Renal sympathetic denervation: Difference between revisions

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__NOTOC__
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{{CMG}} {{AE}} {{JS}}
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{{SK}} RDN; Renal denervation
{{SK}} RDN, renal denervation


==Overview==
==Overview==


'''Renal denervation (RDN)''' is a minimally invasive, [[endovascular]] [[catheter]]-based procedure to treat patients with [[refractory hypertension]] whose blood pressure cannot be controlled by 3 or more [[antihypertensive drugs]] (including a [[diuretic|diuretic drug]]) at maximally tolerated doses, with a baseline [[systolic blood pressure]] of 160 mmHg or more (150 mmHg or more in cases of concomitant [[type 2 diabetes mellitus]]), in the absence of [[secondary hypertension]].<ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref>
'''Renal denervation (RDN)''' is a minimally invasive, [[endovascular]] [[catheter]]-based procedure invented to treat patients with severe [[resistant hypertension]].<ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref> 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.<ref name="Symplicity">{{cite journal|last=SYMPLICITY HTN–1|first=Investigators|title=Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months.|journal=Hypertension|date=2011 May|volume=57|issue=5|pages=911–7|pmid=21403086|doi=10.1161/HYPERTENSIONAHA.110.163014}}</ref><ref name="Symplicity_a">{{cite journal|last=SYMPLICITY HTN–2|first=Investigators|coauthors=Esler, MD, Krum, H, Sobotka, PA, Schlaich, MP, Schmieder, RE, Böhm, M|title=Renal sympathetic denervation in patients with treatment-resistant hypertension (The SYMPLICITY HTN–2 Trial): a randomised controlled trial.|journal=Lancet|date=2010 Dec 4|volume=376|issue=9756|pages=1903–9|pmid=21093036|doi=10.1016/S0140-6736(10)62039-9}}</ref> However, in light of the negative results from SYMPLICITY HTN–3, the beneficial effect of renal denervation remains uncertain.


==Rationale==
==Rationale==


A treatment catheter is introduced into the [[renal artery]] and energy is applied circumferentially at several ablation points within each [[renal artery]] to denervate the [[sympathetic]] endings in the [[adventitia]] of the [[vessel wall]].<ref>{{cite journal|last=Esler|first=MC|coauthors=Krum, H, Sobotka, PA, Schlaich, MP, Schmieder, RE, Böhm, M|title=Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial.|journal=Lancet|date=2010 Dec 4|volume=376|issue=9756|pages=1903–9|pmid=21093036|doi=10.1016/S0140-6736(10)62039-9}}</ref><ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> The drop in [[blood pressure]] presumably results from an overall decrease in [[sympathetic]] activity and a reduction in [[norepinephrine]] release from the [[nerve]] endings, which culminate in decreased [[renin]] secretion, [[vasoconstriction]], and [[sodium]] [[reabsorption]].<ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref>
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]].<ref>{{cite journal|last=Esler|first=MC|coauthors=Krum, H, Sobotka, PA, Schlaich, MP, Schmieder, RE, Böhm, M|title=Renal sympathetic denervation in patients with treatment-resistant hypertension (The SYMPLICITY HTN–2 Trial): a randomized controlled trial.|journal=Lancet|date=2010 Dec 4|volume=376|issue=9756|pages=1903–9|pmid=21093036|doi=10.1016/S0140-6736(10)62039-9}}</ref><ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> 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]].<ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref> [[Renal]] denervation might also be beneficial in [[comorbidities]] of [[hypertension]] such as [[congestive heart failure]], [[chronic kidney disease]], and [[metabolic syndrome]].<ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref>


Early data from international [[clinical trials]] demonstrated an average [[blood pressure]] reduction of approximately 30 mmHg at three year follow up in patients with [[resistant hypertension|treatment-resistant hypertension]].<ref name="Symplicity">{{cite journal|last=Symplicity HTN-1|first=Investigators|title=Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months.|journal=Hypertension|date=2011 May|volume=57|issue=5|pages=911–7|pmid=21403086|doi=10.1161/HYPERTENSIONAHA.110.163014}}</ref><ref name="Symplicity_a">{{cite journal|last=Symplicity HTN-2|first=Investigators|coauthors=Esler, MD, Krum, H, Sobotka, PA, Schlaich, MP, Schmieder, RE, Böhm, M|title=Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.|journal=Lancet|date=2010 Dec 4|volume=376|issue=9756|pages=1903–9|pmid=21093036|doi=10.1016/S0140-6736(10)62039-9}}</ref> Since 2007, over 4000 patients have undergone [[catheter]]-based renal denervation with the Medtronic Symplicity™ Renal Denervation System.<ref name="medtronicrdn">Medtronic. MEDTRONIC SYMPLICITY™ RENAL DENERVATION SYSTEM DEMONSTRATES SIGNIFICANT AND SUSTAINED BLOOD PRESSURE REDUCTION OUT TO THREE YEARS. [Press Release]. Retrieved from: http://www.medtronicrdn.com/pdfs/RDN_ACC_Press_Release_FINAL_03_25_12.pdf. April 4, 2012.</ref> Despite its importance in [[resistant hypertension|drug-resistant hypertensive]] patients, by reducing [[renal]] [[sympathetic]] nerve flow, this procedure will also reduce overall [[sympathetic]] activity, thereby affecting multiple [[organs]], which is why [[renal]] denervation might also be beneficial in other [[disease]] states, such as [[congestive heart failure]], [[chronic kidney disease]], [[metabolic syndrome]] and others.<ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref> Until now, few [[complications]] have been reported, being inconsequential. It's long-term [[efficacy]] is still yet to be determined, however, studies show a permanence of effect at least of 2 to 3 years.<ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
==Device==


==History==
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]].<ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref><ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref>
Prior to [[pharmacological]] management of [[hypertension]], [[surgical]] [[sympathectomy]] was a recognized treatment for [[hypertension]]. Before modern [[pharmacotherapy]], the [[mortality rate]] within 5 years of [[malignant hypertension]] was close to 100%. <ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref> [[Surgical]] treatment of [[hypertension]] was suggested by several independent researchers in 1923, yet the first patient with [[malignant hypertension]] was only treated with [[surgical]] sympathectomy, by Adson in 1925. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> <ref>{{cite journal|last=Doumas|first=M|coauthors=Douma, S|title=Interventional management of resistant hypertension.|journal=Lancet|date=2009 Apr 11|volume=373|issue=9671|pages=1228–30|pmid=19332354|doi=10.1016/S0140-6736(09)60624-3}}</ref> Isolated bilateral [[kidney]] denervation was only performed in 1934 by Page and Heuer, however, because the results were considered unsatisfactory, [[surgical]] [[renal]] denervation was replaced by a more aggressive technique, the ''surgical removal of splanchnic nerves'' or ''splanchnicectomy'', which showed effective results. Subsequently, ''thoracolumbar splanchnicectomy''  became the procedure of choice for [[malignant hypertension]], which did not respond to [[diet]] and the limited [[pharmacological]] therapy of the time, for the following 2 decades. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> Between 1938 and 1947, other studies were made by Smithwick and Thompson, who published results from studying 3500 patients with [[malignant hypertension]]. Of those, 2400 were treated with ''thoracolumbar splanchnicectomy'', while the others took the [[pharmacological]] [[therapy]] available at the time. The group who underwent the [[surgical]] procedure had an inferior [[mortality rate]] and substantial [[blood pressure]] reduction, when compared to the [[pharmacology|pharmacologically]] treated group. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> This technique was often successful in reducing [[blood pressure]] but due to its non-selective nature, the high [[surgical|operative]] [[mortality]] and [[side effects]] were considerable. <ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref> These included [[orthostatic hypotension]], [[palpitations]], [[anhidrosis]], [[intestinal]] disturbances, [[impotence]], [[thoracic duct]] injuries and [[atelactasis]]. <ref>{{cite journal|last=Doumas|first=M|coauthors=Faselis, C, Papademetriou, V|title=Renal sympathetic denervation and systemic hypertension.|journal=The American journal of cardiology|date=2010 Feb 15|volume=105|issue=4|pages=570–6|pmid=20152255|doi=10.1016/j.amjcard.2009.10.027}}</ref><ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref>  


It was only until mid-1950's that the first [[oral]] [[antihypertensive medication]] became available. This allowed for a well-tolerated treatment regimen that [[patients]] could follow on the long term. For the last 50 years, [[medication]] has improved the control of [[hypertension]] in thousands of [[patients]] throughout the world, however,  evidence from the ''National Health and Nutrition Examination Survey'' along with large randomized [[clinical trials]] shows that an estimated 20% to 30% of [[hypertension]] cases require up to 3 or more [[antihypertensive drugs]] to achieve [[blood pressure]] targets. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref><ref>{{cite journal|last=Calhoun|first=DA|coauthors=Jones, D, Textor, S, Goff, DC, Murphy, TP, Toto, RD, White, A, Cushman, WC, White, W, Sica, D, Ferdinand, K, Giles, TD, Falkner, B, Carey, RM, American Heart Association Professional Education, Committee|title=Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.|journal=Circulation|date=2008 Jun 24|volume=117|issue=25|pages=e510-26|pmid=18574054|doi=10.1161/CIRCULATIONAHA.108.189141}}</ref> Recent data from ''National Health and Nutrition Examination Survey'' shows that 12.8% of [[hypertensive]] patients fulfill the criteria for [[resistant hypertension]], which represents about 120 million patients worldwide. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> Failure to reach normal [[blood pressure]] values puts these [[patients]] at an increased risk for development of major [[cardiovascular]] [[complications]]. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
During this time, a major effort in understanding the role of the [[SNS]] in [[hypertension]] has been made, particularly the role of [[renal]] [[sympathetic nerves]] in this process. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> Several models are pointing to a considerable role of the [[SNS]] overactivity in the development and maintenance of [[hypertension]], to which [[renal]] [[sympathetic nerves]] are an important contributor. This overactivity is involved in several others [[diseases]], described below, which justifies the need for more studies to evaluate how relevant this procedure might be in the treatment of other conditions. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref>
==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: <ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref><ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref>WhichMedicalDevice. Symplicity Catheter System (Overview).  http://www.whichmedicaldevice.com/by-manufacturer/113/198/symplicity-catheter-system</ref><ref>Medtronic. RDN Brochure. http://www.medtronicrdn.com/mediakit/RDN%20Brochure.pdf</ref><ref>Medgadget. Medtronic Starts Trial with Symplicity Renal Denervation System for Chronic Heart Failure and Renal Impairment. http://medgadget.com/2012/02/medtronic-starts-trial-with-symplicity-renal-denervation-system-for-chronic-heart-failure-and-renal-impairment.html</ref><ref>WhichMedicalDevice. Symplicity Catheter System (User Reviews).  http://www.whichmedicaldevice.com/by-manufacturer/113/198/symplicity-catheter-system</ref>
*'''''Medtronic's Simplicity™ 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 ''WhichMedicalDevice™'', but concerns have been reported regarding availability and financial reimbursement for the procedure.
*'''''Medtronic's Simplicity™ 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 ''WhichMedicalDevice™'', 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, 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.
*'''''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.
*'''''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.
*'''''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.
*'''''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]].
*'''''Recor's Paradise system''''' - uses an [[ultrasound]] technology [[catheter]] inserted [[percutaneously]] through a [[femoral sheath]].
Any of these systems must be manipulated by skilled operators, in an appropriately equipped catheterization lab. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref> Currently they are available in parts of Europe, Asia, Africa, Australia and the Americas.<ref name="medtronicrdn" /> So far, no [[renal]] denervation device has had [[FDA]] approval.


==Procedure==
==Procedure==
===Overview===
===Overview===
Considering the factors: [[drug resistance|drug-resistant]] [[hypertension]], [[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]] is 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 fibers|C-pain fibers]], [[analgesia]] and [[sedation]], but not [[anesthesia]], are mandatory for this procedure. <ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref><ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref>  
Considering the factors: [[drug resistance|drug-resistant]] [[hypertension]], [[SNS|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 fibers|C-pain fibers]], [[analgesia]] and [[sedation]], but not [[anesthesia]], are mandatory for this procedure.<ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref><ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="AthertonDeep2012">{{cite journal|last1=Atherton|first1=Daniel S.|last2=Deep|first2=Nicholas L.|last3=Mendelsohn|first3=Farrell O.|title=Micro-anatomy of the renal sympathetic nervous system: A human postmortem histologic study|journal=Clinical Anatomy|volume=25|issue=5|year=2012|pages=628–633|issn=08973806|doi=10.1002/ca.21280}}</ref>
 
===Pre-procedure===
===Pre-procedure===
*This technique must take place in a well equipped catheterization lab center, with skilled operators, experienced in handling possible surgical complications.  
*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 [[resistant hypertension|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. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref>
*Preprocedural examinations require the exclusion of [[secondary hypertension]], as a "hidden cause" of [[resistant hypertension|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.<ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref>
*[[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 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. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref><ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref><ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
*[[Renal function tests]] are also required to confirm kidney's ability to sustain preprocedural [[contrast medium]] exposure.<ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref><ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref><ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>


===During procedure===
===During procedure===


*[[Vital signs]] such as [[blood pressure]], [[heart rate]] and [[oxygen saturation]] must be monitored and continuous transcutaneous [[oxygen]] should be provided. <ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref>  
*[[Vital signs]] such as [[blood pressure]], [[heart rate]] and [[oxygen saturation]] must be monitored and continuous transcutaneous [[oxygen]] should be provided.<ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref>  
*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. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
*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.<ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
===Technique===
===Technique===
*Under [[fluoroscopic]] guidance, through a [[femoral sheath]], the [[electrode]] is positioned in each of the [[renal arteries]].  
*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. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref> The energy used for the [[ablation]] also generates heat within the [[vessels]], yet the system is cooled by the high rate of [[blood flow]]. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref> The procedure lasts for about 30 to 60 minutes. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>  
*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.<ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref> The energy used for the [[ablation]] also generates heat within the [[vessels]], yet the system is cooled by the high rate of [[blood flow]].<ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref> The procedure lasts for about 30 to 60 minutes.<ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>  
*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. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref>
*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.<ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref>
 
===Post-procedure===
===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. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref>
*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.<ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref>


==Outcomes==
==Outcomes==


The [[safety]] and [[efficacy]] of renal denervation were first investigated in a ''proof-of-concept study'' on 45 patients with [[resistant hypertension]].<ref name="Krum-2009">{{Cite journal  | last1 = Krum | first1 = H. | last2 = Schlaich | first2 = M. | last3 = Whitbourn | first3 = R. | last4 = Sobotka | first4 = PA. | last5 = Sadowski | first5 = J. | last6 = Bartus | first6 = K. | last7 = Kapelak | first7 = B. | last8 = Walton | first8 = A. | last9 = Sievert | first9 = H. | title = Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. | journal = Lancet | volume = 373 | issue = 9671 | pages = 1275-81 | month = Apr | year = 2009 | doi = 10.1016/S0140-6736(09)60566-3 | PMID = 19332353 }}</ref> 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. These data led to the following trials.
===SYMPLICITY HTN–1===
 
===SYMPLICITY HTN-1===
 
This was designed to be a first-in-human [[observational study|observational evaluation]] of the [[efficacy]] and [[safety]] of selective [[renal sympathetic denervation]]. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref> It looked at [[outcome|outcomes]] of 45 patients, with a mean age of 58 ± 9 years and mean [[blood pressure]] of 177±20/101±15 mm Hg, taking on average 5 [[antihypertensive]] drugs, who underwent [[catheter|catheter-based]] [[renal]] denervation. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>


The [[patients]] were then evaluated at 1, 3, 6, 9 and 12 months. The procedure was noted to be associated with a significant decrease in office [[blood pressure]], with mean decreases of: <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
* The [[safety]] and [[efficacy]] of renal denervation were first investigated in a ''proof-of-concept study'' on 45 patients with [[resistant hypertension]].<ref name="Krum-2009">{{Cite journal | last1 = Krum | first1 = H. | last2 = Schlaich | first2 = M. | last3 = Whitbourn | first3 = R. | last4 = Sobotka | first4 = PA. | last5 = Sadowski | first5 = J. | last6 = Bartus | first6 = K. | last7 = Kapelak | first7 = B. | last8 = Walton | first8 = A. | last9 = Sievert | first9 = H. | title = Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. | journal = Lancet | volume = 373 | issue = 9671 | pages = 1275-81 | month = Apr | year = 2009 | doi = 10.1016/S0140-6736(09)60566-3 | PMID = 19332353 }}</ref> 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.
*1st month: 14±4/10±3 mmHg
*3rd month: 21±7/10±4 mmHg
*6th month: 22±10/11±5 mmHg
*9th month: 24±9/11±5 mmHg
*12th month: 27±16/17±11 mm Hg.


Three-year follow-up data have demonstrated an average [[blood pressure]] reduction of 33/19mm Hg. This [[clinical trial|trial]] confirmed the durability of the procedure, contradicting the [[hypothesis]] that [[sympathetic nerve]] regrowth would nullify the effect.  
* This [[clinical trial|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 [[CNS|central]] [[sympathetic]] activity after the [[renal]] denervation.<ref name="Symplicity" /><ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref>
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 [[CNS|central]] [[sympathetic]] activity after the [[renal]] denervation. <ref name="Symplicity" /><ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref>  


In terms of safety, in this [[clinical trial|trial]], [[renal]] [[angiography]] was performed at the 14th and 30th day post procedure and [[MRI]] [[angiography]] at the 6th month, which showed no sign of [[renal artery]] [[aneurysm]] or [[renal artery stenosis|stenosis]]. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
* 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 [[renal artery stenosis|stenosis]].<ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>


Despite being of great value, this study was too small, lacked [[control group|control groups]] and relied on office [[blood pressure]], instead of ambulatory values. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref>
===SYMPLICITY HTN–2===


===SYMPLICITY HTN-2===
In SYMPLICITY HTN–2, 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.


This was a randomized, controlled [[clinical trial|trial]], with a total of 106 [[patients]] from Australia and Europe, that compared 54 [[control group|control]] patients with 52 active treatment patients, who underwent [[catheter|catheter-based]] [[renal]] denervation. Prior to the study, both groups had similar characteristics and [[antihypertensive]] treatment regimens, except for the estimated [[glomerular filtration rate]], which was inferior in the active treatment group. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
* ''Office-based [[blood pressure]] measurements'' at 6 months were as follows:
*After the procedure, the difference in ''office [[blood pressure]]'' for these two groups at 6 months was:
:* ''Active treatment group'': 147/84 mm Hg, from 178/96 mm Hg at baseline (p<0.0001)
**''Active treatment group'' - mean [[blood pressure]] of 147/84 mmHg, from 178/96 mmHg
:* ''Control group'': 179/96 mm Hg, from 178/97 mm Hg at baseline (p=0.77 systolic and p=0.83 diastolic)
**''Control group'' - no change, with a mean [[blood pressure]] of 179/96 mmHg, from 178/97 mmHg
*After the procedure, the difference in ''[[ambulatory blood pressure]]'' for these two groups at 6 months was:
**''Active treatment group'' - confirmed the observed office changes, with reductions of 20±17 mmHg for [[systolic blood pressure|systolic]] and 12±11 mmHg for [[diastolic blood pressure]]
**''Control group'' - confirmed the absence of changes, with 2±13 mmHg for [[systolic blood pressure|systolic]] and 0±7 mmHg for [[diastolic blood pressure]]


The [[clinical trial|trial]] showed that 20% of [[patients]] in the active treatment group had reductions in [[drug therapy|drug treatment]] before the 6 month period and that 39% of these, saw their [[blood pressure]] controlled to values <140 mmHg, whereas the [[patients]] in the [[control group]], only 6% had this reduction of [[drug therapy|drug treatment]] and only 3% saw their [[blood pressure]] controlled. At the same time, 8% of the [[patients]] in the active treatment group had an increase in the [[drug therapy|drug treatment]] regimen, before the 6 month follow-up visit, while 12% of the [[patients]] in the [[control group]] had this increase. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref> At the 6 months follow-up, the initial [[control group]] underwent the same [[renal]] denervation procedure, which led them to experience the same [[blood pressure]] drops as the initial active treatment group. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref> At 12 months the effects from the [[renal]] denervation were still present. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref>
===SYMPLICITY HTN–3===


It is important to notice that [[blood pressure]] lowerings usually take weeks to months to to settle in, which suggests a slow resetting of [[SNS]] regulation. This should be kept in mind and transmitted to the [[patient]], in order to avoid unrealistic expectations. Also the procedure is intended to improve [[blood pressure]] control in [[patients]] with [[resistant hypertension]], therefore, it is important to inform the [[patient]] that he will most likely continue the [[pharmacological]] therapy. <ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref>
SYMPLICITY HTN–3 is a multi-center, [[prospective study|prospective]], single-blind, [[randomized trial|randomized]], sham-controlled [[clinical trial|study]] on the [[efficacy]] and [[safety]] of renal sympathetic denervation in [[patients]] with severe [[resistant hypertension]] (Clinical Trial No. NCT01418261).<ref name="BhattKandzari2014">{{cite journal|last1=Bhatt|first1=Deepak L.|last2=Kandzari|first2=David E.|last3=O'Neill|first3=William W.|last4=D'Agostino|first4=Ralph|last5=Flack|first5=John M.|last6=Katzen|first6=Barry T.|last7=Leon|first7=Martin B.|last8=Liu|first8=Minglei|last9=Mauri|first9=Laura|last10=Negoita|first10=Manuela|last11=Cohen|first11=Sidney A.|last12=Oparil|first12=Suzanne|last13=Rocha-Singh|first13=Krishna|last14=Townsend|first14=Raymond R.|last15=Bakris|first15=George L.|title=A Controlled Trial of Renal Denervation for Resistant Hypertension|journal=New England Journal of Medicine|volume=370|issue=15|year=2014|pages=1393–1401|issn=0028-4793|doi=10.1056/NEJMoa1402670}}</ref><ref>Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN–3). ClinicalTrials.gov Identifier: NCT01418261 http://clinicaltrials.gov/ct2/show/NCT01418261</ref> 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 [[SBP|systolic blood pressure]] or differences in safety between the two groups.


[[Meta-analyses]] of [[renal]] denervation have yielded conflicting results. <ref name="DoumasAnyfanti2012">{{cite journal|last1=Doumas|first1=Michael|last2=Anyfanti|first2=Panagiota|last3=Bakris|first3=George|title=Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension|journal=Journal of Hypertension|volume=30|issue=5|year=2012|pages=874–876|issn=0263-6352|doi=10.1097/HJH.0b013e328352c3c7}}</ref> Although in [[blood pressure]]-lowering [[clinical trial|trials]] using [[pharmacological]] approaches, office and [[ambulatory blood pressure]] results are normal to show disparities, in this particular case there was a considerable difference between [[blood pressure]] levels in office and ambulatory data. <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref> The reasons for this disparity are so far unclear. Proposed theories include [[renal]] denervation obliterating the [[white coat hypertension|white coat response]], thereby disproportionately reducing clinic values,<ref name="DoumasAnyfanti2012">{{cite journal|last1=Doumas|first1=Michael|last2=Anyfanti|first2=Panagiota|last3=Bakris|first3=George|title=Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension|journal=Journal of Hypertension|volume=30|issue=5|year=2012|pages=874–876|issn=0263-6352|doi=10.1097/HJH.0b013e328352c3c7}}</ref> or the disparity rather being an anomaly due to deficiencies in [[renal]] denervation [[clinical trial|trial]] designs to date.
* Mean changes in [[SBP|office systolic blood pressure]] at 6 months were as follows, for a difference of –2.39 mm Hg:
 
In these two previous [[clinical trial|trials]] patient awareness of the differences in treatment, along with a possible influence of [[observer bias]] might have been a contributor to the results observed, therefore a new [[clinical trial|study]] was designed: <ref name="pmid24021387">{{cite journal| author=Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM et al.| title=International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension. | journal=J Am Coll Cardiol | year= 2013 | volume= 62 | issue= 22 | pages= 2031-45 | pmid=24021387 | doi=10.1016/j.jacc.2013.08.1616 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24021387  }} </ref>
 
===SYMPLICITY HTN-3===
 
SYMPLICITY HTN-3 is a multi-center, [[prospective study|prospective]], single-blind, [[randomized trial|randomized]], sham-controlled [[clinical trial|study]] on [[efficacy]] and [[safety]] of renal sympathetic denervation in [[patients]] with severe [[resistant hypertension]] (Clinical Trial No. NCT01418261).<ref name="BhattKandzari2014">{{cite journal|last1=Bhatt|first1=Deepak L.|last2=Kandzari|first2=David E.|last3=O'Neill|first3=William W.|last4=D'Agostino|first4=Ralph|last5=Flack|first5=John M.|last6=Katzen|first6=Barry T.|last7=Leon|first7=Martin B.|last8=Liu|first8=Minglei|last9=Mauri|first9=Laura|last10=Negoita|first10=Manuela|last11=Cohen|first11=Sidney A.|last12=Oparil|first12=Suzanne|last13=Rocha-Singh|first13=Krishna|last14=Townsend|first14=Raymond R.|last15=Bakris|first15=George L.|title=A Controlled Trial of Renal Denervation for Resistant Hypertension|journal=New England Journal of Medicine|volume=370|issue=15|year=2014|pages=1393–1401|issn=0028-4793|doi=10.1056/NEJMoa1402670}}</ref><ref>Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3). ClinicalTrials.gov Identifier: NCT01418261 http://clinicaltrials.gov/ct2/show/NCT01418261</ref> 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 [[SBP]] or differences in safety between the two groups.
 
* Mean changes in office [[SBP|systolic blood pressure (SBP)]] at 6 months were as follows, for a difference of '''–2.39 mm Hg''':
:* ''Renal denervation group'': –14.13±23.93 mm Hg (p<0.001)
:* ''Renal denervation group'': –14.13±23.93 mm Hg (p<0.001)
:* ''Sham procedure group'': –11.74±25.94 mm Hg (p<0.001)
:* ''Sham procedure group'': –11.74±25.94 mm Hg (p<0.001)


* Mean changes in 24-hour ambulatory [[SBP|systolic blood pressure (SBP)]] at 6 months were as follows, for a difference of '''–1.96 mm Hg''':
* Mean changes in 24-hour [[ambulatory blood pressure|ambulatory systolic blood pressure]] at 6 months were as follows, for a difference of –1.96 mm Hg:
:* ''Renal denervation group'': –6.75±15.11 mmHg (p<0.001)
:* ''Renal denervation group'': –6.75±15.11 mm Hg (p<0.001)
:* ''Sham procedure group'': –4.79±17.25 mmHg (p<0.001)
:* ''Sham procedure group'': –4.79±17.25 mm Hg (p<0.001)


==Risks==
==Risks==
The Symplicity HTN-1 and HTN-2 [[clinical trial|trials]] have demonstrated a good safety profile for [[catheter|catheter-based]] [[renal]] denervation. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> Patients may experience pain during application of [[radiofrequency]] pulses and intraprocedural [[bradycardia]] requiring [[atropine]], has also been reported.<ref name="Symplicity_a" />  Other documented procedure-related [[complications]] include small [[hematoma|hematomas]], [[renal artery stenosis]], [[vasospasm]] of the [[renal artery]] following the procedure, [[femoral artery]] [[pseudoaneurysm]] and [[renal artery]] [[dissection]]. A concern about this technique was if [[renal function]] would be affected. So far data show only minor deterioration of [[eGFR]] and increase in [[serum creatinine]]. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref>
A particular concern is the theoretical risk of damage to [[renal arteries]] during the delivery of [[radiofrequency]] energy. Some published data mentioned that the applied energy could result in acute cellular swelling, transient local de-endothelization, connective tissue coagulation and possible [[thrombus]] formation, hence the advised concomitant administration of [[antiplatelet]] therapy. <ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref> An animal study using swines 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 [[clinical trial|trial]] where follow up imaging has not demonstrated renal vascular damage.<ref>{{cite journal|last=Rippy|first=MK|coauthors=Zarins, D, Barman, NC, Wu, A, Duncan, KL, Zarins, CK|title=Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety.|journal=Clinical research in cardiology : official journal of the German Cardiac Society|date=2011 Dec|volume=100|issue=12|pages=1095–101|pmid=21796327|doi=10.1007/s00392-011-0346-8}}</ref>


Two case reports were published, following reports of rise in [[blood pressure]] secondary to renal sympathetic denervation, caused by progression of [[renal artery stenosis]]. However, it is still yet to be confirmed whether this evolution was due to the procedure or the natural progression of the disease process. <ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref>
Data from SYMPLICITY [[clinical trial|trials]] suggest a favorable safety profile for [[catheter|catheter-based]] [[renal]] denervation.<ref name="Krum-2009">{{Cite journal  | last1 = Krum | first1 = H. | last2 = Schlaich | first2 = M. | last3 = Whitbourn | first3 = R. | last4 = Sobotka | first4 = PA. | last5 = Sadowski | first5 = J. | last6 = Bartus | first6 = K. | last7 = Kapelak | first7 = B. | last8 = Walton | first8 = A. | last9 = Sievert | first9 = H. | title = Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. | journal = Lancet | volume = 373 | issue = 9671 | pages = 1275-81 | month = Apr | year = 2009 | doi = 10.1016/S0140-6736(09)60566-3 | PMID = 19332353 }}</ref><ref name="Esler-2010">{{Cite journal  | last1 = Esler | first1 = MD. | last2 = Krum | first2 = H. | last3 = Sobotka | first3 = PA. | last4 = Schlaich | first4 = MP. | last5 = Schmieder | first5 = RE. | last6 = Böhm | first6 = M. | last7 = Böhm | first7 = M. | last8 = Mahfoud | first8 = F. | last9 = Sievert | first9 = H. | title = Renal sympathetic denervation in patients with treatment-resistant hypertension (The SYMPLICITY HTN–2 Trial): a randomised controlled trial. | journal = Lancet | volume = 376 | issue = 9756 | pages = 1903-9 | month = Dec | year = 2010 | doi = 10.1016/S0140-6736(10)62039-9 | PMID = 21093036 }}</ref><ref name="Krum-2011">{{Cite journal  | last1 = Krum | first1 = H. | last2 = Barman | first2 = N. | last3 = Schlaich | first3 = M. | last4 = Sobotka | first4 = P. | last5 = Esler | first5 = M. | last6 = Mahfoud | first6 = F. | last7 = Bohm | first7 = M. | last8 = Dunlap | first8 = M. | last9 = Sadowski | first9 = J. | title = Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. | journal = Hypertension | volume = 57 | issue = 5 | pages = 911-7 | month = May | year = 2011 | doi = 10.1161/HYPERTENSIONAHA.110.163014 | PMID = 21403086 }}</ref> Procedure-related [[complications]] include small [[hematoma|hematomas]], [[renal artery stenosis]], [[vasospasm]] of the [[renal artery]] following the procedure, [[femoral artery]] [[pseudoaneurysm]], [[renal artery]] [[dissection]], and minor deterioration of [[renal function]].<ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref> 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.<ref name="Steigerwald-2012">{{Cite journal  | last1 = Steigerwald | first1 = K. | last2 = Titova | first2 = A. | last3 = Malle | first3 = C. | last4 = Kennerknecht | first4 = E. | last5 = Jilek | first5 = C. | last6 = Hausleiter | first6 = J. | last7 = Nährig | first7 = JM. | last8 = Laugwitz | first8 = KL. | last9 = Joner | first9 = M. | title = Morphological assessment of renal arteries after radiofrequency catheter-based sympathetic denervation in a porcine model. | journal = J Hypertens | volume = 30 | issue = 11 | pages = 2230-9 | month = Nov | year = 2012 | doi = 10.1097/HJH.0b013e32835821e5 | PMID = 22914572 }}</ref> 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.<ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref>


==Uses of Renal Denervation Beyond Hypertension==
==Uses of Renal Denervation Beyond Hypertension==


The potential benefit of renal denervation is being investigated in other conditions associated with an exaggerated [[sympathetic]] activity including:<ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592  }} </ref><ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref>
Potential benefits of renal denervation are being investigated in [[comorbidities]] of [[hypertension]] that are associated with exaggerated [[sympathetic]] activity, including:
 
* [[Atrial fibrillation]]<ref name="Scherlag-2013">{{Cite journal  | last1 = Scherlag | first1 = MA. | last2 = Scherlag | first2 = BJ. | title = A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. | journal = J Am Coll Cardiol | volume = 62 | issue = 12 | pages = 1129-30 | month = Sep | year = 2013 | doi = 10.1016/j.jacc.2013.05.068 | PMID = 23810880 }}</ref><ref name="Linz-2012">{{Cite journal  | last1 = Linz | first1 = D. | last2 = Mahfoud | first2 = F. | last3 = Schotten | first3 = U. | last4 = Ukena | first4 = C. | last5 = Neuberger | first5 = HR. | last6 = Wirth | first6 = K. | last7 = Böhm | first7 = M. | title = Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea. | journal = Hypertension | volume = 60 | issue = 1 | pages = 172-8 | month = Jul | year = 2012 | doi = 10.1161/HYPERTENSIONAHA.112.191965 | PMID = 22585944 }}</ref><ref name="Linz-2013">{{Cite journal  | last1 = Linz | first1 = D. | last2 = Mahfoud | first2 = F. | last3 = Schotten | first3 = U. | last4 = Ukena | first4 = C. | last5 = Hohl | first5 = M. | last6 = Neuberger | first6 = HR. | last7 = Wirth | first7 = K. | last8 = Böhm | first8 = M. | title = Renal sympathetic denervation provides ventricular rate control but does not prevent atrial electrical remodeling during atrial fibrillation. | journal = Hypertension | volume = 61 | issue = 1 | pages = 225-31 | month = Jan | year = 2013 | doi = 10.1161/HYPERTENSIONAHA.111.00182 | PMID = 23150501 }}</ref>


* [[Atrial fibrillation]]<ref name="Scherlag-2013">{{Cite journal  | last1 = Scherlag | first1 = MA. | last2 = Scherlag | first2 = BJ. | title = A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. | journal = J Am Coll Cardiol | volume = 62 | issue = 12 | pages = 1129-30 | month = Sep | year = 2013 | doi = 10.1016/j.jacc.2013.05.068 | PMID = 23810880 }}</ref><ref name="Linz-2012">{{Cite journal  | last1 = Linz | first1 = D. | last2 = Mahfoud | first2 = F. | last3 = Schotten | first3 = U. | last4 = Ukena | first4 = C. | last5 = Neuberger | first5 = HR. | last6 = Wirth | first6 = K. | last7 = Böhm | first7 = M. | title = Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea. | journal = Hypertension | volume = 60 | issue = 1 | pages = 172-8 | month = Jul | year = 2012 | doi = 10.1161/HYPERTENSIONAHA.112.191965 | PMID = 22585944 }}</ref><ref name="Linz-2013">{{Cite journal  | last1 = Linz | first1 = D. | last2 = Mahfoud | first2 = F. | last3 = Schotten | first3 = U. | last4 = Ukena | first4 = C. | last5 = Hohl | first5 = M. | last6 = Neuberger | first6 = HR. | last7 = Wirth | first7 = K. | last8 = Böhm | first8 = M. | title = Renal sympathetic denervation provides ventricular rate control but does not prevent atrial electrical remodeling during atrial fibrillation. | journal = Hypertension | volume = 61 | issue = 1 | pages = 225-31 | month = Jan | year = 2013 | doi = 10.1161/HYPERTENSIONAHA.111.00182 | PMID = 23150501 }}</ref><ref name="PokushalovRomanov2012">{{cite journal|last1=Pokushalov|first1=Evgeny|last2=Romanov|first2=Alexander|last3=Corbucci|first3=Giorgio|last4=Artyomenko|first4=Sergey|last5=Baranova|first5=Vera|last6=Turov|first6=Alex|last7=Shirokova|first7=Natalya|last8=Karaskov|first8=Alexander|last9=Mittal|first9=Suneet|last10=Steinberg|first10=Jonathan S.|title=A Randomized Comparison of Pulmonary Vein Isolation With Versus Without Concomitant Renal Artery Denervation in Patients With Refractory Symptomatic Atrial Fibrillation and Resistant Hypertension|journal=Journal of the American College of Cardiology|volume=60|issue=13|year=2012|pages=1163–1170|issn=07351097|doi=10.1016/j.jacc.2012.05.036}}</ref><ref name="UkenaBauer2011">{{cite journal|last1=Ukena|first1=Christian|last2=Bauer|first2=Axel|last3=Mahfoud|first3=Felix|last4=Schreieck|first4=Jürgen|last5=Neuberger|first5=Hans-Ruprecht|last6=Eick|first6=Christian|last7=Sobotka|first7=Paul A.|last8=Gawaz|first8=Meinrad|last9=Böhm|first9=Michael|title=Renal sympathetic denervation for treatment of electrical storm: first-in-man experience|journal=Clinical Research in Cardiology|volume=101|issue=1|year=2011|pages=63–67|issn=1861-0684|doi=10.1007/s00392-011-0365-5}}</ref>
* [[Diabetes mellitus]]<ref name="Mahfoud-2011">{{Cite journal  | last1 = Mahfoud | first1 = F. | last2 = Schlaich | first2 = M. | last3 = Kindermann | first3 = I. | last4 = Ukena | first4 = C. | last5 = Cremers | first5 = B. | last6 = Brandt | first6 = MC. | last7 = Hoppe | first7 = UC. | last8 = Vonend | first8 = O. | last9 = Rump | first9 = LC. | title = Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. | journal = Circulation | volume = 123 | issue = 18 | pages = 1940-6 | month = May | year = 2011 | doi = 10.1161/CIRCULATIONAHA.110.991869 | PMID = 21518978 }}</ref>
* [[Diabetes mellitus]]<ref name="Mahfoud-2011">{{Cite journal  | last1 = Mahfoud | first1 = F. | last2 = Schlaich | first2 = M. | last3 = Kindermann | first3 = I. | last4 = Ukena | first4 = C. | last5 = Cremers | first5 = B. | last6 = Brandt | first6 = MC. | last7 = Hoppe | first7 = UC. | last8 = Vonend | first8 = O. | last9 = Rump | first9 = LC. | title = Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. | journal = Circulation | volume = 123 | issue = 18 | pages = 1940-6 | month = May | year = 2011 | doi = 10.1161/CIRCULATIONAHA.110.991869 | PMID = 21518978 }}</ref>
* [[Heart failure]]<ref name="Davies-2013">{{Cite journal  | last1 = Davies | first1 = JE. | last2 = Manisty | first2 = CH. | last3 = Petraco | first3 = R. | last4 = Barron | first4 = AJ. | last5 = Unsworth | first5 = B. | last6 = Mayet | first6 = J. | last7 = Hamady | first7 = M. | last8 = Hughes | first8 = AD. | last9 = Sever | first9 = PS. | title = First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. | journal = Int J Cardiol | volume = 162 | issue = 3 | pages = 189-92 | month = Jan | year = 2013 | doi = 10.1016/j.ijcard.2012.09.019 | PMID = 23031283 }}</ref>
* [[Heart failure]]<ref name="Davies-2013">{{Cite journal  | last1 = Davies | first1 = JE. | last2 = Manisty | first2 = CH. | last3 = Petraco | first3 = R. | last4 = Barron | first4 = AJ. | last5 = Unsworth | first5 = B. | last6 = Mayet | first6 = J. | last7 = Hamady | first7 = M. | last8 = Hughes | first8 = AD. | last9 = Sever | first9 = PS. | title = First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. | journal = Int J Cardiol | volume = 162 | issue = 3 | pages = 189-92 | month = Jan | year = 2013 | doi = 10.1016/j.ijcard.2012.09.019 | PMID = 23031283 }}</ref>
 
* [[obstructive sleep apnea|Sleep apnea]]<ref name="Witkowski-2011">{{Cite journal  | last1 = Witkowski | first1 = A. | last2 = Prejbisz | first2 = A. | last3 = Florczak | first3 = E. | last4 = Kądziela | first4 = J. | last5 = Śliwiński | first5 = P. | last6 = Bieleń | first6 = P. | last7 = Michałowska | first7 = I. | last8 = Kabat | first8 = M. | last9 = Warchoł | first9 = E. | title = Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. | journal = Hypertension | volume = 58 | issue = 4 | pages = 559-65 | month = Oct | year = 2011 | doi = 10.1161/HYPERTENSIONAHA.111.173799 | PMID = 21844482 }}</ref><ref name="FisherYoung2009">{{cite journal|last1=Fisher|first1=James P.|last2=Young|first2=Colin N.|last3=Fadel|first3=Paul J.|title=Central sympathetic overactivity: Maladies and mechanisms|journal=Autonomic Neuroscience|volume=148|issue=1-2|year=2009|pages=5–15|issn=15660702|doi=10.1016/j.autneu.2009.02.003}}</ref><ref name="WitkowskiPrejbisz2011">{{cite journal|last1=Witkowski|first1=A.|last2=Prejbisz|first2=A.|last3=Florczak|first3=E.|last4=Kadziela|first4=J.|last5=Sliwinski|first5=P.|last6=Bielen|first6=P.|last7=Michalowska|first7=I.|last8=Kabat|first8=M.|last9=Warchol|first9=E.|last10=Januszewicz|first10=M.|last11=Narkiewicz|first11=K.|last12=Somers|first12=V. K.|last13=Sobotka|first13=P. A.|last14=Januszewicz|first14=A.|title=Effects of Renal Sympathetic Denervation on Blood Pressure, Sleep Apnea Course, and Glycemic Control in Patients With Resistant Hypertension and Sleep Apnea|journal=Hypertension|volume=58|issue=4|year=2011|pages=559–565|issn=0194-911X|doi=10.1161/HYPERTENSIONAHA.111.173799}}</ref>
* [[obstructive sleep apnea|Sleep apnea]]<ref name="Witkowski-2011">{{Cite journal  | last1 = Witkowski | first1 = A. | last2 = Prejbisz | first2 = A. | last3 = Florczak | first3 = E. | last4 = Kądziela | first4 = J. | last5 = Śliwiński | first5 = P. | last6 = Bieleń | first6 = P. | last7 = Michałowska | first7 = I. | last8 = Kabat | first8 = M. | last9 = Warchoł | first9 = E. | title = Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. | journal = Hypertension | volume = 58 | issue = 4 | pages = 559-65 | month = Oct | year = 2011 | doi = 10.1161/HYPERTENSIONAHA.111.173799 | PMID = 21844482 }}</ref>
 
* [[Polycystic ovary disease]]<ref name="Schlaich-2011">{{Cite journal  | last1 = Schlaich | first1 = MP. | last2 = Straznicky | first2 = N. | last3 = Grima | first3 = M. | last4 = Ika-Sari | first4 = C. | last5 = Dawood | first5 = T. | last6 = Mahfoud | first6 = F. | last7 = Lambert | first7 = E. | last8 = Chopra | first8 = R. | last9 = Socratous | first9 = F. | title = Renal denervation: a potential new treatment modality for polycystic ovary syndrome? | journal = J Hypertens | volume = 29 | issue = 5 | pages = 991-6 | month = May | year = 2011 | doi = 10.1097/HJH.0b013e328344db3a | PMID = 21358414 }}</ref>
* [[Polycystic ovary disease]]<ref name="Schlaich-2011">{{Cite journal  | last1 = Schlaich | first1 = MP. | last2 = Straznicky | first2 = N. | last3 = Grima | first3 = M. | last4 = Ika-Sari | first4 = C. | last5 = Dawood | first5 = T. | last6 = Mahfoud | first6 = F. | last7 = Lambert | first7 = E. | last8 = Chopra | first8 = R. | last9 = Socratous | first9 = F. | title = Renal denervation: a potential new treatment modality for polycystic ovary syndrome? | journal = J Hypertens | volume = 29 | issue = 5 | pages = 991-6 | month = May | year = 2011 | doi = 10.1097/HJH.0b013e328344db3a | PMID = 21358414 }}</ref>
* [[Ventricular tachycardia]]<ref name="Ukena-2012">{{Cite journal  | last1 = Ukena | first1 = C. | last2 = Bauer | first2 = A. | last3 = Mahfoud | first3 = F. | last4 = Schreieck | first4 = J. | last5 = Neuberger | first5 = HR. | last6 = Eick | first6 = C. | last7 = Sobotka | first7 = PA. | last8 = Gawaz | first8 = M. | last9 = Böhm | first9 = M. | title = Renal sympathetic denervation for treatment of electrical storm: first-in-man experience. | journal = Clin Res Cardiol | volume = 101 | issue = 1 | pages = 63-7 | month = Jan | year = 2012 | doi = 10.1007/s00392-011-0365-5 | PMID = 21960416 }}</ref>
* [[Ventricular tachycardia]]<ref name="Ukena-2012">{{Cite journal  | last1 = Ukena | first1 = C. | last2 = Bauer | first2 = A. | last3 = Mahfoud | first3 = F. | last4 = Schreieck | first4 = J. | last5 = Neuberger | first5 = HR. | last6 = Eick | first6 = C. | last7 = Sobotka | first7 = PA. | last8 = Gawaz | first8 = M. | last9 = Böhm | first9 = M. | title = Renal sympathetic denervation for treatment of electrical storm: first-in-man experience. | journal = Clin Res Cardiol | volume = 101 | issue = 1 | pages = 63-7 | month = Jan | year = 2012 | doi = 10.1007/s00392-011-0365-5 | PMID = 21960416 }}</ref>


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

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.[1] 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.[2][3] However, in light of the negative results from SYMPLICITY HTN–3, 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.[4][5] 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.[5][1] Renal denervation might also be beneficial in comorbidities of hypertension such as congestive heart failure, chronic kidney disease, and metabolic syndrome.[6]

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.[1][5]

  • Medtronic's Simplicity™ 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 WhichMedicalDevice™, 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.[1][5][7]

Pre-procedure

During procedure

Technique

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.[6]

Outcomes

SYMPLICITY HTN–1

  • The safety and efficacy of renal denervation were first investigated in a proof-of-concept study on 45 patients with resistant hypertension.[10] 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.

SYMPLICITY HTN–2

In SYMPLICITY HTN–2, 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.

  • 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 HTN–3

SYMPLICITY HTN–3 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).[11][12] 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.

  • Renal denervation group: –14.13±23.93 mm Hg (p<0.001)
  • Sham procedure group: –11.74±25.94 mm Hg (p<0.001)
  • Renal denervation group: –6.75±15.11 mm Hg (p<0.001)
  • Sham procedure group: –4.79±17.25 mm Hg (p<0.001)

Risks

Data from SYMPLICITY trials suggest a favorable safety profile for catheter-based renal denervation.[10][13][14] 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.[5] 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.[15] 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.[8]

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:

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Thukkani, A. K.; Bhatt, D. L. (2013). "Renal Denervation Therapy for Hypertension". Circulation. 128 (20): 2251–2254. doi:10.1161/CIRCULATIONAHA.113.004660. ISSN 0009-7322.
  2. ↑ 2.0 2.1 SYMPLICITY HTN–1, Investigators (2011 May). "Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months". Hypertension. 57 (5): 911–7. doi:10.1161/HYPERTENSIONAHA.110.163014. PMID 21403086. Check date values in: |date= (help)
  3. ↑ SYMPLICITY HTN–2, Investigators (2010 Dec 4). "Renal sympathetic denervation in patients with treatment-resistant hypertension (The SYMPLICITY HTN–2 Trial): a randomised controlled trial". Lancet. 376 (9756): 1903–9. doi:10.1016/S0140-6736(10)62039-9. PMID 21093036. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  4. ↑ Esler, MC (2010 Dec 4). "Renal sympathetic denervation in patients with treatment-resistant hypertension (The SYMPLICITY HTN–2 Trial): a randomized controlled trial". Lancet. 376 (9756): 1903–9. doi:10.1016/S0140-6736(10)62039-9. PMID 21093036. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Papademetriou, V.; Rashidi, A. A.; Tsioufis, C.; Doumas, M. (2014). "Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions". Circulation. 129 (13): 1440–1451. doi:10.1161/CIRCULATIONAHA.113.005405. ISSN 0009-7322.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Böhm M, Linz D, Urban D, Mahfoud F, Ukena C (2013). "Renal sympathetic denervation: applications in hypertension and beyond". Nat Rev Cardiol. 10 (8): 465–76. doi:10.1038/nrcardio.2013.89. PMID 23774592.
  7. ↑ Atherton, Daniel S.; Deep, Nicholas L.; Mendelsohn, Farrell O. (2012). "Micro-anatomy of the renal sympathetic nervous system: A human postmortem histologic study". Clinical Anatomy. 25 (5): 628–633. doi:10.1002/ca.21280. ISSN 0897-3806.
  8. ↑ 8.0 8.1 8.2 Mahfoud, F.; Luscher, T. F.; Andersson, B.; Baumgartner, I.; Cifkova, R.; DiMario, C.; Doevendans, P.; Fagard, R.; Fajadet, J.; Komajda, M.; LeFevre, T.; Lotan, C.; Sievert, H.; Volpe, M.; Widimsky, P.; Wijns, W.; Williams, B.; Windecker, S.; Witkowski, A.; Zeller, T.; Bohm, M. (2013). "Expert consensus document from the European Society of Cardiology on catheter-based renal denervation". European Heart Journal. 34 (28): 2149–2157. doi:10.1093/eurheartj/eht154. ISSN 0195-668X.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM; et al. (2013). "International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension". J Am Coll Cardiol. 62 (22): 2031–45. doi:10.1016/j.jacc.2013.08.1616. PMID 24021387.
  10. ↑ 10.0 10.1 Krum, H.; Schlaich, M.; Whitbourn, R.; Sobotka, PA.; Sadowski, J.; Bartus, K.; Kapelak, B.; Walton, A.; Sievert, H. (2009). "Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study". Lancet. 373 (9671): 1275–81. doi:10.1016/S0140-6736(09)60566-3. PMID 19332353. Unknown parameter |month= ignored (help)
  11. ↑ Bhatt, Deepak L.; Kandzari, David E.; O'Neill, William W.; D'Agostino, Ralph; Flack, John M.; Katzen, Barry T.; Leon, Martin B.; Liu, Minglei; Mauri, Laura; Negoita, Manuela; Cohen, Sidney A.; Oparil, Suzanne; Rocha-Singh, Krishna; Townsend, Raymond R.; Bakris, George L. (2014). "A Controlled Trial of Renal Denervation for Resistant Hypertension". New England Journal of Medicine. 370 (15): 1393–1401. doi:10.1056/NEJMoa1402670. ISSN 0028-4793.
  12. ↑ Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN–3). ClinicalTrials.gov Identifier: NCT01418261 http://clinicaltrials.gov/ct2/show/NCT01418261
  13. ↑ Esler, MD.; Krum, H.; Sobotka, PA.; Schlaich, MP.; Schmieder, RE.; Böhm, M.; Böhm, M.; Mahfoud, F.; Sievert, H. (2010). "Renal sympathetic denervation in patients with treatment-resistant hypertension (The SYMPLICITY HTN–2 Trial): a randomised controlled trial". Lancet. 376 (9756): 1903–9. doi:10.1016/S0140-6736(10)62039-9. PMID 21093036. Unknown parameter |month= ignored (help)
  14. ↑ Krum, H.; Barman, N.; Schlaich, M.; Sobotka, P.; Esler, M.; Mahfoud, F.; Bohm, M.; Dunlap, M.; Sadowski, J. (2011). "Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months". Hypertension. 57 (5): 911–7. doi:10.1161/HYPERTENSIONAHA.110.163014. PMID 21403086. Unknown parameter |month= ignored (help)
  15. ↑ Steigerwald, K.; Titova, A.; Malle, C.; Kennerknecht, E.; Jilek, C.; Hausleiter, J.; Nährig, JM.; Laugwitz, KL.; Joner, M. (2012). "Morphological assessment of renal arteries after radiofrequency catheter-based sympathetic denervation in a porcine model". J Hypertens. 30 (11): 2230–9. doi:10.1097/HJH.0b013e32835821e5. PMID 22914572. Unknown parameter |month= ignored (help)
  16. ↑ Scherlag, MA.; Scherlag, BJ. (2013). "A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension". J Am Coll Cardiol. 62 (12): 1129–30. doi:10.1016/j.jacc.2013.05.068. PMID 23810880. Unknown parameter |month= ignored (help)
  17. ↑ Linz, D.; Mahfoud, F.; Schotten, U.; Ukena, C.; Neuberger, HR.; Wirth, K.; Böhm, M. (2012). "Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea". Hypertension. 60 (1): 172–8. doi:10.1161/HYPERTENSIONAHA.112.191965. PMID 22585944. Unknown parameter |month= ignored (help)
  18. ↑ Linz, D.; Mahfoud, F.; Schotten, U.; Ukena, C.; Hohl, M.; Neuberger, HR.; Wirth, K.; Böhm, M. (2013). "Renal sympathetic denervation provides ventricular rate control but does not prevent atrial electrical remodeling during atrial fibrillation". Hypertension. 61 (1): 225–31. doi:10.1161/HYPERTENSIONAHA.111.00182. PMID 23150501. Unknown parameter |month= ignored (help)
  19. ↑ Pokushalov, Evgeny; Romanov, Alexander; Corbucci, Giorgio; Artyomenko, Sergey; Baranova, Vera; Turov, Alex; Shirokova, Natalya; Karaskov, Alexander; Mittal, Suneet; Steinberg, Jonathan S. (2012). "A Randomized Comparison of Pulmonary Vein Isolation With Versus Without Concomitant Renal Artery Denervation in Patients With Refractory Symptomatic Atrial Fibrillation and Resistant Hypertension". Journal of the American College of Cardiology. 60 (13): 1163–1170. doi:10.1016/j.jacc.2012.05.036. ISSN 0735-1097.
  20. ↑ Ukena, Christian; Bauer, Axel; Mahfoud, Felix; Schreieck, Jürgen; Neuberger, Hans-Ruprecht; Eick, Christian; Sobotka, Paul A.; Gawaz, Meinrad; Böhm, Michael (2011). "Renal sympathetic denervation for treatment of electrical storm: first-in-man experience". Clinical Research in Cardiology. 101 (1): 63–67. doi:10.1007/s00392-011-0365-5. ISSN 1861-0684.
  21. ↑ Mahfoud, F.; Schlaich, M.; Kindermann, I.; Ukena, C.; Cremers, B.; Brandt, MC.; Hoppe, UC.; Vonend, O.; Rump, LC. (2011). "Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study". Circulation. 123 (18): 1940–6. doi:10.1161/CIRCULATIONAHA.110.991869. PMID 21518978. Unknown parameter |month= ignored (help)
  22. ↑ Davies, JE.; Manisty, CH.; Petraco, R.; Barron, AJ.; Unsworth, B.; Mayet, J.; Hamady, M.; Hughes, AD.; Sever, PS. (2013). "First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study". Int J Cardiol. 162 (3): 189–92. doi:10.1016/j.ijcard.2012.09.019. PMID 23031283. Unknown parameter |month= ignored (help)
  23. ↑ Witkowski, A.; Prejbisz, A.; Florczak, E.; Kądziela, J.; Śliwiński, P.; Bieleń, P.; Michałowska, I.; Kabat, M.; Warchoł, E. (2011). "Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea". Hypertension. 58 (4): 559–65. doi:10.1161/HYPERTENSIONAHA.111.173799. PMID 21844482. Unknown parameter |month= ignored (help)
  24. ↑ Fisher, James P.; Young, Colin N.; Fadel, Paul J. (2009). "Central sympathetic overactivity: Maladies and mechanisms". Autonomic Neuroscience. 148 (1–2): 5–15. doi:10.1016/j.autneu.2009.02.003. ISSN 1566-0702.
  25. ↑ Witkowski, A.; Prejbisz, A.; Florczak, E.; Kadziela, J.; Sliwinski, P.; Bielen, P.; Michalowska, I.; Kabat, M.; Warchol, E.; Januszewicz, M.; Narkiewicz, K.; Somers, V. K.; Sobotka, P. A.; Januszewicz, A. (2011). "Effects of Renal Sympathetic Denervation on Blood Pressure, Sleep Apnea Course, and Glycemic Control in Patients With Resistant Hypertension and Sleep Apnea". Hypertension. 58 (4): 559–565. doi:10.1161/HYPERTENSIONAHA.111.173799. ISSN 0194-911X.
  26. ↑ Schlaich, MP.; Straznicky, N.; Grima, M.; Ika-Sari, C.; Dawood, T.; Mahfoud, F.; Lambert, E.; Chopra, R.; Socratous, F. (2011). "Renal denervation: a potential new treatment modality for polycystic ovary syndrome?". J Hypertens. 29 (5): 991–6. doi:10.1097/HJH.0b013e328344db3a. PMID 21358414. Unknown parameter |month= ignored (help)
  27. ↑ Ukena, C.; Bauer, A.; Mahfoud, F.; Schreieck, J.; Neuberger, HR.; Eick, C.; Sobotka, PA.; Gawaz, M.; Böhm, M. (2012). "Renal sympathetic denervation for treatment of electrical storm: first-in-man experience". Clin Res Cardiol. 101 (1): 63–7. doi:10.1007/s00392-011-0365-5. PMID 21960416. Unknown parameter |month= ignored (help)
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