Renal sympathetic denervation

Renal sympathetic denervation (RSDN), often shortened to renal denervation (RDN), is a minimally invasive, endovascular catheter based procedure using radiofrequency ablation aimed at treating resistant hypertension (high blood pressure). By applying radiofrequency pulses to the renal arteries, the nerves in the vascular wall (adventitia layer) can be denuded of nerve endings. This causes reduction of renal sympathetic afferent and efferent activity and blood pressure can be decreased.^[1] Early data from international clinical trials is promising demonstrating average blood pressure reduction of approximately 30 mmHg at three year follow up in patients with treatment-resistant hypertension.^[2][3] Since 2007 over 4000 patients have undergone catheter based renal denervation with the Medtronic Symplicity™ Renal Denervation System.^[4] It is currently unclear which people with high blood pressure should be considered for sympathetic denervation.

History

Prior to pharmacological management of hypertension, surgical sympathectomy was a recognized treatment for hypertension.^[5] This was often successful in reducing blood pressure but due to its non-selective nature the side effects of the procedure were poorly tolerated. Side effects included orthostatic hypotension, palpitations, anhydrosis, intestinal disturbances, loss of ejaculation, thoracic duct injuries and atelactasis.^[6] Modern antihypertensive pharmacological interventions have improved the control of hypertension, but an estimated 30% of hypertension cases are resistant. Resistant hypertension is defined as blood pressure above target (140/90mm Hg) despite concomitant use of 3 or more anti-hypertensives – one of which should be a diuretic.^[7]

Device

Several devices have been approved for this procedure. One of them is the Symplicity™ Renal Denervation System, produced by Medtronic (formerly Ardian)^[8] and consists of an endovascular catheter (6F), radiofrequency generator, dispersive electrodes, foot switch and power cable.^[9]

In Europe, the Symplicity device received CE mark approval in 2010.^[10] The device is available in parts of Europe, Asia, Africa, Australia and the Americas.^[4]

The Symplicity device currently has over 5 years of clinical experience and 3 years of follow up data. The device has received favourable reviews on WhichMedicalDevice, but concerns have been reported regarding availability and financial reimbursement for the procedure.^[11] There are a number of other devices that are currently being evaluated, but these different technologies have limited clinical data and do not have long term data. In addition to Medtronic's Symplicity system, five other renal denervation devices have a CE mark. These include St. Jude Medical’s EnligHTN™ System, Vessix's V2™ Renal Denervation System, Covidien’s OneShot™ System, Recor’s Paradise™ System and Terumo's Iberis™ System. Currently, no renal denervation device has FDA approval today.

Procedure

The Symplicity renal denervation system consists of a generator and a flexible catheter. During this minimally invasive procedure, the interventionalist uses a steerable catheter with a radio frequency (RF) energy electrode tip. The RF energy is delivered to a renal artery via standard femoral artery access. A series of 2-minute ablations are delivered along each renal artery to disrupt the nerves. The procedure does not involve a permanent implant.

Outcomes

The two biggest studies to date have been the Symplicity HTN-1 and HTN-2 trials, conducted with Medtronic's Symplicity RDN System.

Symplicity HTN-1 ^[2] looked at outcomes in 153 patients that underwent catheter-based renal denervation. Three-year follow-up data have demonstrated an average blood pressure reduction of -33/-19mm Hg.

Symplicity HTN-2 ^[3] was a randomized, controlled trial that compared 54 control patients with 52 patients who underwent catheter-based renal denervation. Six month follow-up data demonstrated a blood pressure reduction of -32/12mm Hg in the treated group compared with a change of 1/0 mm Hg in the control group. Longer follow-up, more patients, and improved study design are necessary to further validate catheter-based renal denervation. Currently the Symplicity HTN-3 trial is underway in the US. This is a 530-patient, multi-centre, prospective, single-blind, randomized, controlled study (Clinical Trial No. NCT01418261).^[12]

Meta-analyses of renal denervation have yielded conflicting results.^[13] Whilst office systolic blood pressure reductions typically average around 30 mmHg, reductions observed on ambulatory blood pressure monitoring are typically much smaller, around 10 mmHg.^[14] The reasons for this disparity are so far unclear. Proposed theories include renal denervation obliterating the white coat response, thereby disproportionately reducing clinic pressures,^[13] or the disparity rather being an anomaly due to deficiencies in renal denervation trial designs to date.^[14]

The most recent study, Symplicity HTN-3, however, failed to reach its primary endpoint and showed no difference between renal denervation treatment and the sham control group, which underwent a normal angiography. ^[15]

Risks

The Symplicity HTN-1 and HTN-2 trials have demonstrated a good safety profile for catheter based renal denervation. Patients may experience pain during application of radiofrequency pulses and intraprocedural bradycardia requiring atropine has also been reported.^[3] Other documented procedure related complications include femoral artery pseudoaneurysm and renal artery dissection.

Of particular concern is the theoretical risk of damage to renal arteries during delivery of radiofrequency energy. An animal study using swine showed no damage to the renal arteries at 6 month follow up. This finding is further supported in human studies in the HTN-1 and HTN-2 trial where follow up imaging has not demonstrated renal vascular damage.^[16]

Other indications

Hypertension is associated with an overactive sympathetic drive and renal denervation is the ablation of the renal nerves stopping the cross-talk between the kidneys and brains, thus reducing the sympathetic drive. Similar to hypertension, congestive heart failure (CHF), left ventricular hypertrophy (LVH), atrial fibrillation (AF), obstructive sleep apnea (OSA), and insulin resistance/type 2 diabetes mellitus (DM) all have been associated with an overactive sympathetic drive. Current clinical trials are researching the effect of renal denervation in these clinical conditions as well. ^[17]

References