Renal sympathetic nerves are thought to play a pathophysiological role in hypertension, primarily by three major alterations (mediated by norepinephrine): (1) increased renin secretion via stimulation of β1 adrenoreceptors on the juxtaglomerular apparatus; (2) increased renal tubular sodium reabsorption via stimulation of α1B adrenoreceptors on renal tubular epithelial cells; and (3) decrease of renal blood flow via stimulation of α1A-adrenoreceptors on the renal arterial vasculature. Catheter based renal denervation is an emerging procedure which aims to disrupt sympathetic nerve afferent and efferent activity through application of radiofrequency energy within the renal artery wall.¹

Simplicity HTN-1 was the first major (nonrandomized) study looking at renal denervation in patients with resistant hypertension. Three-year follow-up data confirmed benefit in reducing office blood pressure while maintaining safety.² Simplicity HTN-2 was a randomized unblinded trial conducted soon after HTN-2, and again showed a reduction in office systolic and diastolic blood pressure in the study group compared to controls.³ Simplicity HTN-3 was a large single-blind, randomized, sham-controlled trial that showed no significant differences at 6 months between the renal denervation group and the sham group regarding both systolic office BP and mean systolic ABPM.⁴ Results of Simplicity HTN-3 had a great impact on the medical community, and many centers actually stopped their renal denervation programs. More recently, Neuzil et al demonstrated benefit in office BP reduction through renal denervation executed by an externally delivered, noninvasive ultrasound device.⁵   

Not surprisingly, these studies have all met their share of skepticism.⁶ Various reasons have been proposed for the widely variant results of these studies, including small study populations, lack of blinded, sham-controlled studies, or a need to better assess for compliance of patients with medication regimens. Another observation in most of these studies, including the study by Matejka et al mentioned below, has been the low volume of procedures by most operators, and an improvement in results with the latter half of their study patients. This clearly highlights our current position at the learning curve for this still emerging procedure. 

In the August issue of Vascular Disease Management, the article by Matejka et al evaluates the impact of renal denervation in patients with resistant arterial hypertension.⁷ The authors in this study look at the results from 19 patients with resistant arterial hypertension by monitoring their office BP (blood pressure), heart rate and 24-hour ABPM (ambulatory blood pressure monitoring) at 1-, 3-, 6-, and 12-month follow up visits. The authors were able to document a decline in office blood pressure after renal denervation. On the other hand, the values obtained by 24-hour ABPM were not significantly affected. The question remains whether the decline in office blood pressure in the study group was caused by bias or due to the fact that the patient cohort size was too small to identify any difference in ABPM. 

The authors also found that the change in ABPM at the end of the follow-up was related to the order of procedure. Similarly, more severe hypertension at the beginning predicted a higher chance of response. They also noted higher use of spironolactone and lower use of centrally acting antihypertensives at the end of the study when compared to baseline. In terms of safety, no major periprocedural complications were observed by the authors. 

Having the potential to show benefit, renal denervation is still far from being established as a routine procedure for patients with resistant hypertension. There is a need for large, randomized, sham-controlled trials on patients already on optimal medical therapy for hypertension. Focusing on higher-volume operators to help overcome the learning curve bias, looking at subpopulations such as those with lower stages of hypertension or those with adverse reactions to antihypertensives, and potentially utilizing a biomarker for evaluating hyperadrenergic states are some of the essential steps before the procedure makes it into current guidelines. Until many of these doubts are clarified, renal denervation should be reserved for patients in the setting of clinical research and in highly skilled referral centers.

References

1. Silva JD, Costa M, Gersh BJ, Gonçalves L. Renal denervation in the era of HTN-3. Comprehensive review and glimpse into the future. J Am Soc Hypertens. 2016;S1933-1711(16)30323-0. 
2. 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(9917):622-629. Erratum in: Lancet. 2014;383(9917):602. Sobotka, PA [added]. 
3. Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet. 2010;376(9756):1903-1909. 
4. Bhatt DL, Kandzari DE, O’Neill WW, et al; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401. 
5. Neuzil P, Ormiston J, Brinton TJ, et al. Externally delivered focused ultrasound for renal denervation. JACC Cardiovasc Interv. 2016;9(12):1292-1299. 
6. White CJ, Reilly JP. “Won’t get fooled again.” JACC Cardiovasc Interv. 2016;9(12):1300-1301.
7. Matejka J, Kubrycht M, Vojtisek P, Varvarovsky I, Mezera V. Renal denervation in patients with resistant arterial hypertension: a single-center cohort study and learning curve. Vasc Dis Manag. 2016;13(8):E183-E194.