failed to
go down in 10% of the patients after RSD and only 39% of all patients were able
to get their BP controlled (BP<140/90 mmHg). The large BP variability observed
after RSD may result from several factors. First, the BP response to RSD may
depend on the relative contribution of the kidneys in determining total
sympathetic output. Quantifying sympathetic activity prior to RSD may predict
the efficacy of RSD in lowering BP. Second, because controls received no sham
treatment in the Simplicity-2 study, differences in BP may result from
differences in adherence to BP lowering medication. Third, there is no
certainty whether in humans afferent and efferent renal nerves are truly
ablated by this novel technique. For obvious reasons, the effectiveness of
ablation of renal afferent and efferent nerves has only been tested in animal
studies.
Next to the BP lowering effect, RSD may also exert auxiliary benefits. It is
well-established that diabetes mellitus and insulin resistance are associated
with an increase in sympathetic activity. Furthermore, inhibition of
sympathetic output by sympathicolytic agents such as alpha1 receptor blockers
or centrally acting alpha agonists improves insulin sensitivity. It is
therefore conceivable that RSD, by its decrease in total sympathetic output,
may improve insulin sensitivity.
In addition the decrease in sympathetic tone may also reduce the expression of
inflammatory parameters (e.g. Il-6, TNF-alpha, total WBC count), and alter
central haemodynamics. We recently showed that central BP is lowered after
standing. This effect may be mediated by an increase in sympathetic activity.
It is conceivable that reducing sympathetic output by renal sympathetic
denervation may therefore influence central BP.
Moxonidine, an I1-Imidazoline receptor agonist and centrally acting
antihypertensive drug, is frequently used for the treatment of resistant
hypertension and known to effectively lower sympathetic neural activity. In
this study a matched Moxonidine treated group may serve as a positive control
for RSD in overall sympathetic neural activity dependant outcome parameters.

In this study our overall aim is to more precisely determine which patients
will benefit most from RSD by evaluating both outcome predictors and auxiliary
effects (insulin sensitivity, central haemodynamics and inflammation) of this
new intervention.

Controlled experiment with measurements prior to RSD (<3 weeks) and 6 weeks
after RSD with positive six-week-moxonidine-treated controls (case-control
design).

Patients
Study candidates will be approached by the study physician for participation if
they are referred for RSD because of therapy resistant hypertension. A maximum
of 20 patients will be enrolled to undergo RSD with measurements before and
after intervention. An additional 10 patients who will receive moxonidine
treatment for therapy resistant hypertension will undergo the same measurements
prior to and after six weeks of moxonidine. Patients will be enrolled in the
age-, gender-, BMI-matched moxonidine positive control group if they are deemed
unsuitable for RSD by the treating physician (e.g. inaccessible femoral artery,
or accessory renal artery) and are prone to start treatment with moxonidine for
therapy resistant hypertension.

Visit 1 - Screening visit
Six weeks prior to the first measurements a screening visit will be planned
with the aim to assess whether patients are eligible for inclusion. During the
screening visit a clinical examination will be carried out and laboratory and
imaging results will be obtained to assess whether secondary causes of
hypertension have been sufficiently excluded and whether renal function is
intact (eGFR >45 ml/min/kg). Eligible patients will be informed about the
experiments and the study burden. If patients are willing to participate they
will be asked to provide written informed consent (see InformedConsentRSD).
Next they will receive a questionnaire to assess medication adherence and an
appointment will be made for the 24 hour ambulatory BP recording. 24-hour urine
will be collected for measurement of catecholamines. After the results of the
ambulatory BP measurement are obtained patients will be included in the study.
The screening visit will take approximately 45 min.

Visit 2 - Measurements prior to RSD or moxonidine
Visit 2 will take place 3 weeks prior to RSD. Before the measurements patients
will be asked to return the questionnaire. Thereafter office BP will be
measured and pulse wave analysis will be performed followed by assessment of
pulse wave velocity, central haemodynamics and sympathetic activity. Blood
samples will be drawn during non-invasive assessment of central haemodynamics
and after conclusion of the measurements. A catheter will be inserted to
facilitate for drawing of blood samples. A total of 50ml of blood will be
drawn.

Visits 3 and 4 - Measurements after RSD or moxonidine
Visit 3 will take place approximately 6 weeks after RSD. The measurements
conducted during this visit are identical to the measurements conducted on
visit 2 (including 50ml of venous blood sampling). In addition a
123I-MIBG-scintigraphy, with a single oral dose of furosemide retard 60mg,
will be performed after the non-invasive measurements have been conducted. The
123I-MIBG-scintigraphy includes a scintigram performed 15 minutes after tracer
injection and early in the afternoon (4 hours post injection). A final
scintigram will be performed at visit 4, 24 hours post MIBG tracer injection.
Additionally, an appointment will be made for 24-hour ambulatory blood pressure
measurement.

Additional investigations
All subjects included in this study will undergo the above mentioned
measurements.
Additionally, in a subset of maximum 12 patients undergoing RSD a
hyperinsulinaemic euglycaemic clamp experiment will be performed prior to RSD
and after RSD. The clamping experiments will take place on two different
occasions, adjacent to visit 2 and visit 3. Patients will be asked to
participate in this sub-study if they have insulin-resistance, defined as a
fasting blood insulin level of > 50 pmol/L. For these additional
investigations a separate informed consent will be obtained (see
InformedConsentRSDClamp).

RSD is a minimally invasive technique that has been shown to effectively and
safely reduce BP in 90% of patient with therapy resistant hypertension. Despite
its general beneficial effects on BP control, the magnitude of the BP lowering
response is difficult to predict. We believe that estimates of sympathetic
activity may help in selecting patients who will benefit most from this
intervention. The measurements used for assessment of peripheral and central
haemodynamics are all non-invasive, painless and safe. A total of 2x50ml
(100ml) of venous blood will be drawn for study purposes. Subjects will have a
intravenous cannula inserted on two visits to facilitate for blood drawings and
123I-MIBG injection. Included subjects in this study will be exposed to
radiation as a result of the 123I-MIBG scintigraphy performed. The radiation
exposure is well within the international limits as defined by the WHO (4.2mSv,
ICRP category IIb). In addition, subjects who participate in the sub-study on
insulin sensitivity will have additional blood drawings of 2x150ml (300ml). The
hyperinsulinemic euglycemic clamp is the gold standard to measure glucose
metabolism and is considered to be safe. It will be performed at the metabolic
unit of the department of Endocrinology and Metabolism. The glucose tracer has
no side effects and is provided by the in-house pharmacist. It will be prepared
for infusion by the researcher on the day of the experiment.
The benefits related to the present study consist of the development of new
methods that are able to predict the BP lowering response to this relatively
new BP lowering intervention and to assess whether, apart from lowering BP,
additional beneficial effects exist on insulin resistance and inflammation.