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Renal denervation forDiabetes

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andMetabolic syndrome

RevathyCarnagarin, MarcioG.Kiuchi, LeslieMarisolLugo- Gavidia, andMarkusP.Schlaich

Introduction

The sympathetic nervous system (SNS) plays a vital integrative role in the regulation of cardiovascular and metabolic homeostasis. Heightened sympathetic activation is a hallmark of cardiometabolic disease such as metabolic syndrome and type 2 diabetes (T2DM). Sympathetic overdrive results in chronic dysregulation of cardiometabolic processes and thereby contributes to a clustering of metabolic abnormalities and cardiovascular risk factors that include hypertension (HTN), abdominal obesity, hyperglycemia (prediabetes or overt T2DM), and dyslipidemia (high triglycerides and low high-density lipoproteins), as perhaps best exemplied by the Metabolic Syndrome (MetS) [1]. In addition, the visceral fat accumulation, a characteristic feature in MetS, has been linked to excessive adipokine release, primarily leptin further feeding the SNS hyperactivity [2]. These abnormalities often are associated with insulin resistance, non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases [3–7]. Furthermore, the SNS differentially regulates immunity to sustain a chronic inammatory state that further impairs cardio-metabolic homeostasis [8]. A selfperpetuating cycle develops where sympathetic overdrive contributes to the risk of developing T2DM and insulin resistance, conversely, T2DM and insulin resistance contribute to

a further sympathetic overdrive (Fig.8.1) may lead to progression of the clinical features of the MetS. Ultimately, these disorders combined are associated with a 2–four-fold increase in risk of developing cardiovascular disease (CVD) and all-cause mortality [9].

Therapeutic targeting of the SNS is a rational approach, which is not necessarily limited to the management of cardiovascular disorders such as hypertension, but may be potentially used to restore metabolic homeostasis, as a common pathology is aberrant sympathetic activation. Efforts to contain these combined co-morbidities in MetS includes lifestyle modication either alone or in combination with pharmacotherapy. But these are easier to advocate than to incorporate into clinical practice. Despite the availability of effective pharmacotherapy to target SNS, clinical management of co-existing abnormalities is often challenging due to various patient factors such as inconvenience of life-long therapy, signicant pill burden, pill holidays, unfavourable drug interactions, side effects of medication and other factors

R. Carnagarin (*) · M. G. Kiuchi · L. M. Lugo-Gavidia Dobney Hypertension Centre, School of Medicine- Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Crawley, WA, Australia e-mail: revathy.carnagarin@uwa.edu.au;

marcio.galindokiuchi@uwa.edu.au

M. P. Schlaich Dobney Hypertension Centre, School of Medicine- Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Crawley, WA, Australia

Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA, Australia

Neurovascular Hypertension and Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia e-mail: markus.schlaich@uwa.edu.au

Fig. 8.1 The Self-reinforcing cycle of sympathetic overdrive in the context of metabolic disturbances

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R. Carnagarin et al.

that contribute to non–adherence. Intervention approaches such as catheter-based renal denervation may offer a one-off, safe procedural approach to reduce the central sympathetic overdrive, thereby effectively targeting the cluster of cardiometabolic abnormalities characteristic of MetS.

Renal Sympathetic Denervation forTargeting Sympathetic Overdrive

Renal Denervation (RDN), which is the sympathetic denervation in the renal arteries, though reported as early as 1924 [10], has only recently re-emerged as an effective treatment strategy for hypertension, owing to the plethora of benecial cardiovascular and metabolic effects. The cardiometabolic effects of RDN not only includes improved blood pressure control but also regression of hypertension mediated end organ damage (HMOD) such as left ventricular hypertrophy and diastolic dysfunction, as well as improved glucose metabolism, insulin sensitivity and resistance, and improved lipid prole [11–14]. However, the overall effect of RDN as a possible treatment option for hypertension, has shown diverse results in the various clinical studies [12, 15–17]. The first proof-of-concept RDN trial, SYMPLICITY HTN-1 demonstrated that catheter-based sympathetic denervation led to a substantial reduction in blood pressure without any serious adverse effects [11], at 6months and subsequent further follow up compared with standard pharmacotherapeutic antihypertensive regimen [18, 19]. Soon after, the SIMPLICITY HTN-2 trial also demonstrated signicant BP reduction in a similar pattern in the RDN group compared to control subjects on standard pharmacologic therapy [12]. However, these studies did not include a sham-controlled design and were not blinded, moreover the antihypertensive medication adherence was not assessed and blood pressure measurement was not standardised in these trials.

In order to address the shortcomings of the initial RDN trials, the SYMPLICITY HTN-3 was designed as a prospective sham-controlled study, but unfortunately the RDN procedure failed to demonstrate a signicant reduction of blood pressure compared to the sham counterparts [19, 20]. This outcome of the SYMPLICITY HTN-3 trial tossed sympathetic RDN into a stand still despite the various study-related criticisms, most importantly the failure to achieve complete circumferential, four quadrant sympathetic bre ablation. In view of the SYMPLICITY HTN-3 outcome where RDN failed to meet its primary endpoint, the next in line,

SYMPLICITY HTN-4 clinical trial aimed at investigating the effect of RDN in patients with moderate uncontrolled HTN was halted. Nevertheless, the DENER-HTN trial, which was designed to address the major shortcomings of the SYMPLICITY HTN-3 trial such as the standardization of the antihypertensive regimen and assessment of medication adherence clearly demonstrated the efcacy of the sympathetic RDN when delivered along a standardized stepped-care antihypertensive treatment [21]. Lessons from the SYMPLICITY HTN-3 and DENERHTN trials clearly revealed the need for identifying or characterizing the patient populations, which would be beneted the most from RDN [22]. In view of this context, Kario etal. showed that RDN demonstrated a better favourable response in patients with concomitant obstructive sleep apnea [23].

Following these trials that were suggestive of diverse responses with RDN, three clinical trials namely the SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED, and RADIANCE-HTN SOLO were designed as sham controlled studies with similar protocol design and executed rigorously with an intent to overcome issues identied in previous studies [24–26] and the published results demonstrated a consistent, signicant lowering of blood pressure compared to sham control (Fig. 8.2). Nevertheless, the magnitude of BP lowering was similar to the changes expected from antihypertensive pharmacotherapy and was smaller when compared to the uncontrolled, unblinded RDN studies [19, 22, 27].

Of note, these studies did not include patients with isolated systolic hypertension which forms around 70% of the elderly patient population, and hence, the data from these studies are not applicable to this important isolated systolic hypertension group. Henceforth, future trials are still warranted to clearly identify the true effect of RDN as a therapeutic strategy in the management of hypertension, and the associated cardiometabolic conditions. Nonetheless, RDN is still considered a valuable option for BP lowering in clinical practice. Indeed, the results from these RDN clinical trials impelled the meeting of The US Food and Drug Administration Circulatory System Devices Panel in December 2018 in view of the clinical evaluation of antihypertensive devices and recommendations for clinical management of Hypertension in this perspective [28]. It is henceforth worthwhile to revisit the fundamental mechanisms governing the effects of renal denervation, not only in the regulation of blood pressure but also the associated benecial metabolic effects and its potential in the management of cardiometabolic disorders.

8 Renal denervation forDiabetes andMetabolic syndrome

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SPYRAL HTN-ON MED

End point assessment at 6 months End point assessment at 3 months

24 h SBP

–7.4 (–12.5 to –2.3

p=0–0051

n=36

–2

–4

–6

–8

–10

(–12.7 to –5.3)

p<0.0001

–12

Change in BP from baseline to 6 months (mm Hg)

151.9

–6.0

(–5.2 to –2.0)

p<0.365

–9.0

151.196.9

Baseline ABPM (mmHg)

(–8.5 to –3.5)

p<0.0001

24 h DBP

–4.1 (–7.8 to –0.4

p=0–0292

n=36

–1.9

(–4.7 to –0.9)

p<0.172

–6.0

Renal Denervation Sham control

97.6

SPYRAL HTN-OFF MED

24 h SBP 24 h SBP

–5.0 (–9.9 to –0.2

p=0–0414

–2

–4

–6

–8

–10

–12

Change in blood pressure from baseline to 3 months (mm Hg)

(–9.1 to –2.0)

n=36

n=35

(–3.9 to 2.9)

p<0-76

–5.5

p<0.0031

24.h SBP

153.4 151.6

Baseline ABPM (mmHg)

–0.5

Renal Denervation

Sham control

Fig. 8.2 Comparison of 24-hr systolic and diastolic blood pressure (SBP and DBP) changes in renal denervation vs sham-control groups in the 3 recent randomized, sham-controlled clinical trials showed. ABPM indicates ambulatory BP monitoring; CI, condence interval; HTN-ON MED, Spyral Hypertension on Medication trial; HTN-OFF MED,

RADIANCE-HTN SOLO

End point assessment at 2 months

24 h DBP

–4.4 (–7.2 to –1.6

n=35

–4.8

(–7.0 to –2.6)

p<0.0001

24.h DBP

99.1

p=0–0024

n=36

–0.4

(–2.2 to 1.4)

p<0–65

98.7

Change in 24–h ambulatory blood pressure

–5

–10

difference adjusted for baseline

Change in blood pressure (mm Hg)

–15

–7.0 mm Hg

Between-group

blood pressure

(95% CI

p=0.006

Systolic

–3.1 mm Hg

–7.1 to –1.2)

ABPM (mmHg)

Spyral Hypertension OFF Medication trial; and RADIANCE-HTN SOLO, RADIANCE hypertension solo (off medication) trial. Reprinted from Kandzari etal., 1 Azizi etal., 2 and Townsend etal. 3 with permission. Copyright © 2018, Elsevier

24 h DBP

–3.0 mm Hg

–4.4 mm Hg

Renal Denervatio Sham control

Between-group

difference adjusted for baseline

blood pressure

–1.8 mm Hg

–7.1 to –0.2)

(95% CI

p=0.07

Diastolic

Mechanisms ofRDN-Induced Clinical Benets

The sympathetic renal innervation includes the afferent sensory bres that originate from the kidneys and terminate at the integrating nuclei in the brainstem and the efferent sympathetic bres originate from central nervous system nuclei to pass through to the kidney (Fig.8.3) [8]. Increased central sympathetic outow directed towards the kidneys results in reduced renal blood ow and stimulates the reninangiotensin- aldosterone signalling (RAAS) resulting in enhanced tubular reabsorption of sodium and water [29]. Studies in rat models reported that RDN did not impact the salt sensitivity of arterial pressure and resulted in BP lowering independent of renin release or sodium-water balance [30–33]. In addition, the ablation of the afferent sympathetic signalling by RDN also resulted in an off target antiarrhythmic effect and metabolic effects. Animal studies have demonstrated substantial neuronal remodelling in the brain stem and stellate ganglia following bilateral RDN procedure [34–

37]. The renal efferent sympathetic nerves originate from the

second sympathetic ganglion and forms a network within the adventitia of the renal arteries [38], which in turn is regulated by the rostral ventrolateral medulla (RVLM), the obliteration of which causes substantial blood pressure lowering [39]. Accordingly, the RDN procedure was introduced to disrupt the sympathetic signalling from the brain to the kidneys and vice versa as well as the inter renal sympathetic cross-talk

[40]. RDN-mediated sympathetic ablation, evident from the reduction in gold standard markers of sympathetic activation such as muscle sympathetic nerve activity and noradrenaline spillover [41], reduced systemic vasoconstriction, improved cardiac performance, with favourable renal and metabolic effects [42]. Additionally, RDN blocked the projection of the detrimental renal stimuli such as electrolyte imbalance, oliguria, renal ischemia, high adenosine levels to the relevant nuclei in the brain stem in turn ameliorating the sympathetic outow to other organs.

Furthermore, RDN attenuates sympathetic modulation of immune pathways that causes metabolic perturbations such as hyperinsulinemia and insulin resistance and vice versa. Sympathetic overdrive triggers inammation of the brain, skeletal muscle vasculature and the kidneys resulting in chronic sustained BP elevation [43–45] along with perturbation of the metabolic homeostasis. In most clinical conditions associated with sympathetic overdrive, a chronic low-grade systemic inammation is established and sustained by activated immune cells and increased cytokines and chemokines in the circulation [46–50].

Distinct clinical states such as MetS, type 2 diabetes and as well as obesity related hypertension are characterised by systemic immune activation and circulating inammatory cytokines and chemokines that exert metabolic stress, perturbing homeostasis [49–54]. Bilateral chemical sympathetic denervation of the renal arteries in mice inhibited immune activation, renal inammation and ameliorated Ang

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R. Carnagarin et al.

Fig. 8.3 Renal sympathetic efferent innervation includes bres originating in the central nervous system and traversing to the kidney as well as afferent sensory bres from the kidneys to hypothalamus. Increased sympathetic outow to the renal vascular bed reduces renal blood ow, releases renin, thereby activating the renin-angiotensin-aldosterone

II-induced hypertension [55]. RDN produced a similar effect in the deoxycorticosterone acetate-salt rat model of hypertension where BP elevation was caused by renal inammationmediated augmented afferent sympathetic trafcking [56]. Furthermore, catheter-based renal denervation-mediated amelioration of sympathetic activation reduced monocyte activation and circulating inammatory cytokines in patients with hypertension [57].

The Metabolic Eects ofRDN

Sympathetic overdrive induces insulin resistance [58] and promotes the development of obesity [59], diabetes mellitus [60] and MetS [61] with the resultant hyperinsulinemic state promoting feedforward sympathoexcitation [62, 63]. Insulin resistance was a contemporaneous phenomenon with essential hypertension as seen in around 50% of patients [64] and hypertension often coexisted with obesity as well [65, 66]. Insulin resistance, hyperinsulinemia and increased adiposity have been associated with heightened activation of the sympathetic nervous system, recorded as heightened muscle sympathetic nerve activity [67, 68]. The sympathetic overdrive- mediated vascular resistance shifts the blood ow from the insulin sensitive, striated muscle to the less insulin sensitive viscera, hence the prevalence of hypertension is often associated with insulin resistance and impaired postprandial insulinemia [69]. Dietary and life style modication measures-mediated sympathetic inhibition predicts the weight loss in metabolic syndrome [70, 71]. These ndings

(RAAS) cascade and enhances tubular reabsorption of urinary sodium and water. The cardiometabolic consequence of increased sympathetic ow includes cardiac hypertrophy and arrhythmias, endothelial dysfunction and insulin resistance in the skeletal muscle contributing to the development of diabetes mellitus and metabolic syndrome [8]

instigate RDN as potential strategy for restoring the perturbed metabolic homeostasis to target the underlying pathology, the sympathetic overdrive.

Pharmacological inhibition of the central sympathetic outow with the imidazoline receptor agonist, moxonidine increased the blood ow to the skeletal muscle, decreased glucagon secretion that resulted in reduction of glycogenolysis and gluconeogenesis and resulted in the improvement of overall glucose metabolism [72]. However, the use of central sympatholytic agents is sometimes associated with side effects, which results in medication tolerance and relatively high non-adherence rates [73]. In this context sympatholysis with RDN is a potential option to restore the perturbed glucose metabolism [74]. RDN attenuates the release of norepinephrine, inhibits the α-adrenergic tone, and decreases the RAAS activation with benecial consequences on striated muscle blood ow and metabolism [75]. The improvement in blood ow peripherally to insulin sensitive musculature in turn facilitates insulin delivery and action on the skeletal muscle enhancing glucose uptake and utilisation [76]. Sympathetic overdrive renders patients with hypertension more susceptible to weight gain associated with reduced adrenoceptor responsiveness [77]. Sympathetic activation promotes central adiposity, which has been is associated with higher rates of obstructive sleep apnea [78] and further derangement of glucose homeostasis. In patients with concomitant obesity, resistant hypertension and obstructive sleep apnea, attenuation of sympathetic overdrive by RDN induced signicant weight loss [79], enabled better BP control along with improvement in metabolic parameters [76,

8 Renal denervation forDiabetes andMetabolic syndrome

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78]. Taken together, RDN as a one off approach could pro-

vide a sustainable therapeutic strategy in the management of obesity related hypertension, particularly in those patients with concomitant sleep apnea, to provide a wholistic solution not only with BP reduction but also in restoring the overall metabolic homeostasis. Indeed, the evidence obtained from clinical trials suggest that RDN is a potential intervention in the management of metabolic disorders associated with elevated blood pressure, with a likely reduction in the overall cardiovascular risk.

Sympathetic ablation by RDN besides lowering blood pressure, improved insulin action, glycosylated haemoglobin levels and other metabolic parameters, attenuated the severity of sleep apnea in a resistant hypertension patient population [72, 79]. RDN signicantly reduced the average heart rate of the heart failure patients in the EnligHTN I trial [80]. Moreover, RDN was associated with other cardiac benets such as the reduction in left ventricular mass and improvement of atrial and ventricular arrhythmias [81, 82]. In addition, RDN ameliorated macroalbuminuria and microalbuminuria and improved the renal resistance indices [83]. Interestingly, RDNmediated sympathetic ablation in patients with hypertension and diabetes mellitus showed improvement in insulin sensitivity and glucose metabolism, besides lowering of blood pressure [72, 78]. Furthermore, RDN has demonstrated benecial effects in combined metabolic and endocrine disorders. In patients with polycystic ovary syndrome, RDN improved fasting glucose, insulin sensitivity along with a reduction in glomerular hyperltration and urinary albumin excretion [84]. RDN delayed the progression diabetes mediated renal injury which had already been proven in animal studies [85].

However, sympathetic ablation by RDN in patients with elevated BP and MetS did not demonstrate any change in fasting glucose, insulin sensitivity nor showed any improvement in sympathetic activity as shown by the DREAMSStudy [86, 87]. The DREAMS-Study included near drug-naïve participants with increased sympathetic activity when compared to other clinical trials [88, 89] and was expected to demonstrate at best a reduction in sympathetic activity [90]. May be this nding would have been the result of incomplete or insufcient denervation is uncertain but remains a possibility. The other limitations of the DREAMSStudy include a small cohort size and the lack of a control group which makes it difcult to draw any rm conclusions. Further evaluation is warranted in the form of rigorously designed clinical trials to conrm the previously reported benecial metabolic effects of RDN in type 2 diabetes and MetS.

Future Perspectives andConclusions

The endocrine and metabolic mechanisms by which RDN impacts glucose homeostasis remain to be fully understood. RDN-mediated metabolic effects are likely to involve a concerted interplay of various mechanisms such as the modulation of afferent signaling to attenuate the sympathetic outow centrally, interference with the RAAS cascade, decreased alpha adrenergic vascular tone promoting enhanced blood ow to the skeletal muscle vasculature which in turn promotes insulin delivery, increases insulin and non-esteried fatty acid sensitivity, enhances glucose uptake and metabolism ameliorating insulin resistance [90–93]. The studies which were designed to test RDN in diabetic patients possessed various limitations such as a small sample size, lack of sham-control groups, short duration for follow up and others. Moreover, the RDN induced BP lowering effect by itself could account for the benecial improvements in glucose metabolism. Future RDN studies in the metabolic area are required to address the limitations of the previous studies and identify the magnitude of any effect of RDN-mediated sympathetic ablation on metabolic homeostasis in patients with type 2 diabetes and MetS.The ongoing RDN clinical trials in diabetes (NCT 02081989) and metabolic syndrome (NCT 01911078) performed to determine the effects of sympathetic ablation by RDN on insulin sensitivity and glucose metabolism, will further clarify the role and applicability of RDN in metabolic disorders.

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8 Renal denervation forDiabetes andMetabolic syndrome

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Renal Denervation forChronic Kidney

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Disease

MarcioG.Kiuchi, RevathyCarnagarin, LeslieMarisolLugoGavidia, DagmaraHering, andMarkusP.Schlaich

Introduction

The sympathetic nervous system (SNS) is crucial for homeostatic regulation, mainly with regards to the control of body uids and blood pressure (BP). However, persistent activation of the SNS can trigger harmful cardiorenal alterations [1]. Indeed, preclinical and clinical studies have demonstrated that SNS dysfunction is implicated in the pathogenesis of cardiorenal diseases such as hypertension (HTN), heart failure (HF), and chronic kidney disease (CKD) [2–4].

The notion that the kidneys play a pivotal role in the development and maintenance of HTN was rst desribed in the nineteenth century with the observation that renal ischemia increased vascular resistance resulting in increased systemic BP levels [5, 6]. However, whether renal dysfunction is the cause or the consequence of HTN was unclear. In this context, Guyton etal. proposed that extracellular uid volume is maintained by the kidneys via renal excretion of sodium and water depending on dietary intake [7–9]. The kidney in response to increased renal perfusion pressures

M. G. Kiuchi · R. Carnagarin · L. M. L. Gavidia Dobney Hypertension Centre, Medical School - Royal Perth Hospital Unit, University of Western Australia, Crawley, WA, Australia e-mail: marcio.galindokiuchi@uwa.edu.au; revathy.carnagarin@

uwa.edu.au; lesliemarisol.lugogavidia@research.uwa.edu.au

D. Hering Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland e-mail: hering@gumed.edu.pl

M. P. Schlaich (*) Dobney Hypertension Centre, School of Medicine- Royal Perth Hospital Unit, University of Western Australia, Crawley, WA, Australia

Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA, Australia

Neurovascular Hypertension & Kidney Disease Laboratory and Human Neurotransmitter Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia e-mail: markus.schlaich@uwa.edu.au

alters sodium and water excretion to maintain uid homeostasis, whereby increased pressure translates into increased sodium and water excretion, a concept referred to as “pressure natriuresis”. In normotensive individuals, renal pressure natriuresis is capable of handling transient variations of intravascular volumes triggered by increased heart rate (HR) or increased peripheral vascular resistance. However, it is postulated that with consistent increases in BP, the kidney shifts to a new higher-than-normal equilibrium point for salt and water excretion resulting in higher BP [7–10]. Several renal transplantation studies [11–15] have revealed that HTN follows the kidneys; the rst study demonstrated that transplantation of kidneys from hypertensive rats to normotensive rats resulted in HTN in the normal mice and similarly transplanting kidneys from normotensive rats to hypertensive rats resulted in abrogation of BP in the hypertensive rats, suggesting that the kidney might play an integral role in the development of HTN [11–15]. Hence, the SNS has been identied as an important therapeutic target, particularly the renal nerves that contain both sympathetic (efferent) and sensory (afferent) bers.

Physiology

The Sympathetic Nervous System andChronic Kidney Disease

Increased sympathetic activity has been demonstrated to increase cardiovascular risk in patients with CKD and is a key characteristic of the hypertensive state, occurring even in the early clinical course of the disease [1, 16, 17]. In both conditions, several mechanisms contribute to the hyperadrenergic state, including reex and neuro-humoral pathways [1, 16, 18]. In CKD, sympathetic hyperactivity appears at the earliest clinical stage showing a direct association with the severity of renal impairment [18–21]. Activation of the renal efferent sympathetic nerves regulates kidney function and ultimately BP by modulating tubular sodium reab-

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M. G. Kiuchi et al.

sorption, renal blood ow (RBF), glomerular ltration rate (GFR), and renin release [22, 23]. Hence, surgical or chemical renal denervation (RDN) was used widely in experimental studies to further explore the role of renal nerves in kidney and circulatory physiology. The exact mechanisms by which RDN causes long-term BP lowering have not yet been entirely explored but are likely to include reduced sympathetic activity and effects on the renin-angiotensin system. Pöss etal. described a signicant increase in urinary sodium excretion 6months after RDN in patients with resistant hypertension. This effect remained apparent after consideration of antihypertensive drug therapy [24]. Consistent with previous reports demonstrating decreased renal vascular resistance [25], Delacroix etal. reported an improvement in total blood volume distributed to the kidney per cardiac cycle [26]. This could be especially important in patients demonstrating end organ damage because of constantly high BP levels. RDN has been demonstrated to be safe and can be considered as a promising and novel therapeutic tool for CKD patients with hypertension [27–30], by reducing renin activity, aldosterone and angiotensin-II levels in humans [31].

Meta-analyses have shown that CKD is an independent cardiovascular risk factor [32] and other studies have described that adrenergic activation exhibits an adverse impact on cardiovascular morbidity and in the case of CKD, an adverse effect on cardiovascular mortality [1, 16, 21, 33]. Therefore, preventing further renal impairment is an important therapeutic target [34]. Baseline levels of muscle sympathetic nerve activity (MSNA), a surrogate of sympathetic hyperactivity is increased in mild CKD caused by hypertension. Tinucci etal. found that baseline level of MSNA was signicantly higher (34 bursts/min) in hypertensive subjects presenting with mild CKD when compared to hypertensive patients with normal renal function (24 bursts/min, P<0.05) and normotensive patients (16 bursts/min, P< 0.05), highlighting that high sympathetic activity can be detected in early stage of CKD [35].

Renal Eerent Signaling

The renal efferent sympathetic nerves are mostly adrenergic [36]. Norepinephrine release mediates vasoconstriction of the renal vessels, as well as sodium and water reabsorption at renal tubular epithelial cells, and renin discharge from the juxtaglomerular cells [37].

The mechanisms through which RDN attenuates BP levels remain elusive. One explanation is that RDN increases renal sodium and water excretion and causes a subsequent contraction of blood volume [38] by suppressing sympathetically mediated renin secretion and/or renal tubular sodium reabsorption. However, Foss et al. found no differences in

daily or cumulative sodium and water balance between SHAM and RDN rats [39]. This is consistent with previous reports suggesting that RDN decreases BP in normotensive Sprague Dawley rats independent of sodium balance or renin release [40, 41]. It is important to note that RDN had no effect on salt sensitivity or arterial pressure in Sprague Dawley rats [38] or Dahl salt-sensitive (DS) rats. In line with their ndings that afferent renal nerves are not involved in sodium-sensitive hypertension in DS rat model, these data suggests that the antihypertensive effect of RDN in the DS rat is likely due to reduced renin-angiotensin system activity, renal vascular resistance or a different effect of efferent renal sympathetic nerve ablation. Further investigation is needed to test this hypothesis [42].

The rostral ventrolateral medulla (RVLM) exerts a vital function on the regulation of efferent renal sympathetic nerve activity (RSNA). The level of RSNA is reliant on the neuronal activity in sympathetic premotor nuclei in the brainstem and hypothalamus, including the RVLM and rostral ventromedial medulla (RVMM) as well the paraventricular nucleus (PVN). The notable reduction in BP after destruction of premotor neurons in the RVLM highlights its important regulatory role [43]. Inhibition of renal efferent sympathetic nerve signalling after RDN with downstream effects on the renin-angiotensin-aldosterone cascade are likely contributors to the BP lowering efcacy.

Renal Aerent Signaling

The renal afferent sensory nerves relay signals from the kidney to the central nervous system, and activation of afferent renal nerves in models of renal ischemia has been shown to elevate BP and plasma norepinephrine (NE) spillover [44] and increase renal sympathetic nerve activity [45]. Recently, Tsai and colleagues demonstrated in ambulatory canines that bilateral RDN, possibly via interrupting afferent renal innervation, led to substantial brain stem and bilateral stellate ganglion remodeling, at 8 weeks post-procedure [46]. These changes were associated with reduced 18FDG- uptake in the brainstem, left stellate ganglion nerve activity and atrial tachyarrhythmia events. Neural remodeling in the brain stem and stellate ganglion may therefore at least in part explain the described antiarrhythmic effects of RDN [46].

Trans-synaptic degeneration is a phenomenon in the central and peripheral nervous system that may remain active both at the level of the insult and in remote brain structures for as long as 1year after a trauma [47]. These progressive alterations may underlie some of the long-term functional consequences after initial injury (i.e. RDN) as shown in Fig.9.1, which summarizes the various direct and indirect connections between renal sympathetic nerves and the stellate ganglion. Meckler and colleagues showed that approxi-

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