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Cardiology Research and Practice
Volume 2012 (2012), Article ID 319432, 8 pages
http://dx.doi.org/10.1155/2012/319432
Review Article

Cardiovascular Risk in Chronic Kidney Disease: Role of the Sympathetic Nervous System

1Renal Division, Department of Medicine, Emory University School of Medicine, 1639 Pierce Drive, WMB 338, Atlanta, GA 30322, USA
2Research Service, Department of Veterans Affairs Medical Center, Decatur, GA 30033, USA

Received 19 May 2012; Accepted 24 June 2012

Academic Editor: Kazuko Masuo

Copyright © 2012 Jeanie Park. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Patients with chronic kidney disease are at significantly increased risk for cardiovascular disease and sudden cardiac death. One mechanism underlying increased cardiovascular risk in patients with renal failure includes overactivation of the sympathetic nervous system (SNS). Multiple human and animal studies have shown that central sympathetic outflow is chronically elevated in patients with both end-stage renal disease (ESRD) and chronic kidney disease (CKD). SNS overactivation, in turn, increases the risk of cardiovascular disease and sudden death by increasing arterial blood pressure, arrythmogenicity, left ventricular hypertrophy, and coronary vasoconstriction and contributes to the progression renal disease. This paper will examine the evidence for SNS overactivation in renal failure from both human and experimental studies and discuss mechanisms of SNS overactivity in CKD and therapeutic implications.

1. Introduction

Patients with chronic renal failure are at profoundly higher risk for cardiovascular (CV) morbidity and mortality. Multiple epidemiologic studies have demonstrated that both reduced renal function and proteinuria are significantly and independently associated with an increased risk of CV death [15]. In multivariate adjusted analyses, patients with end-stage renal disease (ESRD) had a 10 to 20-fold higher risk of CV mortality [35]. Such increases in CV risk are not limited to patients with the most advanced renal disease on dialysis. Those with mild-to-moderate chronic kidney disease (CKD) are also at significantly higher risk of CV disease [1, 2], and patients with both overt proteinuria as well as microalbuminuria without a reduction in estimated glomerular filtration rate (eGFR) are also at significantly higher risk [2]. Thus, reduced renal function and proteinuria are powerful and independent risk factors for CV disease and mortality.

The nature of CV disease in patients with renal failure differs from that of the general population. Whereas the most common manifestations of CV disease in the general population include coronary atherosclerotic disease, patients with renal failure are far more likely to suffer from chronic heart failure and sudden cardiac death [3, 6]. Sudden cardiac death is the leading cause of death in ESRD patients, and accounts for approximately 25% of all deaths in this population [7]. In addition, the clinical presentation of CV disease is also different amongst those with renal disease when compared to the general population. For example, CKD patients with acute myocardial infarction are more likely to present with atypical symptoms and shortness of breath than with more typical symptoms [8]. Thus, the pathophysiology of increased CV disease risk in CKD likely differs from that of the general population and may include factors that are specific to the diseased or ischemic kidneys.

The mechanisms underlying CV risk in CKD are multifactorial and begin early in the course of renal disease. Not only are traditional CV risk factors such as hypertension and diabetes highly prevalent in the CKD population, but nontraditional risk factors specific to CKD and ESRD patients are also highly prevalent and contribute to risk [9]. These include oxidative stress, inflammation, decreased nitric oxide (NO) bioavailability, anemia, extracellular volume overload, fluid and electrolyte shifts, malnutrition, abnormal calcium and phosphorus metabolism, infection, uremic toxins, as well as sympathetic nervous system (SNS) overactivity. Multiple human and animal studies have clearly demonstrated that CKD is a state of SNS overactivity [1013]. SNS overactivity contributes to increased risk of CV disease and sudden death by increasing blood pressure, arrythmogenicity, left ventricular hypertrophy, coronary vasoconstriction, and end-organ damage [14, 15]. Moreover, sympathetic overactivity is directly associated with an increased risk of CV mortality in patients with ESRD [16] and correlates with left ventricular hypertrophy (LVH) in this population [17]. The remainder of this paper will focus on mechanisms by which SNS overactivity increases CV risk, the evidence for SNS overactivation in renal failure, potential mechanisms of chronic sympathoexcitation in CKD (Figure 1), and therapeutic considerations.

319432.fig.001
Figure 1: Pathogenesis of sympathetic overactivity in chronic kidney Disease factors contributing to increased sympathetic nervous system (SNS) activity in chronic renal failure, leading to increased cardiovascular (CV) risk. ADMA refers to asymmetric dimethylarginine. NO refers to nitric oxide. Ang II refers to angiotensin II. LVH refers to left ventricular hypertrophy.

2. SNS Overactivity Accelerates CV Risk and End-Organ Damage

Epidemiologic studies have demonstrated that SNS overactivity is independently associated with an increased risk of cardiovascular mortality in patients with renal failure and other disease states [14, 16, 18, 19]. The mechanisms by which chronic SNS overactivation leads to increased CV risk have not been fully elucidated. One potential mechanism is indirect, via increased blood pressure induced by alpha-adrenergic vasoconstriction that leads to an increase in total peripheral resistance. However, there is evidence to suggest that SNS activation itself plays a direct role in increasing CV risk and may accelerate end-organ damage at the level of the heart, vasculature, and kidney [14, 1820]. SNS overactivity is closely linked to the development and progression of chronic heart failure (CHF) [21, 22]. Patients with CHF have elevated levels of plasma NE and MSNA [22, 23], and in animal models, chronic infusion of norepinephrine caused increases in left ventricular weight [19, 24], that were independent of changes in blood pressure, implicating a causal link between SNS overactivity and LVH. In addition, SNS activity has been shown to have a proinflammatory and profibrotic effect on the heart and vasculature [14, 19, 25, 26]. At the level of the vasculature, SNS activation leads to structural changes including arteriolar remodeling and vascular hypertrophy [14, 18, 27], as well as functional reductions in arterial distensibility [28]. SNS activation has also been shown to increase vascular oxidative stress [29], increase arrhythmogenicity [15], and contributes to hyperinsulinemia and insulin resistance [30], further mechanisms by which SNS overactivity contributes to increased CV risk.

Chronic SNS activation likely also plays a role in the progression of chronic kidney disease. Sympathetic innervation of the kidney increases renovascular tone, and leads to activation of the renin-angiotensin aldosterone system, and increased sodium reabsorption, that contributes to extracellular fluid volume expansion and increased BP. SNS activation also contributes to progression of glomerulosclerosis and proteinuria [14, 20, 31, 32]. In subtotally nephrectomized rats, the central sympatholytic drug, moxonidine, given at nonhypotensive doses reduced renal sympathetic nerve activity with concomitant reduction in glomerulosclerosis [20]. In humans, nonhypotensive doses of moxonidine improved urinary albumin excretion in diabetics and hypertensive patients [31, 32]. Together, these data provide evidence that SNS activation contributes to increased CV risk and progression of renal disease, via both BP-dependent and independent mechanisms at the level of the vasculature, myocardium, and kidney.

3. Evidence for Chronic SNS Overactivation in Renal Failure

Studies in humans and animals have provided convincing evidence that chronic renal failure is characterized by SNS overactivity. Plasma norepinephrine levels have been shown to be significantly elevated in patients with ESRD, roughly two-fold higher than in controls [33, 34], and are also elevated in hypertensive CKD patients [35]. Human studies using direct measurements of sympathetic nerve activity directed to muscle (MSNA) via microneurography have shown that SNS activity is chronically elevated in patients with ESRD [13, 36, 37]. SNS overactivity is a feature of earlier stages of CKD as well, and in a stepwise fashion, MSNA increases with worsening eGFR [10, 11, 35, 38]. In an animal model of chronic renal failure induced via 5/6 nephrectomy, the increase in blood pressure was accompanied by increases in NE turnover in areas of the brain responsible for sympathetic regulation, suggesting that elevated BP in CKD is in part mediated via SNS activation [39, 40]. In addition, renal injury without a reduction in eGFR appears to be sufficient in leading to SNS overactivity. In rats, phenol injection into the lower pole of one kidney induces a minimal renal injury without a reduction in eGFR, but results in an immediate increase in blood pressure, NE turnover in the brain, and renal sympathetic nerve activity [4143]. Similarly, hypertensive humans with polycystic kidney disease (PCKD) but without reduction in eGFR had significantly increased levels of MSNA [44].

4. Mechanisms of SNS Overactivity in CKD

4.1. Renal Afferent Nerves

The kidney functions as a sensory organ that is richly innervated with chemoreceptors and baroreceptors [45]. These renal afferent nerves connect with centers in the brain that regulate blood pressure and central sympathetic outflow. Animal studies have highlighted the importance of the renal afferent nerves in the pathogenesis of SNS overactivity and high blood pressure in renal failure. In 5/6th nephrectomized rats, the increase in blood pressure was accompanied by increased NE turnover in the areas of the brain responsible for sympathetic regulation, including the posterior, anterior, and lateral hypothalamic nuclei and the locus ceruleus [39]. In animal models, selective renal afferent nerve denervation can be performed with a dorsal rhizotomy, in which the dorsal roots from T10-L2 are severed, selectively denervating the renal afferent nerves while leaving the efferent nerves intact. Dorsal rhizotomy in 5/6 nephrectomized rats prevented the increase in BP and NE turnover in the posterior and lateral hypothalamic nuclei and the locus ceruleus, suggesting that renal afferent nerve activation by the diseased kidneys modulates central SNS activity in rats with chronic renal failure [39]. Furthermore, in the phenol renal injury model of minimal renal damage without a reduction in renal function, the elevation in blood pressure is concomitant with increased NE turnover in sympathetic brain centers, and increase in renal sympathetic nerve activity [4143]. Again, renal afferent denervation by dorsal rhizotomy normalized blood pressure, NE turnover in the brain, and renal sympathetic nerve activity, in the phenol renal injury model. Thus, renal injury, independent of renal function, activates central SNS outflow via renal afferent nerve activation.

Human studies using direct recordings of MSNA via microneurography corroborate the findings from experimental studies. In hemodialysis patients with intact kidneys, MSNA was significantly elevated when compared to controls [13]. However, after bilateral nephrectomies, dialysis patients had a significant reduction in MSNA to the level of controls, suggesting a role for the diseased kidneys in chronic SNS overactivation in ESRD. Similarly, restoration of renal function through kidney transplantation resulted in no change in MSNA in transplant recipients with intact native kidneys, independent of treatment with calcineurin inhibitors [46]. However, after undergoing bilateral nephrectomies, MSNA was reduced significantly in transplant recipients to the same levels as controls, suggesting that the diseased kidneys themselves, independent of renal function, contribute to sympathetic overactivity in ESRD.

The specific factors that bind and activate the renal nerves are unknown and largely unstudied. Purported ligands include urea, and adenosine, a product of renal ischemia. Chemoreceptor activation via ischemic metabolites may cause reflex increases in SNS outflow in order to attempt to redirect blood flow away from other areas of the body, to the ischemic tissues. In a study of uninephrectomized dogs, changes in blood pressure and renal sympathetic nerve activity were measured during intrarenal infusion of adenosine, before and after renal denervation [47]. There was a concomitant increase in blood pressure, efferent renal sympathetic nerve activity, and renal NE spillover during adenosine infusion, that was eliminated after renal afferent denervation, implicating a role for adenosine in renal nerve stimulation.

4.2. Decreased Nitric Oxide (NO) Bioavailability and Asymmetric Dimethylarginine (ADMA)

Decreased NO bioavailability likely contributes to chronic SNS overactivation in CKD. NO has a tonic inhibitory effect on central SNS outflow. In rats that were chronically treated with N Nitro L arginine methyl ester (L-NAME), an inhibitor of NO synthase (NOS), blood pressure increased due to decreased NO bioavailability [48]. When microinjections of the inhibitory amino acid glycine were injected into the rostral ventral lateral medulla (RVLM), an area of the brain that contains sympathetic premotor neurons important for the control of sympathetic vasomotor tone, there was a reduction in blood pressure during NOS inhibition to the same degree as controls. These data suggest that the increase in blood pressure during NOS inhibition was not entirely due to impaired endothelium-mediated vasodilation, but also due to increased central sympathetic activity. Human studies have also demonstrated that there is an important SNS component to the blood pressure raising effects of NOS inhibition [49, 50]. Alpha adrenergic blockade with phentolamine at doses that had no effect on baseline blood pressure attenuated the increase in blood pressure during NOS inhibition by 40% [49]. Decreased NO bioavailability in humans induced by pharmacological inhibition of NOS caused large increases in blood pressure that are in part mediated by SNS overactivation [49, 50].

ESRD and CKD patients have reduced NO bioavailability due to multiple causes that include oxidative stress, inflammation, uremic toxins, and accumulation of endogenous inhibitors of NOS, including asymmetric dimethylarginine (ADMA). ADMA is an endogenous inhibitor of NOS that accumulates in CKD and ESRD patients and is not removed during dialysis [5156]. The mechanisms underlying the accumulation of ADMA in patients with ESRD and CKD include a reduction in renal elimination (i.e., a uremic toxin), enhancement of ADMA production, and impaired degradation of ADMA due to reduced levels of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes more than 90% of circulating ADMA [52, 54, 55, 57]. Infusion of ADMA increased renal sympathetic nerve activity in conscious rats after removal of the influence of arterial baroreceptors [58]. In humans, ADMA levels have been shown to correlate with both MSNA and plasma NE levels in CKD and ESRD [51, 56]. In ESRD patients, ADMA correlates with left ventricular hypertrophy and left ventricular dysfunction [59], carotid intima-media thickness [60], and is a strong and independent predictor of mortality and cardiovascular outcomes in hemodialysis patients [61]. Together, these data suggest that the accumulation of ADMA plays a crucial role in reduced NO bioavailability in patients with chronic renal failure, leading to increased central SNS outflow and its deleterious effects.

4.3. Oxidative Stress

Patients with CRF have elevated baseline oxidative stress which contributes to increased CV risk [6264]. Oxidative stress is involved in the regulation of SNS activity [65]. The generation of reactive oxygen species (ROS) was increased in the RVLM of hypertensive rats, leading to increased central SNS outflow and blood pressure [66]. Oxidative stress in the brain led to sympathoexcitation and increases in arterial BP in rats with salt-sensitive hypertension [67], renovascular hypertension [68], and salt-induced CKD [69]. In the phenol renal injury model, the rise in blood pressure was accompanied by increased NE turnover as well as increased markers of oxidative stress in key brain centers [42]. Blood pressure and sympathetic nerve activity were reduced with the injection of tempol and superoxide dismutase in the lateral ventricle of these rats [42]. In addition to direct central effects, oxidative stress contributes to SNS overactivity by reducing NO bioavailability [70].

4.4. Angiotensin II (Ang II)

High circulating Ang II levels also likely contribute to sympathetic activation in CKD. Circulating Ang II can easily reach the area postrema of the medulla which lacks a blood brain barrier and has a multitude of AngII receptors [71]. The area postrema is directly connected to CV control centers in the brain that regulate SNS outflow. In addition to its central effects, Ang II resets the arterial baroreflex at a higher blood pressure level and enhances the action of NE at the sympathetic nerve terminal by increasing the release and decreasing the reuptake of NE. In human studies, infusion of both Ang II and phenylephrine decreased MSNA due to increases in BP leading to baroreflex-mediated inhibition of sympathetic outflow [72]. However, for the same degree of rise in BP, there was less of a reduction in MSNA with Ang II than with phenylephrine. Furthermore, when differences in BP response were eliminated with concomitant nitroprusside infusions, thereby unloading sympathetic baroreceptors, a significantly greater increase in MSNA during Ang II infusion was revealed. Furthermore, clinical studies have shown that blockers of the renin angiotensin system, including angiotensin converting enzyme inhibitors (ACE-i), angiotensin receptor blockers (ARBs), and direct renin inhibitors, reduce MSNA in patients with CKD [35, 38, 73]. These findings suggest that Ang II has a stimulatory effect on central SNS activity.

5. Therapeutic Considerations

Clearly, patients with ESRD and CKD have SNS overactivity that contributes to increased risk of CV disease and sudden death, as well as progression of renal dysfunction. However, whether treatment with sympatholytic agents reduces CV risk or modifies the rate of end-organ damage in CKD is yet unknown. Inhibitors of the renin-angiotensin system, including ACE-inhibitors, ARBs, and direct renin inhibitors, have been shown to significantly reduce MSNA in patients with CKD [35, 38, 73]. As these agents are often indicated in CKD patients for treatment of proteinuria and comorbid conditions such as heart failure, in addition to the added beneficial effect on SNS activity, these medications should be highly considered in the treatment of hypertension in this patient population. Whether peripheral sympatholytics, such as beta blockers, are beneficial in CKD is controversial [74, 75]; however, there may be a role for treatment with vasodilating beta blockers such as carvedilol, labetalol, and nebivolol in this patient population. Statins have been shown to reduce MSNA, without a concomitant reduction in blood pressure, in patients with CKD [76]. It is unclear if such reductions are clinically meaningful and will result in long-term improvements in blood pressure or cardiovascular risk in patients with chronic renal failure.

In ESRD patients, short daily dialysis has been shown to reduce ambulatory blood pressure, nocturnal blood pressure dip, and MSNA when compared to conventional hemodialysis [77]. The mechanisms by which short daily dialysis might improve SNS overactivity are unclear, but may include improved clearance of uremic toxins, decreased blood pressure variability, and improved extracellular volume control. Extracellular volume overload may contribute to SNS overactivity in CKD and ESRD by causing nocturnal rostral fluid shifts and peripharyngeal edema [78], resulting in obstructive sleep apnea (OSA), a highly prevalent condition in the ESRD population [79]. Multiple studies have shown that muscle sympathetic nerve activity (MSNA) is chronically elevated in patients with OSA [8082], and more recently, a significant correlation was found between OSA and resistant hypertension among ESRD patients [83]. Adequate dialysis, volume control, and treatment of obstructive sleep apnea should be standard practice and may help ameliorate SNS overactivation in ESRD.

Finally, newer nonpharmacologic approaches to the treatment of hypertension, particularly resistant or difficult to control hypertension, target reduction of central SNS outflow and may become applicable in the treatment of hypertension in patients with renal disease. These include renal denervation and baroreceptor stimulation. Renal denervation is performed via transcatheter ablation of both afferent and efferent renal nerves and has been shown to substantially reduce blood pressure and MSNA in patients with resistant hypertension [8486]. The electric baroreflex stimulator implanted at the level of the carotid sinus significantly reduced blood pressure, MSNA, and plasma NE levels in patients with treatment-resistant hypertension. However, both the renal denervation studies and carotid baroreflex stimulator studies excluded patients with reduced renal function. Whether these therapies will have a role in the treatment of hypertension in patients with CKD remain to be tested.

6. Future Directions

Patients with CKD and ESRD have chronic sympathetic overactivity that contributes to the substantially increased risk of CV disease and mortality [10, 11, 13, 16, 17]. Despite recent advances, many gaps still exist in our understanding of sympathetic regulation in patients with renal failure. The role of the diseased kidneys themselves in SNS overactivation has been established in experimental and human studies [13, 39, 40, 43]. However, the molecular mechanisms by which reflex activation of central SNS outflow occurs in renal parenchymal disease remains unknown. Identifying the ligands that activate the renal afferent nerves, and the specific renal sensory nerve endings (chemoreceptors, baroreceptors) that are sensitized and evoke an increase in SNS activity may help lead to new therapeutic targets to block this pathway and ameliorate SNS hyperactivity. At the clinical level, interventions such as exercise therapy and dietary modification have been shown to reduce SNS overactivity in other patient populations [23, 87, 88] and may have similar benefits in CKD. Drugs that have anti-inflammatory properties such as statins and bardoxolone, an antioxidant inflammatory mediator that has recently been shown to have beneficial effects in diabetic patients with CKD [89], may also have beneficial effects on SNS activation in patients with renal disease. The effects of new and existing therapies on SNS activity, and the long-term effects on CV risk and progression of renal disease, should be investigated in future studies.

Acknowledgments

This work was supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Decatur, GA; the Atlanta Research and Education Foundation; NIH grant K23 HL098744; the Amgen Nephrology Junior Faculty Award.

References

  1. A. S. Go, G. M. Chertow, D. Fan, C. E. McCulloch, and C. Y. Hsu, “Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization,” New England Journal of Medicine, vol. 351, no. 13, pp. 1296–1305, 2004. View at Publisher · View at Google Scholar · View at Scopus
  2. K. Matsushita, M. van der Velde, B. C. Astor, M. Woodward, A. S. Levey, P. E. de Jong, et al., “Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis,” The Lancet, vol. 375, no. 9731, pp. 2073–2081, 2010. View at Publisher · View at Google Scholar
  3. D. Rucker and M. Tonelli, “Cardiovascular risk and management in chronic kidney disease,” Nature Reviews Nephrology, vol. 5, no. 5, pp. 287–296, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. M. J. Sarnak, A. S. Levey, A. C. Schoolwerth et al., “Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention,” Hypertension, vol. 42, no. 5, pp. 1050–1065, 2003. View at Publisher · View at Google Scholar · View at Scopus
  5. C. P. Wen, T. Y. D. Cheng, M. K. Tsai et al., “All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan,” The Lancet, vol. 371, no. 9631, pp. 2173–2182, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. C. A. Herzog, R. W. Asinger, A. K. Berger et al., “Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: improving Global Outcomes (KDIGO),” Kidney International, vol. 80, no. 6, pp. 572–586, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. D. Green, P. R. Roberts, D. I. New, and P. A. Kalra, “Sudden cardiac death in hemodialysis patients: an in-depth review,” American Journal of Kidney Diseases, vol. 57, no. 6, pp. 921–929, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. J. Sosnov, D. Lessard, R. J. Goldberg, J. Yarzebski, and J. M. Gore, “Differential symptoms of acute myocardial infarction in patients with kidney disease: a community-wide perspective,” American Journal of Kidney Diseases, vol. 47, no. 3, pp. 378–384, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. P. Stenvinkel, J. J. Carrero, J. Axelsson, B. Lindholm, O. Heimbürger, and Z. Massy, “Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle?” Clinical Journal of the American Society of Nephrology, vol. 3, no. 2, pp. 505–521, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. G. Grassi, F. Quarti-Trevano, G. Seravalle et al., “Early sympathetic activation in the initial clinical stages of chronic renal failure,” Hypertension, vol. 57, no. 4, pp. 846–851, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. I. H. H. T. Klein, G. Ligtenberg, J. Neumann, P. L. Oey, H. A. Koomans, and P. J. Blankestijn, “Sympathetic nerve activity is inappropriately increased in chronic renal disease,” Journal of the American Society of Nephrology, vol. 14, no. 12, pp. 3239–3244, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. J. A. Joles and H. A. Koomans, “Causes and consequences of increased sympathetic activity inrenal disease,” Hypertension, vol. 43, no. 4, pp. 699–706, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. R. L. Converse Jr., T. N. Jacobsen, R. D. Toto et al., “Sympathetic overactivity in patients with chronic renal failure,” New England Journal of Medicine, vol. 327, no. 27, pp. 1912–1918, 1992. View at Scopus
  14. J. P. Fisher, C. N. Young, and P. J. Fadel, “Central sympathetic overactivity: maladies and mechanisms,” Autonomic Neuroscience, vol. 148, no. 1-2, pp. 5–15, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. P. G. A. Volders, “Novel insights into the role of the sympathetic nervous system in cardiac arrhythmogenesis,” Heart Rhythm, vol. 7, no. 12, pp. 1900–1906, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Zoccali, F. Mallamaci, S. Parlongo et al., “Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease,” Circulation, vol. 105, no. 11, pp. 1354–1359, 2002. View at Publisher · View at Google Scholar · View at Scopus
  17. C. Zoccali, F. Mallamaci, G. Tripepi et al., “Norepinephrine and concentric hypertrophy in patients with end-stage renal disease,” Hypertension, vol. 40, no. 1, pp. 41–46, 2002. View at Publisher · View at Google Scholar · View at Scopus
  18. D. R. Seals and F. A. Dinenno, “Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging,” American Journal of Physiology, vol. 287, no. 5, pp. H1895–H1905, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. G. Grassi, G. Seravalle, R. Dell'Oro, and G. Mancia, “Sympathetic mechanisms, organ damage, and antihypertensive treatment,” Current Hypertension Reports, vol. 13, no. 4, pp. 303–308, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. K. Amann, L. C. Rump, A. Simonaviciene et al., “Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats,” Journal of the American Society of Nephrology, vol. 11, no. 8, pp. 1469–1478, 2000. View at Scopus
  21. A. H. Nguyen, A. Garfinkel, D. O. Walter et al., “Dynamics of muscle sympathetic nerve activity in advanced heart failure patients,” American Journal of Physiology, vol. 271, no. 5, pp. H1962–H1969, 1996. View at Scopus
  22. W. N. Leimbach, B. G. Wallin, and R. G. Victor, “Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure,” Circulation, vol. 73, no. 5, pp. 913–919, 1986. View at Scopus
  23. R. Fraga, F. G. Franco, F. Roveda et al., “Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol,” European Journal of Heart Failure, vol. 9, no. 6-7, pp. 630–636, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. M. B. Patel, J. M. Stewart, A. V. Loud et al., “Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine,” Circulation, vol. 84, no. 5, pp. 2091–2100, 1991. View at Scopus
  25. S. Perlini, G. Palladini, I. Ferrero et al., “Sympathectomy or doxazosin, but not propranolol, blunt myocardial interstitial fibrosis in pressure-overload hypertrophy,” Hypertension, vol. 46, no. 5, pp. 1213–1218, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. S. P. Levick, D. B. Murray, J. S. Janicki, and G. L. Brower, “Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart,” Hypertension, vol. 55, no. 2, pp. 270–276, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. R. D. Bevan, “Trophic effects of peripheral adrenergic nerves on vascular structure,” Hypertension, vol. 6, no. 6, pp. I-19–I-26, 1984. View at Scopus
  28. M. Failla, A. Grappiolo, G. Emanuelli et al., “Sympathetic tone restrains arterial distensibility of healthy and atherosclerotic subjects,” Journal of Hypertension, vol. 17, no. 8, pp. 1117–1123, 1999. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Bleeke, H. Zhang, N. Madamanchi, C. Patterson, and J. E. Faber, “Catecholamine-induced vascular wall growth is dependent on generation of reactive oxygen species,” Circulation Research, vol. 94, no. 1, pp. 37–45, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. K. A. Jamerson, S. Julius, T. Gudbrandsson, O. Andersson, and D. O. Brant, “Reflex sympathetic activation induces acute insulin resistance in the human forearm,” Hypertension, vol. 21, no. 5, pp. 618–623, 1993. View at Scopus
  31. P. G. Krespi, T. K. Makris, A. N. Hatzizacharias et al., “Moxonidine effect on microalbuminuria, thrombomodulin, and plasminogen activator inhibitor-1 levels in patients with essential hypertension,” Cardiovascular Drugs and Therapy, vol. 12, no. 5, pp. 463–467, 1998. View at Publisher · View at Google Scholar · View at Scopus
  32. K. Strojek, W. Grzeszczak, J. Górska, M. I. Leschinger, and E. Ritz, “Lowering of microalbuminuria in diabetic patients by a sympathicoplegic agent: novel approach to prevent progression of diabetic nephropathy?” Journal of the American Society of Nephrology, vol. 12, no. 3, pp. 602–605, 2001. View at Scopus
  33. J. L. Cuche, J. Prinseau, and F. Selz, “Plasma free, sulfo- and glucuro-conjugated catecholamines in uremic patients,” Kidney International, vol. 30, no. 4, pp. 566–572, 1986. View at Scopus
  34. A. N. Elias, N. D. Vaziri, and M. Maksy, “Plasma norepinephrine, epinephrine, and dopamine levels in end-stage renal disease. Effect of hemodialysis,” Archives of Internal Medicine, vol. 145, no. 6, pp. 1013–1015, 1985. View at Publisher · View at Google Scholar · View at Scopus
  35. G. Ligtenberg, P. J. Blankestijn, P. L. Oey et al., “Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure,” New England Journal of Medicine, vol. 340, no. 17, pp. 1321–1328, 1999. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Park, V. M. Campese, and H. R. Middlekauff, “Exercise pressor reflex in humans with end-stage renal disease,” American Journal of Physiology, vol. 295, no. 4, pp. R1188–R1194, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. J. Park, V. M. Campese, N. Nobakht, and H. R. Middlekauff, “Differential distribution of muscle and skin sympathetic nerve activity in patients with end-stage renal disease,” Journal of Applied Physiology, vol. 105, no. 6, pp. 1873–1876, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. I. H. H. T. Klein, G. Ligtenberg, P. L. Oey, H. A. Koomans, and P. J. Blankestijn, “Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure,” Journal of the American Society of Nephrology, vol. 14, no. 2, pp. 425–430, 2003. View at Publisher · View at Google Scholar · View at Scopus
  39. V. M. Campese and E. Kogosov, “Renal afferent denervation prevents hypertension in rats with chronic renal failure,” Hypertension, vol. 25, no. 4, pp. 878–882, 1995. View at Scopus
  40. V. M. Campese, E. Kogosov, and M. Koss, “Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat,” American Journal of Kidney Diseases, vol. 26, no. 5, pp. 861–865, 1995. View at Scopus
  41. S. Ye, B. Ozgur, and V. M. Campese, “Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure,” Kidney International, vol. 51, no. 3, pp. 722–727, 1997. View at Scopus
  42. S. Ye, H. Zhong, and V. M. Campese, “Oxidative stress mediates the stimulation of sympathetic nerve activity in the phenol renal injury model of hypertension,” Hypertension, vol. 48, no. 2, pp. 309–315, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Ye, H. Zhong, V. Yanamadala, and V. M. Campese, “Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity,” American Journal of Hypertension, vol. 15, no. 8, pp. 717–724, 2002. View at Publisher · View at Google Scholar · View at Scopus
  44. I. H. H. T. Klein, G. Ligtenberg, P. L. Oey, H. A. Koomans, and P. J. Blankestijn, “Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension,” Journal of the American Society of Nephrology, vol. 12, no. 11, pp. 2427–2433, 2001. View at Scopus
  45. V. M. Campese, E. Ku, and J. Park, “Sympathetic renal innervation and resistant hypertension,” International Journal of Hypertension, vol. 2011, Article ID 814354, 2011.
  46. M. Hausberg, M. Kosch, P. Harmelink et al., “Sympathetic nerve activity in end-stage renal disease,” Circulation, vol. 106, no. 15, pp. 1974–1979, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. R. E. Katholi, P. L. Whitlow, G. R. Hageman, and W. T. Woods, “Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog,” Journal of Hypertension, vol. 2, no. 4, pp. 349–359, 1984. View at Scopus
  48. C. T. Bergamaschi, R. R. Campos, and O. U. Lopes, “Rostral ventrolateral medulla: a source of sympathetic activation in rats subjected to long-term treatment with L-NAME,” Hypertension, vol. 34, no. 4, pp. 744–747, 1999. View at Scopus
  49. M. Sander, B. Chavoshan, and R. G. Victor, “A large blood pressure-raising effect of nitric oxide synthase inhibition in humans,” Hypertension, vol. 33, no. 4, pp. 937–942, 1999. View at Scopus
  50. M. Sander and R. G. Victor, “Neural mechanisms in nitric-oxide-deficient hypertension,” Current Opinion in Nephrology and Hypertension, vol. 8, no. 1, pp. 61–73, 1999. View at Publisher · View at Google Scholar
  51. G. Grassi, G. Seravalle, L. Ghiadoni, G. Tripepi, R. M. Bruno, G. Mancia, et al., “. Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease,” Clinical Journal of the American Society of Nephrology, vol. 6, no. 11, pp. 2620–2627, 2011. View at Publisher · View at Google Scholar
  52. S. Ueda, S. I. Yamagishi, Y. Matsumoto, K. Fukami, and S. Okuda, “Asymmetric dimethylarginine (ADMA) is a novel emerging risk factor for cardiovascular disease and the development of renal injury in chronic kidney disease,” Clinical and Experimental Nephrology, vol. 11, no. 2, pp. 115–121, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. P. Vallance, A. Leone, A. Calver, J. Collier, and S. Moncada, “Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure,” The Lancet, vol. 339, no. 8793, pp. 572–575, 1992. View at Publisher · View at Google Scholar · View at Scopus
  54. C. Zoccali, “Asymmetric dimethylarginine in end-stage renal disease patients: a biomarker modifiable by calcium blockade and angiotensin II antagonism?” Kidney International, vol. 70, no. 12, pp. 2053–2055, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Zoccali, “Asymmetric dimethylarginine (ADMA): a cardiovascular and renal risk factor on the move,” Journal of Hypertension, vol. 24, no. 4, pp. 611–619, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. F. Mallamaci, G. Tripepi, R. Maas, L. Malatino, R. Böger, and C. Zoccali, “Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease,” Journal of the American Society of Nephrology, vol. 15, no. 2, pp. 435–441, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. R. H. Böger and C. Zoccali, “ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease,” Atherosclerosis Supplements, vol. 4, no. 4, pp. 23–28, 2003. View at Publisher · View at Google Scholar · View at Scopus
  58. R. A. Augustyniak, R. G. Victor, D. A. Morgan, and W. Zhang, “L-NAME- and ADMA-induced sympathetic neural activation in conscious rats,” American Journal of Physiology, vol. 290, no. 3, pp. R726–R732, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. C. Zoccali, F. Mallamaci, R. Maas et al., “Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients,” Kidney International, vol. 62, no. 1, pp. 339–345, 2002. View at Publisher · View at Google Scholar · View at Scopus
  60. C. Zoccali, F. A. Benedetto, R. Maas et al., “Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease,” Journal of the American Society of Nephrology, vol. 13, no. 2, pp. 490–496, 2002. View at Scopus
  61. C. Zoccali, S. M. Bode-Böger, F. Mallamaci et al., “Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study,” The Lancet, vol. 358, no. 9299, pp. 2113–2117, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Cottone, M. C. Lorito, R. Riccobene et al., “Oxidative stress, inflammation and cardiovascular disease in chronic renal failure,” Journal of Nephrology, vol. 21, no. 2, pp. 175–179, 2008. View at Scopus
  63. S. V. Shah, R. Baliga, M. Rajapurkar, and V. A. Fonseca, “Oxidants in chronic kidney disease,” Journal of the American Society of Nephrology, vol. 18, no. 1, pp. 16–28, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. E. L. Schiffrin, M. L. Lipman, and J. F. E. Mann, “Chronic kidney disease: effects on the cardiovascular system,” Circulation, vol. 116, no. 1, pp. 85–97, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. V. M. Campese, S. Ye, H. Zhong, V. Yanamadala, Z. Ye, and J. Chiu, “Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity,” American Journal of Physiology, vol. 287, no. 2, pp. H695–H703, 2004. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. Hirooka, “Oxidative stress in the cardiovascular center has a pivotal role in the sympathetic activation in hypertension,” Hypertension Research, vol. 34, no. 4, pp. 407–412, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. M. Fujita, K. Ando, A. Nagae, and T. Fujita, “Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension,” Hypertension, vol. 50, no. 2, pp. 360–367, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. E. B. Oliveira-Sales, A. P. Dugaich, B. A. Carillo et al., “Oxidative stress contributes to renovascular hypertension,” American Journal of Hypertension, vol. 21, no. 1, pp. 98–104, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. M. Fujita, K. Ando, H. Kawarazaki, C. Kawarasaki, K. Muraoka, H. Ohtsu, et al., “Sympathoexcitation by brain oxidative stress mediates arterial pressure elevation in salt-induced chronic kidney disease,” Hypertension, vol. 59, no. 1, pp. 105–112, 2012. View at Publisher · View at Google Scholar
  70. H. Macarthur, T. C. Westfall, and G. H. Wilken, “Oxidative stress attenuates NO-induced modulation of sympathetic neurotransmission in the mesenteric arterial bed of spontaneously hypertensive rats,” American Journal of Physiology, vol. 294, no. 1, pp. H183–H189, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. I. A. Reid, “Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure,” American Journal of Physiology, vol. 262, no. 6, pp. E763–E778, 1992. View at Scopus
  72. T. Matsukawa, E. Gotoh, K. Minamisawa et al., “Effects of intravenous infusions of angiotensin II on muscle sympathetic nerve activity in humans,” American Journal of Physiology, vol. 261, no. 3, pp. R690–R696, 1991. View at Scopus
  73. L. Siddiqi, P. L. Oey, and P. J. Blankestijn, “Aliskiren reduces sympathetic nerve activity and blood pressure in chronic kidney disease patients,” Nephrology Dialysis Transplantation, vol. 26, no. 9, pp. 2930–2934, 2011. View at Publisher · View at Google Scholar
  74. N. Tangri, S. Shastri, H. Tighiouart, G. J. Beck, A. K. Cheung, G. Eknoyan, et al., “beta-Blockers for prevention of sudden cardiac death in patients on hemodialysis: a propensity score analysis of the HEMO Study,” American Journal of Kidney Diseases, vol. 58, no. 6, pp. 939–945, 2011. View at Publisher · View at Google Scholar
  75. G. L. Bakris, P. Hart, and E. Ritz, “Beta blockers in the management of chronic kidney disease,” Kidney International, vol. 70, no. 11, pp. 1905–1913, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. L. Siddiqi, J. A. Joles, P. L. Oey, and P. J. Blankestijn, “Atorvastatin reduces sympathetic activity in patients with chronic kidney disease,” Journal of Hypertension, vol. 29, no. 11, pp. 2176–2180, 2011. View at Publisher · View at Google Scholar
  77. O. Zilch, P. F. Vos, P. L. Oey et al., “Sympathetic hyperactivity in haemodialysis patients is reduced by short daily haemodialysis,” Journal of Hypertension, vol. 25, no. 6, pp. 1285–1289, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. O. Friedman, T. D. Bradley, C. T. Chan, R. Parkes, and A. G. Logan, “Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension,” Hypertension, vol. 56, no. 6, pp. 1077–1082, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. T. Dudenbostel and D. A. Calhoun, “Resistant hypertension, obstructive sleep apnoea and aldosterone,” Journal of Human Hypertension, vol. 26, no. 5, pp. 281–287, 2012. View at Publisher · View at Google Scholar · View at Scopus
  80. G. Grassi, A. Facchini, F. Q. Trevano et al., “Obstructive sleep apnea-dependent and -independent adrenergic activation in obesity,” Hypertension, vol. 46, no. 2, pp. 321–325, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. K. Narkiewicz, P. J. H. Van De Borne, R. L. Cooley, M. E. Dyken, and V. K. Somers, “Sympathetic activity in obese subjects with and without obstructive sleep apnea,” Circulation, vol. 98, no. 8, pp. 772–776, 1998. View at Scopus
  82. K. Narkiewicz, P. J. H. Van De Borne, N. Montano, M. E. Dyken, B. G. Phillips, and V. K. Somers, “Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea,” Circulation, vol. 97, no. 10, pp. 943–945, 1998. View at Scopus
  83. K. Abdel-Kader, S. Dohar, N. Shah, M. Jhamb, S. E. Reis, P. Strollo, et al., “Resistant hypertension and obstructive sleep apnea in the setting of kidney disease,” Journal of Hypertension, vol. 30, no. 5, pp. 960–966, 2012. View at Publisher · View at Google Scholar
  84. M. D. Esler, H. Krum, P. A. Sobotka et al., “Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial,” The Lancet, vol. 376, no. 9756, pp. 1903–1909, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. M. P. Schlaich, D. Hering, P. Sobotka, H. Krum, G. W. Lambert, E. Lambert, et al., “Effects of renal denervation on sympathetic activation, blood pressure, and glucose metabolism in patients with resistant hypertension,” Frontiers in Physiology, vol. 3, artilce 10, 2012.
  86. M. P. Schlaich, P. A. Sobotka, H. Krum, E. Lambert, and M. D. Esler, “Renal sympathetic-nerve ablation for uncontrolled hypertension,” New England Journal of Medicine, vol. 361, no. 9, pp. 932–934, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. G. Grassi, R. Dell'Oro, G. Seravalle, G. Foglia, F. Q. Trevano, and G. Mancia, “Short- and long-term neuroadrenergic effects of moderate dietary sodium restriction in essential hypertension,” Circulation, vol. 106, no. 15, pp. 1957–1961, 2002. View at Publisher · View at Google Scholar · View at Scopus
  88. F. Roveda, H. R. Middlekauff, M. U. P. B. Rondon et al., “The effects of exercise training on sympathetic neural activation in advanced heart failure: a randomized controlled trial,” Journal of the American College of Cardiology, vol. 42, no. 5, pp. 854–860, 2003. View at Publisher · View at Google Scholar · View at Scopus
  89. P. E. Pergola, P. Raskin, R. D. Toto et al., “Bardoxolone methyl and kidney function in CKD with type 2 diabetes,” New England Journal of Medicine, vol. 365, no. 4, pp. 327–336, 2011. View at Publisher · View at Google Scholar · View at Scopus