Autonomic imbalance, the loss of equilibrium between the sympathetic and parasympathetic nervous systems, is thought to play an important role in the pathophysiology of hypertension . The activation of renal sympathetic fibers, which reside throughout the kidney and abound in the hypertensive state, leads to an increased and excessive secretion of renin, increased sodium reabsorption in the proximal tubule, and decreased renal perfusion . In the not so distant past, these observations seemed to support and promote the use of surgical sympathectomy in patients with severe hypertension, including individuals with end-organ damage, and indeed was associated with significant reduction in blood pressure (BP) accompanied by reduced mortality . Surgical approaches requiring major operative approach became a method of last resort and then a neglected relic of the past until catheter-based approaches promised minimally invasive targeting of renal nerves. An ablation catheter introduced through the femoral or radial artery can be advanced into the renal arteries under fluoroscopic guidance, in which radiofrequency or ultrasound energy can be deployed to ablate the sympathetic nerves . Alternative approaches use chemical denervation by injection of alcohol or other neurotoxic agents in the adventitia of the renal arteries. Although minimal invasiveness was proved and early data seemed promising, unambiguous BP lowering with noninvasive renal denervation (RDN) remains elusive, especially in light of the well executed trials .
In this issue of the Journal, Völz et al. present the first results of the nationwide Swedish Registry for Renal Denervation. Their analysis included 260 consecutive patients, who were scheduled for RDN with six different catheter systems from 2011 to 2015. A total of 252 patients with resistant hypertension (average number of antihypertensive drugs 4.5 ± 1.5) underwent the procedure and were followed for 36 months (6 months: n = 206, 12 months: n = 204, 24 months: n = 79, 36 months: n = 27). Office and ambulatory BP was significantly reduced at 6-month follow-up by 15/6 and 8/5 mmHg (n = 206), and persisted to 36 months. No significant changes in medication were documented, with the caveat that no objective adherence assessments were included in study protocol. Procedural adverse events were ∼3% and included two renal and one femoral artery dissection, one retroperitoneal bleeding, and four local hematomas. Although not provided, it would have been valuable to elucidate, if dissections were treated conservatively or required additional invasive/surgical treatment. Renal function, measured by estimated glomerular filtration rate, remained unchanged over time.
These data are in line with positive results of major registries , for example, from the United Kingdom , Austria , and Greece . Such observational data are key to appreciate the efficacy and safety of real-world patients undergoing RDN outside of controlled clinical studies. Yet, they cannot answer the central question raised by randomized, controlled studies as to whether BP lowering with RDN is effect and cause or driven by nonspecific placebo or Hawthorne effects and the like. Thus, the recently published SPYRAL-OFF Medication Study  is especially enlightening. Here patients with uncontrolled, mild–moderate hypertension without concomitant antihypertensive medication were randomized to RDN with a multielectrode catheter or sham procedure. At 3 months, RDN significantly reduced office (−7.7/−4.9 mmHg, P < 0.01) and ambulatory BP (−5.0/−4.4 mmHg, P < 0.05) more than sham treatments.
What then sets the SPYRAL-OFF apart from previous trials? Three major distinctions were introduced in the patient population, catheter technology employed, and concomitant treatment. SPYRAL-OFF excluded patients with isolated systolic hypertension, as this phenotype has an attenuated response to RDN , and used a modified multielectrode catheter with a revised ablation technique of distally focused treatment allowing a more circumferential and complete RDN . Moreover, patients had to be off medication; therefore, resistant hypertensive individuals were not included. Adherence to the study protocol and especially the lack of antihypertensive medication intake at follow-up was confirmed by toxicological analyses allowing a proper intention to treat and per protocol analysis .
The SPYRAL-OFF Medication study provides biological proof of principle for BP lowering by RDN but must be seen in proper context. Early reports in resistant hypertensive patients documented greater BP drops following RDN compared with changes in mild–moderate hypertensive patients [15,16]. In the Swedish Registry  and other reports, baseline BP predicted future change, which could be related to regression to mean but also to higher sympathetic activity with higher baseline BP. The relationship between baseline office SBP and decrease in BP at 6-month follow-up correlates (Fig. 1) and guides assessing efficacy across studies in different patient populations. In this regard, there is not much difference between results of the Swedish Registry and randomized, sham-controlled SPYRAL-OFF Medication study, is there?
RDN remains therefore an attractive but elusive potential therapy – supported by real-world registries, but with more inconsistent findings in well executed controlled trials. What have we learned? It is in part because we know so little of RDN and even of autonomic imbalance that we cannot converge on a definitive resolution of value assignation. The issues are complex, and high-quality research is needed to understand the potential of new device-based technologies for the treatment of hypertension. Are we sure we understand and characterize hypertension properly and discriminate patients with and without sympathetic overactivation and autonomic imbalance? Do we really have the means to control applied denervation and document effect? In addition, can we indeed consider in aggregate the efficacy and safety profile of many different devices as if there was a single class effect? Further preclinical analyses  are mandated as we have much to learn, now more than ever we need to continue in-depth analysis. Several new studies in resistant and more importantly in untreated hypertensive patients is steering RDN to new shores – let us see, where we end up.
Conflicts of interest
There are no conflicts of interest.
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