# FUNCTION OF RENAL SYMPATHETIC NERVES

EDITED BY: Yutang Wang, Kyungjoon Lim and Kate M. Denton PUBLISHED IN: Frontiers in Physiology

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ISSN 1664-8714 ISBN 978-2-88945-295-8 DOI 10.3389/978-2-88945-295-8

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## **FUNCTION OF RENAL SYMPATHETIC NERVES**

Topic Editors:

**Yutang Wang**, Federation University Australia, Australia **Kyungjoon Lim**, La Trobe University, Australia **Kate M. Denton**, Monash University, Australia

Efferent nerve distribution in the renal cortex in an adult sheep as shown by tyrosine hydroxylase staining (green). Cell nuclei are stained with 4',6-diamidino-2-phenylindole (DAPI, blue). Depicted are two glomeruli (G) and their associated afferent arterioles (AA). Scale bar, 100 um.

Image credit: Reetu Singh

Sympathetic overactivity is associated with the development of hypertension. Renal denervation (RDN) prevents or delays hypertension in a variety of animal models, which laid the groundwork for the introduction of RDN as a clinical therapy in humans. In 2007, a novel, minimally invasive RDN ablation catheter was first trialled in hypertensive patients, with a 93% success rate of lowering blood pressure for at least three years post-RDN. However, a large scale, sham-controlled clinical trial (Symplicity HTN -3) failed to show reductions in BP greater than sham.

The aim of this research topic was to evaluate the efficacy and safety of RDN, to explore the contribution of both afferent and efferent renal nerve activity to hypertension and non-hypertension disorders, and to stimulate future research to better understand the function of the renal nerves and the effects of RDN by highlighting gaps in knowledge.

**Citation:** Wang, Y., Lim, K., Denton, K. M., eds (2017). Function of Renal Sympathetic Nerves. Lausanne: Frontiers Media. doi: 10.3389/978-2-88945-295-8

# Table of Contents

*05 Editorial: Function of Renal Sympathetic Nerves* Yutang Wang, Kyungjoon Lim and Kate M. Denton **Chapter 1: Evaluation of catheter-based renal denervation for the treatment of hypertension and beyond** *08 Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in severe hypertension* Fadl Elmula M. Fadl Elmula, Anne C. Larstorp, Sverre E. Kjeldsen, Alexandre Persu, Yu Jin and Jan A. Staessen *14 A clinician's perspective of the role of renal sympathetic nerves in hypertension* Alexandros Briasoulis and George L. Bakris *21 Is isolated systolic hypertension an indication for renal denervation?* Yutang Wang

*23 Device-based approaches for renal nerve ablation for hypertension and beyond* Alicia A. Thorp and Markus P. Schlaich

## **Chapter 2: Renal denervation and heart failure**

## **Chapter 3: Renal denervation and kidney disease**

## **Chapter 4: Long-term safety concerns following renal denervation**

*86 What is the true incidence of renal artery stenosis after sympathetic denervation?*

Yutang Wang

*88 Renal Denervation Promotes Atherosclerosis in Hypertensive Apolipoprotein E-Deficient Mice Infused with Angiotensin II*

Yutang Wang, Tam N. Dinh, Alexander Nield, Smriti M. Krishna, Kate Denton and Jonathan Golledge

# Editorial: Function of Renal Sympathetic Nerves

Yutang Wang1 \*, Kyungjoon Lim2 and Kate M. Denton3 \*

*1 School of Applied and Biomedical Science, Federation University Australia, Ballarat, VIC, Australia, 2 Neurophysiology, Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, Australia, 3 Cardiovascular Disease Program, Department of Physiology, School of Biomedical Sciences, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia*

Keywords: atherosclerosis, heart failure, hypertension, kidney disease, renal denervation, renal sympathetic nerves

**Editorial on the Research Topic**

**Function of Renal Sympathetic Nerves**

## INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. The incidence of CVD is increasing in association with the growing prevalence of hypertension, diabetes, and obesity. This is occurring despite established effective therapies for hypertension. Thus, new methods for risk reduction are still needed (Cutler et al., 2008). The aim of this research topic was to evaluate the efficacy and safety of renal denervation (RDN), to explore the contribution of both afferent and efferent renal nerve activity to hypertension and non-hypertension disorders, and to stimulate future research to better understand the function of the renal nerves and the effects of RDN by highlighting gaps in knowledge.

Edited and reviewed by: *Carolyn J. Barrett, University of Auckland, New Zealand*

#### \*Correspondence:

*Yutang Wang<EMAIL_ADDRESS>Kate M. Denton<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology*

Received: *05 July 2017* Accepted: *15 August 2017* Published: *28 August 2017*

#### Citation:

*Wang Y, Lim K and Denton KM (2017) Editorial: Function of Renal Sympathetic Nerves. Front. Physiol. 8:642. doi: 10.3389/fphys.2017.00642* EVALUATION OF CATHETER-BASED RENAL DENERVATION FOR THE TREATMENT OF HYPERTENSION

Strong evidence that sympathetic overactivity is associated with the development of hypertension, combined with the demonstration that RDN prevents or delays hypertension in a variety of animal models, laid the groundwork for the introduction of RDN as a clinical therapy in humans (DiBona and Esler, 2010). In 2007, a novel, minimally invasive RDN ablation catheter was first trialed in hypertensive patients, with a 93% success rate of lowering blood pressure (BP) for at least 3 years post-RDN (Krum et al., 2014). These studies were met with acclaim (Lakhanpal and Domanski, 2012). However, a large scale, sham-controlled clinical trial (Symplicity HTN-3) failed to show reductions in BP greater than sham (Bhatt et al., 2014). It is now clear that poor trial design contributed to this outcome; only 19 of the 340 patients received at least the recommended 4+ ablations per artery and in these patients the falls in BP were greatest (Kandzari et al., 2015). In addition, the report by the Global SYMPLICITY Registry of 1,000 consecutively enrolled patients not only confirmed the safety of RDN but also suggested that RDN lowers office and ambulatory BP at 6 months post-procedure (Bohm et al., 2015). In the current volume, Fadl Elmula et al. summarizes the results of recent clinical RDN trials and rightly raised concerns regarding the interpretation of this data and called for caution in the implementation of this procedure. The authors point out that these trials did not confirm the marked BP lowering effect observed by initial RDN studies (Krum et al., 2009; Esler et al., 2010). In addition, they suggested that the BP lowering effect of RDN may be limited to discrete patient populations, and that it would be worthwhile searching for potential predictors of true responders to RDN. Briasoulis and Bakris reviewed the role of renal sympathetic nerves in hypertension and clinical applications of RDN in resistant hypertension. In light of the results from the Symplicity HTN-3 trial, the authors suggested that future randomized trials should be performed in experienced centers, using newer catheters, and in carefully selected compliant patients with true resistant hypertension.

## EFFECTS OF RENAL DENERVATION BEYOND BLOOD PRESSURE CONTROL

It is noteworthy that RDN has also been shown to be effective in the treatment of other conditions coexisting with resistant hypertension. Thorp and Schlaich contributed a comprehensive review on RDN for hypertension and beyond. The nonhypertensive disorders that may also be affected by RDN include chronic kidney disease, chronic heart failure, left ventricular hypertrophy, arrhythmias, and metabolic diseases. Evidence suggests that clinical benefits beyond BP reduction could be gained following RDN in patients with these disorders. However, randomized controlled trials are needed before the application of RDN becomes routine in clinical practice for these patient cohorts. Moreover, these intriguing findings suggest that there is still a lot we don't understand about the function of the renal nerves.

### Heart Failure

The kidney has a rich afferent sensory and efferent sympathetic innervation. It is now apparent that afferent renal nerve activity can reflexly modulate sympathetic outflow, not just to the kidney, but also to other organs, which may be one mechanism whereby RDN might improve outcomes in heart failure. Ramchandra and Barrett reviewed the mechanisms that contribute to enhanced renal sympathetic nerve activity (SNA) during heart failure, with an emphasis on afferent reflexes and central mechanisms. Booth et al. also contributed a review on this topic, focusing on critically assessing recent preclinical and clinical evidence supporting RDN as a potential treatment for heart failure. It was concluded that a reflex reduction in cardiac SNA in heart failure may be one beneficial effect of RDN. Booth et al. also explored the effect of RDN on the renal afferents, and provided evidence for both the destruction and then significant regrowth of afferent renal nerves. However, what effect ablating the afferent nerves play in mediating the responses to RDN is still largely unknown. Finally, Schiller et al. (2015) reviewed the contribution of renal nerves to the pathogenesis of chronic heart failure, providing an overview of clinical RDN studies to date. This culminated in a call for more research to determine how RDN may be employed as a safe and effective treatment in chronic heart failure.

### Kidney Disease

Strong evidence demonstrates that renal SNA is elevated in both acute and chronic kidney disease. Although less robust, evidence also implicates increased afferent sensory nerve activity in kidney disease. In a primary study, Salman et al. demonstrated using telemetry-based recordings in rats with chronic kidney disease (Lewis Polycystic Kidney rats) that renal SNA directly correlated with BP. This study confirmed the notion that elevated renal SNA is likely a key contributor to hypertensive kidney disease. In an acute study, Goulding et al. examined the contribution of the renal nerves to baroreflex control of renal SNA and excretory function in cisplatin-induced renal failure in rats. The authors found that impaired renal function was associated with blunting of baroreflex gain and increased renal SNA, and that RDN restored these abnormalities. The results of this study suggested that dysregulation of renal SNA plays an important role in renal failure and that RDN may provide benefits for patients with kidney disease. In combination, this evidence led to the suggestion that kidney disease may also be amenable to RDN and Sanders and Blankestijn contributed a review of the clinical evidence arguing that RDN may have a place in the management of chronic kidney disease. RDN has been trialed in models of chronic kidney disease and been shown to be effective in lowering BP, though concerns were raised regarding the ability to adequately mount a response to hemorrhage (Singh et al., 2017).

## LONG-TERM SAFETY CONCERNS FOLLOWING RDN

The introduction of catheter-based RDN initially moved forward at a rapid pace and though this has slowed, interest still remains strong. In part, this reduced momentum stems from concerns surrounding the lack of understanding of the long-term impact of RDN. Wang pointed out that although RDN is generally regarded as a safe procedure, some reports with small sample size have shown that the incidence of renal artery stenosis after RDN could be up to 18.2%; though this may depend on operator experience and the type of catheter employed. However, the safety of RDN needs to be continuously monitored.

In another study, Wang et al. examined the possible side effects of RDN in apolipoprotein E-deficient mice with hypertension induced by angiotensin II infusion. It was found that RDN increased atherosclerosis in the aortic arch despite a reduction in systolic BP in the mice. In contrast, RDN has been reported to decrease atherosclerosis in normotensive apolipoprotein E-deficient mice fed a high fat diet (Wang et al., 2015). Therefore, whether RDN promotes atherosclerosis in patients with resistant hypertension requires investigation in follow-up studies. In fact, the consequences of RDN in all patient populations in which this procedure is being trialed requires longer term follow-up, given evidence that the renal nerves regrow over time (Booth et al., 2015).

## CONCLUSION

Thus, the articles contained in this collection, contribute to our understanding of the function of the renal nerves, the effects of RDN as a treatment for hypertension and non-hypertensive disorders, and the side effects of RDN. However, much remains to be learned in terms of intra-procedural verification of the completeness of RDN, patient selection and long-term safety of RDN.

## AUTHOR CONTRIBUTIONS

YW, KL, and KD conceived the content. YW drafted the manuscript. KL and KD revised the manuscript.

## REFERENCES

## ACKNOWLEDGMENTS

YW is supported by a grant from the National Health and Medical Research Council (1062671). KL is supported by a grant from La Trobe University (Understanding Disease RFA). KD is supported by an NHMRC Research Fellowship (1041844).

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2017 Wang, Lim and Denton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

## Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in severe hypertension

#### *Fadl Elmula M. Fadl Elmula1,2, Anne C. Larstorp1,2, Sverre E. Kjeldsen1,2\*, Alexandre Persu3,4, Yu Jin5 and Jan A. Staessen5,6*

*1 Departments of Cardiology and Internal Medicine, Oslo University Hospital, Ullevaal, Norway*

*2 Faculty of Medicine, University of Oslo, Oslo, Norway*

*3 Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium*

*4 Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium*

*5 Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium*

*6 VitaK Development and Research, Maastricht University, Maastricht, Netherlands*

#### *Edited by:*

*Kate Denton, Monash University, Australia*

#### *Reviewed by:*

*Jacqueline Kathleen Phillips, Macquarie University, Australia Kenju Miki, Nara Women's University, Japan Massimo Volpe, University of Rome Sapienza, Italy*

#### *\*Correspondence:*

*Sverre E. Kjeldsen, Oslo University Hospital, Ullevaal, University of Oslo, PO Box 4950, Nydalen, 0424 Oslo, Norway e-mail<EMAIL_ADDRESS>Renal sympathetic denervation (RDN) has been and is still proposed as a new treatment modality in patients with apparently treatment resistant hypertension (TRH), a condition defined as persistent blood pressure elevation despite prescription of at least 3 antihypertensive drugs including a diuretic. However, the large fall in blood pressure after RDN reported in the first randomized study, Symplicity HTN-2 and multiple observational studies has not been confirmed in five subsequent prospective randomized studies and may be largely explained by non-specific effects such as improvement of drug adherence in initially poorly adherent patients (the Hawthorne effect), placebo effect and regression to the mean. The overall blood-pressure lowering effect of RDN seems rather limited and the characteristics of true responders are largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparently TRH, drug monitoring and improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those patients with truly TRH who may respond to RDN.

**Keywords: hypertension, antihypertensive drugs, renal denervation, drug monitoring, treatment resistance**

#### **INTRODUCTION**

Renal sympathetic denervation (RDN) has been and is still proposed as a new treatment modality in patients with apparently treatment resistant hypertension (TRH), a condition defined as persistent blood pressure elevation despite prescription of at least 3 antihypertensive drugs including a diuretic (Krum et al., 2009, 2014; Esler et al., 2010). However, with the recent publication of the Symplicity HTN-3 study in the U.S. (Bhatt et al., 2014) it is questioned whether RDN at all lowers blood pressure (Demaria, 2014). During 2014, a total of 5 prospective and randomized studies of RDN showing modest or no effect on blood pressure in patients with TRH have been published or presented. Other recent studies have shown that patients with TRH have surprisingly low drug adherence. The aim of this paper is to review all prospective and randomized studies of RDN in TRH and, and to review the issue of poor drug adherence and suggest therapeutic drug monitoring (TDM) as a costeffective modality to control blood pressure and improve prognosis in this subset of hypertensive patients who are at risk and difficult-to-treat.

#### **THE RISE AND FALL OF RENAL DENERVATION IN TREATMENT RESISTANT HYPERTENSION**

The initial enthusiasm followed by the setback of RDN can probably be summarized by a handful of explanations: (1) The role of the sympathetic system in the pathophysiology of hypertension is substantiated by a wealth of experimental and clinical arguments (Julius and Esler, 1975; Eide et al., 1979; Kjeldsen et al., 1981). On this background, enthusiasm surged when an intervention in this system seemed to drastically lower blood pressure. (2) Market-driven industry interests significantly influenced the medical community. (3) Subsequently, pitfalls in the treatment of apparent TRH patients, which are simple but well-known for decades, were suddenly forgotten, including well described phenomena such as the placebo effect, poor drug adherence (Gifford, 1988; Klein, 1988; Ceral et al., 2011) and the Hawthorne effect (Mangione-Smith et al., 2002). Regression to the mean could also be involved which means that abnormal BP values tend to change toward normalization without an underlying biological explanation.

The first and for a long time the only prospective randomized clinical trial in this field, the Symplicity HTN-2 study (Esler et al., 2010), was monitored by Ardian (Medtronic) who collected and processed the data. Usually, when such a task is given to industry, all measures are taken to secure confidence and

**Abbreviations:** ABPM, ambulatory blood pressure monitoring; RDN, renal sympathetic denervation; TRH, treatment resistant hypertension; TDM, therapeutic drug monitoring.

trials are double-blinded (Julius et al., 2004). However, in this case, everything was open, making the trial particularly vulnerable to patient and physician related biases (Howard et al., 2013). In a recent editorial (Shun-Shin et al., 2014), the authors wrote that "measurement of a noisy variable by unblinded optimistic staff is a known recipe for calamitous exaggeration." It is also unfortunate that selection of patients enrolled in Symplicity HTN-2 and evaluation of efficacy were based on office rather than ambulatory blood pressure measurements (ABPM), which is state-of-the art (O'Brien et al., 2013), particularly in resistant hypertension (Persu et al., 2014d). ABPM reduces observer bias and measurement error, minimizes the white-coat effect and has greater reproducibility, and therefore provides a better estimate of a patient's usual blood pressure and cardiovascular prognosis (Kikuya et al., 2007; Salles et al., 2008). Notwithstanding the well-known, major contribution of poor drug adherence to apparently resistant hypertension (Gifford, 1988; Klein, 1988; Ceral et al., 2011), drug adherence was not monitored, either at baseline or during follow-up. This made the study vulnerable to the Hawthorne effect, i.e., patients changing behavior—in this case starting taking their drugs as prescribed -, in response to the intervention and massive attention devoted to them. The lack of blood pressure decrease in the control group also raises concerns. One would indeed suspect that patients in the control group had not taken their medications properly, in order to keep their blood pressure at a higher level that made them eligible for cross-over to RDN group (Azizi et al., 2012; Persu et al., 2012). Finally, placebo effect and regression to the mean must also be taken into account. Noteworthy, the placebo effect is small by using ABPM (Staessen et al., 1996; O'Brien et al., 2013); however, ABPM remains as sensitive to the Hawthorne effect as office blood pressure.

#### **THE ROLE OF INDUSTRY IN PROMOTING RENAL DENERVATION**

Despite the major limitations and potential biases of Symplicity HTN-2, RDN was adopted in hundreds of centers worldwide. Medtronic Inc® (Minneapolis, Minnesota) paid \$800 million to purchase Ardian® (Mountain View, California), the company that had developed the technology (Demaria, 2014), and more than 10 companies developed their own RDN systems, five of which obtained the CE mark (Conformité Européenne, European Conformity). CE marking means that the product is assessed before being placed on the market and meets EU safety, health and environmental protection requirements. However, CE marking is unrelated to medical indication at variance with the USA where FDA approves a medical device only when it has been tested and proved effective for a certain medical condition. The procedure was quickly reimbursed in Germany, and later on in Switzerland, Sweden and the Netherlands. While RDN remained an investigational procedure in the U.S., at least 8000 (Lüscher and Mahfoud, 2014), possibly 15,000–20,000 procedures were performed in Europe and in the rest of the world in less than 4 years, most of them using the Ardian -Medtronic® catheter. It may be hypothesized that the massive incomes, generated by selling the Symplicity catheter to enthusiastic Europeans paid for the Symplicity HTN-3 study (Bhatt et al., 2014), required by the FDA before approval of RDN in the U.S. In Symplicity HTN-3, blinding of patients through the use of a sham procedure and wider use of ABPM balanced and limited the differential impact of the Hawthorne, white coat, placebo and regression to the mean effects in both arms, disclosing to the world the true size of blood pressure decrease attributable to RDN, at least in patients meeting the Symplicity criteria; it was less than 2 mmHg systolic based on ABPM.

For all aforementioned reasons, and in view of the complexity and multifactorial character of hypertension, the failure of RDN to normalize or substantially reduce blood pressure in all patients with apparently TRH was a reasonable working hypothesis for us, even before the Medtronic announcement that Symplicity HTN-3 had failed to meet its primary endpoint (http://www*.* tctmd*.*com/show*.*aspx?id=123265). We (Fadl Elmula et al., 2013; Persu et al., 2013a,b) and others (Azizi et al., 2012; Howard et al., 2013) had predicted that the true effect of RDN might have been overestimated and may considerably shrink in properly designed studies (Howard et al., 2013), and that "one size may not fit all" (Persu et al., 2012). In particular, in preliminary analysis of the European Network COordinating research on Renal Denervation (ENCOReD) network (Persu et al., 2014a) we were struck by the imbalance between the 17.6 mmHg decreases in office blood pressure, vs. only 5.9 mmHg for 24-h ambulatory blood pressure.

#### **FINDING PATIENTS WITH TRUE TREATMENT-RESISTANT HYPERTENSION FOR RESEARCH**

When we set out to investigate the effects of RDN in one of the centers with the longest experience in conducting randomized clinical trials in Europe (Helgeland, 1980), we had thus clearly in mind the limitations of previous studies. We needed a simple and practical way to deal with pitfalls in the recruitment of patients with resistant hypertension into a study protocol: Patients had to qualify for the RDN protocols by having elevated daytime ABPM after witnessed intake of their prescribed blood pressure medication (Fadl Elmula et al., 2013). Meanwhile, a leading hypertension center in Germany (Brinkmann et al., 2012) published a welldocumented series of patients whose blood pressure remained unchanged after RDN. We were thus not surprised when we found no change in either office or ABPM following RDN, first in an open series of six patients (Fadl Elmula et al., 2013), later followed by a randomized study (Fadl Elmula et al., 2014). Patients who were randomly assigned to further improvement of drug treatment guided by non-invasive hemodynamic monitoring had normalized blood pressures (**Figures 1**, **2**). In contrast, patients exposed to RDN experienced only a small and probably partly placebo-induced fall in office and ABPM. The decreases averaged 20 mmHg more for office and 9 mmHg more for ambulatory systolic blood pressure in the hemodynamically guided drug treatment group (*n* = 10) compared to the RDN group (*n* = 9). Because of sustained elevation of AMBP in the RDN treated patients at 6 months of follow-up, we stopped randomization for ethical reason according to a pre-specified decision (Fadl Elmula et al., 2013).

#### **THE PITFALLS WITH RENAL DENERVATION IN TREATMENT RESISTANT HYPERTENSION**

In the absence of solid evidence of efficacy, how can we explain the uncontrolled deployment of RDN in Europe and worldwide (with the notable exception of the U.S. where RDN remained

**measurements.** Differences were statistically significant (Fadl Elmula et al., 2014), favoring drug treatment adjustment, which is the recommended method to gain blood pressure control in patients with so-called treatment-resistant hypertension (Gifford, 1988).

an investigational procedure)? Of course, publications of the Symplicity studies and multiple observational studies, and enthusiastic editorials and reviews in top-ranking journals (Mahfoud et al., 2013; Ott et al., 2013) had a substantial impact, and the lack of strict rules for introduction of device-based therapies in Europe facilitated the large-scale implementation of the technique. However, this phenomenon would have remained limited without the huge promotion by device-producing industry. Probably industry has never launched such a strong campaign to market a new technology before. A multitude of national and international advisory boards organized educational meetings, developed a website (www*.*poweroverpressure*.*com) and produced guidelines, and corresponding author of this current review contributed to these. Medical journals were swamped by reviews and meta-analyses showing the powerful blood pressure lowering effects as recorded in observational studies and in the single available randomized study, Symplicity HTN-2. Comments pointing out the defects and inconsistencies in such meta-analysis encountered great delay in getting published (Jin et al., 2014). Many never questioned *whether* RDN should be implemented, but *when* it should start in an institution. By all means, the purpose was to disseminate the enthusiasm for RDN from the technically-oriented invasive radiologists and cardiologists who usually had little interest or experience in the treatment of hypertension to the "hypertension establishment." The European Society of Hypertension issued specific guidelines (Schmieder et al., 2012, 2013), but maintained reservations that more data was needed, and eventually it had to be proven that RDN would lower morbidity and mortality before being generally accepted in the treatment of true or apparent TRH.

In the aftermath of Symplicity HTN-3, it has been suggested that the lack of demonstrated efficacy of RDN in Symplicity HTN-3 may be due to lack of statistical power or even to chance (Lüscher and Mahfoud, 2014) or that the trial was well conceived but not rigorously executed (Esler, 2014; Schmieder, 2014; White et al., 2014; Lobo et al., 2015). In particular, a fraction of African American participants increased their antihypertensive medication, contrary to protocol, which masked a potential BP lowering effect of RDN in contrast to other participants. In addition, legitimate concerns were raised as to whether the denervation procedure was sub-optimal in many cases due to insufficient delivery of appropriate energy in the renal arteries as a consequence of the inexperience of the investigators. However, this criticism is all *post-hoc*, and the Symplicity HTN-3 findings are after all in line with the other RCTs published and presented in 2014 (Azizi et al., 2014; Desch et al., 2014; Fadl Elmula et al., 2014; Rosa et al., 2015). Furthermore, the Symplicity HTN-3 results are diluted by non-scientific comparisons with the Medtronic® registry (Pathak et al., 2014) which is hampered by all the weaknesses touched upon in this review, and even more as it is a pure industry-ran activity. Finally, while RDN will not become available in the U.S., and ongoing research in Asia was stopped, industry continues to make their catheters available for clinical use and promotes the technique in Europe.

#### **COULD THERE BE RESPONDERS TO RENAL DENERVATION IN HYPERTENSION?**

Does the failure of Symplicity HTN-3 mean the end of RDN? Not necessarily. Indeed, it has been shown in cohorts recruited from the third (The effect of progressive sympathectomy on blood pressure, Bradford Cannon, 1931) until the fifth decade of the last century (Smithwick and Thompson, 1953; Longland and Gibb, 1954) that abdominal sympathectomy associated to splanchnicectomy is effective in the treatment of severe hypertension. Accordingly, research should go on to find the minority of patients who are true responders to RDN, and identify predictors of effective RDN. The European Network COordinating research on Renal Denervation (ENCOReD) is set up to include thousands of patients in randomized protocols, observational studies and registries independent of industry. Some early results (Persu et al., 2014a,b) from this joint effort have already been published and suggest that it may be worthwhile searching for potential predictors of response to RDN. When 2 prospective and randomized studies that have been published (Rosa et al., 2015) and reported (Azizi et al., 2014), plus Symplicity Flex, another sham-controlled study very recently reported (Desch et al., 2014) are added to the 3 published studies (Esler et al., 2010; Bhatt et al., 2014; Fadl Elmula et al., 2014) the overall picture shows that RDN is equal to drugs in lowering BP. However, individual data suggests that there may be cause for optimism that some truly responding patients may be identified.

Still, before going ahead, we have to draw the lessons of the RDN story. We must make sure that RDN is beneficial and does no harm. Many patients have probably undergone unneeded procedures. By a careful estimate, 20 000 renal arteries have been exposed to ablation in people with hypertension and an increasing number of cases of renal artery stenosis after RDN are being reported (Persu et al., 2014c). It remains to be seen whether the negative news that RDN is not for most people will reach Time Magazine (Oz, 2012) and Der Spiegel (Blech, 2013), or whether the old lessons (Bramley et al., 2006) remain for clinicians who treat people with hypertension in daily life.

#### **THERAPEUTIC DRUG MONITORING IN RESISTANT HYPERTENSION**

In view of the major contribution of poor drug adherence to apparent TRH, therapeutic drug monitoring (TDM) maybe a useful tool for detecting and reducing non-adherence, leading to substantial blood pressure (BP) improvement in this subset of hypertensive patients. (Chung et al., 2014) have assessed costeffectiveness of TDM using a Markov model based on German data and life statistics to evaluate life-years, quality-adjusted lifeyears (QALYs), costs, and incremental cost-effectiveness ratios in TRH patients receiving either TDM optimized therapy or standard best medical therapy. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality. The authors showed that TDM is a cost-effective health care intervention in patients diagnosed with TRH, and that this finding is valid for a wide range of patients, irrespective of age and sex (Chung et al., 2014).

Poor drug adherence in apparent TRH is a serious issue that has drawn the attention of experienced clinicians for many years (Gifford, 1988; Klein, 1988). Recently, in a study of 84 patients taking on average 5 antihypertensive drugs it was shown by measurements that no drug was detectable in the blood in 34.5% of the patients, and 65.5% of the patients fulfilled the criteria of non-adherence (Ceral et al., 2011). Other investigators have provided similar results (Jung et al., 2013; Strauch et al., 2013; Tomaszewski et al., 2014). Beyond the clinical challenge of convincing people with severe hypertension to take their antihypertensive medication in order to control their high blood pressure and improve their prognosis, changes in drug adherence over time may have major, unpredictable effects on the results of clinical trials including patients with apparent TRH. People may change their behavior when given special attention in research (the Hawthorne-effect). This may introduce important biases, as patients with assumed TRH but with poor drug adherence, may start taking their drugs when exposed to additional intervention. We postulate that much of the recent controversy with RDN can be explained in this way (Esler et al., 2010; Bhatt et al., 2014).

Clinical assessment of non-adherence in routine practice is challenging (Burnier et al., 2003). Drug adherence is usually investigated using written patient's diary or somewhat more sophisticated by electronic pill boxes, or blood and urine measurements of prescribed drugs. Measurements of drugs can provide interesting information, but are not often used in practical clinical work especially in primary care, and the cost has been prohibitive until recently. Neither patient's diary nor electronic pill boxes are perfectly reliable to ensure drug intake. The only methods that 100% ensures true drug intake is witnessed drug intake, an approach that may yield quite interesting results in patients with TRH (Fadl Elmula et al., 2013, 2014). However, while witnessed intake of drugs may identify adherent patients for immediate inclusion into a study, this method is not particularly practical in the long-run for the follow-up in clinical practice or research.

In the long run, TDM in body fluids may thus prove the best tool for evaluation and improvement of adherence to drug therapy (Brinker et al., 2014). This approach allows an objective surveillance of patient adherence by repeatedly measuring concentrations of antihypertensive drugs in blood and urine. Moreover, when non-adherent patients were confronted with their low or undetectable drug levels and were provided additional counseling to overcome barriers of adherence, blood pressure control improved considerably without intensification of therapy (Brinker et al., 2014). While several studies as pointed out above focused on the objective exclusion or confirmation of non-adherence, this recent study (Brinker et al., 2014) utilized the information gained from TDM measurements for therapeutic purposes. The TDM results were discussed with the non-adherent patients to explore barriers to adherence and counseling was provided to overcome these barriers. During follow-up, SBP was reduced by 46 ± 10 mmHg in non-adherent compared to 12 ± 17 mmHg in adherent patients, without intensification of the antihypertensive therapy (Brinker et al., 2014).

TDM identifies and helps to resolve the key problem in many—possibly the majority—of patients with apparent TRH that is poor adherence to prescribed drug regimen. As previously shown, the cost-effectiveness of this approach is supported by a solid rationale (Chung et al., 2014) and should not be compared to similar analyses of controversial device intervention (Geisler et al., 2012; Dorenkamp et al., 2013; Gladwell et al., 2014) in apparent TRH patients. So far, such analyses were indeed based on Symplicity HTN-2, an unblinded study largely open to the Hawthorne and placebo effects, whose results could not be replicated in any of five randomized trials published or presented in 2014.

#### **REFERENCES**

Azizi, M., Monge, M., Pereira, H., and Sapoval, M. (2014). The French DENER-HTN Trial: renal denervation + standardized antihypertensive treatment vs. standardized antihypertensive treatment alone in patients with resistant hypertension. *J. Hypertens.* 32(e-Suppl. 1), e89.

**Conflict of Interest Statement:** Sverre E. Kjeldsen, Fadl Elmula M. Fadl Elmula and Anne C. Larstorp have been supported by grant from Hemo Sapiens; and Sverre E. Kjeldsen by unrestricted grants from AZ and Pronova. Sverre E. Kjeldsen has received lecture and consultancy honoraria from AZ, Bayer, Medtronic, MSD, Novartis, Serodus, and Takeda, and royalty payments from Gyldendal (publisher). Fadl Elmula M. Fadl Elmula has received speaker honorarium from Medtronic and Hemo Sapiens and Anne C. Larstorp from Hemo Sapiens and Merck et Co. Alexandre Persu declares no conflict of interest.

*Received: 21 October 2014; accepted: 08 January 2015; published online: 09 February 2015.*

*Citation: Fadl Elmula FE, Larstorp AC, Kjeldsen SE, Persu A, Jin Y and Staessen JA (2015) Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in severe hypertension. Front. Physiol. 6:9. doi: 10.3389/fphys.2015.00009 This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology.*

*Copyright © 2015 Fadl Elmula, Larstorp, Kjeldsen, Persu, Jin and Staessen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# A clinician's perspective of the role of renal sympathetic nerves in hypertension

Alexandros Briasoulis and George L. Bakris \*

*American Society of Hypertension Comprehensive Hypertension Center, Department of Medicine, The University of Chicago Medicine, Chicago, IL, USA*

The renal sympathetic nerves have significant contribution to the control of different aspects of kidney function. Early animal studies of renal denervation in a large number of different models of hypertension showed that that RDN improved BP control. Recently, data from prospective cohorts and randomized studies showed that renal denervation therapy (RDN) is a safe procedure but is associated with only modest reduction of ambulatory blood pressure (BP) in patients on intensive medical therapy. The main goal of this article is to review the results of preclinical and clinical studies on the contribution of the renal sympathetic nervous system to hypertension and the therapeutic applications of catheter-based renal denervation.

#### Edited by:

*Kate Denton, Monash University, Australia*

#### Reviewed by:

*Gregory Fink, Michigan State University, USA Olaf Grisk, University of Greifswald, Germany Sebastian Kelle, German Heart Institute Berlin, Germany*

#### \*Correspondence:

*George L. Bakris, American Society of Hypertension Comprehensive Hypertension Center, Department of Medicine, The University of Chicago Medicine, 5841 S. Maryland Ave. MC 1027, Chicago, IL 60637, USA<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology*

> Received: *28 January 2015* Accepted: *23 February 2015* Published: *25 March 2015*

#### Citation:

*Briasoulis A and Bakris GL (2015) A clinician's perspective of the role of renal sympathetic nerves in hypertension. Front. Physiol. 6:75. doi: 10.3389/fphys.2015.00075* Keywords: resistant hypertension, renal denervation therapy

## Introduction

Sympathetic activation participates in the development of the hypertension, by promoting the initial blood pressure elevation in the early clinical stages of the disease, and maintaining the blood pressure elevation (Johns et al., 2011). The adrenergic overdrive triggers not only elevations in blood pressure but contributes over time to end-organ damage and metabolic abnormalities detected in hypertensive patients.

Four decades ago Muller and Barajas (1972) reported the anatomical basis for a direct action of the sympathetic nervous system on renal tubular function by showing that norepinephrinecontaining renal sympathetic nerve terminals are in direct contact with the basal membrane of all renal tubular segments, suggesting that renal sympathetic nerve activity can regulate renal tubular transport function. Indeed, the efferent and afferent renal nerves convey sensory stimuli between the sympathetic system and the kidney, thus providing a control system for the regulation of renal function (DiBona and Kopp, 1997). Under normal conditions, the renal sympathetic nerves regulate sodium homeostasis and participate in the arterial blood pressure (BP) control. In hypertensives, pathological alterations of this system contribute to abnormalities in sodium reabsorption and poorly controlled BP.

Despite the success of drug therapy in treating HTN and reducing associated adverse cardiovascular effects, the percentage of patients achieving adequate BP control worldwide remains low. According to the National Health and Nutrition Examination Survey (NHANES) dataset (Egan et al., 2011; Persell, 2011) the prevalence of resistant hypertension (RH) was 8.9% in hypertensives and 12.8% in treated hypertensives. In randomized controlled trials one third of patients did not achieve BP targets despite receiving ≥3 antihypertensive agents (Cushman et al., 2002; Gupta et al., 2011). In a recent report of data from the Kaiser Permanente health care systems, the incidence of RH was 1.9% within 1.5 years (Daugherty et al., 2012) and was related to increased cardiovascular and renal events.

The complex renal sympathetic system recently became of interest as renal sympathetic denervation treatment (RDN) was introduced into the treatment of patients with RH. Early uncontrolled cohort studies of patients with RH confirmed the safety of the procedure and reported substantial office BP reduction (Krum et al., 2009, 2013; Symplicity HTN-2 Investigators, 2010; Esler et al., 2014). However, evidence derived from the first randomized controlled trial Simplicity HTN-3 (Bhatt et al., 2014), failed to meet its primary efficacy end point, suggesting that RDN does not significantly lower office or ambulatory BP compared to medical therapy. The goal of this article is to review the role of the sympathetic renal nervous system in hypertension, in light of the recently reported results of RDN in patients with RH.

## Anatomy and Physiology of the Renal Sympathetic Nerves and Implications in Blood Pressure Control

The neural pathways for the sympathetic innervation of the kidney originate from the intermediolateral column of the spinal cord. Preganglionic fibers connect to ganglia along the sympathetic chain, and the splachnic ganglia including the paravertebral aortorenal ganglia (DiBona and Kopp, 1997). Within the ganglia, the preganglionic fibers connect with postganglionic neurons that then project to the kidney. Sympathetic outflow to the kidney is controlled by neural projections from brain nuclei such as the rostral ventrolateral medulla (RVLM), to intermediolateral column region of the spinal cord. Afferent sensory information arising from the renal sympathetic system travels to the nucleus tractus solitarius (NTS) where the central integration begins and as a result pathways are activated that track to the caudal ventrolateral medulla and RVLM.

The sympathetic nerves pass from the aortorenal ganglia and come in proximity with the renal artery to enter the kidney at the hilus after which they divide into smaller bundles in parallel with the divisions of the arterial circulation. As the nerves traverse deeper into the kidney, they begin to divide further and to form a network of fibers that penetrate throughout the cortex, juxtamedullary regions, and to a lesser extent in the medulla (Fazan et al., 2002). Each renal nerve bundle contains approximately 900 fibers. The vast majority of postganglionic sympathetic nerve fibers entering the kidney are unmyelinated with variable diameters (Sato et al., 2006). In human and animal models the maximal mean number of nerves was observed in the proximal and middle segments of the renal artery, whereas the least average number of nerves was seen in the distal segment. The circumferential distribution was greatest in the ventral and least in the dorsal regions (Tellez et al., 2013; Sakakura et al., 2014). In the main renal artery, distribution of the distance of nerves from the renal arterial lumen varied considerably, from <1 mm to >10 mm; however, the 75th percentile of the distance was 4.28 mm. Interestingly, 20% of hypertensive patients have additional small accessory renal arteries which also have sympathetic nerves (Sakakura et al., 2014).

The primary neurotransmitter released by the renal sympathetic nerves is norepinephrine. Stimulation of the renal sympathetic nerves increases norepinephrine production that results in increased sodium reabsorption by the renal tubular epithelial cells, contraction of smooth muscle cells (Esler et al., 2003), and renin release by the granular cells of the juxtaglomerular apparatus (Kopp et al., 1980).

Afferent nerve fibers are also found intrarenally in close vicinity to efferent sympathetic nerve fibers mainly projecting from the renal pelvis to the first neuron in the dorsal root ganglion (Stella and Zanchetti, 1991). Afferent nerves are less abundant compared to efferent and their proportion is not different between the proximal, middle, and distal segments. The peripheral axons of afferent renal sensory nerves may release substance P and calcitonin gene-related peptide as primary sensory neurotransmitters (Kopp et al., 2001). They exert an inhibitory effect on both ipsilateral and contralateral efferent renal sympathetic nerve activity. Inhibitory renorenal reflexes regulate of arterial pressure and sodium balance in normotensive healthy individuals leading to decreased afferent renal sympathetic nerve activity (Kopp et al., 2009). In various pathological conditions, activation of the afferent renal sensory nerves and the inhibitory renorenal reflexes are impaired. In these conditions, the excitatory renorenal reflexes will contribute to increased sodium retention and arterial pressure (Kopp et al., 2009).

Under normal quiet and unstressed conditions the level of renal sympathetic nerve activity does not affect renal blood flow. However, in states of anxiety and tension or in pathophysiological states, renal sympathetic nerve activity is sufficiently elevated so as to increase renal vascular resistance and decrease renal blood flow (Yoshimoto et al., 2004).

The activation of the renal sympathetic fibers has several effects. Firstly, efferent renal sympathetic activation decreases renal blood flow and glomerular filtration rate via contraction of the preglomerular smooth muscle cells. Secondly, it stimulates the release of norepinephrine from renal sympathetic nerves' terminals leading to direct activation of the postsynaptic alpha-1 adrenoceptors located on the renal tubular epithelial cells and the activation of beta-1 adrenoceptors on juxtaglomerular granular cells (Pettinger et al., 1985). The activation of beta1 adrenoreceptors on juxtaglomerular granular cells increases renin secretion rate, the stimulation of alpha1b-adrenoreceptors on renal tubular epithelial cells increases renal tubular sodium reabsorption, and the stimulation of alpha1a-adrenoreceptors on the renal arterial resistance vessels decreases renal blood flow (Pettinger et al., 1985; Plato, 2001).

The importance of increased renal sympathetic nerve activity in the development of hypertension was supported by the finding that renal denervation in a large number of different experimental animal models of hypertension either prevented, delayed the onset, or reduced the magnitude of the hypertension (Bonjour et al., 1969; Hesse and Johns, 1984; Kompanowska-Jezierska et al., 2001; Yoshimoto et al., 2004; Schlaich et al., 2009; Salman et al., 2010). Bonjour et al., showed that renal denervation in anesthetized dogs (Bonjour et al., 1969), increased in urinary flow rate and sodium excretion while neither renal blood flow nor glomerular filtration rate changed. They concluded that this increased output of water and sodium was due to the withdrawal of a direct action of the renal sympathetic nerves acting on renal tubules. Different groups showed that renal denervation decreases sodium and water reabsorption in all tubular segments including the proximal tubules, the loop of Henle and the distal convoluted tubule (Bello-Reuss et al., 1975, 1977). Additionally, renal denervation blunts the ability of the kidney to increase renin secretion in response to normal renin releasing stimuli (Johns, 1985).

Also, the activation of the renal afferent nerves contributes directly to systemic hypertension by modulating central sympathetic nervous system activity and promoting vasopressin and oxytocin release from the neuro-hypophysis (Echtenkamp and Dandridge, 1989). Patients early in the course of essential hypertension often have been demonstrated to have increased efferent sympathetic activity to the kidneys (Katholi, 1983). On the other hand, patients with essential hypertension with chronic kidney disease have been found to have increased centrally mediated sympathetic activity, possibly mediated by increased afferent renal sensory nerve activity (Hausberg et al., 2002).

Based on results from animal models of hypertension, denervation of efferent nerves can reduce renin release and sodium retention, improve renal blood flow, and facilitate blood pressure control (Holmer et al., 1994) while the denervation of afferent sensory nerves could attenuate the kidneys' contribution to centrally mediated sympathetic nervous system activity (Katholi et al., 1983, 1984).

## Renal Denervation Therapy for Patients with Treatment Resistant Hypertension

Surgical renal denervation has been studied in humans for the treatment of resistant hypertension and shown effective for reducing sympathetic outflow to the kidneys, and renin release, without adversely affecting other functions of the kidney such as glomerular filtration rate (GFR) and RBF. However, these surgical approaches were frequently complicated by severe orthostatic hypotension, and urinary incontinence impotence (Smithwick and Thompson, 1953).

Renal sympathetic denervation treatment (RDT) using a radiofrequency ablation catheter presents several significant advantages over surgical approaches targeting the renal sympathetic nerves. It is a localized procedure, it is minimally invasive, it has no systematic side effects, and its procedural and recovery times are very short. The Symplicity Renal Denervation System and newer multielectrode catheters comprise of endovascular energy delivery catheters and an automated radiofrequency generator. Once in place within the renal artery, the tip of the catheter is placed against the arterial wall in several places where it delivers radiofrequency energy to the surrounding sympathetic nerves according to a proprietary, computer-controlled algorithm. Typical procedure starts distally in the renal artery with the catheter being withdrawn by pulling and rotating the tip, and it involves at least 4 focal treatments with a distance of ≥5 mm between each site (Krum et al., 2009; Symplicity HTN-2 Investigators, 2010). Renal sympathetic nerves are more abundant in the superior area of the arterial ostium. Recent studies have shown that in the proximal segments of renal artery these nerved are localized >5 mm from the lumen, a distance which may be beyond the ablation depth of currently used catheters which is approximately 3–4 mm (Tzafriri et al., 2014).

#### Early Clinical Studies of RDN

The Symplicity HTN-1 study (Krum et al., 2009) assessed safety of RDN. Short-term repeat angiography and 6-month magnetic resonance angiography, available for 34 patients, revealed no residual luminal irregularities at any treatment site. The effectiveness of RDN was confirmed by renal norepinephrine (NE) spillover. This assay confirmed a significant mean post-treatment reduction in renal norepinephrine spillover of 47% in 10 randomly selected patients. In this cohort study, RDN lowered office systolic blood pressure by 27 mm Hg at 12 months, and 85% of the patients responded to therapy with a reduction of systolic blood pressure exceeding 10 mm Hg (Krum et al., 2009). Importantly, six of the 45 patients who underwent catheter-based renal denervation had office systolic blood pressure reductions of less than 10 mm Hg and were non-responders.

At 36 months office BP was reduced by an average of 32/14 mmHg in 88 patients with complete data with 6 nonresponders only (Krum et al., 2013). Although, striking and sustained BP reductions were seen, ambulatory blood pressure monitoring was not used during follow-up and allowed medication adjustments during this period. After three years of followup of Symplicity HTN-1 there was still no indication that the number of antihypertensive medications could be reduced by RDN (Krum et al., 2013).

A recent larger prospective uncontrolled study specifically examined the BP response to RDN as measured by ambulatory BP monitoring (Mahfoud et al., 2013). In 346 subjects who underwent RDN following the Symplicity HTN-2 protocol were followed for up to 12 months, there was a significant reduction in 24-h systolic BP (−12 mm Hg) and diastolic BP (−7 mm Hg) at 12 months which was much smaller than the reported office SBP and DBP reduction. Both these studies had important limitations. Apart from being nonrandomized and uncontrolled, a high rate of subjects were lost to follow-up. In the study by Mahfoud et al (Kopp et al., 1980) the significant discrepancy between office BP and ambulatory BP reduction may have been due to large bias in office BP measurements.

The Symplicity HTN-2 multicenter, prospective, randomized trial (Symplicity HTN-2 Investigators, 2010) assessed the safety and change in office BP in 106 patients with RH. The inclusion criteria were the same with the first proof-of-concept study. Office BP was reduced by 32/12 mm Hg in the renal denervation group, but did not differ from baseline in the control group. Similar differences in home BP were seen between the two groups were observed. Also, RDN reduced BP during exercise without compromising chronotropic competence in patients with resistant hypertension (Ukena et al., 2011). There were no serious complications related to the device or procedure. The results of the 3-year follow-up analysis reported a pronounced sustained office SBP and DBP reduction with approximately 15% nonresponders and not substantial reduction in mean number of medications (Esler et al., 2014). Despite the limited followup time, number of patients and lack of ambulatory BP this study showed a significant reduction in office BP can be safely achieved with catheter-based RDN in patients with resistant hypertension.

#### Symplicity HTN-3 and Recent Studies (Table 1)

The Symplicity HTN-3 (Bhatt et al., 2014) randomized 535 patients with resistant essential hypertension and an estimated glomerular filtration rate above 45 mL/min/1.73 m2 to undergo renal denervation with previous treatment or to maintain previous treatment alone. At 6 months, the decrease in office and ambulatory systolic BP in the RDN group was a mean of 14.13 and 7 mm Hg respectively compared with a fall of 11.74 and 5 mm Hg in the control group. Neither of these differences in BP met the prespecified criteria for statistically significant superiority. Interestingly, the 7 mm Hg decrease in ambulatory systolic BP after RDN was similar to reduction in 24-h ambulatory systolic BP seen in the 12 patients in the Symplicity HTN-1 study (Krum et al., 2013) but less pronounced compared to the 11 mmHg difference seen in 20 patients from Symplicity HTN-2 (Symplicity HTN-2 Investigators, 2010). In the pre-specified subgroup analysis, office SBP was significantly reduced by RDN in the non-African American patients and those younger than age 60, but this was not translated into meaningful difference in ambulatory BP measurements (Bakris et al., 2014).

The major discrepancies between Symplicity HTN-3 and previous studies may be in part attributed to baseline population differences and selection bias. Symplicity HTN-3 included more obese patients, of African-American decent, at higher cardiovascular risk, treated with diuretics and aldosterone antagonists more frequently compared to Symplicity HTN-2. The Symplicity HTN-3 investigators may have been less experienced than the Symplicity HTN-1 and 2 investigators. Additionally, the selection of patients only based on elevated office BP in Symplicity HTN-1 and HTN-2 may have resulted in selection bias due to lack of standardization and substantial variability of BP affected by the regression to the mean phenomenon.

A more recent European cohort study of 109 patients with RH and a prospective uncontrolled trial of a new multielectrode catheter confirmed the disparities between office and ambulatory measurements and showed modest reduction of ambulatory BP (Worthley et al., 2013; Persu et al., 2014). In contrast to the disappointing reports of Symplicity HTN-3 and subsequent small studies, the recently reported Global SYMPLICITY Registry (Böhm et al., 2014) of 1000 consecutively enrolled patients not only confirmed the safety of RDN but also suggested that RDN lowers office and ambulatory BPs at 6 months. It is also noteworthy to mention that beyond BP reduction, RDN has also been shown to be effective in the treatment of other conditions coexisting with resistant hypertension such as impaired glucose tolerance (Mahfoud et al., 2011; Witkowski et al., 2011), obstructive sleep apnea severity (Witkowski et al., 2011), and left ventricular hypertrophy (Brandt et al., 2012). Brandt et al examined the effect of RDN on diastolic function and LVH in patients with resistant hypertension. Besides reduction of systolic and diastolic blood pressure at 1 and 6 months, similar to

 | Prospective therapy Hypertension. Sample size (RDN/Controls) Age Number of antihypertensives Catheter type Method of BP measurement ABPM difference from baseline (mmHg) Office SBP/DBP difference from baseline (mmHg)

TABLE

1

randomized

controlled

trials

of

renal

denervation

in

resistant

Frontiers in Physiology | www.frontiersin.org March 2015 | Volume 6 | Article 75 |

the effect observed in the Symplicity-2 HTN trial, RDN significantly reduced LVH and improved E/E′ prime ratio and isovolumetric relaxation time as well as systolic LV function (Brandt et al., 2012). Notably, in 5 non-responders LV mass index was significantly decreased while in 4 non-responders the diastolic function was significantly improved, indicating BP-independent effects of RD on LVH and diastolic dysfunction. More recently, Mahfoud et al demonstrated a decrease in LV mass index, as assessed by using cardiac Magnetic Resonce, in both responders and non-responders undergoing RDN (Mahfoud et al., 2014). The beneficial effects of RDN on LV mass independently of BP reduction were confirmed by Doltra et al in 23 patients undergoing RDN who exhibited reduction of LV mass not exclusively due to a reversion of myocyte hypertrophy but also to reduction of interstitial myocardial fibrosis (Doltra et al., 2014). It's presumed that these beneficial effects are linked to actions of RDN on renin-angiotensin-aldosterone axis and sympathic nervous system activity as discussed above.

However, the favorable metabolic effects of RDN were not confirmed by Symplicity HTN-3, which did not show any significant between-group difference in the change in glycated hemoglobin levels in the RDN group or in the subgroup of patients with diabetes (Bhatt et al., 2014).

Based on the findings of the first cohorts and randomized trials a number of concerns arise regarding the utility of RDN on patients with RH: (i) A limited number of patients with RH are candidates for the procedure due to presence of secondary form of HTN, CKD, normal home BP measurement or unsuitable anatomy. (ii) A significant portion of patients (15– 30%) will have less than 10/5 mmHg BP reduction with RDT due to procedural-related limitations, operator experience and number of treatment delivered. In a subgroup analysis of Symplicity HTN-3 higher number of ablations (10–13) and also ablations in all for quadrants of the arterial wall cross sections (**Figure 1**) were associated with significant ambulatory BP reduction compared to the sham control group (Kandzari et al., 2015). (iii) Nonadherence to antihypertensive regimens affects more than 50% of patients with difficult to control hypertension (Jung et al., 2013). In Symplicity-HTN 3, appropriate combination and dosage of antihypertensive regimens, improved patient compliance and assessment with home and ambulatory BP led to substantial BP reduction in the control group which was greater compared to previous RDN trials. The importance of medication adherence and structured adjustment of antihypertensive medications was also shown in the recently published Oslo RDN trial (Fadl Elmula et al., 2014), which stopped early in view of the dramatic superiority of adjusted drug treatment and witnessed medication intake compared to RDN at 6 months of follow-up. (iv) Finally, RDN may not be suitable for all subgroups of patients regardless of the degree of sympathetic activity. In SYMPLICITY HTN-3 subgroup analysis revealed that African American control patients demonstrated an unusually greater decrease in systolic blood pressure compared with non-African American controls and a blunted response to RDN compared to non-African Americans. The marked reduction in blood pressure in the sham control group could be related to a change in medical adherence, type

of therapy or degree of sympathetic activation (Kandzari et al., 2015).

### Conclusion

The renal sympathetic nerves have significant contribution to the control of different aspects of kidney function. Early animal studies of renal denervation in a large number of different models of hypertension showed that that RDN either prevented, delayed the onset, or reduced the magnitude of the

#### References

hypertension. Additionally, the preclinical and clinical studies reviewed above, have provided comprehensive insight into the mechanisms that account for the BP lowering during suppression of renal sympathetic outflow and propose an alternative approach to improve BP control in patients with resistant hypertension. Future randomized trials should be performed in experienced centers using newer catheters and better designed techniques in carefully selected compliant patients on appropriate antihypertensive drug combinations in whom all other measures have failed.

**Conflict of Interest Statement:** Professor Bakris is a consultant for Medtronic and Kona and served as co-principal investigator of SYMPLICITY HTN-3. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2015 Briasoulis and Bakris. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

## Is isolated systolic hypertension an indication for renal denervation?

#### *Yutang Wang\**

*School of Applied and Biomedical Sciences, Federation University Australia, Mount Helen, VIC, Australia \*Correspondence<EMAIL_ADDRESS>
#### *Edited by:*

*Carolyn J. Barrett, University of Auckland, New Zealand*

#### *Reviewed by:*

*Rohit Ramchandra, Florey Neuroscience Institute, Australia Mark Knuepfer, Saint Louis University School of Medicine, USA*

**Keywords: blood pressure, clinical trials, isolated systolic hypertension, renal artery stenosis, renal denervation**

#### **A commentary on**

**Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension**

*by Ewen, S., Ukena, C., Linz, D., Kindermann, I., Cremers, B., Laufs, U., et al. (2014). Hypertension. doi: 10.1161/HYPERTENSIONAHA.114.04336*

Ewen et al. recently reported in the journal *Hypertension* that they investigated, for the first time, the effect of renal denervation on blood pressure in 63 patients with isolated systolic hypertension (Ewen et al., 2014). The authors concluded that renal denervation reduced office and ambulatory blood pressure in patients with isolated systolic hypertension (Ewen et al., 2014). However, this conclusion may not be drawn, as renal denervation may not decrease ambulatory blood pressure in these patients. The potential risk of renal denervation may overweigh its benefit in patients with isolated systolic hypertension. Therefore, adjusted drug treatment may be recommended to these patients before renal denervation.

Ambulatory blood pressure monitoring is the gold standard to diagnose true hypertension and removes the white coat effect (Hermida et al., 2013). Ambulatory blood pressure is superior to office blood pressure in predicting cardiovascular events (Staessen et al., 1999) and mortality (Dolan et al., 2005). The 24-h ambulatory systolic blood pressure in these 63 patients in Ewen et al.'s report decreased by 8 ± 8 and 7 ± 8 mm Hg at 6 and 12 months respectively after renal denervation. However, this study lacked a control group as the authors pointed out as a limitation. It has been reported that the sham procedure reduced 24-h ambulatory systolic blood pressure by 5 ± 15 mm Hg at 6 months (Bhatt et al., 2014). Therefore, compared with the sham procedure, renal denervation may not decrease ambulatory blood pressure in those patients with isolated systolic hypertension.

Consequently, the risk posed to patients with isolated systolic hypertension by renal denervation may overweigh the minimal benefit of renal denervation via lowering blood pressure. For example, renal artery stenosis after renal denervation is of concern. The renal artery stenosis rate in the Symplicity HTN trials (*N* = 45, 106, and 535 for the Symplicity HTN-1, HTN-2, and HTN-3 trials, respectively) ranges from 0.3 to 2.2% (Krum et al., 2009; Esler et al., 2010; Bhatt et al., 2014). However, more and more studies with a smaller sample size (Worthley et al., 2013; Versaci et al., 2014) and case reports (Kaltenbach et al., 2012; Vonend et al., 2012; Aguila et al., 2014; Bacaksiz et al., 2014; Chandra et al., 2014; Pucci et al., 2014) showed relatively higher rates of development or progression of renal artery stenosis after renal denervation. Ewen et al. did not observe any hemodynamically significant renal artery stenosis in these 63 patients with isolated systolic hypertension within 12 months (Ewen et al., 2014). However, ultrasonography, which was used by the authors, has limitations in detecting renal artery stenosis (Zhang et al., 2009; Lao et al., 2011).

Renal denervation is regarded as a last resort for patients with resistant hypertension (Persu et al., 2012). It is reported that about 9% of adults with hypertension suffer from resistant hypertension (Persell, 2011), which is often defined as elevated blood pressure despite treatment with at least 3 antihypertensive agents including a diuretic at maximal tolerated or highest recommended doses (Bohm et al., 2014). The prevalence of resistant hypertension is likely overestimated due to drug non-adherence. For example, blood pressure in 20 of 65 patients with resistant hypertension was normalized after witnessed intake of antihypertensive drugs (Fadl Elmula et al., 2014). Resistant hypertension has been classified as "true" resistant hypertension if blood pressure is still elevated after witnessed intake of antihypertensive drugs (Fadl Elmula et al., 2014). Blood pressure in some patients with "true" resistant hypertension could be controlled by adjusted drug treatment. For example, Fadl Elmula et al. reported that adjusted drug treatment significantly decreased ambulatory systolic blood pressure from 152 ± 12 mm Hg at baseline to 133 ± 11 mm Hg at 6 months in 10 patients with "true" resistant hypertension (Fadl Elmula et al., 2014). In addition, adjusted drug treatment lowered ambulatory systolic blood pressure to below 135 mm Hg in 7 of these 10 patients with "true" resistant hypertension (Fadl Elmula et al., 2014). Therefore, patients with isolated systolic hypertension may be offered with adjusted drug treatment before being offered with renal denervation.

In summary, renal denervation may not decrease ambulatory blood pressure in patients with isolated systolic hypertension. Adjusted drug treatment may be recommended to these patients before renal denervation, as the risk might overweigh the benefit of renal denervation in these patients.

#### **ACKNOWLEDGMENT**

Yutang Wang is supported by the National Health and Medical Research Council (1062671).

#### **REFERENCES**

with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. *Lancet* 376, 1903–1909. doi: 10.1016/S0140-6736(10)62039-9

of renal artery stenosis after renal denervation. *Circ. J.* 78, 767–768. doi: 10.1253/circj.CJ-13-0997

**Conflict of Interest Statement:** The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Received: 31 October 2014; accepted: 03 December 2014; published online: 19 December 2014.*

*Citation: Wang Y (2014) Is isolated systolic hypertension an indication for renal denervation? Front. Physiol. 5:505. doi: 10.3389/fphys.2014.00505*

*This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology.*

*Copyright © 2014 Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Device-based approaches for renal nerve ablation for hypertension and beyond

Alicia A. Thorp1, 2 and Markus P. Schlaich1, 3, 4, 5 \*

*1 Neurovascular Hypertension and Kidney Disease Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia, 2 School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia, 3 Department of Cardiovascular Medicine, Alfred Hospital, Melbourne, VIC, Australia, 4 Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia, 5 Royal Perth Hospital Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia*

#### Edited by:

*Yutang Wang, Federation University Australia, Australia*

#### Reviewed by:

*Yutang Wang, Federation University Australia, Australia Maarten Koeners, University Medical Centre Utrecht, Netherlands Luciana A. Campos, Universidade Camilo Castelo Branco, Brazil*

#### \*Correspondence:

*Markus P. Schlaich, Royal Perth Hospital Unit, School of Medicine and Pharmacology, The University of Western Australia, Level 3, MRF Building, Rear 50 Murray St., Perth, WA 6000, Australia<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology*

Received: *28 April 2015* Accepted: *21 June 2015* Published: *08 July 2015*

#### Citation:

*Thorp AA and Schlaich MP (2015) Device-based approaches for renal nerve ablation for hypertension and beyond. Front. Physiol. 6:193. doi: 10.3389/fphys.2015.00193*

Frontiers in Physiology | www.frontiersin.org July 2015 | Volume 6 | Article 193 |

Animal and human studies have demonstrated that chronic activation of renal sympathetic nerves is critical in the pathogenesis and perpetuation of treatment-resistant hypertension. Bilateral renal denervation has emerged as a safe and effective, non-pharmacological treatment for resistant hypertension that involves the selective ablation of efferent and afferent renal nerves to lower blood pressure. However, the most recent and largest randomized controlled trial failed to confirm the primacy of renal denervation over a sham procedure, prompting widespread re-evaluation of the therapy's efficacy. Disrupting renal afferent sympathetic signaling to the hypothalamus with renal denervation lowers central sympathetic tone, which has the potential to confer additional clinical benefits beyond blood pressure control. Specifically, there has been substantial interest in the use of renal denervation as either a primary or adjunct therapy in pathological conditions characterized by central sympathetic overactivity such as renal disease, heart failure and metabolic-associated disorders. Recent findings from pre-clinical and proof-of-concept studies appear promising with renal denervation shown to confer cardiovascular and metabolic benefits, largely independent of changes in blood pressure. This review explores the pathological rationale for targeting sympathetic renal nerves for blood pressure control. Latest developments in renal nerve ablation modalities designed to improve procedural success are discussed along with prospective findings on the efficacy of renal denervation to lower blood pressure in treatment-resistant hypertensive patients. Preliminary evidence in support of renal denervation as a possible therapeutic option in disease states characterized by central sympathetic overactivity is also presented.

Keywords: sympathetic overactivity, renal denervation, blood pressure, resistant hypertension, cardiovascular disease, renal nerve activity

## Introduction

Treatment-resistant hypertension (rHTN) is a clinically important condition that is associated with increased cardiovascular morbidity and mortality risk (Daugherty et al., 2012; Irvin et al., 2014). Defined by the failure to achieve target blood pressure (BP) despite taking ≥3 antihypertensive medications at optimal doses, rHTN is estimated to affect 8−10% of all hypertensive adults (Persell, 2011; De La Sierra et al., 2011). Poor adherence to pharmacotherapy is ubiquitous in this patient cohort hindering efforts for timely and consistent BP management (Jung et al., 2013), which has caused some clinicians to question whether rHTN really exists or is a case of difficult-to-treat hypertension. Despite the controversy, there is compelling evidence that chronic sympathetic outflow to and from the kidneys is involved in the pathophysiology of rHTN (Esler et al., 1989; Schlaich et al., 2004; Smith et al., 2004).

The emergence of catheter-based renal denervation (RDN)- a minimally invasive procedure used to ablate renal sympathetic nerves- has marked a paradigm shift in the therapeutic management of rHTN. The long-term safety and efficacy of RDN to control BP has principally been evidenced by openlabel studies. In the last 12-months, several rigorously designed, randomized controlled trials have brought into question the efficacy of RDN to treat rHTN. Specifically, data from the Symplicity HTN-3 study failed to show the primacy of RDN in lowering BP compared to a sham-procedure in rHTN patients (Bhatt et al., 2014).

In addition to rHTN, sympathetic overactivity is a cardinal feature of several pathological conditions including renal disease, heart failure, left-ventricular hypertrophy, insulin resistance, and sleep apnea. The ability of RDN to alter renal afferent signaling and reduce whole body sympathetic nerve activity in these disease states is currently being explored in a number of preclinical and clinical studies with promising results.

This review will we focus on the importance of renal sympathetic nerves in the pathophysiology of rHTN, technological advancements in ablation modalities for RDN and latest prospective clinical findings. Novel therapeutic applications for RDN beyond BP control will also be discussed along with several critical issues that must be addressed for research going forward.

## Renal Nerves: An Important Target for Blood Pressure Control

The kidneys are connected to the autonomic nervous system via a dense, neuronal network of post-ganglionic sympathetic nerve fibers located within the adventitia of the renal artery (Dibona, 2005). Renal efferent motor fibers innervate all parts of the renal vasculature, tubules, and juxtaglomerular apparatus (Barajas, 1978); while afferent sensory nerves are located principally in the renal pelvic wall and serve to connect the kidneys with autonomic centers in the central nervous system (Kopp, 1992).

Animal (Dibona and Kopp, 1997) and human (Esler, 2000) studies suggest chronic activation of renal sympathetic nerves is important in the pathogenesis and perpetuation of essential hypertension as well as other pathological conditions including heart failure, chronic kidney disease, and diabetes (see review Malpas, 2010). As highlighted in **Figure 1**, sustained efferent sympathetic outflow to the kidneys (via peripheral and central sensory inputs) elevates BP by altering renal vascular resistance (Kirchheim et al., 1989), stimulating renin release from juxaglomerular granular cells (Zanchetti, 1977) and increasing tubular sodium and water reabsorption (Bell-Reuss et al., 1976). Excitatory reflexes originating from afferent renal nerves in the kidney can also contribute to development of hypertension, particularly rHTN (Hering et al., 2014). Under normal physiological conditions, changes in hydrostatic pressures or chemical composition of the renal environment activate sensory afferent renal nerves to stimulate a centrallymediated decrease in efferent renal sympathetic outflow via an inhibitory feedback mechanism, known as the renorenal reflex response.

Pathological activation of renal sensory afferent nerve fibers through renal ischemia, injury or elevated adenosine concentrations (Esler, 2010), can alter the activity of central integrative neuronal circuits involved in cardiovascular homeostasis and shift the renorenal reflex response from inhibitory to excitatory. The consequence is an increase in central efferent sympathetic outflow to the kidneys and to other highly innervated organs (such as the heart and vasculature) initiating the development and/or maintenance of hypertension and other pathological conditions.

The application of radiofrequency energy to ablate renal nerves in the adventitia can reduce efferent renal sympathetic activity [as evidenced by a reduction in noradrenaline spillover in the kidney (Krum et al., 2009)] to promote urinary sodium excretion and BP reduction; while the ablation of afferent renal sympathetic nerves lowers BP via the inhibition of central sympathetic outflow (Schlaich et al., 2009a).

## Changing Face of Renal Denervation: Latest Developments in Device-based Nerve Ablation

Concomitant with the refinement of radiofrequency-based catheter ablation systems, there has been an emergence of novel treatment modalities that use highly differentiated approaches (i.e., ultrasonic nerve, pharmacological, and cryoablation) to ablate renal sympathetic nerves. These next-generation RDN systems may potentially offer several clinical advantages to radiofrequency-based modalities namely the ability to deliver energy circumferentially and penetrate deeper into the adventitia to optimize neural damage, while preserving artery integrity.

Intravascular and fully non-invasive ultrasound nerve ablation modalities have undergone extensive clinical investigation in the last 12–18 months (refer **Table 1**). Intravascular ultrasound ablation modalities use transducerbased catheters to deliver high-intensity, non-focused ultrasonic emissions (rapid mechanical oscillations) to renal nerves at a depth range of 0.5–10 mm. The latest iteration of the ReCor Percutaneous Renal Denervation System (the RADIANCE™ catheter) uses a novel radial access approach to deliver ultrasonic waves to the renal adventitia, promoting minimal invasiveness to the patient. The therapeutic intra-vascular ultrasound (TIVUS™) catheter system (Cardiosonic Ltd, Tel Aviv, Israel) similarly delivers ultrasonic waves to the renal adventitia but in the absence of endoluminal surface contact, preserving the

integrity of the artery. Results from first-in-man studies highlight the efficacy and safety of these latest modalities to reduce BP short-term (Jonas et al., 2014; Shetty et al., 2014; Daemen and Van Mieghem, 2015) with prospective, multi-center, clinical studies currently underway.

The Surround Sound Hypertension Therapy System (Kona Medical, Washington, USA) is the only fully external ultrasoundbased RDN system being investigated as an adjunct therapy to medication in rHTN patients. Circumferential nerve ablation is achieved using externally focused, low-frequency ultrasonic waves delivered to the renal adventitia via an ultrasound imaging transducer. Initial data from a series of small clinical trials (WAVE I and WAVE II) found that 81% of patients (total n = 41 across the two studies) experienced clinically significant reductions in office SBP (≥10 mmHg) at 6-months follow-up with no serious adverse events reported (Neuzil et al., 2014; Ormiston et al., 2014). Primary outcomes from a multi-center randomized, sham-controlled, double-blinded trial involving 132 subjects (WAVE IV) are expected to be released later this year. The findings will be of interest as only the second, sham-controlled clinical trial in rHTN patients and first to include a treatment arm of patients who have failed radiofrequency RDN modalities (Daemen and Van Mieghem, 2015).

## Clinical Findings Update: Where is the Evidence-base on Renal Denervation?

In the past 12-months there have been 5 prospective, randomized controlled trials that have reported either a modest or no effect of RDN on BP reduction in patients with rHTN (Bhatt et al., 2014; Fadl Elmula et al., 2014; Azizi et al., 2015; Desch et al., 2015; Rosa et al., 2015). Of most relevance is the Symplicity HTN-3 study, the largest and most rigorously designed trial to date, which failed to meet its primary efficacy endpoint (mean 6-month change in office SBP) (Bhatt et al., 2014). Previously, the only prospective trial to compare the BP lowering effects of RDN to usual care had been the open-label Symplicity HTN-2 Study (Esler et al., 2010), which reported a significant office BP reduction of −32/−12 mmHg at 6-months following RDN. The Symplicity HTN-2 study is recognized as having several limitations, the most notable being the use of office BP over 24-h ambulatory BP monitoring to assess the efficacy of RDN and the absence of a blinded control drug adherence monitoring in the study.

As the first randomized, double-blinded, sham-controlled trial, the Symplicity HTN-3 study was expected to provide the definitive statement on the superiority of RDN in the treatment of severe rHTN (Bhatt et al., 2014). A total of 535

*rHTN, resistant hypertension.*

patients were assigned in a 2:1 ratio to receive either the RDN or sham-procedure. Treatment rHTN was confirmed at baseline using 24-h ambulatory BP monitoring following 2-weeks of stable, maximally tolerated doses of ≥3 antihypertensive medications of complementary classes (including a diuretic). The 6-month follow-up data revealed significant office BP reductions in both treatment groups (RDN: −14.1/6.8 mmHg vs. SHAM: −11.7/4.8 mmHg; both p < 0.001). However, betweentreatment differences in office BP reduction at 6-months were not significant (−2.4/2.0 mmHg; P = 0.26). Concomitantly, no superior treatment effect of RDN over the sham-procedure for mean change in 24-h (p = 0.98), daytime (p = 0.52), or nighttime (p = 0.06) ambulatory SBP was observed (Bakris et al., 2014).

Clearly, the failure of Symplicity HTN-3 to show a clearcut superiority of RDN over the sham-procedure in lowering BP (modest ∼2 mmHg SBP reduction only) was disappointing, but contemplated by some (Howard et al., 2013). Evidence from a recent meta-analysis that combined office and ambulatory BP data from 10 European centers predicted similar, modest 6-month BP reductions following RDN and large variability in patient's BP responsiveness (Persu et al., 2014). A number caveats with the Symplicity HTN-3 study design have since been identified that may well account for some of the neutral findings. Specifically, despite the inclusion of a sham-procedure, the majority of interventional cardiologists were inexperienced in performing the procedure (one third performed one procedure only), only 6% of patients received bilateral circumferential ablation (as per protocol) with energy preferentially applied to the proximal portion of the renal artery, renal and total body noradrenaline spillover testing (measure of renal efferent activity and central sympathetic drive via renal afferent pathway respectively) was not performed, and patient's medication regime prior to testing at baseline and 6-months was not stable.

In the aftermath of the Symplicity HTN-3 study announcement, 3 rigorously designed, prospective, open-label randomized controlled trials using the same single-electrode Symplicity radiofrequency catheter system (Medtronic Inc, Minnesota, USA) have been published (Fadl Elmula et al., 2014; Azizi et al., 2015; Rosa et al., 2015). As highlighted in **Table 2**, two of the studies showed intensive pharmacotherapy to be equally effective (Fadl Elmula et al., 2014; Rosa et al., 2015) to RDN in lowering BP in patients with true rHTN, highlighting the ability of RDN to lower BP at least to the extent of additional pharmacologic treatment. The third study (DENER-HTN) comparing RDN in combination with standardized, stepped-care antihypertensive treatment (SSAHT) observed a modest, albeit significant reduction in 6-month daytime SBP [adjusted mean difference of −5.9 mmHg (95%CI: −11.3, −0.5); p = 0.03] compared to SSAHT alone (Azizi et al., 2015).

Despite their smaller cohort sizes, a major strength of these latest studies was the careful selection of patients with true treatment rHTN. Patients were only recruited if they had elevated ambulatory daytime systolic BP after witnessed intake (Fadl Elmula et al., 2014) or quantitative plasma/urine levels (Azizi et al., 2015; Rosa et al., 2015) confirmation of prescribed antihypertensive medications. The absence of a sham-procedure in favor of standardized pharmacological intervention in the studies was also compensated by the use of ambulatory BP monitoring to assess the efficacy of RDN (which is preferential to the use of office BP) in combination with drug adherence monitoring. Such measures help to minimize the potential overinflation of treatment-effects caused by white coat hypertension or the Hawthorn effect, which is a criticism of the Symplicity HTN-3 study.

Preliminary data from a recent study using the Symplicity-FLEX catheter is somewhat more encouraging for RDN (Desch et al., 2015). The smaller study (n = 71) designed to emulate the Symplicity HTN-3 in patients with mild refractory hypertension (defined as daytime systolic BP of 135−149 mmHg and/or diastolic BP of 90−94 mmHg on ≥3 antihypertensive medications) found that in the per-protocol analyses, those who underwent RDN (n = 29) experienced a significant reduction in mean 24-h and daytime systolic BP at 6-months followup compared to patients treated with a sham-procedure (n = 34). On average, RDN reduced 24-h and daytime systolic BP by −4.8 mmHg (mean ± SD: −8.3 ± 8.9 mmHg vs. −3.5 ± 9.5 mmHg; p = 0.04) and −6.2 mmHg (mean ± SD: −9.9 ± 9.0 mmHg vs. −3.7 ± 9.9 mmHg; p = 0.01), respectively. In the intention-to-treat analyses (primary outcome) the significant treatment-effects observed in the per-protocol analyses group were attenuated (p = 0.15). The inclusion of patients who should a priori not have been eligible for the study has been suggested as a possible explanation (Desch et al., 2015).

## Beyond Blood Pressure Control: Other Therapeutic Uses of Renal Denervation

The localized effect of disrupting renal afferent signaling suggests RDN may offer distinct clinical benefits beyond BP control in pathological conditions characterized by central sympathetic overactivity. Specifically, there has been intense interest in the application of RDN in patients with renal disease, heart failure, and metabolic disorders (Mahfoud et al., 2011).

#### Chronic Kidney Disease/Dialysis

Excessive sympathetic nerve activity is a hallmark of both chronic kidney disease (CKD) and end-stage renal disease (ESRD). In CKD patients, augmented sympathetic tone is present in the early clinical stages of the disease and increases with disease progression (Grassi et al., 2011). Animal (Campese et al., 1995) and human (Converse et al., 1992; Grassi et al., 2011) studies have identified afferent signaling from diseased kidneys as playing a critical role in the progression of renal function decline. Indeed, in hypertensive patients, increased muscle sympathetic nerve activity is strongly associated with a decline in estimated glomerular filtration rate (eGFR) (Grassi et al., 2011). Bilateral nephrectomy is also shown to normalize elevated muscle sympathetic nerve activity in non-dialysis ESRD patients (Converse et al., 1992).

Despite the known importance of BP control for optimal renal function (Bakris et al., 2000) and mounting evidence that RDN does not induce structural or functional renal damage in hypertensive patients (Mahfoud et al., 2012; Dorr et al., 2013), international consensus states the procedure remain limited to patients with preserved renal indices. Hering et al. first reported on the efficacy and short-term safety of RDN in 15 moderateto-severe CKD (mean creatinine-based eGFR 31.2 mL/min/1.73 m2 ) patients with rHTN (Hering et al., 2012). The study showed RDN safely reduced peripheral arterial stiffness and office BP while preserving renal blood flow, electrolytes and eGFR at 6-months follow-up. Pilot data from 24 predominantly stage 2 CKD patients (mean eGRF 64.4 mL/min/1.73 m2 ) with treatment rHTN (Kiuchi et al., 2013) showed a similar beneficial effect on 24-h ambulatory BP (mean reduction from baseline −19/−7 mmHg; p < 0.001) that was accompanied by short-term improvements in renal function. Compared to baseline, patients reported significantly higher eGFR and reduced urine albumin: creatinine ratio and serum creatinine (all P < 0.001) at 6-months follow-up. The conflicting short-term effects on eGRF reported

#### TABLE 2 | Randomised controlled trials using renal nerve ablation in the treatment of resistant hypertension in the last 12-months.

*(Continued)*

#### TABLE 2 | Continued

*Data presented as mean* ± *SD or mean [95%CI]. RCT, randomized controlled trial; RDN, renal denervation; SHAM* = *invasive sham-procedure; PHAR, pharmacological treatment; rHTN, resistant hypertension; SBP, systolic blood pressure; DBP, diastolic blood pressure; mo, month.*

between these two aforementioned pilot studies, suggests RDN may afford the greatest clinical benefit to patients in the early stages of CKD who have not yet undergone extensive vascular remodeling.

Two recent prospective longitudinal studies have reported sustained benefits in renal function parameters following RDN (Kiuchi et al., 2014; Ott et al., 2015). Kiuchi et al. observed of 27 CKD patients with rHTN that underwent RDN, those (n = 22) who achieved BP control (defined as office SBP <140 mmHg) at 12-months follow-up also reported a significantly higher eGRF (mean ± SD difference 18.54 ± 8.15 ml/min/1.73 m2 ; p = 0.03). Furthermore, improvements in office diastolic BP, serum creatinine and ACR were only observed at 12-months follow-up in patients who achieved BP control (P < 0.05 for all) (Kiuchi et al., 2014).

In a separate multi-center observational study (Ott et al., 2015), RDN was prospectively shown to reduce mean 24-h ambulatory BP (mean ± SD; 9 ± 14/4 ± 7 mmHg; P < 0.02) and improve mean eGFR by 1.5 ± 10 ml/min/1.73 m2 (p = 0.009) after 12-months in 27 rHTN patients with moderate-tosevere CKD. The efficacy of RDN to preserve renal function was evidenced by retrospective analyses showing patients experienced an average decline in eGFR of −4.8 ± 3.8 ml/min/1.73 m2 per year prior to the RDN procedure. Interestingly, the magnitude of change in 24-h ambulatory systolic BP at 12-months was not shown to predict change in eGFR. This contrasts with Kiuchi et al.'s study (Kiuchi et al., 2014) and suggests RDN may attenuate renal function decline via mechanisms unrelated to BP. Importantly, neither procedural complications nor evidence of acute kidney injury following RDN was reported in patients.

Central sympathetic activity present in ESRD patients is driven principally by afferent renal nerve signaling from the diseased native kidneys (Converse et al., 1992). To date, the use of RDN to reduce increased cardiovascular mortality in ESRD patients with renal hypertension has been explored in a limited number of clinical studies (Schlaich et al., 2009b; Spinelli et al., 2014). In a proof-of-concept study of 9 patients with ESRD and hypertension, RDN resulted in sustained reductions in office SBP of −18, −16, and −28 mmHg at 3−, 6−, and 12-months, respectively (Schlaich et al., 2009b). Two patients (n = 2) who underwent additional measures of sympathetic activity at 3-months, also displayed reductions in muscle sympathetic nerve activity, and renal and whole body noradrenaline release. With respect to safety, only 2 patients developed perioperative femoral pseudo-aneurysms that were resolved without further sequelae. Findings from the pilot trial are supported by an elegant case series involving four patients (age range: 22–65 years) with ESRD and difficult anatomy (renal arteries < 4 mm) (Spinelli et al., 2014), which reported a mean reduction in 24-h ambulatory BP of −36/−16 mmHg at 12-months follow-up. With the exception of notches detected on the final angiogram, no other procedure related complications were reported. Larger, randomized controlled clinical trials are planned or currently ongoing to substantiate the seminal findings that RDN is a safe and efficacious therapeutic approach to both lower BP and regulate sympathetic activity in patients with impaired kidney function.

#### Chronic Heart Failure

Chronic heart failure (CHF) patients often exhibit renal dysfunction with augmented sympathetic tone (Hasking et al., 1986). Renal and cardiac noradrenaline spillover is a stronger predictor of mortality (Hasking et al., 1986; Petersson et al., 2005) than whole-body noradrenaline spillover in CHF patients suggesting chronic renal afferent nerve signaling is involved in the maintenance and progression of the pathological state.

Two small-scale trials assessing the potential benefits of RDN have been undertaken in CHF patients (Davies et al., 2013). The REACH pilot study evaluated the safety of RDN in 7 normotensive patients with CHF (class III–IV) and mean ejection fraction of 45% (Davies et al., 2013). At 6-months, all patients showed an improvement in their functional capacity (as assessed by a 6-min walk test) and overall quality of life. Importantly, no procedural complications or symptomatic adverse effects were reported and renal hemodynamics and function were also preserved.

In a larger observational study (OLOMOUC 1 Study) involving 51 patients with advanced CHF (mean ejection fraction 25%), RDN was associated with improved ventricular systolic function compared to standardized drug therapy (betablockers, ACE inhibitors or ARBs and diuretics) (Taborsky et al., 2012). Of the 26 patients randomized to RDN, left ventricular ejection fraction improved by an average of 6% at 12-months follow-up (mean ± SD: 25 ± 12% vs. 31 ± 14%; p < 0.01). No change was reported in the 25 patients randomized to standardized drug therapy (p = 0.36). Patients in the RDN group also reported significant reductions in heart rate and NT-pro brain natriuretic peptide levels and twice as fewer hospitalisations (31 vs. 72%; p < 0.001) during follow-up. Both treatments were shown to preserved patients renal function (as measured by eGFR; p = 0.55).

The stabilizing effect on RDN on heart failure progression is currently being investigated in several larger, randomized controlled trials. Studies in diastolic heart failure patients are also ongoing. Specifically, the DIASTOLE study will use magnetic resonance imaging to assess the efficacy of RDN to improve diastolic functional parameters in a multicenter-randomized controlled trial of 60 heart failure patients with preserved ejection fraction (Verloop et al., 2013).

#### Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) is an indicator of end-organ damage in arterial hypertension and is associated with increased cardiovascular morbidity and mortality risk, independent of BP (Ruilope and Schmieder, 2008; Bombelli et al., 2009). Chronic sympathetic nerve activity is shown to mediate hypertensioninduced cardiac remodeling (Perlini et al., 2005). In hypertensive adults, cardiac noradrenaline spillover is positively related to LV mass index, suggesting a direct relationship between increased cardiac sympathetic activity in the development of LVH (Schlaich et al., 2003).

Two echocardiographic pilot studies have reported beneficial effects of RDN on measures of cardiac function and structure (Brandt et al., 2012; Schirmer et al., 2014). In 46 patients with rHTN, RDN was shown to significantly reduce LV mass (by 17%) and interventricular septum thickness (by −1.6 mm) at 6-months follow-up (both p < 0.001). Improvements in LV ejection fraction, LV end-systolic volume, diastolic LV filling pressures and isovolumic relation time were also observed (all p < 0.006). With the exception of LV mass and left atrial size, which was higher at 6-months follow-up compared to RDN patients, no other significant changes were observed in the control patients (n = 18). The effect of RDN on LV mass regression and diastolic function, while most prominent in patients who displayed the greatest reduction in systolic BP, was not exclusively associated with 6-month BP changes, suggesting RDN exerts effects on cardiac remodeling independent of BP. Schirmer et al. similarly reported in 66 overweight patients with rHTN a reduction in LV mass, improved diastolic function and increased vascular compliance at 6-months following RDN (all P < 0.001) (Schirmer et al., 2014). Compared to baseline, reductions in office BP (mean reduction −22/−10 mmHg) and heart rate (mean reduction −7 bpm) were also observed (both p < 0.001). With the exception of vascular compliance, which was directly correlated with BP reduction (r 2 = 0.29, p < 0.001), the degree of LV mass regression or diastolic improvement reported post-RDN was not dependent on the magnitude of reduction in BP or heart rate.

A recent prospective multi-center, blinded study using cardiac magnetic resonance imaging (a more reliable measure of cardiac function and morphology), confirms the aforementioned echocardiographic findings that RDN reduces LV mass regression and improves LV ejection fraction largely independent of the significant changes in BP (Mahfoud et al., 2014). Compared to 17 patients who received medical treatment only, 55 patients with rHTN treated with RDN reported a significant 7.1% reduction in LV mass (mean ± SD: 46.3 ± 13.6 vs. 43.0 ± 12.6 g/m1.7 ; P < 0.001) and 3.4% improvement in ejection fraction (mean ± SD: 55.7 ± 11.1 vs. 57.6 ± 9.3%; P = 0.048) at 6-months follow-up. Importantly, LV mass was reduced in those patients who did not show significant clinical reductions in systolic BP at 6-months (defined as systolic BP reduction < 10 mmHg). In a sub-group of patients (n = 19) with markedly reduced systolic LV ejection fraction (defined as <50%) at baseline, the effect of RDN was even more pronounced resulting in a 7.3% improvement in LV ejection fraction; P < 0.001) at 6-months. Left ventricular wall stress, defined as a function of chamber size and configuration, thickness of the ventricular wall and intraventricular pressure was also significantly reduced following RDN at 6-months (p = 0.03). No changes in any cardiac parameters were reported in the control group.

Given the current findings support RDN having a prognostic benefit on LVH regression in resistant hypertensive patients who are at heighten risk for heart failure, larger studies analyzing clinical outcomes are warranted.

#### Arrhythmias

Preliminary evidence suggests that RDN may have a salutary effect in the management of recurrent arrhythmias in heart failure patients, particularly those with atrial fibrillation (Pokushalov et al., 2012) and ventricular tachycardia (Ukena et al., 2012; Hoffmann et al., 2013), via a reduction in BP and central sympathetic cardiac stimulation.

The potential antiarrhythmic efficacy of RDN was first described in a normotensive porcine model (Linz et al., 2013a) and canine with pacing-induced heart failure model (Zhao et al., 2013). First-in-man experience comes from a small prospective study of 27 patients with refractory symptomatic atrial fibrillation and rHTN (Pokushalov et al., 2012). Compared to patients who underwent usual treatment for atrial fibrillation pulmonary vein isolation (PVI) (n = 14), patients who underwent a combined therapy of PVI and RDN (n = 13) exhibited a two-fold reduction in the occurrence of atrial fibrillation episodes (defined as <30 s of atrial fibrillation during 9-months follow-up). Patients on combined therapy also demonstrated a significant and sustained BP reduction of −25/−10 mmHg and reduction in LV mass of approximately 10% at follow up. Findings from a two-study meta-analysis suggest the salutary effects of RDN when used as an adjunct therapy to PVI on atrial fibrillation reoccurrence is even more pronounced in patients with severe rHTN (Pokushalov et al., 2014). A recent study by McLellan et al. suggests electrical remodeling, specifically an increase in global and atrial conduction velocity, may in conjunction with structural changes promote a reduction in atrial fibrillation reoccurrence following RDN (McLellan et al., 2015).

Ventricular tachyarrhthmias (VTA) are associated with a high, irregular heart rate (>100 bpm) and significant risk for sudden death. Elevated cardiac sympathetic nerve activity has been linked to the pathogenesis of VTAs (Meredith et al., 1991) with structural changes in myocardial tissue (i.e., myocardial hypertrophy and heart failure) caused by elevations in BP thought to predispose patients to VTA (Anderson, 1984; Bryant et al., 1999).

In a porcine model of acute coronary myocardial infarction, RDN was shown to significantly reduce the incidence of ventricular arrhythmia compared to a sham procedure (86 vs. 17%; p = 0.03) (Linz et al., 2013b). The efficacy of RDN to suppress ventricular tachycardia in adults has only been explored in a few case studies involving patients with ventricular electrical storm (Ukena et al., 2012; Hoffmann et al., 2013). Ukena et al. reported the first-in-man experience in 2 patients suffering from asymptomatic CHF (non-obstructive hypertrophic and dilated cardiomyopathy, NYHA III) and treatment resistance ventricular electrical storm (Ukena et al., 2012). In both patients, RDN was shown to eliminate the occurrence of ventricular tachyarrhythmic episodes at 6-months without altering BP. In a 63 year old male with recurrent ventricular electrical storm in the setting of acute myocardial infarction, the use of RDN in combination with ventricular tachycardia catheter ablation (standard therapy) was shown to eliminate both ventricular tachycardia and ventricular fibrillation episodes at 23, 100, and 160 days follow-up (Hoffmann et al., 2013). The patient also experienced normalization of their BP, which warranted a reduction in their antihypertensive medication.

While the observations reported in these case studies are promising for RDN as an adjunctive therapy for patients with serious cardiac electrical instability they underscore the need for future randomized controlled trials.

#### Metabolic Diseases

Accumulating data from animal and human studies suggest chronic sympathoexcitaion plays a pivotal role in the etiology and complications of metabolic conditions. Even in the absence of hypertension, elevated urinary noradrenaline levels, increased efferent muscle sympathetic nerve activity, and elevated rates of plasma noradrenaline spillover, are present in patients with obesity, insulin resistance and the metabolic syndrome (Lee et al., 2001; Grassi et al., 2005; Straznicky et al., 2008; Schlaich et al., 2015).

Retrospective sub-cohort analyses of 37 rHTN patients who underwent RDN in the Symplicity HTN-1 Study, showed improvements in office BP (−32/−12 mmHg; P < 0.001) were accompanied by significant reductions in fasting plasma glucose, insulin, C-peptide and 2-h post load glucose levels at 3-months follow-up (all p > 0.04) (Mahfoud et al., 2011). Insulin sensitivity as measured by the HOMA-IR and ISQUICKI index measures was also improved by −62 and 13%, respectively, at 3-months followup (both P = 0.001). Importantly, these beneficial metabolic alterations were preserved in patients diagnosed with type 2 diabetes at baseline (n = 20). No BP or metabolic improvements were reported in the control group (n = 13) who continued their usual medication regime.

These impressive findings contrast with the recently published Denervation of the Renal Artery in Metabolic Syndrome (DREAMs) study that prospectively reported no effect of RDN on measures of insulin sensitivity after 12-months in 29 patients with metabolic syndrome on ≤1 antihypertensive and/or diabetic medication (Verloop et al., 2015). Of note, wholebody sympathetic activity, as measured by microneurography (n = 10), and heart rate variability (n = 26) did not change at 12-months post-RDN despite a modest reduction in 24-h ambulatory BP (mean change from baseline −6 ± 12/−5 ± 7 mmHg; p < 0.02).

Improved glucose metabolism following RDN has been reported in patients with polycystic ovary syndrome (Schlaich et al., 2011) and obstructive sleep apnea (Witkowski et al., 2011), two conditions that are characterized by multiple metabolic disturbances. In 2 obese women with polycystic ovary syndrome, RDN was shown to lower fasting plasma glucose, improve insulin sensitivity (assessed by euglycaemic hyperinsulinemic clamp) and reduce both muscle sympathetic nerve activity and wholebody noradrenaline spillover at 3-months follow-up (Schlaich et al., 2011). Importantly, these metabolic effects were shown to occur in the absence of any changes in body weight. In 10 patients with obstructive sleep apnea, RDN was associated with improved 2-h glucose levels (median: 7.0 vs. 6.4 mmol/L; p = 0.05) during an oral glucose tolerance test and reduced HbA1c levels (median: 6.1% vs. 5.6%; p < 0.05) at 6-months follow-up (Witkowski et al., 2011). Improvements in office BP (−34/−13 mmHg: p < 0.01) and severity of obstructive sleep apnoea for 80% of patients was also observed. Overall, the evidence suggests acute improvements in insulin resistance and glycemic control ensue from RDN. Understanding the longer term effects of RDN in patients with metabolic disease is expected to be a focus for further investigation.

## Future of Renal Denervation: Where to from Here?

Despite the recent disappointment of Symplicity HTN-3, support remains for the efficacy of RDN in the real world setting (Bohm et al., 2015). Recent analyses from Medtronic's Global SYMPLICITY Registry showed 998 patients who underwent RDN experienced a significant lowering in office and ambulatory systolic BP by an average of −19.8 and −9.2 mmHg, respectively, after 6-months. For patients with a baseline systolic BP ≥ 160 mmHg, the BP reduction following RDN was even more pronounced. The registry also confirmed the well-established short-term safety profile of RDN with only six procedure-related events reported (<1% of the cohort) during the 6-months. Collectively, the results lend support to RDN being a safe and viable therapeutic option in patients with severe rHTN when traditional pharmacotherapy has failed.

In 2014, the Joint UK societies' consensus statement on RDN for rHTN called for a temporary moratorium on RDN in routine clinical practice following the Symplicity HTN-3 announcement but was hesitant to abandon the therapy entirely, citing the need for further research (Lobo et al., 2015). In this respect, Symplicity HTN-3 has been invaluable in helping guide the design and execution of future clinical studies. The finding that patients who received ablations in all four quadrants of the renal artery were more likely to experience significant reductions in BP in Symplicity HTN-3 (Bhatt et al., 2014) coupled with contemporary anatomical insights into the distribution of renal artery nerves (Sakakura et al., 2014) demonstrates certain ablation patterns are more efficacious for lowing BP than others. Indeed, there is now a preferential shift toward the use of modalities that circumferentially ablate nerves toward the distal portion of both renal arteries. Patient selection is also critical with meticulous identification of true treatment-rHTN using ambulatory BP monitoring during a period of stable medication (>8 weeks) confirmed by drug adherence testing necessary to eliminate patients without "neurogenic" hypertension and those who simply are non-compliant with their BP medication.

At present, there is no intraprocedural marker to confirm whether RDN has been successfully achieved. Instead, physicians have naively relied on changes in BP to define procedural success. Noradrenaline spillover testing has been performed in small subgroups of patients to quantify whole-body (Krum et al., 2009) and renal sympathetic nerve activity (Esler, 2014a) prior to and 30-days post RDN. While a reduction in renal noradrenaline spillover correlates with a reduction in BP, the response can be highly variable between individual patients (Esler, 2014b). Furthermore, the validated test is not suitable for use in largescale trials.

Identification of a novel biomarker of renal nerve injury that can be measured in either urine or plasma immediately following RDN would be the ne plus ultra to inform interventionists of procedural success. Recent animal data suggests intraluminal electrical stimulation of renal arteries pre- and post-RDN may provide valuable insight in the acute efficacy of the procedure. Indeed, Chinushi et al. reported an increase in BP, serum catecholamines and heart rate variability immediately following high-frequency electrical stimulation of renal arteries in a hypertensive canine model, which was attenuated following RDN (Chinushi et al., 2013). Adenosine infusion into the renal artery, which under normal conditions potentiates a rise in BP, has also been suggested as an immediate measure of renal afferent nerve ablation success following RDN (Esler, 2014a).

## Conclusion

Latest clinical trial data suggests RDN is a safe treatment option in patients with true rHTN that is most efficacious

### References

Barajas, L. (1978). Innervation of the renal cortex. Fed. Proc. 37, 1192–1201.

Bell-Reuss, E., Trevino, D. L., and Gottschalk, C. W. (1976). Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption. J. Clin. Invest. 57, 1104–1107. doi: 10.1172/JCI 108355

when used as an adjunct therapy to intensive pharmacotherapy. It is hoped the development of next generation ablation modalities that enable circumferential ablation coupled with more stringent screening of true treatment rHTN will help improve the clinical efficacy of RDN. Encouraging data from a number of pre-clinical studies highlights that clinical benefits beyond BP reduction can be gained following RDN in patients with renal disease, heart failure, arrhythmias and metabolicrelated disease. However, caution is warranted not to overinterpret the findings of these small studies with larger, randomized controlled trials needed before the application of RDN becomes routine in clinical practice for these patient cohorts.

## Author Contributions

AT and MS contributed to the conception and interpretation of data in the review; AT prepared the manuscript, tables, and figures; MS reviewed and edited the manuscript; AT and MS approved the final version of the manuscript and are accountable for all aspects of the review presented.

## Funding

MS is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia. AT is supported by an NHMRC of Australia Grant. This research was funded in part by the grants from the National Health and Research Council of Australia (NHMRC) and the Victorian Government's Operational Infrastructure Support Program.

renal failure in the rat. Am. J. Kidney Dis. 26, 861–865. doi: 10.1016/0272- 6386(95)90456-5

clinical stages of chronic renal failure. Hypertension 57, 846–851. doi: 10.1161/HYPERTENSIONAHA.110.164780

resistant hypertension and sleep apnea. Hypertension 58, 559–565. doi: 10.1161/HYPERTENSIONAHA.111.173799

**Conflict of Interest Statement:** MS is an investigator in studies sponsored by Medtronic and has received honoraria and lecture fees. AT has no conflicts of interest to disclose.

Copyright © 2015 Thorp and Schlaich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Regulation of the renal sympathetic nerves in heart failure

#### Rohit Ramchandra\* and Carolyn J. Barrett

*Department of Physiology, The University of Auckland, Auckland, New Zealand*

Heart failure (HF) is a serious debilitating condition with poor survival rates and an increasing level of prevalence. HF is associated with an increase in renal norepinephrine (NE) spillover, which is an independent predictor of mortality in HF patients. The excessive sympatho-excitation that is a hallmark of HF has long-term effects that contribute to disease progression. An increase in directly recorded renal sympathetic nerve activity (RSNA) has also been recorded in animal models of HF. This review will focus on the mechanisms controlling sympathetic nerve activity (SNA) to the kidney during normal conditions and alterations in these mechanisms during HF. In particular the roles of afferent reflexes and central mechanisms will be discussed.

#### Edited by:

*Kate Denton, Monash University, Australia*

#### Reviewed by:

*Kenju Miki, Nara Women's University, Japan Luciana A. Campos, University Camilo Castelo Branco, Brazil*

#### \*Correspondence:

*Rohit Ramchandra, Department of Physiology, The University of Auckland, Building 503, 85 Park Road, Auckland 1142, New Zealand<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology*

Received: *26 June 2015* Accepted: *07 August 2015* Published: *25 August 2015*

#### Citation:

*Ramchandra R and Barrett CJ (2015) Regulation of the renal sympathetic nerves in heart failure. Front. Physiol. 6:238. doi: 10.3389/fphys.2015.00238* Keywords: heart failure, renal sympathetic nerve activity, central control

## Introduction

Heart failure (HF) is a complex syndrome, arising secondary to a wide range of cardiac structural and functional abnormalities, with the manifestations being shortness of breath, fatigue, exercise intolerance, and oedema. Elevated sympathetic drive is well recognized to play a key role in the pathophysiology of HF, with increased sympathetic nerve activity (SNA) to the kidneys resulting in renal vasoconstriction, increased renal sodium retention and increased renin release, and consequently elevated angiotensin II and aldosterone levels (DiBona and Kopp, 1997). In turn, angiotensin II is known to drive adverse cardiac remodeling and deterioration in cardiac function via a number of different pathways, including inflammatory pathways and fibrosis (Zhao et al., 2014). While initially activation of renal sympathetic nerve activity (RSNA) may assist in maintaining cardiac output, in the long-term neurohumoral activation drives the fluid overload associated with HF, significantly impacting both morbidity and mortality.

The significance of the sympathetic activation in HF is highlighted by the successful use of ACE inhibitors and β-blockers in the clinical management of the syndrome (Yancy et al., 2013). β-Blockers are well established to reduce the rate of mortality (Esler and Kaye, 1998), however, even when the majority of patients are prescribed β-blockers, increased renal norepinephrine (NE) spillover is directly linked to mortality (Petersson et al., 2005). Kidney function is an important determinant of outcomes during HF, with glomerular filtration rate, being an independent predictor of mortality in HF (Hillege et al., 2006). Understanding the mechanisms regulating renal function, and the changes that occur during the development of HF is thus crucial in understanding the pathophysiology of HF. In this review we will review the evidence for an increase in RSNA in HF and focus on three key areas potentially involved in mediating the changes: the arterial baroreceptors, the peripheral chemoreceptors, and the central regulation of RSNA within the paraventricular nucleus of the hypothalamus. A more in depth discussion of additional afferent signals such as from cardiopulmonary volume receptors and the afferent kidney reflex in control of RSNA in HF is presented by Booth et al. in this same special edition.

## Resting Levels of Renal Sympathetic Nerve Activity in HF

Early studies in patients with severe HF have indicated that the spillover of NE from the kidney is increased (Hasking et al., 1986; Aggarwal et al., 2003). **Figure 1** illustrates the progressive increase in spillover of NE from the kidney observed in clinical studies. As the figure indicates, as the progression of HF reaches ejection fractions of below 30%, there is a significant increase in renal spillover of NE. Rundqvist et al. (1997) indicate that at ejection fractions of 29 ± 7%, the renal spillover of NE is not significantly different to a normal matched cohort. However, once ejection fraction decreases below 25%, there is a significant increase in renal spillover of NE. Interestingly at ejection fractions of 29%, a three-fold increase in cardiac spillover of NE is observed indicating that the increase in cardiac spillover of NE occurs earlier than that in the kidney (Rundqvist et al., 1997).

An increase in spillover of NE from the kidney may be driven by changes in directly recorded SNA or may be secondary to changes in reuptake of NE at the synapse. Various animal models have been employed to study the role of the renal sympathetic nerves in HF. These include the myocardial infarction (MI) induced HF model in the rat and pacing induced HF in the rabbit, sheep, and the dog. The majority of studies have indicated an increase in directly recorded RSNA during HF with ejection fractions of 36–45%. The MI induced model of HF in rodents results in a significant increase in baseline resting levels of RSNA (DiBona et al., 1996, 1997). Similar to this, the pacing induced model of HF in rabbits is also associated with an increase in baseline levels of sympathetic drive to the kidney (Sun et al., 1999a; Liu et al., 2000). The finding of a significant increase in RSNA is not universal in all animal models of HF. Previous

studies have found that baseline levels of RSNA are not increased in doxorubicin induced HF (Rossi et al., 2008) or in pacing induced HF in sheep (Ramchandra et al., 2009a). Given the progressive increase in renal spillover of NE as HF worsens, it is possible that these findings merely reflect models of HF which are not severe enough.

#### Clinical Relevance