The Role of Renal Sympathetic Nerves in Hypertension: Has Percutaneous Renal Denervation Refocused Attention on Their Clinical Significance?

doi:10.1016/j.pcad.2009.09.003

Progress in Cardiovascular Diseases

Volume 52, Issue 3, November–December 2009, Pages 243-248

https://doi.org/10.1016/j.pcad.2009.09.003 Get rights and content

Abstract

Renal sympathetic efferent and afferent nerves, which lie within and immediately adjacent to the wall of the renal artery, contribute to the pathogenesis of hypertension. Because the causative factors of hypertension change over time, denervation of both efferent and afferent nerves should result in long-term attenuation of the hypertension. The importance of the renal nerves in patients with hypertension can now be defined with the novel development of percutaneous minimally invasive renal denervation from within the renal artery using radiofrequency energy as a therapeutic strategy. Studies thus far show that catheter-based renal denervation in patients with refractory hypertension lowers systolic blood pressure 27 mm Hg by 12 months with estimated glomerular filtration rate remaining stable. An attenuation of hypertension of this magnitude by catheter-based renal sympathetic denervation in combination with pharmacologic therapy is likely to be valuable in decreasing the risks of stroke, left ventricular hypertrophy, heart failure, and chronic renal failure.

Section snippets

Background and overview

Despite advances in the diagnosis, treatment, and public awareness of hypertension, its continued impact on cardiovascular health continues to command global attention.¹ Hypertension is a major risk factor for stroke, coronary heart disease, heart failure, vascular disease, and chronic renal failure. The kidney plays an essential role in the regulation of blood pressure through sodium, volume, renin modulation, and renal-sympathetic neuronal interactions. Importantly, experimental animal models

Efferent renal nerves in the pathogenesis of hypertension

Mammalian kidneys are richly innervated with postganglionic sympathetic fibers to the afferent and efferent renal arterioles, juxtaglomerular apparatus, proximal renal tubule, loop of Henle, and distal renal tubule. Accordingly, the efferent renal sympathetic nerves can affect control of renal vascular resistance and increase renin release; they have also been shown to regulate sodium and water excretion both by producing arteriolar vasoconstriction, resulting in a change in intrarenal

Renal sensory afferent nerve activity in the pathogenesis of hypertension

Increasing evidence indicates that the kidney is a sensory organ.2, 3, 4, 15, 18, 19 Mechanoreceptors and chemoreceptors have been demonstrated in the kidney. Mechanoreceptors are located both in the renal cortex and in the renal pelvis, whereas chemoreceptive nerve endings are found primarily in the submucosal layers of the renal pelvis. Studies have shown that the renal nerves contain multiple afferent unmyelinated fibers that carry impulses centrally from various renal receptors. There is

Endovascular renal denervation as a therapeutic approach in humans

A recent proof-of-concept trial has demonstrated that the application of discrete low-dose radiofrequency energy to the renal artery endothelial surface via a minimally invasive percutaneous catheter-based procedure results in the effective ablation of sympathetic nerve fibers.⁵ These investigators delivered the treatment catheter (Simplicity Catheter; Ardian Inc, Palo Alto, Calif) via a guiding catheter, introduced through common femoral artery, to apply up to 6 radiofrequency ablations of up

Conclusions and clinical implications

There is much evidence to suggest roles for both renal efferent sympathetic activity and renal sensory afferent nerve activity in patients with hypertension.2, 3, 4 The relative contribution of the renal nerves to hypertension changes during the evolution of all hypertensive processes. The varying contribution of the renal nerves is likely due to interaction with and influence of other factors (renin-angiotensin system activity, sodium, volume, and sympathetic nervous system activity) to

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

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Cited by (27)

Renal Denervation: A Revival or The Same Old Story
2021, Heart Lung and Circulation
Citation Excerpt :
The kidneys are richly innervated by sympathetic nerves, which makes them susceptible to receiving a disproportionately greater amount of sympathetic activation compared to other organs. This abnormal renal sympathetic nerve activity has been proposed to contribute to the pathogenesis of hypertension through alterations in renal vascular resistance, release of renin, and sodium and water reabsorption [9]. The increased renal sympathetic outflow can be quantified by measuring plasma norepinephrine levels and has been shown to be higher in hypertensive individuals [10].
Despite well-established pharmacological treatment, hypertension has remained a large contributor to noncommunicable deaths. Given the well-known association of hypertension with adverse cardiovascular disease the importance of blood pressure control has never been more crucial. Traditionally, pharmacological management has been the mainstay of care, however, with a growing burden of disease alternative and innovative approaches are now being considered. Minimally invasive catheter-based ablation systems, targeting renal sympathetic nerves, has been proposed as a more permanent way to control blood pressure. However, the clinical data supporting renal denervation has had many rises and falls throughout the years. With the promising results of the recent second-generation clinical trials there has been a renewed area of interest for renal denervation in the treatment of hypertension.
Hypotensive effects of renal denervation in spontaneously hypertensive rat based on ultrasonic contrast imaging
2017, Computerized Medical Imaging and Graphics
Citation Excerpt :
The technique using radiotracer-driven measurements of the appearance rates of norepinephrine in different organs has revealed a disproportionate increase in sympathetic activity to the heart and kidneys in hypertension, with half of the increase in noradrenaline being accounted for by the increased SNA to the heart and the kidneys (Malpas et al., 2006). Thus, disruption of sympathetic nerves and renal sympathetic nerves has long been considered an attractive therapeutic target for hypertension (Katholia et al., 2009). Catheter-based renal sympathetic denervation (RSD) for resistant hypertension received great attention when the safety and proof-of-principle study was published in 2009 showing a marked BP lowering effect and only few complications (Krum et al., 2009).
Sympathetic nerves-fire rate is generally enhanced in some types of hypertension models. Renal sympathetic denervation(RSD) by the radiofrequency ablation was used to treat the hypertension has achieved curative effect.HTN-1 and HTN-2 trial reported catheter-based renal denervation may cause substantial and sustained blood-pressure reduction in patients with resistant hypertension. However, recent controlled HTN-3 trial questioned the BP lowering effect of Renal denervation treatment. The controversial results maybe arised from the incompleted RSD which implemented inside the renal artery. Now renal denervation therapy for resistant hypertension is in attractive and controversial status. Our aim is to define the hyotensive value of complete renal denervation in adult spontaneous hypertensive rats.
Male spontaneous hypertensive rats(SHR) aged 12 weeks were randomly selected for either unilateral renal artery sympathetic nerves ablation (URSNA), or conventional technique of renal denervation (CRD), or bilateral renal artery sympathetic nerves ablation (BRSNA) and sham operation. Blood pressure, sodium and water balance,serum reninangiotensin II and Norepinephrine concentration were measured during 20 weeks after renal denervation operation. Internal diameters of renal arteries and renal blood flow rate was tested by ultrasonic contrast imaging.
The continued increased blood pressure in SHR was delayed and significantly reduced by conventional renal denervation over a period of 8 weeks. Both the bilateral and unilateral renal sympathetic nerve ablation procedure did not prevent the development of hypertension in SHR. The attenuation of hypertension was accompanied with the increase of urinary sodium excretion and depression of rennin angiotensin system (RAS).
We concluded that renal denervation may not be an effective therapeutic method in the long-term control of hypertension in adult SHR.
Anatomical eligibility of the renal vasculature for catheter-based renal denervation in hypertensive patients
2014, JACC: Cardiovascular Interventions
This study sought to determine the vascular anatomical eligibility for catheter-based renal artery denervation (RDN) in hypertensive patients.
Arterial hypertension is the leading cardiovascular risk factor for stroke and mortality globally. Despite substantial advances in drug-based treatment, many patients do not achieve target blood pressure levels. To improve the number of controlled patients, novel procedure- and device-based strategies have been developed. RDN is among the most promising novel techniques. However, there are few data on the vascular anatomical eligibility.
We retrospectively analyzed 941 consecutive hypertensive patients undergoing coronary angiography and selective renal artery angiography between January 1, 2010, and May 31, 2012. Additional renal arteries were divided into 2 groups: hilar (accessory) and polar (aberrant) arteries. Anatomical eligibility for RDN was defined according to the current guidelines: absence of renal artery stenosis, renal artery diameter ≥4 mm, renal artery length ≥20 mm, and only 1 principal renal artery.
A total of 934 hypertensive patients were evaluable. The prevalence of renal artery stenosis was 10% (n = 90). Of the remaining 844 patients without renal artery stenosis, 727 (86%) had nonresistant hypertension and 117 (14%) had resistant hypertension; 62 (53%) of the resistant hypertensive and 381 (52%) of the nonresistant hypertensive patients were anatomically eligible for sympathetic RDN.
The vascular anatomical eligibility criteria of the current guidelines are a major limiting factor for the utilization of RDN as a therapeutic option. Development of new devices and/or techniques may significantly increase the number of candidates for these promising therapeutic options.
Renal nerve stimulation for the treatment of neurocardiogenic syncope
2013, Cardiovascular Revascularization Medicine
Citation Excerpt :
There is a pressing need for more effective treatment strategies that address both pathophysiologic mechanisms; both on the heart and on the vasculature. Renal vessels are richly innervated by afferent and efferent renal sympathetic nerves [4] which, when stimulated, raise blood pressure through vasoconstriction and are therefore a potential target for treatment of neurocardiogenic syncope. In order to assess the efficacy of renal sympathetic nerve stimulation to increase systemic blood pressure, we performed studies of renal nerve stimulation in 5 dogs and 1 baboon using a 4-mm quadripolar catheter in the renal vein (Fig. 1) with a Grass stimulator (square wave, 120 V, 900 pps, 30–200 s, Grass Technologies).
Neurocardiogenic syncope is a common disorder resulting from a transient increase in vagal tone and central sympathetic withdrawal leading to varying degrees of vasodilation and bradycardia. Hence an effective treatment should address both the bradycardia and vasodilation. We hypothesized that, stimulation of the renal sympathetic nerves using high frequency stimulation in the renal vein will increase blood pressure through an increase in sympathetic output and therefore may be of use in treating neurocardiogenic syncope. Renal nerve stimulation was performed under Isoflurane anesthesia in 5 dogs and 1 baboon using a 4 mm quadripolar catheter in unilateral renal vein using a Grass stimulator (square wave, 120 V, 900 pps, 30–200 s). A consistent increase in arterial systolic BP [mean (SD) pre- vs peak-stimulation 103 (± 27) vs. 122 (± 41) mmHg] and diastolic BP [69 (± 19) vs. 82 (± 31) mmHg] was noted during stimulation. Median interquartile change in systolic BP was 11 (5–22) mmHg and 6 (− 2–16) mmHg in diastolic BP. To conclude, renal nerve stimulation through the renal vein increased BP. Potential applications include treatment of vasodilatory component of neurocardiogenic syncope and confirmation of successful renal nerve ablation for the treatment of hypertension.
Renal denervation using an irrigated radiofrequency ablation catheter for management of drug-resistant hypertension: A demonstrated value?
2012, JACC: Cardiovascular Interventions
Renal Vascular Disease: A Vexing Challenge for the Clinician
2009, Progress in Cardiovascular Diseases

View all citing articles on Scopus

: Statement of Conflict of Interest: see page 248.

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The Role of Renal Sympathetic Nerves in Hypertension: Has Percutaneous Renal Denervation Refocused Attention on Their Clinical Significance?

Abstract

Section snippets

Background and overview

Efferent renal nerves in the pathogenesis of hypertension

Renal sensory afferent nerve activity in the pathogenesis of hypertension

Endovascular renal denervation as a therapeutic approach in humans

Conclusions and clinical implications

Statement of Conflict of Interest

Lancet

Am J Kidney Dis

Am J Hypertension

Lancet

Am J Med

Renal nerves in the pathogenesis of hypertension in experimental animals and humans

Am J Physiol

Renal nerves and hypertension: an update

Fed Proc

Sympathetic nervous system and the kidney in hypertension

Curr Opin Nephrol Hypertension

Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study

Lancet

Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption

J Clin Invest

Neural control of renal function

Physiol Rev

Neural control of the kidney: past, present and future

Hypertension

Neural control of renal circulation

Miner Electrolyte Metab

Sympathetic modulation of renal hemodynamics, renin release and sodium excretion

Klin Wochenschr

Neural regulation of renin release: experimental evidence and clinical implications in arterial hypertension

Circulation

Role of renal nerves for the expression of renin in adult rat kidney

Am J Physiol

Arterial chemoreceptors and sympathetic nerve activity: implications for hypertension and heart failure

Hypertension