159Renal Denervation
Since excessive renal sympathetic activation has been demonstrated to play a major
role in promoting hypertension and sympathoexcitation is common in patients with
resistant hypertension, renal denervation appeared as the logical therapeutic solu-
tion for those patients whose blood pressure cannot be controlled by medication. A
novel catheter-based, radio-frequency ablation technique was designed to selec-
tively eliminate renal innervation. Following successful proof-of-concept studies,
the Symplicity device (Medtronic) was tested in two open label, uncontrolled trials
in patients with resistant hypertension (SYMPLICITY HTN-1 and SYMPLICITY
HTN-2). These studies have confirmed a significant reduction in systolic blood
pressure of more than 30 mmHg which was sustained for as long as 3 years after the
renal denervation [ 45 ]. The larger SYMPLICITY HTN-3 trial was designed to
include a sham procedure, blinding, and more rigorous inclusion criteria for resis-
tant hypertension. Although this trial met the safety end points, it however failed to
achieve the primary end point, as patients with renal denervation had a reduction in
systolic blood pressure of only 2 mmHg more pronounced than those who received
pharmacological therapy alone [ 46 ]. The disappointing results of this last clinical
trial have received numerous explanations including changes in medication and
dosing, preferential use of classes of drugs in certain ethnic groups but were not
found to be substantiated. Another possibility considered was that the extent of
denervation was not uniform, a hypothesis difficult to assess since measurement of
renal spillover of norepinephrine to quantitatively ascertain the degree of denerva-
tion has not been performed due to technical challenges [ 36 ]. However, the identifi-
cation of those physiological factors that determine the blood pressure response to
renal nerve ablation in the heterogeneous group of patients with resistant hyperten-
sion has remained unsolved. First of all, the iconoclastic contention that renal sym-
pathetic activity is necessarily increased in all forms hypertension and that renal
denervation invariably lowers blood pressure is challenged by multiple experimen-
tal studies which suggest that only those animal models where hypertension is sym-
pathetically mediated respond to renal denervation. It is therefore unfortunate that
the technology used to assess RSNA by renal norepinephrine spillover is not avail-
able for current clinical use since very little inference about the relationship between
basal RSNA and the blood pressure response to renal denervation can be made in
the absence of these measurements. Second, if the activity of the renin-angiotensin-
aldosterone system escapes sympathetic modulation, such as would be the case dur-
ing treatment with blockers of RAS [ 36 ] which may also lead to aldosterone
breakthrough [ 47 ], or resistant hypertensive patients with CKD who may have nor-
mal aldosterone levels but increased sensitivity of the mineralocorticoid receptor
[ 47 ], renal denervation would not be expected to cause sustained reductions in
blood pressure [ 36 ]. Third, as volume expansion is a consistent pathological finding
in patients with resistant hypertension, especially when CKD is a comorbid condi-
tion [ 48 ], experimental observations indicating that the renal nerves are not primary
mediators of the modulation of renin secretion by dietary salt [ 49 ] suggest that the
10 Secondary Causes: Work-Up and Its Specificities in CKD: Influence of Autonomic...