Renal denervation to treat resistant hypertension: Guarded optimism
ABSTRACTRenal sympathetic denervation has shown promise in treating hypertension resistant to drug therapy. This procedure lowers blood pressure via targeted attenuation of renal sympathetic tone, and it has a favorable safety profile. But although there is reason for cautious optimism, we should keep in mind that the mechanisms of hypertension are complex and multifactorial, and further study of this novel therapy and its long-term effects is needed.
KEY POINTS
- Renal sympathetic nerves help regulate volume and blood pressure as they innervate the renal tubules, blood vessels, and juxtaglomerular apparatus. They carry both afferent and efferent signals between the central nervous system and the kidneys.
- Surgical sympathectomy was done in the 1950s for malignant hypertension. It had lasting antihypertensive results but also caused severe procedure-related morbidity. A new percutaneous procedure for selective renal denervation offers the advantage of causing few major procedure-related adverse effects.
- Selective renal denervation decreases norepinephrine spillover and muscle sympathetic nerve activity, evidence that the procedure reduces sympathetic tone.
- The major clinical trials done so far have found that renal denervation lowers blood pressure significantly, and the reduction is sustained for at least 3 years.
SYMPLICITY HTN-2
The Symplicity HTN-2 trial was a larger, randomized, efficacy study that built on the earlier results, providing additional evidence of therapeutic benefit.15
An international cohort of 106 patients with resistant hypertension, defined as systolic blood pressure of 160 mm Hg or higher (or ≥ 150 mm Hg in patients with type 2 diabetes) despite the use of three or more antihypertensive medications, were randomly assigned to undergo renal denervation with the Symplicity device (n = 52) or to continue their previous treatment with antihypertensive medications alone (n = 54). The primary effectiveness end point was the change in seated office blood pressure from baseline to 6 months (Table 1).
Effect on blood pressure. In the denervation group, at 6 months, office blood pressure had changed by a mean of −32/−12 mm Hg (standard deviation [SD] 23/11 mm Hg) compared with a mean change of 1/0 mm Hg (SD 21/10 mm Hg) in the control group. Fortyone (84%) of the 49 patients who underwent denervation had a decrease in systolic blood pressure of 10 mm Hg or more at 6 months compared with baseline values, while five (10%) had no decline in systolic blood pressure. Nineteen patients had a reduction in systolic pressure to less than 140 mm Hg in the denervation group.
A subset of patients (20 in the denervation group and 25 in the control group) underwent 24-hour ambulatory blood pressure monitoring at 6 months. This showed a similar though less pronounced fall in blood pressure in the denervation group and no change in the controls. A subanalysis that censored all data for patients whose medication was increased during the follow-up period showed a blood pressure reduction of −31/−12 mm Hg (SD 22/11 mm Hg) in the renal denervation group.
Adverse events. Procedure-related adverse events included a single femoral artery pseudoaneurysm, one case of postprocedural hypotension requiring a reduction in antihypertensive medications, and 7 (13%) of 52 patients who experienced intraprocedural bradycardia requiring atropine.
Effect on renal function. No significant difference was noted between groups in the mean change in renal function at 6 months, whether assessed by eGFR, serum creatinine level, or cystatin C level. At 6 months, no patient had a decrease of more than 50% in eGFR, although two patients who underwent renal denervation and three controls had more than a 25% decrease in eGFR.
At 6 months, the urine albumin-to-creatinine ratio had changed by a median of −3 mg/g (range −1,089 to 76) in 38 patients in the treatment group and by 1 mg/g (range −538 to 227) in 37 controls.
Most patients (88%) undergoing renal denervation underwent renal arterial imaging at 6 months, on which a single patient showed possible progression of an underlying atherosclerotic lesion that was unrelated to the procedure and that did not require intervention.
Denervation and the normal stress response. Whether renal denervation negatively affects the body’s physiologic response to stress that is normally mediated by sympathetic nerve activity was addressed in an extended investigation of Symplicity HTN-2 using cardiopulmonary exercise tests at baseline and 3 months after renal denervation.18 In the denervation group, blood pressure during exercise was significantly lower at 3 months than at baseline, but the heart rate increase at different levels of exercise was not affected. Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.
Comments. The Symplicity HTN-2 trial benefited from a randomized trial design and strict inclusion criteria of treatment resistance, but it still had notable limitations. A pretrial evaluation for causes of secondary hypertension or white-coat hypertension was not explicitly described. The control group did not undergo a sham procedure, and data analyzers were not masked to treatment assignment. Although not analyzed as a primary end point, the use of home-based and 24-hour ambulatory blood pressure assessment—measures important for determining white-coat hypertension—revealed substantial differences in blood pressure changes relative to office measurements. Because nearly all the patients (97%) were white, the generalizability of treatment results to black patients with resistant hypertension may be limited. Isolated diastolic hypertension (defined as diastolic pressure ≥ 90 mm Hg with systolic pressure < 140 mm Hg), which is more common in younger patients, was not studied.
DOES RENAL DENERVATION REDUCE SYMPATHETIC TONE?
A subgroup of 10 patients in the Symplicity HTN-1 trial whose mean 6-month office blood pressure was reduced by 22/12 mm Hg underwent assessment of renal norepinephrine spillover. A substantial (47%) reduction in renal norepinephrine spillover was noted 1 month after the procedure.14
The investigators additionally described a marked reduction in renal norepinephrine spillover from both kidneys in one patient, with a reduction of 48% from the left kidney and 75% from the right kidney 1 month after the procedure. Whole-body norepinephrine spillover in this patient was reduced by 42%. This effect was accompanied by a 50% decrease in plasma renin activity and by an increase in renal plasma flow. Aldosterone levels were not reported.19
Thus, the decrease in renal norepinephrine spillover suggests a reduction of renal efferent activity, and the decrease in total body norepinephrine spillover suggests a reduction in central sympathetic drive via the renal afferent pathway.
Microneurography in this same patient showed a gradual reduction in muscle sympathetic nerve activity to normal levels, from 56 bursts per minute at baseline to 41 at 30 days and 19 at 12 months).19 Decreased renin secretion, via circulating angiotensin II, may affect central sympathetic outflow as well.
Comments. While these findings address some of the underlying mechanisms, the small number of patients in whom these studies were done limits the generalizability of the results. The impact of the procedure on renal hemodynamics will need to be studied, including possible direct effects of the procedure, and whether there are differences in different study populations or differences based on blood pressure levels.
WHICH PATIENTS RESPOND BEST TO THIS PROCEDURE?
Although the Symplicity HTN-2 investigators report some predictors of increased reduction in blood pressure on multivariate analysis, including increased blood pressure at baseline and reduced heart rate at baseline, these are not specific enough to enable patient selection.
Interestingly, results from the expanded cohort of the Symplicity HTN-1 study found that patients on central sympatholytic agents such as clonidine had a greater reduction in blood pressure, although the reason for this is unclear.16 Identifying specific predictors of treatment success at baseline will be essential in future studies.
The earlier Symplicity trials and the ongoing Symplicity HTN-3 trial are in patients who have high blood pressure not responding to three or more antihypertensive drugs. The mean baseline systolic blood pressure in the Symplicity HTN-1 and HTN-2 trials was 178 mm Hg, and patients were taking an average of five antihypertensive drugs (Table 1). It is not known whether denervation will produce similar blood-pressure-lowering results across the spectrum of hypertension severity.
