Renal denervation:history，today and tomorrow

BAO Ruo-tai，CHEN Zhong，MA Gen-shan

(Department of Cardiology，Zhongda Hospital，Southeast University，Najing 210009，China)

1 Introduction

Hypertension is one of the most prevalent cardiovascular diseases.Nearly 34%of adults worldwide have hypertension and this number is still rising［1-2］.Available data indicate that patients with resistant hypertension have an approximately three times increased risk for adverse cardiovascular outcomes compared with patients with wellcontrolled hypertension.Despite a broad availability of effective pharmaceutical agents，only 32%of treated men and 37%of treated women achieved hypertension-treatment goals［3］.This low success ratio can be addressed by non-compliance of patients to medical therapy，secondary causes of hypertension and other reasons.However，a subgroup of patients do fulfil the criteria of the phenomenon called‘resistant hypertension’.

In 2008，the American Heart Association(AHA)defined resistant hypertension as a blood pressure(BP)that remains above treatment goals despite the use of at least three different antihypertensive drugs at the same time，including a diuretic，with all agents prescribed at doses that provide optimal benefit［4-5］.The sympathetic nervous system has been recognized to play an important role in the process of hypertension［6］and splanchnicectomy or radical sympathectomy had been considered an effective way of treating severe hypertension and related cardiovascular morbidities several decades ago［7］.Modern pharmacological therapy for hypertension，with several classes of effective antihypertensive agents，has made splanchnicectomy and radical sympathectomy obsolete because of the unfavorable side effects including orthostatic hypotension，impotence and incontinence.The recent development of minimally invasive，catheter-based，renal denervation presents an innovative and promising new approach in the treatment of resistant hypertension.This review will address the role of the renal sympathetic nervous system，recent trial results of renal denervation，the accompanying adverse events and future sights.

2 The sympathetic nervous system(SNS)

Although the exact pathogenesis of an elevated BP remains unclear，it has become clear that over-activation of the SNSis an important factor in the development and progression of systemic hypertension［8］. The SNS is known to be responsible for the homeostasis mechanism of multiple organ systems.Anderson et al［9］.measured noradrenalin spillover and muscle sympathetic nerve activity(MSNA)in normotensive and hypertensive subjects.They demonstrated that central sympathetic neural outflow is elevated in subjects with hypertension.Moreover，the degree of SNS over-activation correlated with the severity of BP elevation.The response of the kidneys to SNSsignalling is one mechanism by which sympathetic activation increases BP［10］.

Renal sympathetic stimulation promotes renin secretion，reduces urinary sodium excretion，and induces renal vasoconstriction.The renal SNScomprises both efferent and afferent renal nerves.Efferent renal sympathetic nerves originate from the thoracic and lumbar sympathetic trunk，and terminate in the blood vessels，the juxtaglomerular apparatus，and the renal tubules［8-11］.When stimulated，these nerves achieve an increased sodium reabsorption，increased renin release leading to antinatriuresis，and a decreased renal blood flow［12-14］.Communication from the kidneys into the central nervous system drives through the renal afferent nerves.Stimulation of these afferent nerves directly contributes to systemic hypertension［15］.Both the efferent and afferent renal sympathetic nerves lie within the wall of the renal artery and offer a potential option for ablation treatment［16］.

3 Denervation of the SNS

The concept of renal denervation，and thereby lowering SNSactivity to treat hypertension，is not new.Based on the findings that surgical nephrectomy in humans could result in a reduction of MSNA［17］.The concept arose that surgical denervation would be an effective treatment for patients with hypertension.Indeed，surgical denervation has been shown to be effective in lowering BP［18］.However，these methods were associated with high perioperative morbidity，long-term complications and mortality［19］.Taday，a percutaneous，catheter-based approach has been developed using radiofrequency energy to distroy renal sympathetic nerves without affecting other abdominal，pelvic，or lower extremity nervations［20］.The catheter is introduced into the renal arteries via femoral artery.A bilateral treatment of the renal arteries is performed with the use of radiofrequency(RF)energy delivery.The ablations in two renal arteries are conducted in a distal to proximal direction in a circumferentially rotating manner with 5 mm spacing between each ablation point.In preclinical studies this has shown to be effective，reducing norepinephrine levels by 80%-90%，without adverse effects on the vessel wall［21］.

4 Clinical studies

Therapeutic benefits in terms of office blood pressure reduction weremonstrated with the symplicity renal denervation system(Medtronic，Minneapolis，Minnesota)in a proof-of-principle study(Symplicity HTN-1)［22］，followed by a small open-label randomized efficacy study(Symplicity HTN-2)［23］.Blood pressure reduction achieved on ambulatory monitoring was less than in the office.The symplicity system was launched in Europe in 2010 and is also currently available in Asia，Africa countries，Australia and Canada.No renal denervation system has yet been approved in the United States.The Cleveland Clinic nominated renal denervation as the number one healthcare innovation of 2012［24］.Four different new systems have become available in Europe since the launch of the symplicity system，and many others are under development worldwide.

5 About the simplicity clinical program

The symplicity clinical program is comprised of a series of trials，including the Symplicity HTN-1 and Symplicity HTN-2 studies and the Global SYMPLICITY Registry.The robust SYMPLICITY global dataset will evaluate blood pressure reduction as well as long-term cardiovascular outcomes from hypertension，which include stroke，myocardial infarction(MI)，heart failure and cardiovascular(CV)death.In total，Medtronic's global symplicity clinical program will involve more than 8 000 patients worldwide.These studies could provide evidence to support or not the use of renal denervation in conditions associated with hyperactive sympathetic nervous system and resistant hypertension.

The ongoing Symplicity HTN-3 trial is a multicenter，randomized，controlled trial testing the safety and effectiveness of the treatment in patients with uncontrolled hypertension incorporating ambulatory blood-pressure monitoring in contrast to previous trials，which relied only on office blood-pressure measurements.It is expected to provide the strongest evidence on the catheter-based renal denervation procedure，because it will be the largest trial on renal denervation and will compare the catheter-based renal denervation to a catheter-based sham procedure.In anticipation of the potential benefits of renal denervation，patients who are enrolled in the sham procedure arm will be offered catheter-based renal denervation upon completion of the 6-month follow-up.

In a recently published study［25］，compared to the control group，the intervention group of 88 subjects had significant reductions in systolic，diastolic，and pulse pressure at 3 and 6 months，respectively.In addition，the renal denervation resulted in a decrease in the renal resistive index from baseline at 3 and 6 months，respectively，but with no effects on cystatin C-based glomerular filtration rate and urinary albumin excretion.There were no renal artery stenoses，dissections，or aneurysms during the 6-month follow-up.In a recent small sample study，15 patients who had resistant hypertension and moderate to severe renal function impairment with mean estimated glomerular filtration rate of 31 ml·min-1·1.73 m-2underwent the same catheter-based bilateral renal denervation procedure and had similarly impressive mean blood pressure reductions at 1，3，6，and 12 months following denervation，respectively［26］.In addition，nighttime ambulatory blood pressure decreased significantly，restoring to a more physiologic nocturnal dipping pattern.Renal function assessed by estimated glomerular filtration rate(eGFRR)did not change significantly up to 12 months.This study supports the potential utility of catheter-based renal denervation in patients with impaired renal function.

More importantly，the improvement of left ventricular hypertrophy seemed to be somewhat independent of BP lowering effects，suggesting possible benefits of renal denervation in cardiovascular conditions beyond BP decrease［27］.In addition，there was no angiographic or histological evidence of renal artery stenosis or thrombosis at 6-month follow up.Consistent with the animal data，the clinical data have demonstrated impressive efficacy，durability，and safety of the symplicity renal denervation system.However，the optimism of renal denervation will remain un-guarded given the complicated mechanism of hypertension and the lack of long-term outcomes［28］.

6 Adverse events

No immediate serious complications occurred related to the device or procedure during the Symplicity trials［19-20，22-23］.Minor procedural complications included hematomas at the femoral artery access site and renal artery dissections.Six-month renal vascular imaging identified one case of progression of a pre-existing renal artery stenosis during HTN-1 and one case of progression of an underlying atherosclerotic lesion during HTN-2.Both cases occurred at a location unrelated to the site of radiofrequency energy application.No stenoses，aneurysms，or new atherosclerotic lesions were observed at the radiofrequency energy delivery sites.No late procedure-related safety events or vascular complications were reported during follow-up in either Symplicity trial.

Other minor adverse events occurring during the Symplicity HTN-2 trial in the renal denervation group included one post-procedural drop in blood pressure，one urinary tract infection，one prolonged hospitalization for investigation of paresthesia，and one case of back pain.Other events included transient bradycardia during the procedure，which resolved with venous atropine treatment，hospital admissions，hypotensive episode occurred in the crossover group，which resolved with medication.No additional adverse events were reported at the 24-month follow-up. Renal function did not deteriorate after the denervation procedure.There was no decline in renal function during the first year of follow-up during HTN-1.Avail data from 10 patients at the two-year follow-up in HTN-1showed(eGFR)decreased by 16.0 ml·min-1·1.73 m-2.Five of these patients had spironolactone or another diuretic added after the one-year followup.In patients without a newly added diuretic，eGFR decreased by 7.8 ml·min-1·1.73 m-2.None of these patients experienced a doubling of serum creatinine，developed class IV chronic kidney disease，or progressed to dialysis.

A prospective cohort study assessed biomarkers of acute renal injury to identify if any structural kidney damage during the early post-procedural period occurred in 62 consecutive patients with treatment-resistant hypertension.Patients with moderate or severe kidney disease(eGFR ＜ 45 ml·min-1·1.73 m-2)were included in the study population.Results showed no evidence of renal denervation-related functional or structural kidney damage or decreases in renal function two days after the procedure and after a three-month follow-up［29-30］.Several studies have also suggested that patients with resistant hypertension undergoing renal denervation may experience beneficial effects on other coexistent chronic conditions.One study has shown that patients with stage 3 and stage 4 chronic kidney disease undergoing the procedure experienced reduction in their blood pressure without any deterioration in renal function［31］.The hope therefore is that renal denervation might slow down deterioration in renal function in patients with chronic kidney disease，due to its beneficial blood pressure-lowering effects and the attendant attenuation of end-organ damage［32］，but this remains to be proven.

7 More studies

Right now for instance，several companies such as Vessix，with its V2，and St.Jude with its EnligHTN ?，have European studies underway.Medtronic's Symplicity HTN 2 study is the only one in the U.S.That study isn't likely to be completed before deep into 2014，so it's too early to tell whether the treatment has a place as a routine treatment for uncontrolled high blood pressure.Indeed it's already available in Europe which will in itself make clinical studies.

A footnote by the way，is that a recent study，has backed the treatment on cost-effectiveness grounds too.Very recently St.Jude Medical has announced the plan for a landmark trial that will evaluate whether renal denervation and medication can provide health benefits to patients beyond lowering high blood pressure.The international，multicenter，randomized controlled trial，called EnligHTNment，will test the long-term effects of the company's renal denervation system(EnligHTN)in patients with uncontrolled hypertension.EnligHTNment will be the first large-scale trial to examine whether renal denervation can provide health benefits other than lowering blood pressure，including whether it can also reduce the risk of major CV events，including MI，stroke and death.

The EnligHTNⅡ(IntErnational non-randomized，single-arm，long-term follow-up study of patients with uncontrolled HyperTensioN)trial expands upon the research conducted in the EnligHTN I trial，which demonstrated that patients with drug-resistant hypertension treated with the St.Jude Medical EnligHTN system had a rapid and sustained drop in blood pressure.After thirty days，systolic blood pressure was reduced by an average of 28 mmHg that remained stable with a reduction of 26 mmHg points six months after treatment，an important finding as the risk of cardiovascular death drops by half with every systolic decrease of 20 mmHg.Expanding this research to patients with less severe forms of hypertension is important as this minimally invasive approach allows for a shorter procedure time and a potentially faster recovery time，which may benefit more patients with uncontrolled hypertension.Through the course of the EnligHTNⅡstudy，we expect to gain additional insights into the benefits and sustainability of blood pressure reductions achieved through use of the EnligHTN Renal Denervation System in an expanded patient population.

8 What are the long-term results of denervation?

Antihypertensive efficacy persists up to 2 years after the procedure，with recent unpublished data suggesting efficacy up to 3 years，but longer follow-up is needed to prove whether these effects are finite.Transplant models have shown anatomic regrowth of efferent nerves and 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.

9 Conclusion

Renal sympathetic denervation using radiofrequency energy represents the new frontier in resistant-hypertension management.Current data derived from clinical trials are promising，but many unanswered questions exist.Future larger scale，improved study designs may help clarify current ambiguities.Innovation is necessary to reduce the global burden of hypertension and multiple renal denervation devices are being developed to solve this demand.As research progresses，the link between the SNS，the kidney and other diseases may become clearer，thus expanding the clinical applicability of renal denervation.

［1］KEARNEY P M，WHELTON M，REYNOLDSK，et al.Global burden of hypertension:analysis of worldwide data［J］.Lancet，2005，365(9455):217-223.

［2］EGAN B M，ZHAO Y，AXON R N.UStrends in prevalence，awareness，treatment，and control of hypertension，1988-2008［J］.JAMA，2010，303:2043-2050.

［3］PEREIRA M，LUNET N，AZEVEDO A，et al.Differences in prevalence，awareness，treatment and control of hypertension between developing and developed countries［J］.JHypertens，2009，27:963-975.

［4］EGAN B M，ZHAO Y，AXON R N，et al.Uncontrolled and apparent treatment resistant hypertension in the United States，1988 to 2008［J］.Circulation，2011，124:1046-1058.

［5］LEWINGTONS，CLARKE R，QIZILBASH N，et al.Prospective studies collaboration.Age-specific relevance of usual blood pressure to vascular mortality:a meta-analysis of individual data for one million adults in 61 prospective studies［J］.Lancet，2002，360:1903-1913.

［6］GRASSI G.Assessment of sympathetic cardiovascular drive in human hypertension:achievements and perspectives［J］.Hypertension，2009，54:690-697.

［7］SMITHWICK R H，THOMPSON JE.Splanchnicectomy for essential hypertension;results in 1，266 cases［J］.J Am Med Assoc，1953，152:1501-1504.

［8］SCHLAICH M P，SOBOTKA PA，KRUM H，et al.Renal denervation as a therapeutic approach for hypertension:novel implications for an old concept［J］.Hypertension，2009，54:1195-1201.

［9］ANDERSON E A，SINKEY C A，LAWTON W J，et al.Elevated sympathetic nerve activity in borderline hypertensive humans.Evidence from direct intraneural recordings［J］.Hypertension，1989，14:177-183.

［10］SIDDIQI L，JOLES J A，GRASSI G，et al.Is kidney ischemia the central mechanism in parallel activation of the renin and sympathetic system?［J］.J Hypertens，2009，27:1341-1349.

［11］BARAJASL，LIU L，POWERSK.Anatomy of the renal innervation:intrarenal aspects and ganglia of origin［J］.Can J Physiol Pharmacol，1992，70:735-749.

［12］DIBONA G F.Neural control of the kidney:past，present，andfuture［J］.Hypertension，2003，41(3 Pt 2):621-624.

［13］DiBONA G F，KOPP U C.Neural control of renal function［J］.Physiol Rev，1997，77:75-197.

［14］KOPP U，AURELL M，SJOLANDER M，et al.The role of prostaglandins in the alpha-and beta-adrenoceptor mediated renin release response to graded renal nerve stimulation［J］.Pflugers Arch，1981，391:1-8.

［15］STELLA A，ZANCHETTI A.Functional role of renal afferents［J］.Physiol Rev，1991，71:659-682.

［16］ATHERTON D S，DEEP N L，MENDELSOHN F O.Micro-anatomy of the renal sympathetic nervous system［J］.Clin Anat，2012，25(5):628-633.

［17］TAM GM，YAN B P，SHETTY SV，et al.Transcatheter renal artery sympathetic denervation for resistant hypertension:an old paradigm revisited［J］.Int J Cardiol，2013，164(3):277-281.

［18］SMITHWICK R H，THOMPSON J E.Splanchnicectomy for essential hypertension;results in 1，266 cases［J］.JAm Med Assoc，1953，152:1501-1504.

［19］MORRISSEY D M，BROOKES V S，COOKE W T.Sympathectomy in the treatment of hypertension;review of 122 cases［J］.Lancet，1953，1(6757):403-408.

［20］KRUM H，SCHLAICH M，WHITBOURN R，et al.Catheterbased renal sympathetic denervation for resistant hypertension:a multicentre safety and proof-of-principle cohort study［J］.Lancet，2009，373:1275-1281.

［21］VOSKUIL M，VERLOOPW L，BLANKESTIJN PJ，et al.Percutaneous renal denervation for the treatment of resistant essential hypertension;the first Dutch experience［J］.Neth Heart J，2011，19:319-323.

［22］KRUM H，SCHLAICH M，WHITBOURN R，et al.Catheterbased renal sympathetic denervation for resistant hypertension:a multicentre safety and proof-of-principle cohort study［J］.Lancet，2009，373:1275-1281.

［23］ESLER M D，KRUM H，SOBOTKA P A，et al.Renal sympathetic denervation in patients with treatment-resistant hypertension(The Symplicity HTN-2 Trial):a randomized controlled trial［J］.Lancet，2010，376:1903-1909.

［24］VASE H，MATHIASSEN O N，KALTOFT A.Catheter-based renal denervation for treatment of resistant hypertension［J］.Dan Med J，2012，59(6):A4439.

［25］MAHFOUD F，CREMERS B，JANKER J，et al.Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension［J］.Hypertension，2012，60:419-424.

［26］RIPPY M K，ZARINS D，BARMAN N C，et al.Catheterbased renal sympathetic denervation:chronic preclinical evidence for renal artery safety［J］.Clin Res Cardiol，2011，100:1095-1101.

［27］THOMASG，SHISHEHBOR M H，BRAVO E L，et al.Renal denervation to treat resistant hypertension:Guarded optimism［J］.Cleve Clin J Med，2012，79:501-510.

［28］RIPPY M K，ZARINS D，BARMAN N C，et al.Catheterbased renal sympathetic denervation:chronic preclinical evidence for renal artery safety［J］.Clin Res Cardiol，2011，100:1095-1101.

［29］MAHFOUD F，CREMERS B，JANKER J，et al.Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension［J］.Hypertension，2012，60(2):419-424.

［30］DORR O，LIEBETRAU C，MOLLMANN H，et al.Renal sympathetic denervation does not aggravate functional or structural renal damage［J］.J Am Coll Cardiol，2013，61(4):479-480.

［31］HERING D，MAHFOUD F，WALTON A S，et al.Renal denervation in moderate to severe CKD［J］.J Am Soc Nephrol，2012，23:12507.

［32］NKESTIJN P J，JOLES J A.Hypertension:Renal denervation in chronic kidney disease［J］.Nat Rev Nephrol，2012，8:43940.