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.
WHAT ARE THE LONG-TERM RESULTS OF DENERVATION?
Enthusiasm for the results from the Symplicity trials is tempered by concerns about the durability of the effects of the procedure, the need for better understanding of the impact of renal denervation on a wide array of pathophysiologic cascades leading to hypertension, and the effect on renal hemodynamics.
Antihypertensive efficacy has been reported to persist up to 2 years after the procedure,16 with recent unpublished data suggesting efficacy up to 3 years, but longer follow-up is needed to address whether these effects are finite.
Although reinnervation of afferent renal nerves has not been described, transplant models have shown anatomic regrowth of efferent nerves; the impact of this efferent reinnervation on blood pressure remains unclear. Experience from renal transplantation also shows that implanted kidneys that are “denervated” can still maintain fluid and electrolyte regulation.
Follow-up renal imaging in the Symplicity trials did not indicate renal artery stenosis at the sites of denervation in patients who underwent the procedure. Animal studies using the Symplicity catheter system showed renal nerve injury as evidenced by nerve fibrosis and thickened epineurium and perineurium, but no significant smooth muscle hyperplasia, arterial stenosis, or thrombosis by angiography or histology at 6 months.20
WHAT ARE THE RISKS?
Adverse effects that were noted in the short term are detailed under discussion of the trials and in Table 2.
Long-term adverse events in the Symplicity HTN-2 trial that required hospitalization were reported in five patients in the denervation group and three patients in the control group (Table 2). These included transient ischemic attacks, hypertensive crises, hypotensive episodes, angina, and nausea.
Renal function was maintained for the duration of both trials, and details regarding eGFR change have been described above under the discussion of the trials.
Diffuse visceral pain at the time of the procedure is reported as an expected occurrence, managed with intravenous analgesic medications.
DOES SYMPATHETIC DENERVATION HAVE A ROLE IN OTHER CONDITIONS?
Interestingly, other sympathetically driven diseases, such as diabetes mellitus and polycystic ovary syndrome, may prove to be targets for this therapy in the future.21
Mahfoud et al22 conducted a pilot study in 37 patients with resistant hypertension undergoing renal denervation and 13 control patients. Fasting glucose levels declined from 118 ± 3.4 mg/dL to 108 ± 3.8 mg/dL after 3 months in the intervention group (P = .039), compared with no change in the control group. Insulin and C-peptide levels were also lower in the intervention group. The reported improvement in glucose metabolism and insulin sensitivity suggests that the beneficial effects of this procedure may extend beyond blood pressure reduction.
Brandt et al23 reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.
Witkowski et al24 reported lowering of blood pressure in 10 patients with refractory hypertension and obstructive sleep apnea who underwent renal denervation, which was accompanied by improvement of sleep apnea severity.
Ukena et al25 reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.
A recent pilot study in 15 patients with stage 3 and 4 chronic kidney disease (mean eGFR 31 mL/min/1.73 m2) showed significantly improved office blood pressure control up to 1 year, restoration of nocturnal dipping on 24-hour monitoring, as well as a nonsignificant trend towards increased hemoglobin levels and decreased proteinuria. No additional deterioration of renal function was reported in these patients (2 patients had renal function assessed up to 1 year).26
Thus, the benefits of this procedure may extend to other diseases that have a common underlying thread of elevated sympathetic activity, by targeting the “sympathorenal” axis.27
GUARDED OPTIMISM AND FUTURE DIRECTIONS
Given the well-known cardiovascular risks and health care costs associated with uncontrolled hypertension and the continued challenge that physicians face in managing it, novel therapies such as renal denervation may provide an adjunct to existing pharmacologic approaches.
While there is certainly cause for guarded optimism, especially with the striking blood pressure-lowering results seen in trials so far, it should be kept in mind that the mechanisms leading to the hypertensive response are complex and multifactorial, and further understanding of this therapy with long-term follow-up is needed. A comparison study with spironolactone, which is increasingly being used to treat resistant hypertension (in the absence of a diagnosis of primary aldosteronism)28,29 would help to further establish the role of this procedure.
Studies of carotid baroreceptor stimulation via an implantable device have shown sustained reduction in blood pressure in patients with resistant hypertension. A study comparing this technique with renal denervation for efficacy and safety end points could be considered in the future.30,31
The planned Symplicity HTN-3 study in the United States will be the largest trial to date, with a targeted randomization of more than 500 patients using strict enrollment criteria, including the use of maximally tolerated doses of diuretics and more focus on the use of ambulatory blood pressure monitoring and on the blinding of participants. This study will help further analysis of this technology in a more diverse population.32,33
Future studies should be designed to clarify pathophysiologic mechanisms, patient selection criteria, effects on target organ damage, and efficacy in patients with chronic kidney disease, obesity, congestive heart failure, and in less severe forms of hypertension.
A CALL FOR PARTICIPANTS IN A CLINICAL TRIAL
The Departments of Cardiology and Nephrology and Hypertension at Cleveland Clinic are currently enrolling patients in the Symplicity HTN-3 trial. For more information, please contact George Thomas, MD (thomasg3@ccf.org), or Mehdi Shishehbor, DO, MPH (shishem@ccf.org), or visit www.symplifybptrial.com.
