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The rise, fall, and possible resurrection of renal denervation

Abstract

Renal denervation has a chequered history. Dramatic reductions in blood pressure after denervation of the renal arteries were observed in early trials, but later trials in which denervation was tested against a sham procedure produced neutral results. Although a sound pathophysiological basis exists for interruption of the renal sympathetic nervous system as a treatment for hypertension, trial data to date are insufficient to support renal denervation as an established clinical therapy. In this Perspectives article, we summarize the currently available trial data, device development, and trials in progress, and provide recommendations for future trial design.

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Figure 1: Effect of increased efferent renal sympathetic activity on three renal nerve effectors.
Figure 2: Magnitude of SBP reduction in early studies of renal denervation compared with later trials.
Figure 3: Renal denervation: where are we now and where are we headed?

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References

  1. World Health Organization. Global Status Report on Noncommunicable Diseases 2010 (WHO, 2011).

  2. Lim, S. S. et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2224–2260 (2012).

    PubMed  PubMed Central  Google Scholar 

  3. Lewington, S. et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).

    Article  PubMed  Google Scholar 

  4. Jung, O. et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J. Hypertens. 31, 766–774 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Tomaszewski, M. et al. High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart 100, 855–860 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Persell, S. D. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension 57, 1076–1080 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Brown, M. J. Resistant hypertension: resistance to treatment or resistance to taking treatment? Heart 100, 821–822 (2014).

    Article  PubMed  Google Scholar 

  8. Smithwick, R. H. & Thompson, J. E. Splanchnicectomy for essential hypertension; results in 1,266 cases. J. Am. Med. Assoc. 152, 1501–1504 (1953).

    Article  CAS  PubMed  Google Scholar 

  9. Newcombe, C. P., Shucksmith, H. S. & Suffern, W. S. Sympathectomy for hypertension; follow-up of 212 patients. Br. Med. J. 1, 142–144 (1959).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Esler, M. The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. Exp. Physiol. 96, 611–622 (2011).

    PubMed  Google Scholar 

  11. DiBona, G. F. & Esler, M. Translational medicine: the antihypertensive effect of renal denervation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R245–R253 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Schmieder, R. E. et al. Updated ESH position paper on interventional therapy of resistant hypertension. EuroIntervention 9 (Suppl.), R58–R66 (2013).

    Article  PubMed  Google Scholar 

  13. Campese, V. M. & Kogosov, E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension 25, 878–882 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Ye, S., Gamburd, M., Mozayeni, P., Koss, M. & Campese, V. M. A limited renal injury may cause a permanent form of neurogenic hypertension. Am. J. Hypertens. 11, 723–728 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Henegar, J. R. et al. Catheter-based radiofrequency renal denervation: location effects on renal norepinephrine. Am. J. Hypertens. 28, 909–914 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mahfoud, F. et al. Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design. Eur. Heart J. 36, 2219–2227 (2015).

    Article  PubMed  Google Scholar 

  17. Krum, H. et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373, 1275–1281 (2009).

    Article  PubMed  Google Scholar 

  18. Schlaich, M. P., Sobotka, P. A., Krum, H., Lambert, E. & Esler, M. D. Renal sympathetic-nerve ablation for uncontrolled hypertension. N. Engl. J. Med. 361, 932–934 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Krum, H. et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 383, 622–629 (2014).

    Article  PubMed  Google Scholar 

  20. Esler, M. D. et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 376, 1903–1909 (2010).

    Article  PubMed  Google Scholar 

  21. Bhatt, D. L. et al. A controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 370, 1393–1401 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Bakris, G. L. et al. 12-month blood pressure results of catheter-based renal artery denervation for resistant hypertension. J. Am. Coll. Cardiol. 65, 1314–1321 (2015).

    Article  PubMed  Google Scholar 

  23. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  24. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  25. Mathiassen, O. N. et al. Renal sympathetic denervation in treatment resistant essential hypertension. A sham-controlled, double-blinded randomized trial (ReSET trial). J. Am. Coll. Cardiol. 66, B41 (2015).

    Article  Google Scholar 

  26. Fadl Elmula, F. E. M. et al. Renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure. Hypertension 62, 526–532 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Rosa, J. et al. Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study. Hypertension 65, 407–413 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Azizi, M. 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 385, 1957–1965 (2015).

    Article  PubMed  Google Scholar 

  29. Desch, S. et al. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension 65, 1202–1208 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Mahfoud, F. & Lüscher, T. F. Renal denervation: symply trapped by complexity? Eur. Heart J. 36, 199–202 (2015).

    Article  PubMed  Google Scholar 

  31. Persu, A. et al. Renal denervation in treatment-resistant hypertension: a reappraisal. Curr. Opin. Pharmacol. 21, 48–52 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Esler, M. Illusions of truths in the Symplicity HTN-3 trial: generic design strengths but neuroscience failings. J. Am. Soc. Hypertens. 8, 593–598 (2014).

    Article  PubMed  Google Scholar 

  33. Kandzari, D. E. et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur. Heart J. 36, 219–227 (2015).

    Article  PubMed  Google Scholar 

  34. Weber, M. A. et al. Renal denervation for the treatment of hypertension: making a new start, getting it right. Catheter Cardiovasc. Interv. 38, 447–454 (2015).

    Google Scholar 

  35. Twain, M. Christian Science 1st edn (Hewlett Press, 1907).

    Google Scholar 

  36. Sud, S. et al. The expectation effect and cardiac pacing for refractory vasovagal syncope. Am. J. Med. 120, 54–62 (2007).

    Article  PubMed  Google Scholar 

  37. Bannuru, R. R. et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis. Ann. Intern. Med. 162, 46 (2015).

    Article  PubMed  Google Scholar 

  38. Howard, J. P. et al. Unintentional overestimation of an expected antihypertensive effect in drug and device trials: mechanisms and solutions. Int. J. Cardiol. 172, 29–35 (2014).

    Article  PubMed  Google Scholar 

  39. McCarney, R. et al. The Hawthorne Effect: a randomised, controlled trial. BMC Med Res Methodol. 7, 30 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Brewster, L. M. & Seedat, Y. K. Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review. BMC Med. 11, 141 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ewen, S. et al. Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis. Clin. Res. Cardiol. 104, 1097–1105 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Myat, A. et al. Renal sympathetic denervation therapy for resistant hypertension: a contemporary synopsis and future implications. Circ. Cardiovasc. Interv. 6, 184–197 (2013).

    Article  PubMed  Google Scholar 

  43. Bakris, G. L. et al. Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3. J. Am. Coll. Cardiol. 64, 1071–1078 (2014).

    Article  PubMed  Google Scholar 

  44. Tzafriri, A. R. et al. Innervation patterns may limit response to endovascular renal denervation. J. Am. Coll. Cardiol. 64, 1079–1087 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Vink, E. E. et al. Limited destruction of renal nerves after catheter-based renal denervation: results of a human case study. Nephrol. Dial. Transplant. 29, 1608–1610 (2014).

    Article  PubMed  Google Scholar 

  46. Sakakura, K. et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J. Am. Coll. Cardiol. 67, 635–643 (2014).

    Article  Google Scholar 

  47. Henegar, J. R. et al. Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs. Am. J. Hypertens. 27, 1285–1292 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mahfoud, F. et al. Impact of lesion placement on efficacy and safety of catheter-based radiofrequency renal denervation. J. Am. Coll. Cardiol. 66, 1766–1775 (2015).

    Article  PubMed  Google Scholar 

  49. Id, D. et al. Does the presence of accessory renal arteries affect the efficacy of renal denervation? JACC Cardiovasc. Interv. 6, 1085–1091 (2013).

    Google Scholar 

  50. Tellez, A. et al. Renal artery nerve distribution and density in the porcine model: biologic implications for the development of radiofrequency ablation therapies. Transl. Res. 162, 381–389 (2013).

    Article  PubMed  Google Scholar 

  51. Tzafriri, A. R. et al. Arterial microanatomy determines the success of energy-based renal denervation in controlling hypertension. Sci. Transl. Med. 7, 285ra65 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  52. White, W. B. et al. Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive forum held in Bethesda, MD, U.S.A., October 10th 2013. J. Am. Soc. Hypertens. 8, 743–757 (2014).

    Article  PubMed  Google Scholar 

  53. Esler, M., Jennings, G. & Lambert, G. Measurement of overall and cardiac norepinephrine release into plasma during cognitive challenge. Psychoneuroendocrinology 14, 477–481 (1989).

    Article  CAS  PubMed  Google Scholar 

  54. Leenen, F. H., Coletta, E. & White, R. Sympatho-excitatory responses to once-daily dihydropyridines in young versus older hypertensive patients: amlodipine versus felodipine extended release. J. Hypertens. 24, 177–184 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Parati, G., Esler, M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur. Heart J. 33, 1058–1066 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Ewen, S. et al. Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension. Hypertension 65, 193–199 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. O'Rourke, M. F. & Nichols, W. W. Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension. Hypertension 45, 652–658 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Lobo, M. D. et al. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial. Lancet 385, 1634–1641 (2015).

    Article  PubMed  Google Scholar 

  59. Al-Khatib, S. M. et al. Placebo-controls in short-term clinical trials of hypertension. Science 292, 2013–2015 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. DeFelice, A. et al. The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis. J. Hum. Hypertens. 22, 659–668 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Sakakura, K. et al. Methodological standardization for the pre-clinical evaluation of renal sympathetic denervation. JACC Cardiovasc. Interv. 7, 1184–1193 (2014).

    Google Scholar 

  62. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  63. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  64. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  65. Böhm, M. et al. First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension 65, 766–774 (2015).

    Article  PubMed  Google Scholar 

  66. Kario, K. et al. SYMPLICITY HTN-Japan — first randomized controlled trial of catheter-based renal denervation in Asian patients. Circ. J. 79, 1222–1229 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Sievert, H. et al. Renal denervation with a percutaneous bipolar radiofrequency balloon catheter in patients with resistant hypertension: 6-month results from the REDUCE-HTN clinical study. EuroIntervention 10, 1213–1220 (2015).

    Article  PubMed  Google Scholar 

  68. Verheye, S. et al. Twelve-month results of the Rapid Renal Sympathetic Denervation for Resistant Hypertension Using the OneShot Ablation System (RAPID) study. EuroIntervention 10, 1221–1229 (2015).

    Article  PubMed  Google Scholar 

  69. Fadl Elmula, M. et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension 63, 991–999 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Fadl Elmula, F. E. et al. Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension. Blood Press. 24, 263–274 (2015).

    Article  PubMed  Google Scholar 

  71. Mahfoud, F. et al. Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 128, 132–140 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Vogel, B. et al. Renal sympathetic denervation therapy in the real world: results from the Heidelberg registry. Clin. Res. Cardiol. 103, 117–124 (2013).

    Article  PubMed  Google Scholar 

  73. Worthley, S. G. et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur. Heart J. 34, 2132–2140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hering, D. et al. Renal denervation in moderate to severe CKD. J. Am. Soc. Nephrol. 23, 1250–1257 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mabin, T. Interim clinical results of novel circumferential catheter-based ultrasound technology for renal denervation (Recor Medical). PCRonline [online], (2012).

    Google Scholar 

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Authors and Affiliations

Authors

Contributions

R.G. and C.E.R. researched data for the article. B.J.G., R.G., and S.J.P. provided substantial contributions to discussion of the content. B.J.G., R.G., and C.E. contributed equally to writing the article. B.J.G., R.G., C.E., M.N., and S.J.P. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Bernard J. Gersh.

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Competing interests

M.N. is an employee of Medtronic. S.J.P. has received research grants from Boston Scientific. B.J.G. has served on data safety monitoring boards or other trial committees for Boston Scientific and Medtronic. The other authors declare no competing interests.

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Gulati, R., Raphael, C., Negoita, M. et al. The rise, fall, and possible resurrection of renal denervation. Nat Rev Cardiol 13, 238–244 (2016). https://doi.org/10.1038/nrcardio.2016.1

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