Renal Denervation

Introduction

Hypertension is a leading cause of death worldwide, with 13% of all deaths attributed to it in 2004 (World Health Organization, 2009). A prevalence of 29% (1.56 billion) has been predicted for 2025. In the United States, approximately 65 million individuals have hypertension. It is associated with cardiovascular and cerebrovascular morbidity and mortality with a direct relationship of blood pressure and event risk. Antihypertensive therapy has been shown to reduce strokes, heart attacks, and cardiovascular deaths. However, some patients' blood pressures remain in a suboptimal range despite multi-drug antihypertensive therapy. If the blood pressure remains below target despite ≥3 antihypertensive medications of different classes, one of which optimally should be a diuretic, or requires ≥4 antihypertensive medications for adequate control, it is generally considered to be “resistant.” The reported prevalence of resistant hypertension varies widely depending on definitions used and populations studied. In some nonpopulation-based tertiary referral studies and clinical trials, the prevalence ranges between 12% and 34%. In population-based studies, the reported prevalence is lower. For example, in the National Health and Nutrition Examination Surveys (NHANES) it was 9% and, in a population study from northern California and Colorado, 2%. Risk factors for developing resistant hypertension include male gender, age, diabetes, obesity, chronic kidney disease, and Framingham10-year coronary risk >20%. Importantly, patients with resistant hypertension have a higher risk for cardiovascular events. The sympathetic nervous system plays a substantial role in develop­ment and maintenance of resistant hypertension and has recently been the target of catheter-based intervention. In this context, the physiology of the renal sympathetic nervous system, the role in hypertension, and the effects and techniques of interrupting the renal sympathetic nervous system are discussed.

Role of the Kidney in Hypertension

Before reviewing the specifics of the renal sympathetic nervous system in blood pressure regulation, an important concept should be mentioned first: Kidneys have a dominant role in blood pressure control. This has been shown by kidney cross-transplantation. When kidneys from hypertensive rats are removed and implanted into normotensive rats and vice versa, normotensive rats become hypertensive and hypertensive rats normotensive. It is, therefore, the kidney and not the host that primarily determines blood pressure. The kidneys' ability to regulate blood pressure can take place (regardless of external influences) by the principle of pressure natriuresis. It is the ability to conserve or excrete sodium and water to an extent that maintains blood pressure at an intrinsic goal unique to the kidney. In support of this concept, when kidneys are isolated from external influences by denervation, bilateral adrenalectomy, and continuous infusion of high doses of catecholamines and glucocorticoids, cross clamping the aorta (thereby increasing perfusion pressure of the kidneys) causes pronounced natriuresis and diuresis. Hence, the kidneys largely determine blood pressure by maintaining an intrinsic blood pressure goal by pressure natriuresis. Though this can be achieved in the absence of external influences, external signals can change the intrinsic blood pressure goal. One such signal comes from the renal sympathetic nervous system.

Anatomy and Physiology of the Renal Sympathetic Nervous System

Every component of the kidney is supplied by efferent sympathetic nerve fibers. Equally important, the kidneys send signals to the central nervous system via afferent sympathetic fibers.

Efferent Fibers ( Figure 22-1 )

Signals from the central nervous system (amygdala, ventrolateral nucleus of the hypothalamus, cortex, pons) and chemo- and baroreceptors are integrated in the medulla oblongata (solitary tract nucleus and rostral ventral medulla oblongata) from where sympathetic nerve fibers course within the spinal cord to the intermediolateral nucleus (Th10-L2). In the intermediolateral nucleus, signals are relayed to presynaptic fibers that exit the spinal cord and terminate at postsynaptic fibers in the celiac, superior, and inferior mesenteric ganglion. Postsynaptic fibers (located predominantly within the adventitia of the renal arteries) supply the tubuloepithelial cells, granular cells of the juxtaglomerular apparatus, and arteriolar smooth muscle cells. Norepinephrine and neuropeptide Y are released ( Figure 22-2 ). Norepinephrine binds to both alpha-1b receptors and beta-receptors (located in the adluminal membrane of the tubuloepithelial cells ) causing stimulation and inhibition of the sodium/potassium ATPase, respectively, with an overall neutral effect. However, neuropeptide Y enhances the stimulatory effect of norepinephrine. The net effect is a stimulation of the sodium/potassium ATPase causing sodium and water retention and a blood pressure increase. At the granular cells of the juxtaglomerular apparatus, norepinephrine binds to beta-1 receptors, causing G-protein-coupled activation of adenyl cyclase, generating cyclic AMP that stimulates renin release ( Figure 22-3 ). Renin causes activation of the renin angiotensin system, generating angiotensin II and aldosterone and causing vasoconstriction and sodium and water retention, respectively, with subsequent blood pressure increase. Hormones of the angiotensin-aldosterone system also cause vascular remodeling and changes in cardiac architecture such as left ventricular hypertrophy and fibrosis. At arteriolar smooth muscle cells, norepinephrine binds to alpha-1a receptors and (via G-protein-coupled mechanism) activates phospholipase C, releasing inositol trisphosphate and diacylglycerol ( Figure 22-4 ). Inositol trisphosphate stimulates calcium release from the sarcoplasmic reticulum that binds to the contractile apparatus, triggering smooth muscle contraction and vasoconstriction.

Animal and Human Data Supporting a Link Between the Renal Sympathetic Nervous System and Hypertension

Several pivotal animal experiments, in addition to those previously described, warrant mention. Direct stimulation of the splanchnic nerve in a dog model causes a blood pressure increase, whereas interruption of the renal sympathetic fibers (by removal and re-implantation of the kidneys) causes diuresis and blood pressure reduction. Similarly, splanchnic nerve transection causes natriuresis and diuresis. An increase in blood pressure seen in the Goldblatt model of a single kidney supplied by a stenotic artery or in the Goldblatt two kidneys, one clip model (only one of the renal arteries has a stenosis in this model), can be attenuated by denervation of the clipped renal artery. Hypertension in a rat model caused by renal injury, for example, by intrarenal phenol injection, can be attenuated by renal sympathetic denervation. Comparison of genetically spontaneous hypertensive rats with genetically normotensive rats identified increased renal sympathetic nerve activity in the hypertensive rats. Renal denervation in spontaneous hypertensive rats was shown to delay the onset of hypertension and to mitigate the hypertensive response. It is noteworthy that hypertension returned to spontaneously hypertensive because of re-innervation of renal sympathetic nerves but was again attenuated by repeat denervation. Renal denervation in other animal hypertensive models, including other rats, dogs, pigs, and rabbits, has also been shown to prevent or delay the development of hypertension and diminish the severity of hypertension.

In humans, the sympathetic nervous system has been shown to play an important role in the pathogenesis and maintenance of hypertension. Increased plasma catecholamine levels have been shown in borderline hypertension and in young patients with hypertension. However, the plasma catecholamine concentrations are not universally elevated. Particularly in older hypertensive patients, levels similar to normotensive individuals have been reported. Plasma catecholamine concentrations depend not only on its release at the nerve terminals but also on metabolism and reuptake. In addition, differences in sympathetic nerve activity between end organs have been demonstrated ; therefore, it may not consistently reflect overall and regional sympathetic nervous system activity. Instead, muscle sympathetic nervous system activity and norepinephrine spillover measurements are more reliable indicators of overall and regional sympathetic tone. In this context, compared with normotensive individuals, higher muscle sympathetic nerve activity and reduced norepinephrine reuptake have been described in hypertensive patients. Increased sympathetic nerve activity has also been identified in individuals with secondary hypertension related to renal artery stenosis, obesity, and obstructive sleep apnea.

The consequences of interrupting the renal sympathetic nervous system on blood pressure have also been demonstrated in humans. The increased sympathetic tone in patients with chronic kidney disease requiring dialysis normalizes following bilateral nephrectomy. The increased sympathetic activity persists following kidney transplant if the native kidneys remain. Blood pressure reductions following nephrectomy in patients with kidney disease including those with unilateral disease and single nephrectomy (e.g., for pyelonephritis or congenital hypoplasia) and in patients with bilateral disease and bilateral nephrectomy have been reported. Though the improvements in blood pressure control could be explained by elimination of sympathetic signals to and from the diseased kidneys, it is also possible that explantation of the diseased kidneys causes the blood pressure improvement by a reduction in renin-angiotensin-aldosterone system activity that is typically increased in patients with chronic kidney disease whose kidneys remain in place. However, the renal sympathetic nervous system appears to have a greater impact. For example, patients with chronic kidney disease generally experience a greater blood pressure reduction with central sympatholytic therapy (e.g., clonidine) than with blockade of the renin-angiotensin system. The mechanism for increased renal sympathetic activity is unclear but could be related to renal ischemia as sympathetic nervous system activity decreases following angioplasty in patients with renal artery stenosis. Blood pressure has also been shown to improve following unilateral nephrectomy in patients with renal artery stenosis.

Surgical sympathectomy provides further insight into the role of the renal sympathetic nervous system in hypertension control. It was used to treat severe hypertension until the1970s and involved resection of distal thoracic and proximal lumbar sympathetic ganglia and bilateral splanchnic nerve transection. The surgery was accompanied by dramatic blood pressure and mortality reductions compared with control groups. Further, improvements in cardiac size, precordial pain, renal function, cerebrovascular events, and headaches were reported. However, these studies were uncontrolled, nonrandomized comparisons subject to a number of limitations related to placebo effect, Hawthorne effect, selection bias, and patient and operator bias. Operative morbidity and mortality together with the advent of novel antihypertensive agents led to the discontinuation of surgical sympathectomy for the treatment of hypertension in the 1970s. Nonetheless, the results further support the importance of the renal sympathetic nervous system in the pathogenesis of hypertension and potential benefits after sympathectomy.

Percutaneous Renal Sympathetic Denervation

The aforementioned physiological and clinical observations underlining the importance of the renal sympathetic nervous system in blood pressure control and the convenient location of the sympathetic nerve fibers (predominantly in the renal artery adventitia and perivascular space) led to the concept and evaluation of catheter-based renal sympathetic denervation by radiofrequency application. The efficacy and safety were first assessed in pigs. Renal denervation using the Symplicity Flex Renal Denervation System (Medtronic Inc., Minneapolis, Minnesota) ( Figure 22-5 ) was accompanied by histological evidence of neuronal injury in the perivascular space of the renal artery, as well as a reduction in sympathetic axons in the renal cortex (by tyrosine hydroxylase staining) and a 90% reduction in renal norepinephrine concentration (unpublished report by Medtronic). Optical coherence tomography (OCT) examination of the renal artery after renal denervation in a pig demonstrated endothelial denudation, transmural tissue coagulation followed by tissue fibrosis, and re-endothelialization and renal nerve necrosis 10 days after ablation. Six months after ablation, histology demonstrated necrotic nerve fibers and fibrosis involving 10% to 25% of the media and adventitia without stenosis.

In Symplicity-1, 45 patients with severe resistant hypertension underwent radiofrequency renal sympathetic denervation. A significant 27/17 mm Hg 1-year office blood pressure reduction was observed. An increase in antihypertensive therapy occurred in four patients; however, a significant and pronounced blood pressure reduction remained after excluding these patients from analysis. In addition, blood pressure medications were reduced in nine patients due to improved blood pressure control. Thirteen percent of patients were considered nonresponders (defined as systolic blood pressure reduction of <10 mm Hg). Ambulatory blood pressure reductions were less pronounced (11 mm Hg systolic) than office blood pressures, a common theme in all subsequent studies examining renal denervation.

Renal and total body norepinephrine spillover decreased after renal denervation (n = 10), supporting the notion that renal denervation reduces renal and overall sympathetic nervous system activity. A reduction in overall sympathetic tone assessed by muscle sympathetic nerve activity has been demonstrated in one patient from Symplicity HTN-1 and subsequently in a separate study. One guide catheter–induced renal artery dissection requiring stenting and one femoral artery pseudoaneurysm were reported.

In a registry including Symplicity HTN-1 patients and others, office blood pressure reductions were durable, 33/14 mm Hg at 24 months and 32/14 mm Hg at 36 months (n = 87), regardless of age, diabetic status, or baseline renal function. Furthermore, the responder rate increased over time from 70% at 1 month to 93% at 36 months. One de novo renal artery stenosis possibly related to renal denervation requiring stenting, one renal artery stenosis at a site remote from the treatment site (with some degree of preexistent stenosis) requiring stenting, and two hemodynamically insignificant mild renal artery stenoses were reported throughout the 36-month follow-up.

In Symplicity HTN-2 (n = 106), patients with severe resistant hypertension were randomized to renal sympathetic denervation (in addition to conventional medical therapy) or conventional medical therapy alone. There was a significant 32/12 mm Hg office blood pressure reduction in the denervation group versus none in the control group at 6 months with a responder rate of 84% (vs. 35% in the control group). The ambulatory pressure (11/7 mm Hg) was, once again, less pronounced than the office blood pressure reduction after renal denervation; however, it remained significant (vs. no change in the control group). There were no major adverse events. No changes in renal function or urine albumin to creatinine ratios were seen in either group. Forty-six patients from the control group crossed over to renal denervation and experienced a significant 24/8 mm Hg blood pressure reduction 6 months after cross-over. In addition, a lasting 33/14 mm Hg reduction in office blood pressure has been demonstrated in those 40 patients of the initial group who underwent 36-month follow-up.

Renal denervation has more recently been studied in a small number (n = 20) of patients with milder forms of resistant hypertension (systolic office blood pressure 140 to 160 mm Hg) with significant 13/5 mm Hg office and 11/4 mm Hg ambulatory blood pressure reductions at 6 months. Similar findings were reported subsequently in 54 patients with mild resistant hypertension with 13/7 mm Hg and 14/7 mm Hg office and ambulatory blood pressure reductions at 6 months. Therefore, it appears that hypertension severity predicts the magnitude of response.