Skip to main content
SpringerLink
Log in

Catheter-based Renal Artery Denervation for Resistant Hypertension: Promise Unfulfilled or Unsettled?

  • Clinical Trials and Their Interpretations (J Kizer, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Resistant hypertension affects approximately 10–15 % of the hypertensive population and is associated with an increased occurrence of adverse cardiovascular outcomes. Recently, renal denervation (RDN) has emerged as a novel, non-pharmacologic therapy for resistant hypertension that is designed to ablate the sympathetic nerves distributed around the renal arteries, thus diminishing sympathetic nervous system activity and its influence on hypertension. RDN appeared to have a powerful BP-lowering effect in early clinical trials. However, a pivotal follow-up trial, SYMPLICITY HTN-3, showed no additional benefit of the therapy when compared with a sham procedure. Various aspects of the trial have been examined to explain this inconsistency, including a potent placebo effect and uncertainty about whether RDN actually occurred. Further research is needed to clarify the role of RDN in the management of resistant hypertension.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA. 2005;294:466–72.

    Article  CAS  PubMed  Google Scholar 

  2. Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension. 2011;57:1076–80.

    Article  CAS  PubMed  Google Scholar 

  3. Smith SM, Gong Y, Handberg E, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014;32:635–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Acelajado MC, Pisoni R, Dudenbostel T, et al. Refractory hypertension: definition, prevalence, and patient characteristics. J Clin Hypertens (Greenwich). 2012;14:7–12.

    Article  Google Scholar 

  5. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23:1296–310.

    Article  CAS  PubMed  Google Scholar 

  6. Kjeldsen SE, Schork NJ, Leren P, Eide IK. Arterial plasma norepinephrine correlates to blood pressure in middle-aged men with sustained essential hypertension. Am Heart J. 1989;118:775–81.

    Article  CAS  PubMed  Google Scholar 

  7. Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA. Relationship between central sympathetic activity and stages of human hypertension. Am J Hypertens. 2004;17:217–22.

    Article  PubMed  Google Scholar 

  8. Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DA. Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension. Circulation. 2003;108:3097–101.

    Article  CAS  PubMed  Google Scholar 

  9. Ishii M, Ikeda T, Takagi M, et al. Elevated plasma catecholamines in hypertensives with primary glomerular diseases. Hypertension. 1983;5:545–51.

    Article  CAS  PubMed  Google Scholar 

  10. Grassi G, Seravalle G, Cattaneo BM, et al. Sympathetic activation in obese normotensive subjects. Hypertension. 1995;25:560–3.

    Article  CAS  PubMed  Google Scholar 

  11. Narkiewicz K, van de Borne PJ, Cooley RL, Dyken ME, Somers VK. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation. 1998;98:772–6.

    Article  CAS  PubMed  Google Scholar 

  12. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension. 1998;31:68–72.

    Article  CAS  PubMed  Google Scholar 

  13. Grassi G, Seravalle G, Quarti-Trevano F, et al. Adrenergic, metabolic, and reflex abnormalities in reverse and extreme dipper hypertensives. Hypertension. 2008;52:925–31.

    Article  CAS  PubMed  Google Scholar 

  14. Greenwood JP, Scott EM, Stoker JB, Mary DA. Hypertensive left ventricular hypertrophy: relation to peripheral sympathetic drive. J Am Coll Cardiol. 2001;38:1711–7.

    Article  CAS  PubMed  Google Scholar 

  15. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003;108:560–5.

    Article  PubMed  Google Scholar 

  16. Katholi RE. Renal nerves in the pathogenesis of hypertension in experimental animals and humans. Am J Physiol. 1983;245:F1–14.

    CAS  PubMed  Google Scholar 

  17. Harris SH. Renal sympathectomy: its scope and limitations: (section of urology). Proc R Soc Med. 1935;28:1497–510.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Grimson KS, Orgain ES, et al. Results of treatment of patients with hypertension by total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy. Ann Surg. 1949;129:850–71.

    Article  PubMed Central  Google Scholar 

  19. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med. 2009;361:932–4.

    Article  CAS  PubMed  Google Scholar 

  20. Hering D, Lambert EA, Marusic P, et al. Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension. Hypertension. 2013;61:457–64.

    Article  CAS  PubMed  Google Scholar 

  21. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.

    Article  PubMed  Google Scholar 

  22. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2014;383:622–9. A report on long-term follow-up of patients who underwent RDN. Significant BP reduction was sustained after 3 years.

    Article  PubMed  Google Scholar 

  23. Symplicity HTNI, Esler MD, Krum H, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903–9.

    Article  Google Scholar 

  24. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126:2976–82.

    Article  CAS  PubMed  Google Scholar 

  25. Demaria AN. Reflections on renal denervation. J Am Coll Cardiol. 2014;63:1452–3.

    Article  PubMed  Google Scholar 

  26. Ormiston JA, Watson T, van Pelt N, et al. Renal denervation for resistant hypertension using an irrigated radiofrequency balloon: 12-month results from the Renal Hypertension Ablation System (RHAS) trial. EuroIntervention. 2013;9:70–4.

    Article  PubMed  Google Scholar 

  27. Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J. 2013;34:2132–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–401. Major trial that was the largest, first to include a US cohort, and the first to perform a sham procedure in the control group. Contrary to prior studies, there was no difference in BP reduction between groups.

    Article  CAS  PubMed  Google Scholar 

  29. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J. 2015;36:219–27. These analyses delved deeper into the results from SYMPLICITY HTN-3 to identify possible explanations for the latter study’s findings and to identify predictors of BP response to RDN.

    Article  PubMed  Google Scholar 

  30. Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet. 2015. First RCT to examine the role of RDN in patients with less severe hypertension than those enrolled in previous trials.

  31. Desch S, Okon T, Heinemann D, et al.: randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension. 2015.

  32. O’Brien E, Parati G, Stergiou G, et al. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hyperten. 2013;31:1731–68.

    Google Scholar 

  33. Warren RE, Marshall T, Padfield PL, Chrubasik S. Variability of office, 24-hour ambulatory, and self-monitored blood pressure measurements. Br J Gen Pract. 2010;60:675–80.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Mancia G, Zanchetti A, Agabiti-Rosei E, et al. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. SAMPLE Study Group. Study on ambulatory monitoring of blood pressure and lisinopril evaluation. Circulation. 1997;95:1464–70.

    Article  CAS  PubMed  Google Scholar 

  35. Sakakura K, Ladich E, Cheng Q, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol. 2014;64:635–43.

    Article  PubMed  Google Scholar 

  36. Mahfoud F, Edelman ER, Bohm M. Catheter-based renal denervation is no simple matter: lessons to be learned from our anatomy? J Am Coll Cardiol. 2014;64:644–6.

    Article  PubMed  Google Scholar 

  37. Bohm M, Mahfoud F, Ukena C, et al. First report of the global SYMPLICITY registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension. 2015;65:766–74.

    Article  PubMed  Google Scholar 

  38. Bacaksiz A, Uyarel H, Jafarov P, Kucukbuzcu S. Iatrogenic renal artery stenosis after renal sympathetic denervation. Int J Cardiol. 2014;172:e389–90.

    Article  PubMed  Google Scholar 

  39. Jaen Aguila F, Mediavilla Garcia JD, Molina Navarro E, Vargas Hitos JA, Fernandez-Torres C. Bilateral renal artery stenosis after renal denervation. Hypertension. 2014;63:e126–7.

    Article  PubMed  Google Scholar 

  40. Kaltenbach B, Id D, Franke JC, et al. Renal artery stenosis after renal sympathetic denervation. J Am Coll Cardiol. 2012;60:2694–5.

    Article  PubMed  Google Scholar 

  41. Versaci F, Trivisonno A, Olivieri C, Caranci F, Brunese L, Prati F. Late renal artery stenosis after renal denervation: is it the tip of the iceberg? Int J Cardiol. 2014;172:e507–8.

    Article  PubMed  Google Scholar 

  42. Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure after renal denervation. Lancet. 2012;380:778.

    Article  PubMed  Google Scholar 

  43. Geisler BP, Egan BM, Cohen JT, et al. Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol. 2012;60:1271–7.

    Article  PubMed  Google Scholar 

  44. Brandt MC, Reda S, Mahfoud F, Lenski M, Bohm M, Hoppe UC. Effects of renal sympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension. J Am Coll Cardiol. 2012;60:1956–65.

    Article  PubMed  Google Scholar 

  45. Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to severe CKD. JASN. 2012;23:1250–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Schlaich MP, Bart B, Hering D, et al. Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. Int J Cardiol. 2013;168:2214–20.

    Article  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Matthew G. Denker declares that he has no conflict of interest.

Debbie L. Cohen has received a grant and travel support from Medtronic.

Raymond R. Townsend has received consulting fees/honorarium from Medtronic and funding from the NIH.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Matthew G. Denker, Debbie L. Cohen & Raymond R. Townsend

  2. Renal, Electrolyte and Hypertension Division, University of Pennsylvania, 1 Founders Building, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Raymond R. Townsend

Authors
  1. Matthew G. Denker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debbie L. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raymond R. Townsend
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raymond R. Townsend.

Additional information

This article is part of the Topical Collection on Clinical Trials and Their Interpretations

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Denker, M.G., Cohen, D.L. & Townsend, R.R. Catheter-based Renal Artery Denervation for Resistant Hypertension: Promise Unfulfilled or Unsettled?. Curr Atheroscler Rep 17, 56 (2015). https://doi.org/10.1007/s11883-015-0535-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-015-0535-4

Keywords

Search

Navigation