Renal Sympathetic Nerve Fibers Research Articles

Update on Renal Sympathetic Denervation for the Treatment of Hypertension.

Hypertension is a leading risk factor for all-cause mortality in adults; however, medication non-adherence and intolerance present an enormous treatment challenge. Given the critical role of renal sympathetic nerves in neurogenic control of blood pressure and pathophysiology of hypertension, renal sympathetic denervation (RDN) has been explored as a therapeutic strategy in hypertension treatment over the last 15years. In this review, we will discuss the role of renal sympathetic nerves in the pathophysiology of hypertension, provide an update on the available evidence regarding the short- and long-term safety and effectiveness of RDN in the treatment of hypertension, and consider its future perspectives. RDN is a percutaneous endovascular catheter-based neuromodulation approach that enables ablation of renal sympathetic nerve fibers within the adventitial layer of the renal arteries using radiofrequency (most extensively studied), ultrasound energy, or neurolytics (e.g., alcohol). In the last decade, advancements in procedural techniques and well-designed sham-controlled trials utilizing 24-h ambulatory blood pressure measurements have demonstrated that RDN has an excellent safety profile and results in a modest reduction of blood pressure, in a wide range of hypertensive phenotypes (mild to resistant), irrespective of antihypertensive drug use and this effect is sustained over a 3-year period. Superiority of a particular RDN modality has not been yet established. Despite strong evidence demonstrating efficacy and safety of RDN, current data does not support its use as a primary approach in the treatment of hypertension due to its modest treatment effect and concerns around long-term sustainability. Perhaps the best utility of RDN is in hypertensives intolerant to antihypertensive medications or as an adjunct to aldosterone antagonists in the management of resistant hypertension. Patient selection will be critical to demonstrate a meaningful benefit of RDN. Future well-designed studies are necessary to determine predictors and measures of response to RDN, long-term efficacy given question of renal nerve regeneration, comparison of available technologies, safety in patients with advanced kidney disease, and improvement in patient quality of life measures.

Current Status and Future Perspectives of Renal Denervation.

Catheter-based renal denervation (RDN) therapy, a new procedure that uses radiofrequency ablation to interrupt efferent and afferent renal sympathetic nerve fibers, is a complementary or alternative treatment to antihypertensive medications for optimal control of blood pressure (BP). Although several single-arm early proof-of-concept studies showed significant BP reduction, the largest sham-controlled study using the first-generation RDN device (SYMPLICITY HTN-3) failed to significantly reduce BP in patients with resistant hypertension who were taking the guideline-based combination of antihypertensive medications. Since then, new devices and techniques have been developed to improve the efficacy and safety of RDN procedures. Sham-controlled trials using second-generation RDN devices (radiofrequency- and ultrasound-based) have provided solid evidence for their BP-lowering efficacy with and without the use of concomitant antihypertensive medication. Moreover, the safety profile of RDN in several registries and clinical trials appears to be excellent. This review summarizes the current evidence for RDN and discusses its current issues, future trials, Asian perspectives, and potential roles in both hypertension and other morbidities.

Animal model evaluation of a novel renal denervation system for future laparoscopic treatment of resistant hypertension.

PurposeAlthough percutaneous catheter-based ablation of renal sympathetic nerve fibers has been used in the treatment of patients with resistant hypertension, a recent phase III study did not confirm its efficacy. In this study, we developed a novel laparoscopic renal denervation system and evaluated its safety and initial feasibility using an animal model.Materials and MethodsA novel surgical instrument that uses a smart algorithm with temperature-monitoring feedback was developed. We used 4 male pigs (6 weeks old, weighing approximately 45 kg each) to evaluate the safety and efficacy of the laparoscopic renal denervation system. We performed immunohistochemical staining analysis after renal denervation using various tip temperatures and over various durations through an open approach.ResultsWhen the temperature of the outer wall of the renal artery was maintained at 90℃ for 180 seconds, the artery was completely denervated without damaging its inner layer, as evaluated using Masson's trichrome staining. When the temperature ranged from 70℃ to 90℃ and the duration ranged from 90 to 420 seconds, partial or complete denervation without significant vessel injury was confirmed with anti- growth-associated protein 43 and anti-S100 staining.ConclusionsThis animal study confirmed the safety and feasibility of the novel laparoscopic renal denervation system. A safe and effective protocol was developed with ablation at a constant tissue temperature of 70℃ to 90℃ within 180 seconds. However, further developments are necessary before its clinical use.

Anatomic Conformation of Renal Sympathetic Nerve Fibers in Living Human Tissues

Renal denervation using radiofrequency catheter ablation is known to eliminate the renal sympathetic nerve and to lower blood pressure in patients with resistant hypertension. We sought to investigate the detailed anatomic conformation of the peri-renal arterial sympathetic nerve fibers with living human specimens. Peri-renal arterial tissue was harvested from patients undergoing elective radical or simple nephrectomy. Digital images of each section from the distal arterial bifurcation to the proximal margin were obtained and analyzed after immunohistochemical staining with anti-tyrosine hydroxylase antibodies. A total of 3,075 nerve fibers were identified from 84 sections of peri-renal arterial tissue from 28 patients (mean age 62.5 ± 10.2 years, male 68%). Overall, 16% of nerve fibers were located at distances greater than 3 mm from the endoluminal surface of the renal artery. The median distance from the arterial lumen to the nerve fibers of the proximal, middle, and distal renal arterial segments was 1.51 mm, 1.48 mm, and 1.52 mm, respectively. The median diameter of the nerve fibers was 65 μm, and there was no significant difference between the segments. A substantial proportion of the sympathetic nerve fibers were located deeper in the peri-arterial soft tissue than in the lesion depth created by the conventional catheter-based renal sympathetic denervation system.

Renal Nerve Stimulation as Procedural End Point for Renal Sympathetic Denervation.

Renal sympathetic denervation (RDN) as treatment option for hypertension has a strong rationale; however, variable effects on blood pressure (BP) have been reported ranging from non-response to marked reductions in BP. The absence of a procedural end point for RDN is one of the potential factors associated with the variable response. Studies have suggested the use of renal nerve stimulation (RNS) to adequately address this issue. This review aims to provide an overview of the clinical and experimental data available regarding the effects of RNS in the setting of RDN. Animal studies have shown that high-frequency electrical stimulation of the sympathetic nerves in the adventitia of the renal arteries elicits an increase in BP and leads to an increased norepinephrine spillover as a marker of increased sympathetic activity and these effects of stimulation were attenuated or blunted after RDN. In a human feasibility study using RNS both before and after RDN, similar BP responses were observed. Moreover, in patients with resistant hypertension, RNS-induced changes in BP appeared to be correlated with 24-h BP response after RDN. These data suggest that RNS is a useful tool to identify renal sympathetic nerve fibers in patients with treatment-resistant hypertension undergoing RDN, and to predict the likely effectiveness of RDN treatments. In acute procedural settings both in animal and human models, RNS elicits increase in BP and HR before RDN and these effects are blunted after RDN. Up to now, there is preliminary evidence that the RNS-induced BP changes predict 24-h ABPM outcome at follow-up in patients with resistant hypertension. Of note, studies are small sized and results of large trials comparing conventional RDN to RNS-guided RDN are warranted.

Anatomic Assessment of Sympathetic Peri-Arterial Renal Nerves in Man

BackgroundAlthough renal sympathetic denervation therapy has shown promising results in patients with resistant hypertension, the human anatomy of peri-arterial renal nerves is poorly understood. ObjectivesThe aim of our study was to investigate the anatomic distribution of peri-arterial sympathetic nerves around human renal arteries. MethodsBilateral renal arteries were collected from human autopsy subjects, and peri-arterial renal nerve anatomy was examined by using morphometric software. The ratio of afferent to efferent nerve fibers was investigated by dual immunofluorescence staining using antibodies targeted for anti–tyrosine hydroxylase and anti–calcitonin gene–related peptide. ResultsA total of 10,329 nerves were identified from 20 (12 hypertensive and 8 nonhypertensive) patients. The mean individual number of nerves in the proximal and middle segments was similar (39.6 ± 16.7 per section and 39.9 ± 1 3.9 per section), whereas the distal segment showed fewer nerves (33.6 ± 13.1 per section) (p = 0.01). Mean subject-specific nerve distance to arterial lumen was greatest in proximal segments (3.40 ± 0.78 mm), followed by middle segments (3.10 ± 0.69 mm), and least in distal segments (2.60 ± 0.77 mm) (p < 0.001). The mean number of nerves in the ventral region (11.0 ± 3.5 per section) was greater compared with the dorsal region (6.2 ± 3.0 per section) (p < 0.001). Efferent nerve fibers were predominant (tyrosine hydroxylase/calcitonin gene–related peptide ratio 25.1 ± 33.4; p < 0.0001). Nerve anatomy in hypertensive patients was not considerably different compared with nonhypertensive patients. ConclusionsThe density of peri-arterial renal sympathetic nerve fibers is lower in distal segments and dorsal locations. There is a clear predominance of efferent nerve fibers, with decreasing prevalence of afferent nerves from proximal to distal peri-arterial and renal parenchyma. Understanding these anatomic patterns is important for refinement of renal denervation procedures.

What are the benefits of renal denervation in patients with resistant hypertension?

Systemic arterial hypertension is one of the most important public health issues, affecting more than one-quarter of the adult population in industrialized countries [1]. It is a major risk factor for cardiovascular disease morbidity and mortality [2,3]. In most patients, hypertension can be effectively managed by a combination of lifestyle interventions and medication [4]. However, a significant portion of patients treated for hypertension are resistant to therapy. Conventionally, resistant hypertension is defined as persistent elevation of blood pressure above goal levels despite the use of at least three hypertensive agents from different classes, including a diuretic, in optimal doses [5]. Current prevalence estimates suggest that 10–30% of patients with hypertension may be resistant to drug therapy [6]. Renal sympathetic overactivity seems to play a crucial role in the development of arterial hypertension and resistance to treatment. Activation of efferent renal sympathetic nerve fibers results in an increased renin secretion rate, increased renal vasoconstriction and enhanced sodium and water retention [7]. In addition, afferent sympathetic activation from the kidneys to the CNS, seems to enhance sympathetic nerve discharge itself again, leading to a vicious circle in the development of arterial hypertension and cardiovascular morbidity [8]. Both effects, the activation of efferent renal sympathetic nerve fibers as well as the afferent ‘feedback’ from the kidneys seem to play a crucial role in the pathogenesis and maintenance of arterial hypertension. The idea of treating arterial hypertension by targeting the autonomic nervous system is decades old. In the predrug era, treatment of malignant hypertension was limited to surgical approaches, such as nephrectomy and surgical lysis of the autonomic nerves. Nonselective surgical sympathectomy (thoracolumbar splanchnicectomy), the so-called Smithwick intervention,

489 Activation by Human Heart Failure of a Sympathoexcitatory Cardiopulmonary Reflex

Functionally specific efferent renal sympathetic nerve fibers fire in response to discrete afferent stimuli. We hypothesize that individual efferent sympathetic fibers directed at other vascular beds also may be activated reflexively by specific afferent inputs. Previous work from our group, involving quantification of cardiac norepinephrine spillover, detected activation in heart failure (HF) by high atrial pressure of a normally quiescent cardio-cardiac sympatho-excitatory reflex. Whether individual vasoconstrictor neurons directed at skeletal muscle vessels respond concordantly or differentially to changes in atrial pressure is unknown.

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin-angiotensin system

Functionally specific renal sympathetic nerve fibers: role in cardiovascular regulation

The sympathetic nervous system provides differentiated regulation of the functions of various organs. This differentiated regulation occurs through mechanisms that operate at multiple sites within the classic reflex arc: peripherally at the level of afferent input stimuli to various reflex pathways, centrally at the level of interconnections between various central neuron pools, and peripherally at the level of efferent fibers targeted to various effectors within the organ. In the kidney, increased renal sympathetic nerve activity regulates the functions of the intrarenal effectors: the tubules, the blood vessels, and the juxtaglomerular granular cells. This enables a physiologically appropriate coordination between the circulatory, filtration, reabsorptive, excretory, and renin secretory contributions to overall renal function. Anatomically, each of these effectors has a dual pattern of innervation consisting of a specific and selective innervation by unmyelinated slowly conducting C-type renal sympathetic nerve fibers and an innervation that is shared among all the effectors. This arrangement facilitates maximum flexibility in the coordination of the tubules, the blood vessels, and the juxtaglomerular granular cells so as to produce physiologically appropriate responses to a variety of homeostatic requirements.

Neural control of the kidney: functionally specific renal sympathetic nerve fibers.

The sympathetic nervous system provides differentiated regulation of the functions of various organs. This differentiated regulation occurs via mechanisms that operate at multiple sites within the classic reflex arc: peripherally at the level of afferent input stimuli to various reflex pathways, centrally at the level of interconnections between various central neuron pools, and peripherally at the level of efferent fibers targeted to various effectors within the organ. In the kidney, increased renal sympathetic nerve activity regulates the functions of the intrarenal effectors: the tubules, the blood vessels, and the juxtaglomerular granular cells. This enables a physiologically appropriate coordination between the circulatory, filtration, reabsorptive, excretory, and renin secretory contributions to overall renal function. Anatomically, each of these effectors has a dual pattern of innervation consisting of a specific and selective innervation by unmyelinated slowly conducting C-type renal sympathetic nerve fibers in addition to an innervation that is shared among all the effectors. This arrangement permits the maximum flexibility in the coordination of physiologically appropriate responses of the tubules, the blood vessels, and the juxtaglomerular granular cells to a variety of homeostatic requirements.

Renal hemodynamic effects of activation of specific renal sympathetic nerve fiber groups.

To examine the effect of activation of a unique population of renal sympathetic nerve fibers on renal blood flow (RBF) dynamics, anesthetized rats were instrumented with a renal sympathetic nerve activity (RSNA) recording electrode and an electromagnetic flow probe on the ipsilateral renal artery. Peripheral thermal receptor stimulation (external heat) was used to activate a unique population of renal sympathetic nerve fibers and to increase total RSNA. Total RSNA was reflexly increased to the same degree with somatic receptor stimulation (tail compression). Arterial pressure and heart rate were increased by both stimuli. Total RSNA was increased to the same degree by both stimuli but external heat produced a greater renal vasoconstrictor response than tail compression. Whereas both stimuli increased spectral density power of RSNA at both cardiac and respiratory frequencies, modulation of RBF variability by fluctuations of RSNA was small at these frequencies, with values for the normalized transfer gain being approximately 0.1 at >0.5 Hz. During tail compression coherent oscillations of RSNA and RBF were found at 0.3-0.4 Hz with normalized transfer gain of 0.33 +/- 0.02. During external heat coherent oscillations of RSNA and RBF were found at both 0.2 and 0.3-0.4 Hz with normalized transfer gains of 0. 63 +/- 0.05 at 0.2 Hz and 0.53 +/- 0.04 to 0.36 +/- 0.02 at 0.3-0.4 Hz. Renal denervation eliminated the oscillations in RBF at both 0.2 and 0.3-0.4 Hz. These findings indicate that despite similar increases in total RSNA, external heat results in a greater renal vasoconstrictor response than tail compression due to the activation of a unique population of renal sympathetic nerve fibers with different frequency-response characteristics of the renal vasculature.

Reflex effects on components of synchronized renal sympathetic nerve activity.

The effects of peripheral thermal receptor stimulation (tail in hot water, n = 8, anesthetized) and cardiac baroreceptor stimulation (volume loading, n = 8, conscious) on components of synchronized renal sympathetic nerve activity (RSNA) were examined in rats. The peak height and peak frequency of synchronized RSNA were determined. The renal sympathoexcitatory response to peripheral thermal receptor stimulation was associated with an increase in the peak height. The renal sympathoinhibitory response to cardiac baroreceptor stimulation was associated with a decrease in the peak height. Although heart rate was significantly increased with peripheral thermal receptor stimulation and significantly decreased with cardiac baroreceptor stimulation, peak frequency was unchanged. As peak height reflects the number of active fibers, reflex increases and decreases in synchronized RSNA are mediated by parallel increases and decreases in the number of active renal nerve fibers rather than changes in the centrally based rhythm or peak frequency. The increase in the number of active renal nerve fibers produced by peripheral thermal receptor stimulation reflects the engagement of a unique group of silent renal sympathetic nerve fibers with a characteristic response pattern to stimulation of arterial baroreceptors, peripheral and central chemoreceptors, and peripheral thermal receptors.

Reflex effects on renal nerve activity characteristics in spontaneously hypertensive rats.

The effects of arterial and cardiac baroreflex activation on the discharge characteristics of renal sympathetic nerve activity were evaluated in conscious spontaneously hypertensive and Wistar-Kyoto rats. In spontaneously hypertensive rats compared with Wistar-Kyoto rats, (1) arterial baroreflex regulation of renal sympathetic nerve activity was reset to a higher arterial pressure and the gain was decreased and (2) cardiac baroreflex regulation of renal sympathetic nerve activity exhibited a lower gain. With the use of sympathetic peak detection analysis, the inhibition of integrated renal sympathetic nerve activity, which occurred during both increased arterial pressure (arterial baroreflex) and right atrial pressure (cardiac baroreflex), was due to parallel decreases in peak height with little change in peak frequency in both spontaneously hypertensive and Wistar-Kyoto rats. Arterial and cardiac baroreflex inhibition of renal sympathetic nerve activity in Wistar-Kyoto and spontaneously hypertensive rats is due to a parallel reduction in the number of active renal sympathetic nerve fibers.

Reflex influences on renal nerve activity characteristics in nephrosis and heart failure.

Cardiac baroreflex regulation of efferent renal sympathetic nerve activity (ERSNA) is abnormal in nephrotic syndrome (NS). The purpose of the present study was to examine the responses of amplitude and frequency of synchronized ERSNA discharge in anesthetized NS rats subjected to reflex maneuvers that alter the activity of and the interaction between aortic and cardiac baroreceptors. Steady-state ERSNA was analyzed in three groups of anesthetized rats: control, NS, and congestive heart failure (CHF) (in the latter, the defect in cardiac baroreflex regulation of ERSNA is peripheral rather than central). In protocol A, analysis was performed during control, after bilateral aortic depressor nerve section, after bilateral cervical vagus nerve section, and during central vagus nerve stimulation (VAGSTIM). In protocol B, analysis was performed during control, after bilateral cervical vagus nerve section, after bilateral aortic depressor nerve section, and during central aortic depressor nerve stimulation. In protocol A, VAGSTIM decreased ERSNA and peak height (fewer active fibers), but not peak frequency, in control and CHF but not NS rats. In NS rats, this lack of effect of VAGSTIM was specific for ERSNA, because depressor and bradycardia responses to VAGSTIM were unaffected. In protocol B, central aortic depressor nerve stimulation decreased ERSNA and peak height, but not peak frequency, in control, CHF, and NS rats similarly. It is concluded that the defect in cardiac baroreflex function in NS is specific for ERSNA, is central rather than peripheral, and affects the number of active renal sympathetic nerve fibers rather than their firing frequency.

Cardiopulmonary baroreflex in NaCl-induced hypertension in borderline hypertensive rats.

Borderline hypertensive rats fed an 8% NaCl diet develop increased arterial pressure in association with increased cardiopulmonary baroreflex sensitivity compared with rats fed a 1% NaCl diet. We performed experiments to localize the site of sensitization within the cardiopulmonary baroreflex. To determine whether decreased cardiopulmonary baroreflex sensitivity, as seen in other models of NaCl-induced hypertension, develops later in the course of the disease, we studied an older backcross population derived from borderline hypertensive rats and Wistar-Kyoto rats. Anesthetized borderline hypertensive rats fed 1% and 8% NaCl diets were volume-loaded while right atrial pressure, afferent vagal nerve activity, and renal sympathetic nerve activity were recorded. In 28- to 30-week-old backcross rats fed an 8% NaCl diet, renal sympathetic nerve activity, natriuresis, and diuresis were measured before and during volume loading. Renal sympathetic nerve activity was analyzed with the sympathetic peak detection algorithm. Increases in afferent vagal nerve activity and renal sympathoinhibition were similar in borderline hypertensive rats on either diet during a right atrial pressure rise of 3 mm Hg. In backcross rats, correlations between arterial pressure and renal sympathoinhibition, natriuresis, or diuresis were not found. During volume loading, the peak height of synchronized renal sympathetic nerve discharges decreased while their frequency increased. Attenuated renal sympathoinhibition during acute increases in intravascular volume is not involved in the development or maintenance of NaCl-induced hypertension in borderline hypertensive rats. Renal sympathetic nerve activity decreases because of a reduction in the number of active renal sympathetic nerve fibers.

Differentiated sympathetic neural control of the kidney.

Anatomic and neurophysiological methods were used to identify functionally specific subgroups of renal sympathetic nerve fibers. The distribution of diameters of the predominating unmyelinated fibers showed a major mode at 1.1 microns and a minor mode at 1.6 microns. The conduction velocity was 2.10 +/- 0.10 m/s, consistent with unmyelinated C fibers. Analysis of strength-duration relationships during renal nerve stimulation showed that both rheobase and chronaxie values for renal blood flow were greater than those for urinary flow rate and were independent of stimulation frequency. This difference suggests a higher stimulation threshold (smaller diameter) for those renal nerve fibers involved in the renal blood flow response (renal vasoconstriction) compared with those for the urinary flow rate response (antidiuresis) to renal nerve stimulation. Single renal units that responded to preganglionic splanchnic nerve stimulation were studied. Those with spontaneous activity (88%) responded to stimulation of arterial baroreceptors, arterial and central chemoreceptors, and peripheral thermoreceptors, whereas those that lacked spontaneous activity (12%) responded only to stimulation of peripheral thermoreceptors (known to produce renal vasoconstriction). A minority population of single renal units has been identified that, although renal vasoconstrictor, does not exhibit other characteristic features of vasoconstrictor neurons (i.e., responsiveness to stimulation of arterial baroreceptors and arterial and central chemoreceptors). These findings suggest the existence of functionally specific subgroups of renal nerve fibers.

Characteristics of renal sympathetic nerve activity in sodium-retaining disorders.

Characteristics of renal sympathetic nerve activity in conscious rats with established congestive heart failure, cirrhosis, or nephrotic syndrome were analyzed using three methods: mean integrated voltage over time, power spectrum analysis, and sympathetic peak detection analysis. Compared with control rats, all three disease models had increased mean integrated voltage. On power spectrum analysis, all three disease models had increased relative power at the heart rate frequency, indicating that it was related to renal sympathetic nerve discharge coupled to the cardiac cycle. Congestive heart failure and nephrotic syndrome rats showed increased relative power in the low-frequency range, whereas cirrhotic and nephrotic syndrome rats showed decreased relative power in the high-frequency range. On sympathetic peak detection analysis, the frequency of sympathetic peaks was greater in the three disease models compared with the control rats. In cirrhotic rats, the distribution of sympathetic peak heights was shifted toward an increased number of peaks of lesser height. It is concluded that basal renal sympathetic nerve activity is chronically increased in these disease models. This is manifest as increased power coupled to the cardiac cycle, which may reflect the disease-specific defects in arterial and cardiac baroreflex control. In cirrhosis, there is possible selective activation of a subgroup of renal sympathetic nerve fibers.

The effect of rANP on the efferent activity of the autonomic nerves.

It is well known that the Atrial Natriuretic Peptide (ANP) plays a major role in vasorelaxation and in lowering systolic blood pressure. However, little information is available concerning its effect on the autonomic outflows. The present study deals with the effect of rat ANP (rANP) on the efferent activity of the sympathetic and vagal outflows. Under anesthesia (urethane 700 mg/kg and chrolarose 50 mg/kg, intraperitoneal), the effect of intravenous administration of rANP was observed in rats. A suppression of the efferent activity was recognized after administration of rANP in adrenal, renal and splenic sympathetic nerve fibers, and also in vagal gastric, pancreatic and hepatic nerve fibers. The smallest effective dose was 100 pg. In decerebrated preparations no change in efferent activity after administration of rANP was recognizable. The results indicate that rANP released from the atrium to systemic circulation modulates autonomic outflows through the hypothalamic neurons surrounded by an insufficient blood brain barrier.