1 - Renal sympathetic nerves in pathophysiology of resistant hypertension
The pivotal role of sympathetic nerves in essential hypertension has been recognised for decades. First attempts to treat hypertension were based on inhibition of sympathetic tone by sympathectomy or sympatolytic medication. The role of both afferent and efferent sympathetic renal nerves in the pathophysiology of hypertension has been recently reappraised, resistant hypertension especially. This form of hypertension is defined as blood pressure (BP) above therapeutic target despite the use of 3 antihypertensive agents including a diuretic prescribed in optimal doses (1). Patients have increased risk of stroke and other major cardiovascular events as well as end-organ damage (2).
Figure 1: Role of renal sympathetic nerves in pathophysiology of hypertension and metabolic syndrome
Figure legend: Kidneys are innervated by afferent and efferent sympathetic fibers located in the adventitia of renal arteries. Efferent sympathetic stimulation produces renal vasoconstriction, decreases renal blood flow, increases release of rennin and epinephrine as well as sodium reuptake. Afferent stimulation through renal sympathetic nerves increases central sympathetic activity.
Given the central role of renal sympathetic nerves in the development of resistant hypertension, evidenced by renal norepinephrine spillover and increased muscle sympathetic-nerve activity, modulation of their activity would be a targeted treatment for this form of hypertension (1, 3).
2 - Catheter-based renal denervation
Modulation of renal sympathetic-nerve activity through catheter-based radiofrequency ablation has been developed based on experimental and clinical data.
The mechanism by which renal sympathetic denervation improves management of BP is complex and involves the following factors:
- Decreasing efferent sympathetic signaling to kidneys
- Reducing norepinephrine spillover
- Increasing renal blood flow
- Lowering plasma rennin activity
- Decreasing renal afferent signalling and central sympathetic activation (3)
Vascular access is similar to renal angiography and angioplasty. Current 5F system uses 6F guide catheters. After engaging the renal artery, and angiography to evaluate the anatomy of the renal arteries, the ablation catheter is placed under fluoroscopic guidance in the distal segment of the renal artery. Each RF application is followed by retraction by at least 5 mm and rotation by 90 degrees of the catheter tip, from the first distal main renal artery bifurcation to the ostium. To achieve complete denervation, multiple (4-6) RF applications are used depending on the length of the trunk of both renal arteries. This approach provides circumferential disruption of sympathetic nerves. The procedure is performed under analgetic or conscious sedation to lessen the pain (5).
Symplicity Catheter System Design (Medtronic Vascular) offers a technique of renal artery denervation based on application of radiofrequency (RF) energy through the endovascular electrode placed in the renal artery for sympathetic nerves ablation. The system is shown on figure 2.
Figure 2: Ablation of afferent and efferent sympathetic nerves
Figure legend: Device consists of a catheter with deflectable tip connected to the radiofrequency generator (50 Hz, 5–8 W).
The energy increases the local temperature in the limited area of the vascular wall and leads to ablation of afferent and efferent sympathetic nerves.
Procedure-related complications are:
- Access site complication (hematoma, pseudoaneurysm, dissection)
- Renal artery dissection
- Progression of a pre-existing renal artery stenosis
- Regeneration of efferent nerves leading to relapse of resistant hypertension
3 - Clinical trials
Safety and efficacy of RD has been evaluated in two clinical studies (Symplicity HTN-1 and Symplicity HTN-2) involving patients with refractory hypertension. Data from 1-year follow-up of cohort of 45 patients (first-in-man) has been reported in Lancet in 2009 and complete 2-year follow-up of 153 patients with elevated SBP ≥160 mm Hg despite the use of ≥3 antihypertensive medications including diuretic was recently published in Hypertension.
A proof-of-concept non-randomised Symplicity HTN-1 pilot trial involved 153 patients with mean office BP of 176/98±17/15 mm Hg taking the mean of 5 BP lowering medications. Treatment consisted of treatment of bilateral renal arteries with an average of 4 RF applications per artery. The pilot trial showed a low risk of periprocedural complications - 3%, which were mainly related to access site pseudoaneurysms. There was also one case of renal artery dissection which was successfully treated. Control angiography in 20 patients showed no increased risk of renal artery stenosis. Efficacy analysis showed a significant reduction in office BP values of 25/11 mmHg at 6 months and 32/14 mm Hg at 2 years. Overall, 92% of patients had a reduction of BP ≥10 mm Hg, however number of antihypertensive medications remained unchanged after completion of the study. Importantly the renal function was stable over a 2-year follow-up period. Two factors were predictive of significant reductions in BP – initial values of systolic BP and use of central sympatholytic medications (5, 6).
The results of the pilot trial were recently confirmed with randomised controlled Symplicity HTN2 study which enrolled 106 patients randomised in 1:1 manner to RF renal denervation or control groups (7). Inclusion Criteria consisted of office SBP values of ≥ 160 mmHg or ≥ 150 mmHg in patients with type II diabetes mellitus despite use of ≥3 antihypertensive medications. Patients with eGFR < 45 mL/min/1.73m2, prior renal artery intervention, type 1 diabetes mellitus or recent acute coronary syndromes were excluded. A substantial number (57-67%) of patients used ≥5 antihypertensive medications and in the whole cohort the mean number of medications was 5.2± 1.5 in denervation group and 5.3± 1.8 in the control group. Primary endpoint of this study was office BP at 6-months after denervation. Overall 84% of treated patients had SBP reduction of ≥ 10 mmHg. There was a significantly better reduction of BP after denervation than in the control group with a mean difference between the groups of 33/11 mmHg. The safety profile was excellent with no procedure-related or device-related serious complications. Consistently with Symplicity HTN-1 the groups of 10% of patients had no significant reduction in SBP (7).
Currently multi-center, randomised, single-blind (active versus sham treatment), controlled Symplicity HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension, NCT01418261) is enrolling patients in the US sites. The primary end-point is change in Office Systolic Blood Pressure after 6 months post denervation. Expected enrollment is 530 patients [www.clinicaltrials.gov].
4- Clinical practice
Proper evaluation of patients referred for such treatment should consist of assessment by multidisciplinary team (hypertension specialist, cardiologist) and only patients with true refractory hypertension should be treated .
The indications for renal denervation are:
- Refractory hypertension with office SBP >160 mmHg despite treatment with the least 3 antihypertensive medications including diuretic in optimal doses
- Exclusion of secondary forms of hypertension
- Exclusion of “white coat” hypertension using ambulatory blood pressure monitoring
- Increased bleeding risk (bleeding diathesis, thrombocytopenia, severe anemia)
- Chronic renal disease
- eGFR < 45 mL/min/1.73m2
- Type 1 diabetes
- Previous renal artery intervention (angioplasty, stent implantation), anatomic abnormalities and variants of renal artery including aneurysms, severe stenosis, reference diameter < 4 mm, excessive tortuosity, aortic aneurysm
- Age < 18 years
5 - Potential new applications
- Sleep apnea
Hypertension, impaired insulin tolerance and obesity often coexist with sleep apnea. Sleep apnea increases the risk of cardiovascular events and impairs the control of BP in hypertensives. Frequency in this population can reach 80% (9). A recent study of Witkowski et. al (Renal Denervation in Patients With Refractory Hypertension Study (NCT00483808) published recently in Hypertension demonstrated that treatment of resistant hypertension might not only improve BP control, but importantly, reduce the frequency of apnea/hypopnea in patients with coexisting sleep apnea. The study evaluated the outcome in 10 patients with refractory hypertension (systolic office BP >160 mm Hg on ≥3 antihypertensive medications) and sleep apnea (5 with mild- and 10 with moderate-to-severe apnea) treated with bilateral renal denervation.
Besides the significant reduction in BP 6 months after the procedure the polysomnographic studies revealed a clear trend towards reduction of the apnea/hypopnea index in patients treated with renal denervation (median: 4.5 vs. 16.3 events/hour). Study also showed significant reduction of Epworth Sleepiness Scale score at 6 months' follow-up (7.00 points vs. median: 9.00 points) and a non-significant trend towards a lower number of episodes of oxygen desaturation (8.7 vs. 13.0 events per hour) in actively treated patients (10). The mechanism of such effect of renal denervation of sleep apnea is unknown, however the influence on sodium retention and volemic status is likely to be involved. Patients with sleep apnea and resistant hypertension have more fluid shift to the neck in the supine position leading to peripharyngeal fluid accumulation dependent on sympathetic activity which might explain the improvement after the denervation procedure. Denervation can also increase venous compliance which dependent of the sympathetic system and increased capacity may alleviate the blood pooling in the peripharyngeal tissues. Better BP control can also contribute to the apnea improvement through it’s influence on baroreflex reactivity and central respiratory control (10, 11).
- Insulin Resistance/type 2 diabetes mellitus
Since impaired glucose tolerance (IGT) or type2 diabetes mellitus coexist with hypertension, obesity and lipid disorders in patients with hypertension (metabolic syndrome), more effective BP control should be accompanied by treatment of these abnormalities as well – with weight reduction, lipid lowering medication and improvement of glucose metabolism. Importantly, obesity, hypertension and insulin resistance have a common pathophysiology. Hyperinsulinemia and increased sympathetic tone can lead to sodium retention and hyperaldosteronemia.
Mahfoud et al. showed that in patients with resistant hypertension treated with renal denervation, significant reduction of BP, as well as improvement of glucose tolerance evidenced by lower fasting glucose levels as well as a reduction of insulin and C-peptide levels 3 months post procedure occured. Additionally, there was an improvement of HOMA index and reduction of glucose levels at 2-hours during oral glucose tolerance test (12). These findings were recently confirmed by Witkowski et al. also who found decreased levels of glycosylated hemoglobin in patients treated with renal denervation (11).
The beneficial effects on glucose metabolism may be explained by several effects of renal denervation: inhibition of central sympathetic tone, reduced release of norepinephrine, better perfusion of skeletal muscles mediated via a decrease of alpha-adrenergic tone leading to increased glucose uptake (13). Other factors include inhibitory effects on the renin-angiotensin system, reduced gluconeogenesis and attenuation of glucagon secretion (14).
The role of renal denervation is currently being evaluated in DREAMS (Denervation of the REnal Artery in Metabolic Syndrome) study (NCT01465724) which will assess the improvement of insulin resistance in 1-year follow-up after renal denervation in patients with metabolic syndrome and elevated fasting glucose.
- Congestive Heart Failure
Increased sympathetic activity is present in patients with heart failure and it is correlated with functional class. The renal afferent sympathetic activity might contribute to this phenomenon, so effective modulation by renal denervation might help to treat patients with heart failure (15). Increased renal sympathetic activity might also play a role in the development of resistance to atrial natriuretic peptide (16).
Renal Denervation in Patients With Chronic Heart Failure & Renal Impairment Clinical Trial (SymplicityHF) study (NCT01392196) is a feasibility study which will assess the safety of renal denervation in 40 patients with heart failure over a 6-months follow-up. Secondary end-points are left ventricle function and renal function (GFR). The inclusion criteria for this study are NYHA II-III despite optimal medical therapy, renal Impairment GFR 30 to 75 mL/min/1.73m2 and LVEF <40%.
Renal sympathetic denervation has proven safe and effective in treatment of resistant hypertension. Moreover, initial clinical reports suggest it might also be useful in treatment of patients with hypertension coexisting with sleep apnea and metabolic syndrome.