Renal sympathetic denervation
Synonyms and keywords: RDN, renal denervation

# Overview
Renal denervation (RDN) is a minimally invasive, endovascular catheter-based procedure invented to treat patients with severe resistant hypertension. Preliminary data suggest that renal denervation is safe and results in a sustained blood pressure reduction of approximately 30 mm Hg at a three-year follow up. However, in light of the negative results from SYMPLICITY HTN3, the beneficial effect of renal denervation remains uncertain.

# Rationale
A treatment catheter is introduced into the renal artery and energy is applied circumferentially at several ablation points within each renal artery to target the sympathetic endings in the adventitia of the vessel wall. The drop in blood pressure presumably results from a reduction in norepinephrine release from the nerve endings and an overall decrease in sympathetic activity, which culminates in diminished renin secretion, vasoconstriction, and sodium reabsorption. Renal denervation might also be beneficial in comorbidities of hypertension such as congestive heart failure, chronic kidney disease, and metabolic syndrome.

# Device
As of today, several percutaneous renal sympathetic nerve ablation systems are being studied and tested, 6 of them have already received CE marking to be used for renal nerve ablation. So far, no renal denervation device has been approved by the FDA.
- Medtronic's SimplicityTM System - produced by Medtronic (formerly Ardian), was the first device to be used in humans, receiving market approval in 2010. It uses a radio frequency catheter (6F) inserted percutaneously through a femoral sheath, under fluoroscopic control. Despite being easily used, it has a tendency to create lesions with a less predictable pattern. This device now has over 5 years of clinical experience and 3 years of follow up data. The device has received favourable reviews on WhichMedicalDeviceTM, but concerns have been reported regarding availability and financial reimbursement for the procedure.
- St. Jude's EnligHTN system - also uses a radio frequency catheter inserted percutaneously through a femoral sheath, under fluoroscopic control, however, it is equipped with 4 electrodes on a basket structure. This allows it to create lesions in a more circumferential pattern, being able to create thermal injury and fiber interruption in a more predictable way.
- Vessix's V2 system - also uses a radio frequency catheter inserted percutaneously through a femoral sheath, under fluoroscopic control, however, the electrodes are mounted in a balloon, allowing for a good distribution of the energy.
- Covidien's One Shot system - also uses a radio frequency catheter inserted percutaneously through a femoral sheath, under fluoroscopic control, however, the electrodes are mounted in a balloon, allowing for a good distribution of the energy.
- Iberis system - also uses a radio frequency catheter and a 4-French shaft, enabling radial access.
- Recor's Paradise system - uses an ultrasound technology catheter inserted percutaneously through a femoral sheath.

# Procedure

## Overview
Considering the factors: drug-resistant hypertension, sympathetic nervous system (SNS) involvement in hypertension, importance of renal nerves for the overall sympathetic activity of the body, along with the ease of approach of the renal nerves through catheter techniques, hypertension was thought to be a good candidate for a catheter-based interventional approach. Knowing that sympathetic nerve fibers are located in the adventitia of the renal arteries, they can be easily reached by a catheter through a transvascular approach and interrupted using thermal energy. However, considering that sympathetic nerves share their location with C-pain fibers, analgesia and sedation, but not anesthesia, are mandatory for this procedure.

## Pre-procedure
- This technique must take place in a well equipped catheterization lab center, with skilled operators, experienced in handling possible surgical complications.
- Preprocedural examinations require the exclusion of secondary hypertension, as a "hidden cause" of resistance, as well as confirmation of uncontrolled blood pressure, while on medical treatment. This last criterion may involve the testimonial of a third party, confirming that the patient took the medication, since a common cause of "resistance" is noncompliance with the regimen.
- Renal artery suitability must be assessed, which is done with a duplex ultrasound or MRI, and adequate anticoagulation should be attained and confirmed by activated clotting time test (with a target of 200-250 seconds). Ideally the renal artery must be >20 mm in length and >4 mm in diameter.
- Renal function tests are also required to confirm kidney's ability to sustain preprocedural contrast medium exposure.

## During procedure
- Vital signs such as blood pressure, heart rate and oxygen saturation must be monitored and continuous transcutaneous oxygen should be provided.
- Although not confirmed by clinical trials, it has been suggested the administration of periprocedural anti-platelet therapy, for up to 4 weeks after the procedure, to prevent thrombus formation.

## Technique
- Under fluoroscopic guidance, through a femoral sheath, the electrode is positioned in each of the renal arteries.
- In patients with single renal arteries, 4 ablation points are recommended. The catheter should be placed at the periphery of the second order renal artery branch point, with the help of a guide wire. The lesions made in the artery wall should have a circumferential pattern, to decrease the risk of artery stenosis, which can be achieved by rotating the catheter while pulling it back to the ostium of the artery, at the same time that the energy is being delivered. For a successive and safe ablation, the points of lesion should be distanced by >5 mm. In areas of atherosclerotic plaque, the ablation should be avoided. The energy used for the ablation also generates heat within the vessels, yet the system is cooled by the high rate of blood flow. The procedure lasts for about 30 to 60 minutes.
- Up until now, the devices used for this procedure have used either a single-tip electrode catheter, or a multielectrode system. The multielectrode systems have simplified this process by making it less painful and faster than the single-tip electrode version.

## Post-procedure
- After the procedure, the patient should be monitored until the sedation wears off, and closely followed to access the safety and efficacy of the procedure. Some studies also recommend the evaluation of the renal arteries, using duplex ultrasound, in order to exclude renal artery stenosis. Despite having been reported in single cases, this complication might not be due to the technique itself, but to pre-existing atherosclerotic plaques.

# Outcomes

## SYMPLICITY HTN1
- The safety and efficacy of renal denervation were first investigated in a proof-of-concept study on 45 patients with resistant hypertension. Office blood pressures after procedure were reduced by 14/10, 21/10, 22/11, 24/11, and 27/17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. Three-year follow-up data demonstrated an average blood pressure reduction of 33/19 mm Hg.
- This trial confirmed the durability of the procedure, contradicting the hypothesis that sympathetic nerve regrowth would nullify the effect. It has also noted a reduction of 47% in renal norepinephrine spillover, accompanied by a decrease in overall body norepinephrine spillover, confirming a reduction in central sympathetic activity after the renal denervation.
- In terms of safety, follow-up renal angiography was performed at the 14th and 30th day and MRI angiography at the 6th month, which showed no sign of renal artery aneurysm or stenosis.

## SYMPLICITY HTN2
In SYMPLICITY HTN2, a total of 106 patients from Australia and Europe were enrolled and randomized into two balanced groups. Six month follow-up data demonstrated a blood pressure reduction of 32/12mm Hg in the treatment group compared with a change of 1/0 mm Hg in the control group.
- Office-based blood pressure measurements at 6 months were as follows:
- Active treatment group: 147/84 mm Hg, from 178/96 mm Hg at baseline (p<0.0001)
- Control group: 179/96 mm Hg, from 178/97 mm Hg at baseline (p=0.77 systolic and p=0.83 diastolic)

## SYMPLICITY HTN3
SYMPLICITY HTN3 is a multi-center, prospective, single-blind, randomized, sham-controlled study on the efficacy and safety of renal sympathetic denervation in patients with severe resistant hypertension (Clinical Trial No. NCT01418261). A total of 535 patients were randomized in a 2:1 ratio to receive renal denervation or sham procedure. There was no significant reduction in office and ambulatory systolic blood pressure or differences in safety between the two groups.
- Mean changes in office systolic blood pressure at 6 months were as follows, for a difference of 2.39 mm Hg:
- Renal denervation group: 14.1323.93 mm Hg (p<0.001)
- Sham procedure group: 11.7425.94 mm Hg (p<0.001)
- Mean changes in 24-hour ambulatory systolic blood pressure at 6 months were as follows, for a difference of 1.96 mm Hg:
- Renal denervation group: 6.7515.11 mm Hg (p<0.001)
- Sham procedure group: 4.7917.25 mm Hg (p<0.001)

# Risks
Data from SYMPLICITY trials suggest a favorable safety profile for catheter-based renal denervation. Procedure-related complications include small hematomas, renal artery stenosis, vasospasm of the renal artery following the procedure, femoral artery pseudoaneurysm, renal artery dissection, and minor deterioration of renal function. In an animal study, applied radiofrequency energy resulted in morphologic alterations of the renal arteries such as transient loss of endothelium, acute cellular swelling, and thrombus formation. Two case reports described a secondary rise in blood pressure associated with progression of renal artery stenosis. However, it is unclear whether this progression is related to the procedure.

# Uses of Renal Denervation Beyond Hypertension
Potential benefits of renal denervation are being investigated in comorbidities of hypertension that are associated with exaggerated sympathetic activity, including:
- Atrial fibrillation
- Diabetes mellitus
- Heart failure
- Sleep apnea
- Polycystic ovary disease
- Ventricular tachycardia