Journal of Hypertension:
Renal denervation: still more questions than answers
Taddei, Stefanoa; Bruno, Rosa Mariaa,b
aDepartment of Clinical and Experimental Medicine, University of Pisa
bInstitute of Clinical Physiology – CNR, Pisa, Italy
Correspondence to Stefano Taddei, MD, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126 Pisa, Italy. Tel: +39 050 553699; fax: +39 050 551110; e-mail: firstname.lastname@example.org
The process for drug development is long and difficult. Antihypertensive drugs become available in the market after a long and articulated process of testing, to demonstrate their safety and effectiveness. And even when they can be prescribed, their utilization is mainly driven by the results of controlled clinical trials. The recent history of aliskiren can be considered paradigmatic. This compound is well tolerated and effective in lowering blood pressure (BP) values. However, the lack of evidence of reduction of cardiovascular events in controlled clinical trials strongly limits its utilization in the daily clinical practice .
At variance with this cautious behavior, we are now facing the ‘uncontrolled’ explosion of renal denervation. This technique is largely employed only on the basis of small proof-of-concept or randomized trials, which did not answer all the questions concerning the indications, the effectiveness and the safety [2–3].
In this issue of the Journal of Hypertension, Ezzahti et al. demonstrated that in a group of 17 patients with resistant hypertension renal denervation does not reduce BP values. Although the number of patients is low (but it is also low in positive studies), these results deserve attention, as they confirm the negative results of another recent article , therefore, reinforcing the concern raising about this technique .
It is beyond doubt that renal denervation is a promising device with the potential to solve one of the most challenging aspects in the treatment of hypertension, which is the low drug compliance. However, the problem is that, while in some patients renal denervation can lower BP values, in other patients the technique is absolutely not effective and, up to now, no predictive marker exists to indicate the degree of BP-lowering response. Thus, when we ‘prescribe’ this procedure to a patient we cannot guarantee the result. If this is ethically acceptable for pharmacological treatment, it is more difficult to accept for an invasive technique, which causes permanent vascular alterations. As Templin and coauthors recently demonstrated by an optical coherence tomography study, the procedure causes a very high incidence of edema (96%), vasospasm (42%) and intraluminal thrombosis (67%), raising the hypothesis that these patients should be treated with an antiplatelet therapy. Furthermore, long-term safety of the procedure is still largely unknown, as no long-term follow-up is available yet .
Other still unsolved problems in the clinical application of renal denervation are the impossibility to evaluate whether the procedure has really destroyed renal sympathetic nerves and the lack of evidence that resistant hypertension is the right indication.
In the effort to evaluate the technical success of renal denervation, many authors have measured plasma renin or sympathetic activity, with disappointing results. Usually, no effect plasma renin activity is observed [4,7], although this could be at least partially explained by the maintenance of concomitant treatment with drugs activating this hormone, including diuretics, renin–angiotensin system blockers and calcium channel-blockers. Concerning the sympathetic nervous system, it is interesting to observe that plasma norepinephrine shows a significant reduction, which, however, was found both in responders and nonresponders . In addition, muscle sympathetic nerve activity evaluation has given diverging results in papers from independent groups [5,8].
The lack of clear clinical indications is also a major problem. Renal denervation is proposed for patients with resistant hypertension, but only for ethical considerations, as the lack of controlled clinical trials permits to treat only this category of patients. However, resistant hypertension does not define an incurable form of the disease. According to Guidelines, resistant hypertension identifies patients who should be more in deep investigated to identify the cause of the poor response to treatment . In the daily life, most patients with resistant hypertension can solve their problems when referred to a hypertension specialist center. It is conceivable that the erratic results with renal denervation might depend on differences in patients screening. It is not a case that in the first published trials screening of secondary hypertension prior to enrollment was not mandatory or structured . The possibility exists that when renal denervation is performed in true incurable hypertensive patients, the technique is not effective. In these patients, profound vascular structural alterations, usually represent the cause of the lack of responsiveness to treatment and can be poorly reversed . It is also difficult to explain why patients not responding to combined α- and β-blockade at full dose should respond to renal denervation. In contrast, the possibility exists that renal denervation might be really effective in patients with white-coat hypertension, a clinical condition characterized by an increased sympathetic activity . Indeed, for each kind of antihypertensive drug, office BP reduction is higher than 24-h BP reduction, but for renal denervation the difference is even higher .
It is important to observe that in the study of Ezzahti et al., office and 24-h BP behavior was similar. It is conceivable that the careful measurement of office BP (1-h monitoring at 5 min intervals and the mean of the whole observational period was used for the analysis) might have reduced the incidence of the white-coat effect, therefore, producing similar results with 24-h BP monitoring.
Another important aspect is that the impact of a low compliance to treatment is always underestimated in clinical studies (as well as in the clinical practice). Thus, part of the effectiveness of renal denervation, probably the best therapeutic strategy for this particularly category of patients, might be explained by the enrollment of noncompliant patients. It is worth noting that positive studies with renal denervation do not show a significant downstepping of antihypertensive treatment , raising the possibility that compliance might not be very high.
In conclusion, evidence clearly indicates that renal denervation is still an experimental technique. With the same amount of clinical evidence available for this therapeutic device, no one antihypertensive drug could have ever been introduced in the clinical practice. Thus, at the present time, renal denervation should be performed in few selected patients, in which no other option is available, until the results of controlled clinical trials, including Simplicity III  and EnligHTN II, will clarify the real effectiveness of this technique in reducing BP values, measured by ambulatory 24-h BP monitoring and cardiovascular events.
Conflicts of interest
There are no conflicts of interest.
1. Angeli F, Reboldi G, Mazzotta G, Poltronieri C, Garofoli M, Ramundo E, et al. Safety and efficacy of aliskiren in the treatment of hypertension and associated clinical conditions. Curr Drug Saf. 2012; 7:76–85.
2. Bruno RM, Di Giulio A, Bernini G, Virdis A, Ghiadoni L, Taddei S. Device-based therapies for resistant hypertension. Curr Pharm Des. 2013; 19:2401–2408.
3. Persu A, Renkin J, Thijs L, Staessen JA. Renal denervation: ultima ratio or standard in treatment-resistant hypertension. Hypertension. 2012; 60:596–606.
4. Ezzahti M, Moelker A, Friesma ECH, van der Linde NAJ, Krestin GP, van den Meiracker AH. Blood pressure and neurohormonal responses to renal nerve ablation in treatment-resistant hypertension. J Hypertens. 2014; 32:135–141.
5. Brinkmann J, Heusser K, Schmidt BM, Menne J, Klein G, Bauersachs J, et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: prospective case series. Hypertension. 2012; 60:1485–1490.
6. Schmieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz K, et al. ESH position paper: renal denervation – an interventional therapy of resistant hypertension. J Hypertens. 2012; 30:837–841.
7. Ahmed H, Neuzil P, Skoda J, Petru J, Sediva L, Schejbalova M, et al. Renal sympathetic denervation using an irrigated radiofrequency ablation catheter for the management of drug-resistant hypertension. JACC Cardiovasc Interv. 2012; 5:758–765.
8. Hering D, Lambert EA, Marusic P, Walton AS, Krum H, Lambert GW, et al. Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension. Hypertension. 2013; 61:457–464.
9. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013; 31:1281–1357.
10. Williams B. The aorta and resistant hypertension. J Am Coll Cardiol. 2009; 53:452–454.
11. Fagard RH, Stolarz K, Kuznetsova T, Seidlerova J, Tikhonoff V, Grodzicki T, et al. Sympathetic activity, assessed by power spectral analysis of heart rate variability, in white-coat, masked and sustained hypertension versus true normotension. J Hypertens. 2007; 25:2280–2285.
12. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010; 376:1903–1909.
13. Kandzari DE, Bhatt DL, Sobotka PA, O’Neill WW, Esler M, Flack JM, et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol. 2012; 35:528–535.
© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins