Cardiovascular Autonomic Dysfunction in Chronic Kidney Disease: a Comprehensive Review.

Curr Hypertens Rep (2015) 17:59 DOI 10.1007/s11906-015-0571-z

HYPERTENSION AND THE KIDNEY (RM CAREY, SECTION EDITOR)

Cardiovascular Autonomic Dysfunction in Chronic Kidney Disease: a Comprehensive Review Ibrahim M. Salman 1

# Springer Science+Business Media New York 2015

Abstract Cardiovascular autonomic dysfunction is a major complication of chronic kidney disease (CKD), likely contributing to the high incidence of cardiovascular mortality in this patient population. In addition to adrenergic overdrive in affected individuals, clinical and experimental evidence now strongly indicates the presence of impaired reflex control of both sympathetic and parasympathetic outflow to the heart and vasculature. Although the principal underlying mechanisms are not completely understood, potential involvements of altered baroreceptor, cardiopulmonary, and chemoreceptor reflex function, along with factors including but not limited to increased renin–angiotensin–aldosterone system activity, activation of the renal afferents and cardiovascular structural remodeling have been suggested. This review therefore analyzes potential mechanisms underpinning autonomic imbalance in CKD, covers results accumulated thus far on cardiovascular autonomic function studies in clinical and experimental renal failure, discusses the role of current interventional and therapeutic strategies in ameliorating autonomic deficits associated with chronic renal dysfunction, and identifies gaps in our knowledge of neural mechanisms driving cardiovascular disease in CKD. Keywords Chronic kidney disease . Hypertension . Cardiovascular disease . Autonomic dysfunction . Sympathetic nerve activity . Vagal tone This article is part of the Topical Collection on Hypertension and the Kidney * Ibrahim M. Salman [email protected] 1

The Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia

Introduction Chronic kidney disease (CKD) is a growing public health problem, affecting 5–7 % of the world’s population [1], and the number of clinical cases eventuating in end-stage renal disease (ESRD) is increasing at an alarming rate of 3 % annually [2]. Individuals with CKD are more likely to die of cardiovascular complications than to develop kidney failure [3, 4] because of the high prevalence of cardiovascular disease (CVD) in this patient population [5]. Therefore, the focus recently shifted to optimizing patient care during the phase of CKD before the onset of ESRD [6]. Hypertension, which is present in ~80–85 % of CKD patients [4, 5], is a powerful indicator of CVD and an independent risk factor for disease progression both in adult and in pediatric patients with CKD [5, 7]. Several mechanisms have been implicated in the pathogenesis of hypertension and CVD in CKD, including sodium retention and fluid overload due to defects in the pressure natriuresis relationship, activation of the renin–angiotensin– aldosterone system (RAAS) [8, 9, 10•], sympathetic nervous system (SNS) hyperactivity [9, 11, 12••, 13••], autonomic dysfunction [13••, 14, 15], endogenous and environmental stress [5, 16], impaired endothelial function, vascular remodeling, and arterial calcification [17, 18], thus highlighting a complex interplay of neural, hormonal, and vascular mechanisms linking kidney disease to high blood pressure (BP) and the associated cardiovascular problems that consequently arise. Among the myriad factors contributing to or arising from CKD, cardiovascular autonomic dysfunction is a serious yet poorly understood long-term clinical problem in the CKD population. Autonomic dysfunction as a broad term mainly refers to a condition in which tonic and reflex control of autonomic outflows is altered, favoring increased SNS activity and depressed parasympathetic function [19, 20]. Indeed,

59

Curr Hypertens Rep (2015) 17:59

Page 2 of 20

CKD patients with cardiovascular autonomic dysfunction consistently have shown an enhanced risk of premature death [21•, 22, 23], suggesting direct detrimental effects on the clinical prognosis of renal failure. Dysfunctional vagal control of heart rate (HR), as assessed by reductions in HR variability (HRV) and spontaneous baroreflex sensitivity (BRS), also is prevalent and poses an increased risk of sudden cardiac death [24]. SNS activity is elevated in patients with CKD, as evidenced by increased plasma catecholamine levels [12••, 25] and increased muscle sympathetic nerve activity (SNA) [9, 12••, 26]. Sympathetic overactivity is implicated in the development, maintenance, and progression of renal disease [26–28] and is recognized as an important mechanism contributing to the strong association between CKD and increased cardiovascular morbidity and mortality [12••, 25]. Although the contribution of autonomic neural mechanisms to the development of hypertension and CVD in CKD is now well established, the exact mechanisms contributing to altered sympathetic and parasympathetic tone in patients with CKD are unclear. Abnormalities in cardiovascular reflexes central to autonomic function control, such as baroreceptor, chemoreceptor, and cardiopulmonary reflexes, have been proposed as possible underlying mechanisms [29–31]. However, deficits in these reflex pathways and, more importantly, the mechanisms underlying these deficits (e.g., altered afferent, central, or efferent signaling pathway; inability of target organs such as the heart or vasculature to respond to autonomic inputs) are incompletely understood. Current evidence also suggests that autonomic deficits are driven by the diseased kidneys, because nephrectomy, renal denervation, and kidney transplantation have been shown to correct BP, lower sympathetic overdrive, and improve vagal control of HR in humans and experimental animals [32, 33, 34••, 35]. One of the goals of clinical and experimental research in hypertension is to identify innovative diagnostic and advanced treatment approaches to limit hypertension and target endorgan damage. However, this approach is hampered by our lack of a complete understanding of the mechanisms binding the complex interactions among the autonomic, cardiovascular, and renal systems as well as the nonspecificity of the current therapeutic strategies for the primary and secondary prevention of CVD in patients with CKD. In the absence of solid evidence, clinical judgment suggests effective control of modifiable and uremia-specific risk factors in the early stages of renal disease, with priority given to maintaining optimal or near-optimal BP control [5, 33, 34••, 35, 36]. Accordingly, this article provides an overview of the literature on dysfunctional autonomic nervous system (ANS) activity in CKD, examines perspectives on the contribution of altered tonic and reflex control of BP in CKD-mediated hypertension, analyzes potential mechanisms underlying autonomic dysfunction in CKD, discusses the implications of modern interventional and therapeutic strategies in restraining

CKD-driven autonomic deficits, explores major recent developments, and identifies gaps in research accumulated thus far that are worth future investigation.

CVD in CKD CVD is prevalent in patients with CKD and ESRD, with a range of traditional cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, obesity, older age, male sex, and uremia-specific risk factors (anemia, volume overload, hyperphosphatemia, and hyperparathyroidism), underlying the development and progression of renal disease [5, 6, 19]. CVD in CKD/ESRD occurs as a result of functional and structural adaptations to chronically elevated BP, triggered by factors such as increased sympathetic vasomotor tone, altered autonomic control of HR, activation of RAAS, enhanced production of reactive oxygen species, endothelial dysfunction, atherosclerosis, arteriosclerosis, and vascular calcification [9, 5, 18, 37]. Vascular injury and resultant vasculopathies in turn may contribute to the increased prevalence of coronary artery disease, heart failure, stroke, and peripheral vascular disease in this patient population [5]. Consequently, people with CKD are exposed to increased morbidity and mortality as a result of cardiovascular events. Indeed, sudden cardiac death is a major cause of cardiac mortality in ESRD patients, with the incidence increasing with the stage of renal failure [4, 38]. Therefore, CVD prevention and treatment are critical in the management of individuals with CKD.

CKD and Hypertension There is a strong relationship between CKD and hypertension, with renal insufficiency contributing to half of all cases of secondary hypertension [8]. Although kidney disease may cause hypertension, hypertension is also a key driver of ESRD, contributing to the disease itself or, more commonly, underlying the progressive decline in glomerular filtration rate (GFR) and hence renal function [6, 8]. Hypertension almost invariably is encountered in patients with CKD, with 80 % of patients beginning renal replacement therapy presenting with elevated BP [4, 5]. High BP in CKD plays a powerful role in the increased cardiovascular morbidity and mortality in this population, predisposing affected individuals to cardiac arrhythmias, myocardial damage, coronary ischemia, and eventually left ventricular hypertrophy (LVH) [8, 23]. The pathogenesis of hypertension in CKD is very complex and multifactorial, with patients who have vascular disease, diabetes, and polycystic kidney disease (PKD) being more prone to developing hypertension [8]. Besides the classic factors promoting BP increase in CKD, including sodium retention, intravascular hypervolemia, and excessive RAAS


activity [37, 39], new key players have been recognized, including SNS hyperactivity [9, 11, 12••, 13••, 40], autonomic imbalance [13••, 14, 15], endothelial dysfunction, and vascular remodeling [17, 18, 41].

Altered Autonomic Control of Cardiovascular Function in CKD Autonomic neuroregulation of cardiovascular function, which controls periodic fluctuations in HR and BP, depends on a balance between sympathetic and parasympathetic (vagal) activity to the heart and vasculature [20, 42]. During CKD, a state of functional disharmony between sympathetic and vagal components of the ANS, with altered tonic and reflex control of autonomic outflows, is observed, contributing to autonomic dysfunction [13••, 14, 15, 21•, 43]. Cardiovascular autonomic dysfunction is a serious yet poorly understood long-term complication in CKD and, in most cases, is associated with SNS hyperactivity and a blunted parasympathetic nervous system [19, 20], further aiding the deleterious impact of sympathetic activation. Nevertheless, reports also have shown that vagal withdrawal might be the principal mechanism in initiating sympathovagal imbalance [20]. Empirically, sympathovagal imbalance has been recognized as a major mechanism underlying many cardiovascular morbidities and comorbidities in general [44] and might possibly be the final common pathway of sudden cardiac death particularly in CKD [21•, 22, 23]. SNS overactivity is implicated in the development and progression of renal disease [26–28] and is recognized as an important mechanism contributing to the poor prognosis in CKD patients and the consequent cardiovascular morbidity and mortality [45•]. Various clinical studies demonstrated increased concentrations of plasma norepinephrine (NE) in CKD patients and proposed this measurement not only as the first indicator of increased SNS activity in these patients but also as a powerful predictor of both survival and cardiovascular complications [25, 40, 46]. These observations were substantiated further by evidence from human studies showing enhanced depressor responses to central sympathoinhibition by clonidine [47] or debrisoquine [46] and animal models of CKD showing a pronounced hypotensive effect in response to ganglionic blockade [11, 48]. In addition to elevated catecholamine levels, SNA levels in muscle [9, 12••, 31, 37, 49••, 50], but not skin [50], assessed clinically using microneurography, also are elevated, independent of resting BP [40] or circulating uremia-related toxins [45•, 51]. Further evidence of altered sympathetic activity in CKD patients has come from reports showing abnormal BP responses to standing or to a handgrip exercise [52], as well as augmented low-frequency (LF) oscillations of systolic blood pressure variability (SBPV), suggesting increased sympathetic vasomotor tone [53]. Similarly, upregulated adrenergic

Page 3 of 20 59

control of cardiac function also is documented in CKD, with evidence of enhanced bradycardic responses to β-adrenergic receptor blockade [54]. Sympathetic hyperactivity has considerable adverse consequences on both the renal and cardiovascular systems and may exacerbate hypertension and proteinuria in individuals with CKD. Indeed, in stage 2–4 CKD patients, Grassi et al. [55] demonstrated a strong negative association between increased muscle SNA and decreased GFR, as well as a significant positive correlation between high muscle SNA and proteinuria. Interstitial fibrosis, glomerulosclerosis [56], accelerated atherosclerosis, vasoconstriction, and proliferation of smooth muscle cells and adventitial fibroblasts in the vessel wall are other deleterious consequences of sympathetic overactivity related to progression of renal damage [57, 58]. NE released by the sympathetic nerve endings may (1) directly induce proliferation of smooth muscle cell and adventitial fibroblasts in the vascular wall and exert a trophic influence on cardiac myocytes [57, 58] or (2) indirectly evoke cardiac and vessel wall remodeling [59] via RAAS pathway activation and angiotensin II (Ang II) formation [60]. Studies also have demonstrated that cardiac sympathetic activity is related to LVH in patients with primary [61] or CKDmediated hypertension [62]. Besides increased sympathetic control of the heart in CKD individuals, cardiac vagal tone, in contrast, is reduced, as evaluated by decreased measures of vagal tachycardic reserve in response to the nonspecific muscarinic receptor antagonist atropine [63], reduced high-frequency (HF) oscillations of HRV [64], and low HR scores on forceful exhalation against a closed airway (Valsalva maneuver), deep breathing, and standing [52, 65]. Vagal withdrawal, along with sympathetic activation, is closely linked to cardiac arrhythmias [66] and is responsible, at least partly, for the higher incidence of sudden cardiac death in CKD patients [38].

Possible Mechanisms Contributing to Autonomic Imbalance in CKD The contribution of autonomic neural mechanisms to the development of hypertension and CVD in CKD is well established; however, the exact mechanisms contributing to altered sympathetic and parasympathetic tone in patients with CKD remain unclear. Here, several mechanisms are proposed, although they are not mutually exclusive or thoroughly characterized (Fig. 1). Altered Reflex Control Mechanisms of Autonomic Outflows in CKD Several autonomic reflexes are involved in modulating sympathetic and parasympathetic outflows to the heart and

59

Page 4 of 20


Fig. 1 Possible mechanisms contributing to cardiovascular autonomic dysfunction in CKD

vasculature to effectively fine-tune BP. Deficits in the regulatory influence, physiologically exerted by a range of cardiovascular reflexes, have been demonstrated in hypertension and CKD. However, compared with studies describing altered sympathetic and parasympathetic tone in CKD, little is known about reflex control of autonomic function in CKD and how it ultimately affects sympathovagal imbalance. One mechanism long thought to underlie altered autonomic outflow and elevated BP in CKD is reduced arterial baroreflex function. In clinical practice, prognostic information on cardiovascular morbidity and mortality in CKD may be derived by (1) measuring cardiac BRS, an independent predictor of sudden cardiac death accompanying CKD [24], and (2) using the baroreflex effectiveness index (BEI), a measure of the number of times baroreflex is active in controlling HR in response to BP fluctuations [67]; both tools are recognized as strong independent predictors of long-term survival in the CKD population [24]. Indeed, HR BRS, either spontaneous [24, 68–70] or evoked by pharmacologic manipulation of BP [31, 65, 70], and BEI [24] are reduced in CKD, and, most importantly, deficits correlate with reductions in the GFR [69], suggesting a direct association between deterioration in renal function and alterations in the cardiac baroreflex mechanism, rendering these markers useful in assessing cardiovascular risk in CKD. In contrast to studies of HR baroreflex, those assessing sympathetic baroreflex function in CKD patients are still lacking, perhaps because of the more technically challenging experimental setup compared with the easy method for assessing HR. To date, only two studies have investigated baroreflex

control of SNA in humans with CKD [31, 49••], the results of which are dissimilar. Ligtenberg and colleagues [49••] assessed baroreflex control of muscle SNA in 14 hypertensive CKD patients and 14 normotensive controls. Their results demonstrated comparable sympathetic BRS in both groups, although a resetting of the sympathetic baroreflex function to a higher BP range occurred in the CKD group. Tinucci et al. [31] used a similar experimental approach to measure muscle SNA baroreflex in seven hypertensive CKD patients and seven hypertensive controls with normal renal function. Their data, in contrast to those of Ligtenberg et al. [49••] and despite both study groups showing comparably low GFR, high serum creatinine levels, and elevated plasma renin activity, revealed markedly blunted sympathetic BRS in CKD patients relative to the control group. These findings, together with the lack of data assessing SNA baroreflex in animal models of CKD, suggest the need for more studies to elucidate the role of altered sympathetic baroreflex control in mediating sympathetic overactivity in CKD. Using a genetic rat model of CKD, the Lewis polycystic kidney (LPK) rat, our laboratory was the first to provide direct experimental evidence of impaired baroreflex control of renal SNA, with reduced sensitivity and operating range in response to a given BP change [13••, 71••]. In a more recent study, we also showed that sympathetic baroreflex dysfunction is differentially expressed within different sympathetic nerve beds, exhibiting reduced renal and splanchnic, but not lumbar, SNA baroreflex function [10•]. With the aim of providing early interventional strategies to limit CKD progression, these data highlight the importance


of individually characterizing sympathetic outflows to different target organs and perhaps correlating the deficit, if any, with the stage of renal dysfunction. Still to be determined, however, is whether a more pronounced and widespread sympathetic baroreflex dysfunction occurs as the disease progresses from CKD to ESRD. Deficits in the reflex control of autonomic outflow in CKD may not be limited only to defects in the regulatory pathways that operate the baroreceptor reflex but also may be the result of other reflex mechanisms known to be impaired in CKD, including the cardiopulmonary and chemoreceptor reflexes. Intact cardiopulmonary reflex control of autonomic outflow is required to maintain normal fluid volume regulation [72]. A few studies found deficits in the mechanosensitive (volumedependent) cardiopulmonary reflex control of sympathetic but not parasympathetic activity both in CKD patients [73, 74] and in animal models of nephrotic syndrome [29, 75]. An inability of the cardiopulmonary reflexes to restrain SNA properly, which is suggested as a potential predisposing factor to salt and water retention, inappropriately high levels of systemic vascular resistance, and reduced GFR [29], may provide another mechanistic explanation for altered autonomic balance and maintenance of hypertension in CKD. Whether a similar deficit extends to the chemosensitive cardiopulmonary (Bezold–Jarisch [BZJ]) reflex control of autonomic outflow remains to be determined; however, activation of this pathway has been proposed as the main mechanism underlying dialysis-induced hypotension in CKD patients, in which hypovolemia and consequent tissue hypoperfusion provoke adenosine release to activate the BZJ reflex [76]. The chemoreceptor reflex plays a pivotal role in monitoring changes in arterial blood oxygen concentration, and chemosensation also is mechanistically linked to cardiorespiratory control by the ANS [77]. Dysfunctional chemoreflex control of HR and SNA also is evident in CKD, suggesting impaired chemoreflex function as another principle contributor to autonomic imbalance in CKD. Supporting this notion, Rassaf et al. [30, 77] demonstrated depressed cardiac chemoreflex sensitivity in CKD/ESRD patients, indicating altered autonomic control of HR in response to chemoreflex activation during renal disease. Data from our laboratory show that, unlike our observations in the control animals, activation of both peripheral chemoreflex, with 10 % O2 in N2 or 100 % N2, and central chemoreflex, with 5 % CO2 in O2, did not increase renal, splanchnic, or lumbar SNA in CKD rats, perhaps because of the inability to increase SNA further in this model [10•]. Recent evidence also suggests that tonic arterial chemoreceptor activation is involved in sympathetic overactivity of CKD, because deactivation of the arterial chemoreceptors by inhalation of 100 % O2 noticeably reduces muscle SNA in patients with renal failure [78]. Various mechanisms that impair the oxygen-carrying capacity of blood and therefore sensitize the carotid bodies have been suggested

Page 5 of 20 59

with respect to chemoreceptor-induced activation of SNA, including sleep apnea, metabolic acidosis [79], and anemia associated with chronic renal failure [45•]. Although altered cardiovascular reflexes are thought to underlie the sympathovagal imbalance in CKD, the exact mechanism leading to this impairment is unclear. Clearly, every site within the baroreceptor, cardiopulmonary, and chemoreceptor reflexes may be responsible for blunted reflex autonomic activity and altered sympathovagal balance in CKD. However, only fragmentary experimental evidence exists to support this assumption, owing to the inability of clinical cardiovascular autonomic function tests to differentiate the roles of the afferent, central, and efferent components of individual reflex arcs. Possibly, deficits in the afferent arm of these reflexes and impaired sensory afferent traffic conveyed via the aortic depressor nerve, carotid sinus nerve, and vagal afferent neurons to the brain may relate to (1) altered mechanostimulation of baroreceptors within the carotid sinus and aortic arch due to arterial stiffening, (2) impaired responsiveness of the volumeand/or chemosensitive receptors in the cardiac chambers due to altered cardiac structure and LVH, and/or (3) structural changes of arterial chemoreceptors in the carotid and aortic bodies. Alternatively, abnormal central mechanisms (e.g., altered central processing of vagal afferent input of the cardiopulmonary reflex, as shown in a nephrotic syndrome model of CKD [29, 75]) may be responsible. These may be the result of (1) deficits in key medullary regions common to these reflex pathways, including the nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM), rostral ventrolateral medulla (RVLM), and nucleus ambiguus; (2) altered neuronal activity of higher brain areas, such as the paraventricular and hypothalamic supraoptic nuclei and their subsequent regulation of these medullary nuclei; or (3) the inability of the heart and vasculature to respond to autonomic inputs. A comprehensive investigation of overall reflex function in CKD is still lacking, and more experiments are required to delineate the role of altered reflex function in skewing normal control of sympathetic and vagal outflows. To address this issue, recent studies from our laboratory assessed mechanisms contributing to dysfunctional baroreflex function in CKD. In these studies, we found that temporal deficits in the functionality of the afferent and/or central components of the baroreflex arch most likely contribute to altered sympathetic and cardiac baroreflex function [13••, 71••]. Activation of the RAAS in CKD Central and peripheral activation of the RAAS occurs in many forms of renal disease [5] and is a leading cause of potentiating SNS activity [80]. The central action of Ang II on AT1 receptors is implicated in determining the baroreceptor set point of BP regulation and upregulation of central sympathetic outflow [20, 80]. These effects are substantiated by experimental evidence

59

Page 6 of 20

associating intracerebral infusion of Ang II with systemic vasoconstriction and resetting of the baroreflex toward a higher BP range [81]. The mechanism by which Ang II is believed to alter sympathetic outflow to the heart and vasculature involves activation of a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased levels of reactive oxygen species in neuroanatomic regions in the brain central to sympathetic stimulation, such as the RVLM, circumventricular organs, and paraventricular nucleus (PVN) [82, 83]. Similar crosstalk occurs between the RAAS and SNS at the peripheral level. Ang II modulates regional sympathetic outflow via presynaptic facilitation of NE release and inhibition of neuronal reuptake, a mechanism known to enhance neuronal transmission within sympathetic ganglia and to amplify αadrenoceptor-mediated vasoconstriction [80, 81]. This view is supported by studies showing marked attenuation of muscle SNA in CKD patients treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) [9, 37, 49••], suggesting an imperative role for RAAS activation in mediating autonomic imbalance in CKD. Recent evidence from our group also shows a pivotal role for Ang II in promoting altered autonomic reflexes in CKD, whereby acute intravenous administration of the ARB losartan ameliorated splanchnic SNA BRS and restored peripheral chemoreflex responses in renal, splanchnic, and lumbar SNA [10•]. Role of the Renal Afferents in CKD The kidney contains afferent sensory nerve fibers located primarily in the corticomedullary connective tissue of the renal pelvic wall and the major vessels, where they sense stretch or chemostimulation [84, 85]. The afferents project to the ipsilateral dorsal root ganglia and the dorsal horn in the spinal cord [86]. They synapse onto neurons in medullary and hypothalamic regions, including the NTS, RVLM, and PVN [87]. Stretch activation of renal afferent fibers evokes an inhibitory renorenal reflex response in which a compensatory natriuresis and diuresis due to diminished efferent renal SNA is observed in the contralateral kidney. This is important in the coordination of renal excretory function and facilitation of homeostatic regulation of sodium and water balance [88]. A negative feedback loop also exists in which efferent renal SNA facilitates increases in afferent renal nerve activity, which in turn triggers a reflex renal sympathoinhibitory response. This mechanism is crucial for the regulation of excess renal sodium [88]. In states of renal insult, activation of excitatory renal afferent nerve fibers and impaired inhibitory renorenal reflex ensue, contributing to increased peripheral SNA, vasoconstriction, and increased arterial BP [27, 88]. In CKD, signals arising in the failing kidneys appear to mediate sympathetic activation [26], hence constituting another mechanism by which autonomic imbalance may be driven in renal disease. The role of the renal afferents in driving


sympathetic overactivity in CKD remains an area of active investigation; however, current evidence from animal studies suggests that abrogation of the afferent sensory signals by nephrectomy or dorsal rhizotomy, a selective severing of the afferent renal nerves at their entrance to the ganglionic dorsal root, prevents increases in the turnover rate and secretion of NE from the posterior hypothalamic nuclei, reduces SNA, ameliorates elevations in BP, improves renal function, and slows CKD progression [89, 90••, 91]. These findings indicate that afferent impulses from the diseased kidney to central integrative structures in the brain elicit increased sympathetic nerve discharge and contribute to hypertension and deterioration of renal function in CKD. Various factors are thought to play a role in activation of the renal afferents and the consequent upregulation of the neuroadrenergic drive. Animal studies show that circulating uremia-related toxins likely excite the renal afferent nerves, provoking a sustained activation of SNA and increasing BP [26, 45•]. However, Hausberg et al. [90••] showed that correction of uremia in patients who had received renal transplantation did not alter baseline levels of muscle SNA relative to patients on regular hemodialysis therapy. These data indicate that increased SNA appears to be mediated by signals arising in the native kidneys that possibly are independent of circulating uremia-related toxins. Another possible activator of the renal afferent neurons, and perhaps one of the most important primary events in SNA, is renal ischemic damage and resultant fibroproliferative scarring in the failing kidneys [92]. This notion is supported by animal studies in which normal BP was restored upon deafferentation of the clipped kidney in the two-kidney, oneclip (2K-1C) rat model of hypertension [93]. Further evidence from human studies shows normalization of BP and muscle SNA responses following amelioration of impaired renal perfusion and local tissue ischemia in patients with renal artery stenosis [94]. A similar ischemic injury due to renal cyst growth is observed in hypertensive PKD patients, in whom increases in muscle SNA are thought to be driven by stimulation of the renal afferent fibers [28, 95]. The mechanism by which renal ischemia activates the renal afferents is complex; however, a role for mechano- and chemoreceptor-mediated secretion of adenosine, a chemical mediator, in response to local hypoxia has been proposed based on studies showing that an adenosine infusion in humans and experimental animals stimulated SNA [93, 96]. The RAAS pathway also is activated by local ischemia, possibly contributing further to sympathetic stimulation [45•]. Cardiovascular Remodeling in CKD Up to this point, this review shows how altered autonomic function and particularly increased SNS activity might contribute to changes in cardiovascular structure and function in


CKD. However, it also is important to note that the relationship between changes in autonomic outflow and cardiovascular remodeling is bidirectional and that altered structure of the heart and vasculature similarly may influence sympathetic and cardiovagal tone during renal disease (Fig. 2). Vascular remodeling and arterial stiffness are evident both in animal models of CKD and in humans with chronic renal failure [97, 98]. The process is characterized mainly by arterial hypertrophy and calcification, elevated tissue collagen deposition, and increased focal rupture of elastin fibers in the vascular wall [17, 98–100]. These effects may have a negative impact on arterial distensibility and the velocity of BP pulse wave propagation [51], ultimately impairing the ability of arterial baroreceptors to signal BP to the central nervous system (CNS) effectively. The inability to transduce BP changes to the brain, as recently shown in our CKD model in which impaired baroreceptor afferent function correlated with vascular remodeling in the aortic arch [13••], then is associated with defective baroreflex control of autonomic outflows and altered tonic levels of sympathetic and vagal efferent activity. Indeed, studies have shown a negative association between BRS and the magnitude of vascular calcification [97, 101] and arterial stiffness [70] in chronic hemodialysis patients. In renal transplant patients, increased levels of muscle SNA were correlated Fig. 2 Effects of cardiovascular remodeling on sensory afferent and reflex efferent activity in CKD. Note that the ability to evoke a reflex change in sympathetic and parasympathetic outflows depends on the magnitude of the sensory afferent signal traveling to the brain. With arterial remodeling and cardiac hypertrophy, afferent nerve traffic is reduced, which corresponds to a parallel reduction in reflex sympathetic and parasympathetic nerve activity

Page 7 of 20 59

with impaired arterial distensibility [102]. Together, these observations indicate an imperative role for vascular remodeling in cardiovascular autonomic dysfunction in CKD. In addition to vascular abnormality, cardiac structural changes also may be identified in CKD patients, leading to LVH or dilated cardiomyopathy [103, 104]. Factors increasing myocardial oxygen demand, including volume overload [105], sympathetic overstimulation [78, 105], anemia [73, 105], and hypertension [104], or trophic effects exerted by catecholamines [25, 45•], Ang II [59], and aldosterone [106, 107, 41] on cardiac myocytes have been implicated in the pathogenesis of cardiac damage in CKD, leading to fibroblast proliferation, interstitial accumulation of collagen, and microvessel disease [59]. Regarding reflex regulation of autonomic outflow, cardiac structural abnormalities also may influence reflex control of sympathetic and parasympathetic nerve activity, perhaps by interfering with the normal function of autonomic reflexes (e.g., the cardiopulmonary reflex) initiated at the level of the heart. This view is supported by studies showing greater cardiopulmonary reflex deficits, evidenced by impaired reflex changes in forearm vascular resistance to passive leg raising and manipulation of central venous and body negative pressures, in hypertensive patients with LVH compared with hypertensive subjects with no evidence of altered cardiac structure [108], suggesting impaired cardiopulmonary

59

Page 8 of 20

reflex control of sympathetic vasomotor tone in LVH. In the spontaneously hypertensive rats (SHR), in which LVH is evident, cardiopulmonary reflexes activated via changes in cardiac filling pressure (volume-sensitive reflex) and chemical stimulation (chemosensitive reflex) are impaired [109]. Regression of LVH with ACEI therapy restores the volume-sensitive, but not the chemosensitive, reflex control of SNA and HR in these animals [109]. It therefore is possible that LVH-mediated abnormalities in the reflex control of autonomic outflow may relate to polymorphic changes in the mechanosensitive and chemosensitive receptors in the cardiac chambers, rendering them less efficient in detecting and/or signaling changes in ventricular filling pressures and blood composition in CKD. Altered Nitric Oxide Bioavailability in CKD Nitric oxide, perhaps the most important molecule produced by the vascular endothelium [110], is synthesized from the amino acid L-arginine by the action of the enzyme NO synthase (NOS) [51]. Evidence suggests an interaction between NO and the ANS at both central and peripheral levels [51], hence the importance of this molecule in the regulation of autonomic activity. It now is well accepted that NO retains a tonic sympathoinhibitory effect on the CNS [111]. Intravenous or intracerebroventricular administration of NOS inhibitors increases plasma NE levels and/or SNA [112, 113], and these effects are abolished by cervical spine section [113], ganglionic blockade [114], sympathectomy [115], and βadrenoceptor blockade [112]. Further confirmation of the putative dependency of the ANS on the modulatory effect of NO was derived from experiments showing increased sympathetic nerve responses to microinjection of NOS inhibitors into the NTS [116] and RVLM [117]. NOS-positive neurons capable of modulating SNA also were identified in the PVN [118]. Nitric oxide also plays a key role in the autonomic control of HR, as NOS inhibition increases sympathetic drive to the heart yet virtually blunts cardiac vagal tone [114]. A role for NO in regulating baroreflex function was described in studies reporting impaired baroreflex control of HR, but not SNA, in human subjects following NOS inhibition [119]. Many lines of evidence suggest the presence of endothelial dysfunction, progressive attenuation of NOS activity, and therefore reduced NO bioavailability in CKD [5, 120, 121]. A reduction in NO bioavailability in CKD patients may relate to reduced availability of the NO precursor L-arginine, impaired NOS activity, or accumulation of natural inhibitory metabolites of NO synthesis, such as asymmetric dimethyl arginine and elevated cholesterol levels [5, 45•, 55]. Despite reports emphasizing a key role for NOS and NO in restraining central sympathetic outflow in normotensive [112, 113] and hypertensive conditions [122], little is known about its central action in CKD. In 5/6 nephrectomized rats in which NOS was


inhibited with Nω-nitro-L-arginine methyl ester (L-NAME), Ye et al. [123] demonstrated a significant increase in NE turnover rate in the posterior hypothalamic nuclei, the locus coeruleus, and the NTS and a marked increase in BP. Enhanced local NOS gene expression partially mitigated these effects, and L-arginine supplementation produced an opposite effect on brain NE turnover rate. These data suggest an imperative role for NO in the central regulation of sympathetic outflow and neurogenic control of BP. The mechanism by which NO depletion triggers activation of the SNS in CKD is incompletely understood; however, it likely is the result of increased production of reactive oxygen species and oxidative stress [122, 124]. Mental Stress in CKD Emotional, psychosocial, and environmental stressors are major but modifiable risk factors for hypertension and CVD [20, 44], with augmented reactivity to [125] and delayed recovery from [126] stress associated with increased morbidity and mortality. Impaired autonomic control of HR, evidenced by a reduction in HRV [127], and increased sympathetic activity [128], possibly due to primary central sympathetic excitation [129], have been associated with stress exposure. Adrenergic stimulation during psychological stress is governed by a complex mechanism, with central neuropeptides believed not only to evoke direct sympathetic activation but also to induce the release of other stress hormones that may feed forward sympathetic activation, including glucocorticoids and renin [130]. Accordingly, observations from these studies suggest a pivotal role for stress factors in mediating autonomic imbalance and CVD. Altered autonomic activity and psychological distress are related to increased cardiovascular morbidity and mortality in CKD patients [131]. However, research perhaps has not given enough credit to the role of mental stress in driving altered sympathovagal balance in CKD. Given the feasibility by which stress can be modified in CKD relative to other modifiable risk factors, more investigations are required to characterize the role of stress in driving CVD in CKD patients. Most recently, in 4/6 nephrectomized rats, Palkovits et al. [132] demonstrated that CKD elicits high activity in several stressand pain-related brain regions, including the limbic system, hypothalamus, and circumventricular organs [132]. However, it remains to be determined whether stress-mediated activation of these brain regions promotes altered autonomic function in CKD and subsequent cardiovascular complications. Other Factors Contributing to Autonomic Imbalance in CKD Other potential factors that may affect autonomic balance in CKD are as follows:


Insulin Insulin resistance and compensatory hyperinsulinemia are common in both diabetic and nondiabetic CKD patients and increase as the GFR decreases over the course of the disease [133, 134]. Evidence exists that insulin resistance and elevated circulating plasma insulin levels cause sympathetic activation, impaired BRS, and hypertension or potentiate the hypertensive effects of other pressor agents, including Ang II [135, 136]. It therefore is possible that insulin resistance can promote increased sympathetic activity and altered autonomic balance in CKD. Endothelin Endothelin, a vasoconstrictor peptide produced by endothelial cells, plays an important role in regulating vascular tone and renal function [137], and levels are elevated in hypertensive CKD and non-CKD patients [138]. A role for endothelin in SNA regulation was proposed based on studies illustrating heightened sympathetic and BP responses to intracerebral administration of endothelin in normotensive [139] and hypertensive [140] animals. Further evidence supporting a role for endothelin in regulating autonomic function has come from studies reporting an action of endothelin on carotid bodies and cervical superior and nodose ganglia to influence baroreflex and chemoreflex regulation [141]. A role for endothelin in modulating catecholamine release from sympathetic nerve terminals and the adrenal gland also has been shown [141]. Activation of endothelin synthesis is linked to autonomic dysfunction in CKD [142]; however, additional studies are required to characterize these findings further. Renalase The discovery of renalase, an established regulator of sympathetic activity, has made the participation of SNS in the pathogenesis of autonomic imbalance in CKD more complex. Renalase is a soluble monoamine oxidase predominantly expressed in the glomeruli and proximal renal tubules as well as in cardiomyocytes and skeletal muscle [143]. Renalase, whose secretion is regulated by renal function, renal perfusion, and catecholamine levels, metabolizes catecholamines in the following order: dopamine→epinephrine→NE [143, 144]. Under basal conditions, renalase lacks significant amine oxidase activity; however, when a modest increase in BP is evoked by epinephrine, a 10-fold increase in renalase activity is observed [145]. Interestingly, renalase is readily detectable in venous plasma of healthy individuals but not in the plasma of uremic patients [5, 45•, 143, 144], suggesting that normal kidneys are a prerequisite for renalase secretion and that the protective effects of renalase against

Page 9 of 20 59

SNS overactivity are lost in CKD patients. The latter view is supported by evidence demonstrating that renalase activation induced by epinephrine was significantly reduced in magnitude and duration in a 5/6 nephrectomy rat model of CKD [145]. More recent reports also show decreased renalase secretion in the ischemic kidney compared with the nonischemic one in a rat model of unilateral renal artery stenosis [146], implicating changes in renal perfusion as a determinant. Accordingly, alterations in renalase secretion, expression, and/or enzyme activity may lead to increased plasma catecholamine and sympathetic hyperactivity in CKD. However, to what extent the impairment of renalase production contributes to sympathetic overstimulation and BP elevation in CKD remains to be elucidated. Salt Derangements in mechanisms regulating central sympathetic inhibition and consequent peripheral sympathetic activation have been linked to high salt content [147], suggesting a crucial role for salt intake/retention in mediating altered sympathetic control of cardiovascular function and evoking autonomic imbalance. The exact mechanism by which high salt intake aggravates sympathetic stimulation and hypertension in CKD is an active area of research, with salt restriction now being considered more frequently as a means of controlling BP in CKD/ESRD patients [148]. In nondialysis CKD patients, a linear relationship between salt intake and systolic BP has been identified, with salt sensitivity of BP increasing as renal function declines [149]. An inhibitory action for salt on neuronal NOS expression in the posterior hypothalamic nuclei, the locus coeruleus, and the PVN was suggested by Campese et al. [150] as a possible mechanism related to the high-salt-mediated action of the SNS. A role also was proposed for brain oxidative stress in driving sympathoexcitation in response to salt load in uninephrectomized rats [151]. Atrial Natriuretic Peptide Circulating levels of atrial natriuretic peptide (ANP), a powerful vasodilator produced by the atrial myocytes, are elevated in both hypertensive [152] and CKD [153] patients. Studies suggest a critical role for ANP in inhibiting hypothalamic NE release [154, 155] and enhancing cardiac vagal baroreflex and cardiopulmonary reflex function [156, 157], suggesting a potential role for ANP in modulating autonomic function. In the SHR, ANPmediated facilitation of cardiac baroreflex is absent, indicating altered ANP–ANS interaction during disease [157, 158]. The relationship between ANP and autonomic neuroregulation in health and disease is far from being completely understood, and clearly CKD is no exception.

59

Page 10 of 20

The Effect of Sex on Autonomic Function Several epidemiologic studies revealed that the prevalence, incidence, and severity of CVD in premenopausal women are markedly lower than in men of the same age [159–161]. Because these differences are lost after the onset of menopause, it has been proposed that these effects are related mainly to sex hormones that protect women against cardiovascular complications. A key question is whether the relative protection of female sex against the development of CVD is the result of a hormone-driven neuromodulatory effect on cardiovascular homeostasis. Substantial literature exists to suggest that ANS functioning and its pivotal role in cardiovascular regulation vary between men and women in health and disease. However, to date, consistent evidence has not been forwarded regarding differences in autonomic function in males and females, perhaps because of the limited number of investigations in humans and animal models comparing autonomic function in males versus females or different phases of the estrous cycle during which autonomic function was assessed. Under normal conditions, healthy men and women appear to have similar resting BP and HR [162–165]. Indices of SNS activity show either similar baseline levels in men and women [165] or reduced levels in women [162]. Relative to males, and perhaps depending on the point in the reproductive cycle at which measurements were taken [166], baroreflex control of HR in females was enhanced [163], depressed [167], or comparable [165], whereas sympathetic baroreflex function was either enhanced [162] or unchanged in both males and females [165]. Clinical studies have shown that women respond with greater changes in HR and/or total peripheral resistance when the cardiopulmonary baroreflex is activated by a head-up tilt [164] or deactivated by orthostasis [168] and that deactivation of the cardiopulmonary reflex when lower negative pressure is applied results in less change in HR in women than men [169]. Cardiopulmonary reflex control of SNA triggered by chemical and mechanical activation of the cardiopulmonary receptors in rats exhibits a greater response range in females compared with males, a phenomenon that may in turn contribute to greater renal excretory function in females [170]. Despite this range of findings, research shows that hormone replacement therapy improves baroreflex control of HR and vascular sympathetic outflow in postmenopausal women [171]. Likewise, ovariectomy enhances sympathetic activation and attenuates HR BRS, which may be ameliorated by estrogen replacement therapy [172, 173]. These observations therefore support sexual dimorphism in the control of autonomic outflows to the heart and vasculature. Likely underpinning these dissimilarities between males and females are developmental and functional variations in the reflex arc, including differences in the sensory afferent pathways (baroreceptors, cardiopulmonary receptors, or chemoreceptors),


central neurotransmission, or efferent and postsynaptic signaling pathways. Indeed, cumulative evidence confirms an impact of ovarian hormones on central mediation of vagal and sympathetic outflow [173, 174], peripheral efferent nerves [175], and signaling pathways of effector organs that respond to neurotransmitters [176]. Supporting sexual dimorphism in the central processing of autonomic outflows is the demonstration that women elicit greater reductions in plasma NE and BP in response to central inhibition of sympathetic outflow by the α2-adrenoceptor agonist clonidine [177]. Accordingly, an appreciation of sex differences in ANS functioning is critical to fully understand several common and important clinical presentations in men and women. In hypertensive conditions, women and female animal models of hypertension, including SHRs [178], Dahl saltsensitive rats [179], and renal wrap [180] and Ang II hypertension animals [181], have lower BP readings compared with hypertensive males. In some of these models where ovariectomized females were used, removal of the ovaries augmented hypertension. With regard to autonomic functions, Hogarth et al. [182] showed that hypertensive women have lower muscle SNA but comparable resting HR relative to hypertensive men. On the other hand, HRV and HR BRS are markedly lower in hypertensive women than in hypertensive men [183]. However, in rat and mouse models of hypertension, females show lower or unchanged resting HR, greater HRV and HR BRS, lower resting BP and BP variability, and/or lower sympathetic vasomotor tone, as assessed by ganglionic blockade [181, 184]. In CKD, sexual dimorphism appears to play a significant but ill-defined role in the incidence, prevalence, and progression of renal disease. Data from clinical and animal studies provide conflicting results, reporting both a slower [185] and faster [186] decline in renal function in females relative to males. Perhaps these discrepancies are a result of the lack of attention paid to the importance of sex differences in CKD pathology; clearly, studies with more standardized experimental criteria are required to characterize these findings accurately. With respect to CVD in CKD, current evidence suggests that women are at relatively lower risk of developing CVD and related complications compared with men [6]; however, it is unknown whether these effects, as shown in hypertension, are driven by a differential influence of sex on cardiovascular neuroregulatory function in CKD. Despite the many studies assessing autonomic functions in CKD, it appears that sex effects have not been well considered. Another likely reason for this scarcity of information is that most women with CKD are postmenopausal, which may be why this issue has been overlooked [187]. Therefore, plenty of work still needs to be done, as our current knowledge indicates that males and females experience CKD differently. Indeed, data from our laboratory strongly support this view; we observed that cardiac and sympathetic baroreflex dysfunction in male CKD rats was


related to temporal deficits in the functionality of the afferent and central components of the baroreflex arc [13••], whereas impaired HR and sympathetic baroreflex in the female rats appeared to result primarily from a decline in the central processing of baroreceptor afferent input only [71••]. These data highlight the importance of sexual dimorphism in investigating pathophysiologic mechanisms relating to CKD and that females should not be underrepresented in research investigations or clinical trials.

Current Interventional Strategies Targeting the ANS in CKD Cardiovascular autonomic dysfunction is a major contributor to CVD in CKD patients and likely underlies the high morbidity and mortality rates in this patient population [21•]. Current evidence suggests that deficits in autonomic function and elevated BP are driven by the diseased kidneys, because nephrectomy, renal denervation, kidney transplantation, and pharmacotherapy targeting sympathetic activation have been shown to correct BP, lower sympathetic overdrive, improve vagal control of HR, and/or limit the progression of renal damage in humans and experimental animals [32, 33, 34••, 35]. Pharmacologic Treatment Pharmacologic agents that directly or indirectly modulate autonomic function currently are used to limit hypertension and progression of renal disease in CKD. Based on the suggested reciprocal potentiation of RAAS and SNS in renal disease [188], inhibition of the RAAS pathway seems to be a logical step in treating CKD. Indeed, RAAS inhibitors, including ACEIs and ARBs, are recommended as first-line therapy in patients with CKD [40, 189]. In addition to counteracting direct cardiovascular manifestations of Ang II, ACEIs and ARBs indirectly suppress SNA in CKD patients [9, 49••] and have comparable sympathoinhibitory and antihypertensive effects [37]. The combination of ACEIs and ARBs provides more effective RAAS inhibition, better BP control, and superior reductions in serum creatinine levels and proteinuria [190]. However, no reports exist in the literature of additional sympathoinhibition with combination therapy. RAAS blockers also are shown to reset sympathetic baroreflex function toward a lower BP with [10•] or without altering sympathetic BRS [10•, 49••], and HRV appears to improve in patients receiving ACEIs and ARBs [22, 191]; however, a worsening of HRV with ACEIs also has been observed [192]. The extent to which RAAS inhibitors can reduce SNA in CKD, on the other hand, is debated. Ligtenberg et al. [193•] measured muscle SNA response in CKD patients treated with an intravenous infusion of the ACEI enalapril. They found that

Page 11 of 20 59

enalapril normalized muscle SNA to levels comparable with those of controls. In a series of studies by Neumann et al. [9], muscle SNA normalized only when the ARB eprosartan was combined with the central sympatholytic agent moxonidine, but not when ACEI or ARB monotherapy was given. Although the reason for these controversial findings is not completely understood, it may relate to differences in drug potency, dosage, and/or route of administration. More recently, a similar sympathoinhibitory effect of the renin inhibitor aliskiren was demonstrated in CKD patients when it was used with statin therapy [194]. However, like the findings of Neumann et al., normalized muscle SNA responses were not observed with aliskiren alone, nor did statins improve HRV in ESRD patients receiving chronic hemodialysis [195]. Studies evaluating the effects of adrenergic blockers and central sympatholytics in CKD are scarce, with reports of beneficial effects only when these agents were combined with RAAS blockers or calcium channel antagonists [132, 193•, 196, 197]. β-Blockers and central imidazoline α 2 adrenoceptor agonists are reported to slow the deterioration of renal structure and function in CKD, based on observations of reduced glomerulosclerosis and progression of renal failure in 5/6 or subtotal nephrectomized rats [198, 199] and a reduction in albuminuria in hypertensive CKD patients [200]. Current evidence also suggests that β-blockers, relative to RAAS inhibitors, are underused in CKD [200], despite data reporting cardioprotective action [201] and renoprotective effects comparable to those of ACEIs [196]. With regard to autonomic function, β-receptor blockade appears to markedly improve HRV and cardiac autonomic balance in ESRD patients [64]. Likewise, moxonidine appears to lower muscle SNA in ESRD on preexisting antihypertensive therapy [64, 202]. Surprisingly, though, studies directly assessing SNA in CKD patients treated with adrenoceptor blockers are lacking. In patients with essential hypertension, however, long-term βadrenoceptor blockade with metaprolol [203], but not atenolol [204], appears to lower muscle SNA. Long-term treatment with calcium channel blockers (e.g., amlodipine) appears to increase muscle SNA in CKD patients [49••], which perhaps is mediated by the baroreflex-induced activation of SNA in the face of the significant drop in BP elicited by this class of compounds. Percutaneous Renal Denervation As reviewed earlier, afferent signaling derived from the native kidney may play a role in efferent sympathoexcitation in CKD. Consequently, interrupting the efferent and afferent renal nerve fibers by renal denervation is an attractive approach to mitigate sympathetic hyperactivity and reverse autonomic imbalance in CKD. Accordingly, percutaneous renal denervation, a catheter-based approach that uses radiofrequency bursts to disrupt the renal sympathetic nerves in the adventitia

59

Page 12 of 20

of the renal arteries, has emerged as a promising treatment for sympathetic excitation in CKD [188]. The concept of renal denervation is not new; this method has been used often to study the influence of the SNS on renal function in experimental animals. Smithwick et al. [205], in 1953, were the first to bring surgical renal denervation into clinical practice when they used it to treat patients with resistant hypertension. Despite compelling benefits and improved survival, the invasiveness of the surgery and the discovery of more effective antihypertensive drugs rendered this procedure obsolete. Today, our knowledge of and renewed interest in renal denervation are based on decades of refining what had been known as an extremely invasive procedure with a high risk of intraoperative mortality and long-term complications. A population of patients with hypertension unresponsive to conventional pharmacotherapy and the substantial risks associated with polypharmacy has led to renewed interest in this approach to lower BP, counteract the sympathetic overdrive observed in patients with essential hypertension and CKD, and limit cardiovascular complications and end-organ damage. Besides lowering BP, which itself can slow the progression of kidney disease [206], renal denervation appears to offer a range of therapeutic benefits independent of BP reduction, including decreased renin production, improved renal hemodynamics, enhanced GFR, and reduced albuminuria [32, 207]. In patients with moderate to severe CKD, however, BP reduction after renal denervation was not associated with improved GFR [33]. With regard to autonomic function, it remains to be determined whether renal denervation reduces muscle SNA or improves reflex control of HR and SNA in CKD in the long term. Studies on basal muscle SNA in renally denervated hypertensive CKD or non-CKD patients yielded mixed results, with reports of lowered [34••, 208] or unchanged [209] muscle SNA. Similar controversial findings also were reported regarding the effect of renal denervation on HR and SNA baroreflex function in hypertensive humans and animals. In studies using pharmacologic manipulation of BP, baroreflex control of HR and muscle SNA remained unaltered in hypertensive patients [209]. Spontaneous BRS, in contrast, appears to be improved in the SHR as well as in patients with resistant hypertension following renal denervation [210]. The reimplementation of this procedure in clinical practice is relatively new. Most recently, the SYMPLICITY HTN-3 study, a controlled trial of renal denervation for resistant hypertension, showed no significant reduction in systolic BP in patients with resistant hypertension compared with sham controls 6 months after renal artery denervation [211]; however, conclusive evidence regarding long-term safety was not provided. Therefore, more studies are required to determine the safety, feasibility, efficacy, and durability of this approach [212]. Intriguingly, however, preliminary data show that the BP-lowering effect of renal denervation appears to correlate inversely with kidney function at baseline, suggesting that renal denervation in CKD patients


may have more therapeutic advantage than in hypertensive patients with normal renal function. Carotid Baroreceptor Stimulation Carotid baroreceptor stimulation is an invasive procedure involving the implantation of a device that electrically stimulates the baroreceptors in the carotid sinus of a hypertensive patient. The result is baroreflex-mediated sympathoinhibition and enhanced reflex control of vagal drive. Accordingly, this surgical technique serves two purposes: to provide information on the functioning of baroreflex mechanisms in hypertensive patients and to achieve satisfactory BP control in patients with resistant hypertension, including those with CKD [213]. Indeed, research shows that carotid stimulation of baroreceptors evokes a profound sympathoinhibitory response and sustained reductions in BP [214, 215]. These observations suggest the importance of adrenergic overdrive in maintaining high BP in hypertensive subjects and the potent BP-lowering effects of the intervention in resistant hypertensive states. The reflex-mediated sympathoinhibition, evidenced by reductions in plasma NE and muscle SNA, is not associated with changes in plasma renin activity or differences in sympathetic and HR baroreflex function [214]. Although this technique has not yet been studied in CKD patients or animal models of renal disease, preliminary findings in hypertensive subjects suggest its potential as a new treatment option for resistant hypertension in CKD patients. Renal Replacement Therapy Renal replacement therapy does not treat uremic autonomic disturbances in CKD directly; rather, a relative correction of autonomic parameters emerges as a consequence of the treatment. Renal replacement therapy, including hemodialysis (nocturnal and short daily home hemodialysis), peritoneal dialysis (continuous ambulatory peritoneal dialysis, automated peritoneal dialysis, and a combination of both), and kidney transplantation, aims to correct and/or maintain plasma biochemistry (uremic toxins, electrolytes, and acid–base balance) within acceptable limits and is reserved for patients with advanced renal failure. Transplantation is superior to chronic dialysis and offers the best chance of long-term survival [216]. Dialysis therapy may trigger sympathetic overactivity and vagal withdrawal as a result of intradialytic hypotension caused by acute fluid removal [217]. The efficacy of longterm dialysis in ameliorating abnormalities in the ANS, on the other hand, is a subject of considerable debate. In patients receiving chronic hemodialysis or continuous ambulatory peritoneal dialysis, Dursun et al. [21•] showed significant improvements in cardiac vagal tone and HRV parameters, with patients receiving continuous ambulatory peritoneal dialysis displaying better treatment outcomes. In nondiabetic, but not diabetic, ESRD patients receiving chronic hemodialysis


therapy, Giordano et al. [218] reported a marked improvement in HRV, which correlated negatively with uremia. Mylonopoulou et al. [219], in contrast, observed enhanced HRV parameters in both diabetic and nondiabetic ESRD patients, but the effect was more pronounced in the nondiabetic population. Conversion from conventional to nocturnal hemodialysis, which allows more efficient removal of uremic toxins, was associated with improved BRS, increased HF (vagal) power of HRV, and a normalized LF/HF ratio of HRV [101, 220]. A marked drop in muscle SNA in patients receiving frequent hemodialysis also was reported [221]. Although removal of the toxic effects of uremia might explain the effects of dialysis in ameliorating tonic levels and/or reflex control of autonomic function in CKD, studies reporting no beneficial effects suggest otherwise [65, 222]. Supporting the latter view is that bilaterally nephrectomized hemodialysis patients show muscle SNA levels comparable with those of controls [26], providing substantive proof that signals arising from the diseased kidneys, rather than uremic toxins, drive changes in autonomic function in CKD. Nonetheless, the reasons for the discrepant results obtained in the dialysisdependent patients with respect to autonomic function are not fully understood; however, the differences may be related, at least partly, to factors such as age, severity of renal dysfunction, existing comorbidities, dialysis technique, and/or the composition of the dialysate solution [15]. Clearly, further studies are required to delineate the mechanisms by which longer-term dialysis therapy may or may not improve autonomic dysfunction in CKD patients. Reports describing beneficial effects of renal transplantation on parasympathetic function appear to be more consistent. Indeed, a significant improvement in tonic and reflex control of parasympathetic functions, as assessed by HF power of HRV [35, 223], spontaneous BRS [43], the BRS phenylephrine test [65, 222], and HR responses to respiration, orthostatic change, and Valsalva maneuver [65, 224], often is observed in renal transplant recipients. Although muscle SNA does not change after renal transplantation [90••], LF power of SBPV is markedly reduced [43], perhaps indicating a differential effect of renal transplantation on various sympathetic beds [65]. Reflex sympathetic function, as assessed by BP responses to orthostatic change, sustained handgrip, cold pressor, mental arithmetic, and/or sudden loud noise, either improved [65] or was unchanged [224] following kidney transplantation. Chemoreflex sensitivity derived from HRV responses to chemoreceptor deactivation by 100 % O2, on the other hand, improved in kidney transplant patients relative to patients on maintenance hemodialysis [77]. Treatment Limitations Although there is significant consensus regarding autonomic dysfunction in CKD, current interventions to contain this

Page 13 of 20 59

condition provide less clear-cut conclusions with respect to efficacy, specificity, and reproducibility. Several pharmacologic treatments have been developed to decrease sympathetic activity and BP; however, these medications have limitations. Clinical practice is limited mainly by the feasibility of current diagnostic technologies and the inability to standardize test conditions, making it a challenge to identify critical pathways driving autonomic dysfunction within the nervous system. Most methods used today to assess autonomic function in the clinic are indirect and rely mostly on simple acquisition of an ECG signal, HR, and/or BP. Perhaps the only direct, albeit time-consuming, measurement of autonomic activity is muscle or skin SNA, which may not predict changes in other sympathetic nerve beds key to BP regulation. Clearly, the pathogenesis of autonomic dysfunction in CKD is far from being completely understood, and human studies performed to date have had a limited scope for investigating specific mechanisms. The underlying mechanisms require further study before specific treatment options can be developed.

Conclusions The relationship between hypertension and CKD is complex and multifactorial. Elevated BP in CKD plays a key role in the progression of renal damage and forms the basis for cardiovascular complications and mortality. Although this point is widely recognized, BP control in CKD patients often is poor, whether the disease is in an early or advanced stage or whether the patient is receiving dialysis therapy, suggesting a limited knowledge of the underlying etiology. A better understanding of these pathologic processes is imperative to improve our treatment strategies and reduce the number of cardiovascular adverse events in the CKD population. As outlined in this review, a large body of evidence points to neurogenic mechanisms as potential drivers of increased SNA, autonomic dysfunction, and hypertension in CKD; however, our understanding of these mechanisms is only beginning to grow. With regard to the autonomic network, the central pathways regulating tonic and reflex function appear to have a critical role in promoting autonomic deficits and, thus, altered control of BP in CKD. Yet to be determined are the prevalent pathophysiologic mechanisms underlying CKD-related hypertension, the best antihypertensive therapies for CKD patients, and whether the treatment approach should be chosen based on sex. Acknowledgments The author acknowledges constructive feedback on the manuscript provided by Professor Jacqueline Phillips, Dr Cara Hildreth (Macquarie University, Australia), Dr Clive May (University of Melbourne, Australia), Dr Virginia Brooks (Oregon Health and Science University, USA), and Dr Ann Schreihofer (University of North Texas Health Science Center, USA).

59

Page 14 of 20

Compliance with Ethics Guidelines Conflict of Interest Ibrahim M. Salman declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.•

11.

Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int. 2011;80(12):1258–70. doi:10.1038/ki.2011.368. Collins AJ, Foley RN, Gilbertson DT, Chen SC. The state of chronic kidney disease, ESRD, and morbidity and mortality in the first year of dialysis. Clin J Am Soc Nephrol CJASN. 2009;4 Suppl 1:S5–11. doi:10.2215/cjn.05980809. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol. 2006;17(7):2034–47. doi:10.1681/asn. 2005101085. U.S. renal data system. U.S. renal data system annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. National institutes of health, national institute of diabetes and digestive and kidney diseases, Bethesda, MD2013 Jan. Report No.: 1523–6838 (Electronic) 0272–6386 (Linking). Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116(1):85– 97. doi:10.1161/circulationaha.106.678342. Kidney disease outcomes quality initiative (KDOQI) clinical practice guideline for chronic kidney disease care [database on the Internet]. National kidney foundation http://www.kidney.org/. 2013. Accessed. Wuhl E, Schaefer F. Managing kidney disease with blood-pressure control. Nat Rev Nephrol. 2011;7(8):434–44. doi:10.1038/ nrneph.2011.73. Morgado E, Neves PL. Hypertension and chronic kidney disease: cause and consequence—therapeutic considerations. In: Babaei H, editor. Antihypertensive drugs. Rijeka: InTech; 2012. Neumann J, Ligtenberg G, Klein IH, Boer P, Oey PL, Koomans HA, et al. Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment. Hypertension. 2007;49(3):506–10. doi:10.1161/01.HYP. 0000256530.39695.a3. Yao Y, Hildreth CM, Farnham MM, Saha M, Sun QJ, Pilowsky PM, et al. The effect of losartan on differential reflex control of sympathetic nerve activity in chronic kidney disease. J Hypertens. 2015. doi:10.1097/hjh.0000000000000535. This recent observational study assessed the role of the renin– angiotensin system in triggering differential reflex sympathetic responses in a rat model of CKD. Ameer OZ, Hildreth CM, Phillips JK. Sympathetic overactivity prevails over the vascular amplifier phenomena in a chronic kidney disease rat model of hypertension. Physiol Rep 2014;2(11). doi:10.14814/phy2.12205.

Curr Hypertens Rep (2015) 17:59 12.•• Grassi G, Quarti-Trevano F, Seravalle G, Arenare F, Volpe M, Furiani S, et al. Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension. 2011;57(4):846–51. This well-executed clinical study demonstrated increases in SNA during the early stages of renal disease that contribute to further decline in GFR in patients with CKD. 13.•• Salman IM, Hildreth CM, Ameer OZ, Phillips JK. Differential contribution of afferent and central pathways to the development of baroreflex dysfunction in chronic kidney disease. Hypertension. 2014;63(4):804–10. doi:10.1161/hypertensionaha.113.02110. This was the first study to provide a comprehensive investigation of mechanisms of altered baroreflex function in a rat model of CKD. 14. Hildreth CM, Kandukuri DS, Goodchild AK, Phillips JK. Temporal development of baroreceptor dysfunction in a rodent model of chronic kidney disease. Clin Exp Pharmacol Physiol. 2013;40(7):458–65. 15. Robinson TG, Carr SJ. Cardiovascular autonomic dysfunction in uremia. Kidney Int. 2002;62(6):1921–32. 16. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med. 2003;139(9):761–76. 17. Ameer OZ, Salman IM, Avolio AP, Phillips JK, Butlin M. Opposing changes in thoracic and abdominal aortic biomechanical properties in rodent models of vascular calcification and hypertension. Am J Physiol Heart Circ Physiol. 2014. doi:10.1152/ ajpheart.00139.2014. 18. Passauer J, Pistrosch F, Bussemaker E, Lassig G, Herbrig K, Gross P. Reduced agonist-induced endothelium-dependent vasodilation in uremia is attributable to an impairment of vascular nitric oxide. J Am Soc Nephrol. 2005;16(4):959–65. doi:10.1681/asn. 2004070582. 19. Hildreth CM. Prognostic indicators of cardiovascular risk in renal disease. Front Physiol. 2011;2:121. doi:10.3389/fphys.2011. 00121. 20. Pal GK, Pal P, Nanda N, Amudharaj D, Adithan C. Cardiovascular dysfunctions and sympathovagal imbalance in hypertension and prehypertension: physiological perspectives. Futur Cardiol. 2013;9(1):53–69. doi:10.2217/fca.12.80. 21.• Dursun B, Demircioglu F, Varan HI, Basarici I, Kabukcu M, Ersoy F, et al. Effects of different dialysis modalities on cardiac autonomic dysfunctions in end-stage renal disease patients: one year prospective study. Ren Fail. 2004;26(1):35–8. This prospective clinical study not only demonstrated cardiac autonomic dysfunction in ESRD patients but also showed that continuous ambulatory peritoneal dialysis had a better effect on cardiac autonomic indices than hemodialysis. 22. Ranpuria R, Hall M, Chan CT, Unruh M. Heart rate variability (HRV) in kidney failure: measurement and consequences of reduced HRV. Nephrol Dial Transplant. 2008;23(2):444–9. 23. Shamseddin MK, Parfrey PS. Sudden cardiac death in chronic kidney disease: epidemiology and prevention. Nat Rev Nephrol. 2011;7(3):145–54. doi:10.1038/nrneph.2010.191. 24. Johansson M, Gao SA, Friberg P, Annerstedt M, Carlstrom J, Ivarsson T, et al. Baroreflex effectiveness index and baroreflex sensitivity predict all-cause mortality and sudden death in hypertensive patients with chronic renal failure. J Hypertens. 2007;25(1):163–8. 25. Zoccali C, Mallamaci F, Tripepi G, Parlongo S, Cutrupi S, Benedetto FA, et al. Norepinephrine and concentric hypertrophy in patients with end-stage renal disease. Hypertension. 2002;40(1):41–6. 26. Converse Jr RL, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992;327(27):1912–8. 27. Campese VM, Krol E. Neurogenic factors in renal hypertension. Curr Hypertens Rep. 2002;4(3):256–60.

Curr Hypertens Rep (2015) 17:59 28.

Koomans HA, Blankestijn PJ, Joles JA. Sympathetic hyperactivity in chronic renal failure: a wake-up call. J Am Soc Nephrol. 2004;15(3):524–37. 29. Neahring JC, Jones SY, DiBona GF. Cardiopulmonary baroreflex function in nephrotic rats. J Am Soc Nephrol. 1995;5(12):2082–6. 30. Rassaf T, Schueller P, Westenfeld R, Floege J, Eickholt C, Hennersdorf M, et al. Peripheral chemosensor function is blunted in moderate to severe chronic kidney disease. Int J Cardiol. 2012;155(2):201–5. 31. Tinucci T, Abrahao SB, Santello JL, Mion Jr D. Mild chronic renal insufficiency induces sympathetic overactivity. J Hum Hypertens. 2001;15(6):401–6. 32. Gattone 2nd VH, Siqueira Jr TM, Powell CR, Trambaugh CM, Lingeman JE, Shalhav AL. Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease. Exp Biol Med (Maywood, NJ). 2008;233(8):952–7. doi:10.3181/ 0802-rm-54. 33. Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol. 2012;23(7):1250–7. 34.•• Schlaich MP, Bart B, Hering D, Walton A, Marusic P, Mahfoud F, et al. Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. Int J Cardiol. 2013;168(3):2214–20. doi: 10.1016/j.ijcard.2013.01.218. This unique clinical study showed reductions in both BP and muscle SNA in renally denervated hypertensive patients with ESRD. 35. Yildiz A, Sever MS, Demirel S, Akkaya V, Turk S, Turkmen A, et al. Improvement of uremic autonomic dysfunction after renal transplantation: a heart rate variability study. Nephron. 1998;80(1):57–60. 36. Harris DC, Rangan GK. Retardation of kidney failure—applying principles to practice. Ann Acad Med Singap. 2005;34(1):16–23. 37. Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure. J Am Soc Nephrol. 2003;14(2):425–30. 38. Herzog CA. Cardiac arrest in dialysis patients: approaches to alter an abysmal outcome. Kidney Int Suppl. 2003;84(200):S197–200. 39. Kashihara N, Satoh M. Molecular pathogenesis of chronic kidney disease. Nihon Rinsho Jpn J Clin Med. 2008;66(9):1671–7. 40. Masuo K, Lambert GW, Esler MD, Rakugi H, Ogihara T, Schlaich MP. The role of sympathetic nervous activity in renal injury and end-stage renal disease. Hypertens Res Off J Jpn Soc Hypertens. 2010;33(6):521–8. doi:10.1038/hr.2010.35. 41. Jeewandara TM, Ameer OZ, Boyd R, Wyse BF, Underwood CF, Phillips JK. Protective cardiorenal effects of spironolactone in a rodent model of polycystic kidney disease. Clin Exp Pharmacol Physiol. 2015;42(4):353–60. doi:10.1111/1440-1681.12372. 42. Li Y-L. Cardiovascular autonomic dysfunction in diabetes as a complication: cellular and molecular mechanisms. In: Wagner D, editor. Type 1 diabetes complication. Rijeka: InTech; 2011. 43. Rubinger D, Backenroth R, Sapoznikov D. Restoration of baroreflex function in patients with end-stage renal disease after renal transplantation. Nephrol Dial Transplant. 2009;24(4):1305–13. doi:10.1093/ndt/gfn732. 44. Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol. 2010;141(2):122–31. doi:10.1016/j. ijcard.2009.09.543. 45.• Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, Straznicky N, et al. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009;20(5):933–9. This excellent review summarizes the deleterious effects of SNS hyperactivity in CKD, as well as its possible underlying mechanisms.

Page 15 of 20 59 46.

47.

48.

49.••

50.

51.

52.

53.

54.

55.

56. 57.

58.

59.

60.

61.

62.

Schohn D, Weidmann P, Jahn H, Beretta-Piccoli C. Norepinephrine-related mechanism in hypertension accompanying renal failure. Kidney Int. 1985;28(5):814–22. Levitan D, Massry SG, Romoff M, Campese VM. Plasma catecholamines and autonomic nervous system function in patients with early renal insufficiency and hypertension: effect of clonidine. Nephron. 1984;36(1):24–9. Phillips JK, Hopwood D, Loxley RA, Ghatora K, Coombes JD, Tan YS, et al. Temporal relationship between renal cyst development, hypertension and cardiac hypertrophy in a new rat model of autosomal recessive polycystic kidney disease. Kidney Blood Press Res. 2007;30(3):129–44. Ligtenberg G, Blankestijn PJ, Oey PL, Klein IH, Dijkhorst-Oei LT, Boomsma F, et al. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med. 1999;340(17):1321–8. This clinical study was one of the first to assess sympathetic baroreflex function in CKD patients. Park J, Campese VM, Nobakht N, Middlekauff HR. Differential distribution of muscle and skin sympathetic nerve activity in patients with end-stage renal disease. J Appl Physiol (Bethesda, Md : 1985). 2008;105(6):1873–6. doi:10.1152/japplphysiol.90849. 2008. Bruno RM, Ghiadoni L, Seravalle G, Dell'oro R, Taddei S, Grassi G. Sympathetic regulation of vascular function in health and disease. Front Physiol. 2012;3:284. doi:10.3389/fphys.2012.00284. Sahin M, Kayatas M, Urun Y, Sennaroglu E, Akdur S. Performing only one cardiovascular reflex test has a high positive predictive value for diagnosing autonomic neuropathy in patients with chronic renal failure on hemodialysis. Ren Fail. 2006;28(5):383–7. doi: 10.1080/08860220600683722. Lewanski R, Chrzanowski W. Assessment of autonomic nervous system by spectral analysis of heart rate and blood pressure in hemodialysed patients. Pol Merkur Lekarski Org Polskiego Towarz Lekarskiego. 2003;15(88):391–3. Badve SV, Roberts MA, Hawley CM, Cass A, Garg AX, Krum H, et al. Effects of beta-adrenergic antagonists in patients with chronic kidney disease: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(11):1152–61. doi:10.1016/j.jacc.2011.04. 041. Grassi G, Seravalle G, Ghiadoni L, Tripepi G, Bruno RM, Mancia G, et al. Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease. Clin J Am Soc Nephrol CJASN. 2011;6(11):2620–7. doi:10.2215/cjn.06970711. Adamczak M, Zeier M, Dikow R, Ritz E. Kidney and hypertension. Kidney Int Suppl. 2002;80:62–7. Erami C, Zhang H, Ho JG, French DM, Faber JE. Alpha(1)adrenoceptor stimulation directly induces growth of vascular wall in vivo. Am J Physiol Heart Circ Physiol. 2002;283(4):H1577–87. doi:10.1152/ajpheart.00218.2002. Zhang H, Faber JE. Trophic effect of norepinephrine on arterial intima-media and adventitia is augmented by injury and mediated by different alpha1-adrenoceptor subtypes. Circ Res. 2001;89(9): 815–22. Raizada V, Hillerson D, Amaram JS, Skipper B. Angiotensin IImediated left ventricular abnormalities in chronic kidney disease. J Investig Med Off Publ Am Fed Clin Res. 2012;60(5):785–91. doi: 10.231/JIM.0b013e318250b101. Grisk O, Rettig R. Interactions between the sympathetic nervous system and the kidneys in arterial hypertension. Cardiovasc Res. 2004;61(2):238–46. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003;108(5): 560–5. doi:10.1161/01.cir.0000081775.72651.b6. Guizar-Mendoza JM, Amador-Licona N, Lozada EE, Rodriguez L, Gutierrez-Navarro M, Dubey-Ortega LA, et al. Left ventricular

59

63.

64.

65.

66.

67.

68.

69.

70.

71.••

72.

73.

74.

75.

76. 77.

78.


Page 16 of 20 mass and heart sympathetic activity after renal transplantation in children and young adults. Pediatr Nephrol. 2006;21(10):1413–8. doi:10.1007/s00467-006-0238-8. Mircoli L, Rivera R, Bonforte G, Fedele L, Genovesi S, Surian M, et al. Influence of left ventricular mass, uremia and hypertension on vagal tachycardic reserve. J Hypertens. 2003;21(8):1547–53. doi:10.1097/01.hjh.0000084720.53355.ad. Tory K, Horvath E, Suveges Z, Fekete A, Sallay P, Berta K, et al. Effect of propranolol on heart rate variability in patients with endstage renal disease: a double-blind, placebo-controlled, randomized crossover pilot trial. Clin Nephrol. 2004;61(5):316–23. Agarwal A, Anand IS, Sakhuja V, Chugh KS. Effect of dialysis and renal transplantation on autonomic dysfunction in chronic renal failure. Kidney Int. 1991;40(3):489–95. de Ferrari GM, Vanoli E, Stramba-Badiale M, Hull Jr SS, Foreman RD, Schwartz PJ. Vagal reflexes and survival during acute myocardial ischemia in conscious dogs with healed myocardial infarction. Am J Physiol. 1991;261(1 Pt 2):H63–9. Di Rienzo M, Parati G, Castiglioni P, Tordi R, Mancia G, Pedotti A. Baroreflex effectiveness index: an additional measure of baroreflex control of heart rate in daily life. Am J Physiol Regul Integr Comp Physiol. 2001;280(3):R744–51. Johnson PL, Shekhar A. Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. J Neurosci Off J Soc Neurosci. 2006;26(26): 7093–104. doi:10.1523/jneurosci.0408-06.2006. Lacy P, Carr SJ, O'Brien D, Fentum B, Williams B, Paul SK, et al. Reduced glomerular filtration rate in pre-dialysis non-diabetic chronic kidney disease patients is associated with impaired baroreceptor sensitivity and reduced vascular compliance. Clin Sci (London, England : 1979). 2006;110(1):101–8. doi:10.1042/ cs20050192. Studinger P, Lenard Z, Mersich B, Reusz GS, Kollai M. Determinants of baroreflex function in juvenile end-stage renal disease. Kidney Int. 2006;69(12):2236–42. doi:10.1038/sj.ki. 5000307. Salman IM, Phillips JK, Ameer OZ, Hildreth CM. Abnormal central control underlies impaired baroreflex control of heart rate and sympathetic nerve activity in female Lewis polycystic kidney rats. J Hypertens. 2015. This was the first observational study to provide a mechanistic explanation for baroreflex dysfunction in a female rat model of CKD. Merrill DC, Segar JL, McWeeny OJ, Robillard JE. Sympathetic responses to cardiopulmonary vagal afferent stimulation during development. Am J Physiol. 1999;277(4 Pt 2):H1311–6. Frank H, Heusser K, Hoffken B, Huber P, Schmieder RE, Schobel HP. Effect of erythropoietin on cardiovascular prognosis parameters in hemodialysis patients. Kidney Int. 2004;66(2):832–40. doi: 10.1111/j.1523-1755.2004.00810.x. Grassi G, Parati G, Pomidossi G, Giannattasio C, Casadei R, Bolla GB, et al. Effects of haemodialysis and kidney transplantation on carotid and cardiopulmonary baroreflexes in uremic patients. J Hypertens. 1987;5 suppl 5:S367–9. Hinojosa-Laborde C, Jones SY, DiBona GF. Hemodynamics and baroreflex function in rats with nephrotic syndrome. Am J Physiol. 1994;267(4 Pt 2):R953–64. Daugirdas JT. Pathophysiology of dialysis hypotension: an update. Am J Kidney Dis. 2001;38(4 Suppl 4):S11–7. Rassaf T, Westenfeld R, Balzer J, Lauer T, Merx M, Floege J, et al. Modulation of peripheral chemoreflex by neurohumoral adaptations after kidney transplantation. Eur J Med Res. 2010;15 Suppl 2:83–7. Despas F, Detis N, Dumonteil N, Labrunee M, Bellon B, Franchitto N, et al. Excessive sympathetic activation in heart failure with chronic renal failure: role of chemoreflex activation. J

79.

80.

81.

82.

83.

84.

85. 86.

87.

88. 89.

90.••

91.

92.

93.

94.

95. 96.

97.

H y pe r t e n s. 2 00 9; 27 ( 9 ) : 1 84 9– 54 . d oi: 10 .1 09 7/ HJH . 0b013e32832e8d0f. Kotanko P. Cause and consequences of sympathetic hyperactivity in chronic kidney disease. Blood Purif. 2006;24(1):95–9. doi:10. 1159/000089444. Grassi G. Renin-angiotensin-sympathetic crosstalks in hypertension: reappraising the relevance of peripheral interactions. J Hypertens. 2001;19(10):1713–6. Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992;262:E763–78. Gao L, Wang WZ, Wang W, Zucker IH. Imbalance of angiotensin type 1 receptor and angiotensin II type 2 receptor in the rostral ventrolateral medulla: potential mechanism for sympathetic overactivity in heart failure. Hypertension. 2008;52(4):708–14. doi:10. 1161/hypertensionaha.108.116228. Zucker IH. Novel mechanisms of sympathetic regulation in chronic heart failure. Hypertension. 2006;48(6):1005–11. doi:10.1161/ 01.hyp.0000246614.47231.25. Barajas L, Wang P. Myelinated nerves of the rat kidney. A light and electron microscopic autoradiographic study. J Ultrastruct Res. 1978;65(2):148–62. Recordati G, Moss NG, Genovesi S, Rogenes P. Renal chemoreceptors. J Auton Nerv Syst. 1981;3(2–4):237–51. Donovan MK, Wyss JM, Winternitz SR. Localization of renal sensory neurons using the fluorescent dye technique. Brain Res. 1983;259(1):119–22. Solano-Flores LP, Rosas-Arellano MP, Ciriello J. Fos induction in central structures after afferent renal nerve stimulation. Brain Res. 1997;753(1):102–19. Johns EJ, Kopp UC, DiBona GF. Neural control of renal function. Compr Physiol. 2011;1(2):731–67. doi:10.1002/cphy.c100043. Campese VM, Kogosov E, Koss M. Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat. Am J Kidney Dis. 1995;26(5):861–5. Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, et al. Sympathetic nerve activity in end-stage renal disease. Circulation. 2002;106(15):1974–9. This fascinating clinical study demonstrated increased SNA despite correction of uremia in renal transplant recipients with diseased native kidneys, indicating a possible role for renal afferents in triggering heightened efferent sympathetic discharge. Ye S, Ozgur B, Campese VM. Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure. Kidney Int. 1997;51(3):722–7. Ye S, Gamburd M, Mozayeni P, Koss M, Campese VM. A limited renal injury may cause a permanent form of neurogenic hypertension. Am J Hypertens. 1998;11(6 Pt 1):723–8. Katholi RE, Whitlow PL, Winternitz SR, Oparil S. Importance of the renal nerves in established two-kidney, one clip Goldblatt hypertension. Hypertension. 1982;4(3 Pt 2):166–74. Miyajima E, Yamada Y, Yoshida Y, Matsukawa T, Shionoiri H, Tochikubo O, et al. Muscle sympathetic nerve activity in renovascular hypertension and primary aldosteronism. Hypertension. 1991;17(6 Pt 2):1057–62. Fall PJ, Prisant LM. Polycystic kidney disease. J Clin Hypertens (Greenwich, Conn). 2005;7(10):617–9. 25. Costa F, Diedrich A, Johnson B, Sulur P, Farley G, Biaggioni I. Adenosine, a metabolic trigger of the exercise pressor reflex in humans. Hypertension. 2001;37(3):917–22. Chesterton LJ, Sigrist MK, Bennett T, Taal MW, McIntyre CW. Reduced baroreflex sensitivity is associated with increased vascular calcification and arterial stiffness. Nephrol Dial Transplant. 2005;20(6):1140–7.


99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

Temmar M, Liabeuf S, Renard C, Czernichow S, Esper NE, Shahapuni I, et al. Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens. 2010;28(1):163–9. doi:10.1097/HJH.0b013e328331b81e. Ng K, Hildreth CM, Phillips JK, Avolio AP. Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model. Am J Physiol Renal Physiol. 2011;300(6):6. Pai A, Leaf EM, El-Abbadi M, Giachelli CM. Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. Am J Pathol. 2011;178(2):764–73. Chan CT, Jain V, Picton P, Pierratos A, Floras JS. Nocturnal hemodialysis increases arterial baroreflex sensitivity and compliance and normalizes blood pressure of hypertensive patients with endstage renal disease. Kidney Int. 2005;68(1):338–44. doi:10.1111/j. 1523-1755.2005.00411.x. Kosch M, Barenbrock M, Kisters K, Rahn KH, Hausberg M. Relationship between muscle sympathetic nerve activity and large artery mechanical vessel wall properties in renal transplant patients. J Hypertens. 2002;20(3):501–8. Diwan V, Gobe G, Brown L. Glibenclamide improves kidney and heart structure and function in the adenine-diet model of chronic kidney disease. Pharmacol Res Off J Ital Pharmacol Soc. 2014;79: 104–10. doi:10.1016/j.phrs.2013.11.007. Fedecostante M, Spannella F, Cola G, Espinosa E, Dessi-Fulgheri P, Sarzani R. Chronic kidney disease is characterized by Bdouble trouble^ higher pulse pressure plus night-time systolic blood pressure and more severe cardiac damage. PLoS One. 2014;9(1), e86155. doi:10.1371/journal.pone.0086155. Wang AY, Li PK, Lui SF, Sanderson JE. Angiotensin converting enzyme inhibition for cardiac hypertrophy in patients with endstage renal disease: what is the evidence? Nephrology (Carlton, Vic). 2004;9(4):190–7. doi:10.1111/j.1440-1797.2004.00260.x. Edwards NC, Steeds RP, Stewart PM, Ferro CJ, Townend JN. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial. J Am Coll Cardiol. 2009;54(6):505–12. doi:10. 1016/j.jacc.2009.03.066. Moody WE, Edwards NC, Chue CD, Ferro CJ, Townend JN. Arterial disease in chronic kidney disease. Heart. 2013;99(6): 365–72. doi:10.1136/heartjnl-2012-302818. Grassi G, Giannattasio C, Cleroux J, Cuspidi C, Sampieri L, Bolla GB, et al. Cardiopulmonary reflex before and after regression of left ventricular hypertrophy in essential hypertension. Hypertension. 1988;12(3):227–37. Uggere TA, Abreu GR, Sampaio KN, Cabral AM, Bissoli NS. The cardiopulmonary reflexes of spontaneously hypertensive rats are normalized after regression of left ventricular hypertrophy and hypertension. Braz J Med Biol Res Rev Bras Pesqui Med Biol Soc Bras Biofisica [et al]. 2000;33(5):589–94. Furchgott RF, Jothianandan D. Endothelium-dependent and independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991;28(1–3):52–61. Hirooka Y, Kishi T, Sakai K, Takeshita A, Sunagawa K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am J Physiol Regul Integr Comp Physiol. 2011;300(4):R818–26. doi:10.1152/ajpregu.00426.2010. Nurminen ML, Ylikorkala A, Vapaatalo H. Central inhibition of nitric oxide synthesis increases blood pressure and heart rate in anesthetized rats. Methods Find Exp Clin Pharmacol. 1997;19(1): 35–41. Sakuma I, Togashi H, Yoshioka M, Saito H, Yanagida M, Tamura M, et al. NG-methyl-L-arginine, an inhibitor of L-arginine-derived

Page 17 of 20 59

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130. 131.

nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone? Circ Res. 1992;70(3):607–11. Cunha RS, Cabral AM, Vasquez EC. Evidence that the autonomic nervous system plays a major role in the L-NAME-induced hypertension in conscious rats. Am J Hypertens. 1993;6(9):806–9. Sander M, Hansen PG, Victor RG. Sympathetically mediated hypertension caused by chronic inhibition of nitric oxide. Hypertension. 1995;26(4):691–5. Harada S, Tokunaga S, Momohara M, Masaki H, Tagawa T, Imaizumi T, et al. Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits. Circ Res. 1993;72(3):511–6. Zanzinger J, Czachurski J, Seller H. Inhibition of basal and reflexmediated sympathetic activity in the RVLM by nitric oxide. Am J Physiol. 1995;268(4 Pt 2):R958–62. Zhang K, Mayhan WG, Patel KP. Nitric oxide within the paraventricular nucleus mediates changes in renal sympathetic nerve activity. Am J Physiol. 1997;273(3 Pt 2):R864–72. Spieker LE, Corti R, Binggeli C, Luscher TF, Noll G. Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans. J Am Coll Cardiol. 2000;36(1):213–8. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol. 2004;15(8):1983–92. doi:10.1097/01.asn.0000132474. 50966.da. Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int. 2000;58(3): 1261–6. doi:10.1046/j.1523-1755.2000.00281.x. Shinohara K, Hirooka Y, Kishi T, Sunagawa K. Reduction of nitric oxide-mediated gamma-amino butyric acid release in rostral ventrolateral medulla is involved in superoxide-induced sympathoexcitation of hypertensive rats. Circ J. 2012;76(12): 2814–21. Ye S, Nosrati S, Campese VM. Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF). J Clin Investig. 1997;99(3):540–8. doi:10.1172/ jci119191. Montezano AC, Touyz RM. Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies. Ann Med. 2012;44 Suppl 1:S2–16. doi:10.3109/07853890.2011.653393. Matthews KA, Woodall KL, Allen MT. Cardiovascular reactivity to stress predicts future blood pressure status. Hypertension. 1993;22(4):479–85. Schuler JL, O'Brien WH. Cardiovascular recovery from stress and h y p e r t e n s i o n r i s k f a c t o r s : a m e t a - a n a l y t i c r e v i e w. Psychophysiology. 1997;34(6):649–59. Chandola T, Britton A, Brunner E, Hemingway H, Malik M, Kumari M, et al. Work stress and coronary heart disease: what are the mechanisms? Eur Heart J. 2008;29(5):640–8. doi:10. 1093/eurheartj/ehm584. Niebylski A, Boccolini A, Bensi N, Binotti S, Hansen C, Yaciuk R, et al. Neuroendocrine changes and natriuresis in response to social stress in rats. Stress Health J Int Soc Investig Stress. 2012;28(3):179–85. doi:10.1002/smi.1411. Wallin BG, Esler M, Dorward P, Eisenhofer G, Ferrier C, Westerman R, et al. Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans. J Physiol. 1992;453:45–58. Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun. 2002;16(6):622–53. Kouidi E, Karagiannis V, Grekas D, Iakovides A, Kaprinis G, Tourkantonis A, et al. Depression, heart rate variability, and exercise training in dialysis patients. Eur J Cardiovasc Prev Rehabil Off J Eur Soc Cardiol Work Groups Epidemiol Prev Card Rehabil Exerc Physiol. 2010;17(2):160–7. doi:10.1097/HJR. 0b013e32833188c4.

59 132.

Page 18 of 20

Palkovits M, Sebekova K, Klenovics KS, Kebis A, Fazeli G, Bahner U, et al. Neuronal activation in the central nervous system of rats in the initial stage of chronic kidney disease-modulatory effects of losartan and moxonidine. PLoS One. 2013;8(6), e66543. doi:10.1371/journal.pone.0066543. 133. Sit D, Kadiroglu AK, Kayabasi H, Yilmaz ME. The prevalence of insulin resistance in nondiabetic nonobese patients with chronic kidney disease. Adv Ther. 2006;23(6):988–98. 134. Svensson M, Eriksson JW. Insulin resistance in diabetic nephropathy—cause or consequence? Diabetes Metab Res Rev. 2006;22(5):401–10. doi:10.1002/dmrr.648. 135. Hall JE, Brands MW, Zappe DH, Alonso Galicia M. Insulin resistance, hyperinsulinemia, and hypertension: causes, consequences, or merely correlations? Proc Soc Exp Biol Med Soc Exp Biol Med (New York, NY). 1995;208(4):317–29. 136. Ryan JP, Sheu LK, Verstynen TD, Onyewuenyi IC, Gianaros PJ. Cerebral blood flow links insulin resistance and baroreflex sensitivity. PLoS One. 2013;8(12), e83288. doi:10.1371/journal.pone. 0083288. 137. Schneider MP, Mann JF. Endothelin antagonism for patients with chronic kidney disease: still a hope for the future. Nephrol Dial Transplant. 2014;29 Suppl 1:i69–73. doi:10.1093/ndt/gft339. 138. Shichiri M, Hirata Y, Ando K, Emori T, Ohta K, Kimoto S, et al. Plasma endothelin levels in hypertension and chronic renal failure. Hypertension. 1990;15(5):493–6. 139. Gulati A, Rebello S, Kumar A. Role of sympathetic nervous system in cardiovascular effects of centrally administered endothelin1 in rats. Am J Physiol. 1997;273(3 Pt 2):H1177–86. 140. Nakamura K, Sasaki S, Moriguchi J, Morimoto S, Miki S, Kawa T, et al. Central effects of endothelin and its antagonists on sympathetic and cardiovascular regulation in SHR-SP. J Cardiovasc Pharmacol. 1999;33(6):876–82. 141. Mortensen LH. Endothelin and the central and peripheral nervous systems: a decade of endothelin research. Clin Exp Pharmacol Physiol. 1999;26(12):980–4. 142. Smirnov AV, Petrishchev NN, Panina I, Mnuskina MM, Achkasova VV, Rumiantsev A, et al. The level of endothelin-1 and reactivity of skin microvessels in patients with early stages of chronic kidney disease. Ter Arkh. 2011;83(6):13–8. 143. Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, et al. Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest. 2005;115(5):1275–80. doi:10. 1172/jci24066. 144. Desir GV, Peixoto AJ. Renalase in hypertension and kidney disease. Nephrol Dial Transplant. 2014;29(1):22–8. doi:10.1093/ndt/ gft083. 145. Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, et al. Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008;117(10):1277–82. doi:10.1161/ circulationaha.107.732032. 146. Gu R, Lu W, Xie J, Bai J, Xu B. Renalase deficiency in heart failure model of rats—a potential mechanism underlying circulating norepinephrine accumulation. PLoS One. 2011;6(1), e14633. doi:10.1371/journal.pone.0014633. 147. Brooks VL, Haywood JR, Johnson AK. Translation of salt retention to central activation of the sympathetic nervous system in hypertension. Clin Exp Pharmacol Physiol. 2005;32(5–6):426– 32. doi:10.1111/j.1440-1681.2005.04206.x. 148. Mailloux LU. The overlooked role of salt restriction in dialysis patients. Semin Dial. 2000;13(3):150–1. 149. Meng L, Fu B, Zhang T, Han Z, Yang M. Salt sensitivity of blood pressure in non-dialysis patients with chronic kidney disease. Ren Fail. 2014;36(3):345–50. doi:10.3109/0886022x.2013.866008. 150. Campese VM, Mozayeni P, Ye S, Gumbard M. High salt intake inhibits nitric oxide synthase expression and aggravates

Curr Hypertens Rep (2015) 17:59 hypertension in rats with chronic renal failure. J Nephrol. 2002;15(4):407–13. 151. Fujita M, Ando K, Kawarazaki H, Kawarasaki C, Muraoka K, Ohtsu H, et al. Sympathoexcitation by brain oxidative stress mediates arterial pressure elevation in salt-induced chronic kidney disease. Hypertension. 2012;59(1):105–12. doi:10.1161/ hypertensionaha.111.182923. 152. Wambach G, Gotz S, Suckau G, Bonner G, Kaufmann W. Plasma levels of atrial natriuretic peptide are raised in essential hypertension during low and high sodium intake. Klin Wochenschr. 1987;65(5):232–7. 153. Akiba T, Tachibana K, Togashi K, Hiroe M, Marumo F. Plasma human brain natriuretic peptide in chronic renal failure. Clin Nephrol. 1995;44 Suppl 1:S61–4. 154. Peng N, Oparil S, Meng QC, Wyss JM. Atrial natriuretic peptide regulation of noradrenaline release in the anterior hypothalamic area of spontaneously hypertensive rats. J Clin Investig. 1996;98(9):2060–5. doi:10.1172/jci119011. 155. Vatta MS, Papouchado ML, Bianciotti LG, Fernandez BE. Atrial natriuretic factor inhibits noradrenaline release in the presence of angiotensin II and III in the rat hypothalamus. Comp Biochem Physiol C Comp Pharmacol Toxicol. 1993;106(2):545–8. 156. Toader E, McAllen RM, Cividjian A, Woods RL, Quintin L. Effect of systemic B-type natriuretic peptide on cardiac vagal motoneuron activity. Am J Physiol Heart Circ Physiol. 2007;293(6): H3465–70. doi:10.1152/ajpheart.00528.2007. 157. Woods RL, Courneya CA, Head GA. Nonuniform enhancement of baroreflex sensitivity by atrial natriuretic peptide in conscious rats and dogs. Am J Physiol. 1994;267(3 Pt 2):R678–86. 158. Hood SG, Woods RL. Vagal reflex actions of atrial natriuretic peptide survive physiological but not pathological cardiac hypertrophy in rat. Exp Physiol. 2004;89(4):445–54. doi:10.1113/ expphysiol.2004.027557. 159. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, et al. Prevalence of hypertension in the US adult population. Results from the third national health and nutrition examination survey, 1988–1991. Hypertension. 1995;25(3):305–13. 160. Maric C. Sex differences in cardiovascular disease and hypertension: involvement of the renin-angiotensin system. Hypertension. 2005;46(3):475–6. doi:10.1161/01.HYP.0000178600.88820.b2. 161. Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension. 2001;37(5):1199–208. 162. Hogarth AJ, Mackintosh AF, Mary DA. Gender-related differences in the sympathetic vasoconstrictor drive of normal subjects. Clin Sci. 2007;112(6):353–61. 163. Kim A, Deo SH, Vianna LC, Balanos GM, Hartwich D, Fisher JP, et al. Sex differences in carotid baroreflex control of arterial blood pressure in humans: relative contribution of cardiac output and total vascular conductance. Am J Physiol Heart Circ Physiol. 2011;301(6):H2454–65. 164. Shoemaker JK, Hogeman CS, Khan M, Kimmerly DS, Sinoway LI. Gender affects sympathetic and hemodynamic response to postural stress. Am J Physiol Heart Circ Physiol. 2001;281(5): H2028–35. 165. Tank J, Diedrich A, Szczech E, Luft FC, Jordan J. Baroreflex regulation of heart rate and sympathetic vasomotor tone in women and men. Hypertension. 2005;45(6):1159–64. 166. Brooks VL, Cassaglia PA, Zhao D, Goldman RK. Baroreflex function in females: changes with the reproductive cycle and pregnancy. Gend Med. 2012;9(2):61–7. 167. Abdel-Rahman AR, Merrill RH, Wooles WR. Gender-related differences in the baroreceptor reflex control of heart rate in normotensive humans. J Appl Physiol (Bethesda, Md : 1985). 1994;77(2):606–13.


169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

Frey MA, Tomaselli CM, Hoffler WG. Cardiovascular responses to postural changes: differences with age for women and men. J Clin Pharmacol. 1994;34(5):394–402. Convertino VA. Gender differences in autonomic functions associated with blood pressure regulation. Am J Physiol. 1998;275(6 Pt 2):R1909–20. Scislo TJ, DiCarlo SE. Gender difference in cardiopulmonary reflex inhibition of sympathetic nerve activity. Am J Physiol. 1994;267(4 Pt 2):H1537–43. Hunt BE, Taylor JA, Hamner JW, Gagnon M, Lipsitz LA. Estrogen replacement therapy improves baroreflex regulation of vascular sympathetic outflow in postmenopausal women. Circulation. 2001;103(24):2909–14. Fadel PJ, Zhao W, Thomas GD. Impaired vasomodulation is associated with reduced neuronal nitric oxide synthase in skeletal muscle of ovariectomized rats. J Physiol. 2003;549(Pt 1):243–53. Mohamed MK, El-Mas MM, Abdel-Rahman AA. Estrogen enhancement of baroreflex sensitivity is centrally mediated. Am J Physiol. 1999;276(4 Pt 2):R1030–7. Saleh TM, Connell BJ. 17beta-estradiol modulates baroreflex sensitivity and autonomic tone of female rats. J Auton Nerv Syst. 2000;80(3):148–61. Du XJ, Dart AM, Riemersma RA. Sex differences in the parasympathetic nerve control of rat heart. Clin Exp Pharmacol Physiol. 1994;21(6):485–93. Schroeder C, Adams F, Boschmann M, Tank J, Haertter S, Diedrich A, et al. Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function. Am J Physiol Regul Integr Comp Physiol. 2004;286(5):R851–6. Esler M, Jennings G, Lambert G, Meredith I, Horne M, Eisenhofer G. Overflow of catecholamine neurotransmitters to the circulation: source, fate, and functions. Physiol Rev. 1990;70(4):963–85. Reckelhoff JF, Zhang H, Srivastava K. Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system. Hypertension. 2000;35(1 Pt 2):480–3. Crofton JT, Ota M, Share L. Role of vasopressin, the reninangiotensin system and sex in Dahl salt-sensitive hypertension. J Hypertens. 1993;11(10):1031–8. Haywood JR, Hinojosa-Laborde C. Sexual dimorphism of sodium-sensitive renal-wrap hypertension. Hypertension. 1997;30(3 Pt 2):667–71. Xue B, Pamidimukkala J, Hay M. Sex differences in the development of angiotensin II-induced hypertension in conscious mice. Am J Physiol Heart Circ Physiol. 2005;288(5):H2177–84. doi:10. 1152/ajpheart.00969.2004. Hogarth AJ, Mackintosh AF, Mary DA. The effect of gender on the sympathetic nerve hyperactivity of essential hypertension. J Hum Hypertens. 2007;21(3):239–45. doi:10.1038/sj.jhh. 1002132. Pavithran P, Madanmohan T, Nandeesha H. Sex differences in short-term heart rate variability in patients with newly diagnosed essential hypertension. J Clin Hypertens. 2008;10(12):904–10. Johnson MS, DeMarco VG, Heesch CM, Whaley-Connell AT, Schneider RI, Rehmer NT, et al. Sex differences in baroreflex sensitivity, heart rate variability, and end organ damage in the TGR(mRen2)27 rat. Am J Physiol Heart Circ Physiol. 2011;301(4):H1540–50. Eriksen BO, Ingebretsen OC. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age. Kidney Int. 2006;69(2):375–82. doi:10.1038/sj.ki. 5000058. Jafar TH, Schmid CH, Stark PC, Toto R, Remuzzi G, Ruggenenti P, et al. The rate of progression of renal disease may not be slower in women compared with men: a patient-level meta-analysis.

Page 19 of 20 59

187.

188.

189.

190.

191.

192.

193.•

194.

195.

196.

197.

198.

199.

200.

201.

202.

Nephrol Dial Transplant. 2003;18(10):2047–53. doi:10.1093/ndt/ gfg317. Carrero JJ. Gender differences in chronic kidney disease: underpinnings and therapeutic implications. Kidney Blood Press Res. 2010;33(5):383–92. doi:10.1159/000320389. Vink EE, de Jager RL, Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease: pathophysiology and (new) treatment options. Curr Hypertens Rep. 2013;15(2):95–101. doi:10.1007/ s11906-013-0328-5. Weir MR. The renoprotective effects of RAS inhibition: focus on prevention and treatment of chronic kidney disease. Postgrad Med. 2009;121(1):96–103. doi:10.3810/pgm.2009.01.1958. Weir MR. Effects of renin-angiotensin system inhibition on endorgan protection: can we do better? Clin Ther. 2007;29(9):1803– 24. doi:10.1016/j.clinthera.2007.09.019. Sato R, Mizuno M, Miura T, Kato Y, Watanabe S, Fuwa D, et al. Angiotensin receptor blockers regulate the synchronization of circadian rhythms in heart rate and blood pressure. J Hypertens. 2013;31(6):1233–8. doi:10.1097/HJH.0b013e32836043c9. Ondocin PT, Narsipur SS. Influence of angiotensin converting enzyme inhibitor treatment on cardiac autonomic modulation in patients receiving haemodialysis. Nephrology (Carlton, Vic). 2006;11(6):497–501. doi:10.1111/j.1440-1797.2006.00680.x. Neumann J, Ligtenberg G, Oey L, Koomans HA, Blankestijn PJ. Moxonidine normalizes sympathetic hyperactivity in patients with eprosartan-treated chronic renal failure. J Am Soc Nephrol. 2004;15(11):2902–7. doi:10.1097/01.asn.0000143471.10750.8c. This clinical study showed that normalized sympathetic nerve discharge in CKD patients can be achieved only with combination therapy comprising a central sympatholytic agent and an ARB. Siddiqi L, Oey PL, Blankestijn PJ. Aliskiren reduces sympathetic nerve activity and blood pressure in chronic kidney disease patients. Nephrol Dial Transplant. 2011;26(9):2930–4. doi:10.1093/ ndt/gfq857. Narsipur SS, Srinivasan B, Singh B. Effect of simvastatin use on autonomic function in patients with end stage renal disease. Cardiovasc Hematol Disord Drug Targets. 2011;11(1):53–7. Suzuki H, Moriwaki K, Kanno Y, Nakamoto H, Okada H, Chen XM. Comparison of the effects of an ACE inhibitor and alphabeta blocker on the progression of renal failure with left ventricular hypertrophy: preliminary report. Hypertens Res Off J Jpn Soc Hypertens. 2001;24(2):153–8. Vonend O, Marsalek P, Russ H, Wulkow R, Oberhauser V, Rump LC. Moxonidine treatment of hypertensive patients with advanced renal failure. J Hypertens. 2003;21(9):1709–17. doi:10.1097/01. hjh.0000084733.53355.c3. Amann K, Koch A, Hofstetter J, Gross ML, Haas C, Orth SR, et al. Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers. Kidney Int. 2001;60(4):1309– 23. doi:10.1046/j.1523-1755.2001.00936.x. Amann K, Rump LC, Simonaviciene A, Oberhauser V, Wessels S, Orth SR, et al. Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats. J Am Soc Nephrol. 2000;11(8):1469–78. Bakris GL, Hart P, Ritz E. Beta blockers in the management of chronic kidney disease. Kidney Int. 2006;70(11):1905–13. doi:10. 1038/sj.ki.5001835. Cice G, Ferrara L, D'Andrea A, D'Isa S, Di Benedetto A, Cittadini A, et al. Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol. 2003;41(9):1438–44. Hausberg M, Tokmak F, Pavenstadt H, Kramer BK, Rump LC. Effects of moxonidine on sympathetic nerve activity in patients with end-stage renal disease. J Hypertens. 2010;28(9):1920–7. doi:10.1097/HJH.0b013e32833c2100.

59 203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.


Page 20 of 20 Wallin BG, Sundlof G, Stromgren E, Aberg H. Sympathetic outflow to muscles during treatment of hypertension with metoprolol. Hypertension. 1984;6(4):557–62. Burns J, Mary DA, Mackintosh AF, Ball SG, Greenwood JP. Arterial pressure lowering effect of chronic atenolol therapy in hypertension and vasoconstrictor sympathetic drive. Hypertension. 2004;44(4):454–8. doi:10.1161/01.HYP. 0000141411.94596.0f. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc. 1953;152(16):1501–4. Ravera M, Re M, Deferrari L, Vettoretti S, Deferrari G. Importance of blood pressure control in chronic kidney disease. J Am Soc Nephrol. 2006;17(4 Suppl 2):S98–103. doi:10.1681/ asn.2005121319. Kiuchi MG, Maia GL, de Queiroz Carreira MA, Kiuchi T, Chen S, Andrea BR, et al. Effects of renal denervation with a standard irrigated cardiac ablation catheter on blood pressure and renal function in patients with chronic kidney disease and resistant hypertension. Eur Heart J. 2013;34(28):2114–21. doi:10.1093/ eurheartj/eht200. Hering D, Lambert EA, Marusic P, Walton AS, Krum H, Lambert GW, et al. Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension. Hypertension. 2013;61(2):457–64. doi:10.1161/hypertensionaha. 111.00194. Brinkmann J, Heusser K, Schmidt BM, Menne J, Klein G, Bauersachs J, et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: prospective case series. Hypertension. 2012;60(6):1485–90. doi:10.1161/hypertensionaha.112.201186. Hart EC, McBryde FD, Burchell AE, Ratcliffe LE, Stewart LQ, Baumbach A, et al. Translational examination of changes in baroreflex function after renal denervation in hypertensive rats and humans. Hypertension. 2013;62(3):533–41. doi:10.1161/ hypertensionaha.113.01261. Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393–401. doi:10. 1056/NEJMoa1402670. Jin Y, Persu A, Staessen JA. Renal denervation in the management of resistant hypertension: current evidence and perspectives. Curr Opin Nephrol Hypertens. 2013;22(5):511–8. doi:10.1097/MNH. 0b013e3283640024. Grassi G, Bertoli S, Seravalle G. Sympathetic nervous system: role in hypertension and in chronic kidney disease. Curr Opin Nephrol Hypertens. 2012;21(1):46–51. doi:10.1097/MNH. 0b013e32834db45d.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. 2010;55(3):619–26. doi:10.1161/hypertensionaha. 109.140665. Lohmeier TE, Iliescu R, Dwyer TM, Irwin ED, Cates AW, Rossing MA. Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex. Am J Physiol Heart Circ Physiol. 2010;299(2):H402–9. doi: 10.1152/ajpheart.00372.2010. Goddard J, Turner AN. Kidney and urinary tract disease. In: Walker BR, Colledge NR, Ralston SH, Penman ID, editors. Davidson's principles and practice of medicine. 22nd ed. Philadelphia: Churchill Livingstone Elsevier; 2014. Chesterton LJ, Selby NM, Burton JO, Fialova J, Chan C, McIntyre CW. Categorization of the hemodynamic response to hemodialysis: the importance of baroreflex sensitivity. Hemodial Int Int Symp Home Hemodial. 2010;14(1):18–28. doi:10.1111/j.15424758.2009.00403.x. Giordano M, Manzella D, Paolisso G, Caliendo A, Varricchio M, Giordano C. Differences in heart rate variability parameters during the post-dialytic period in type II diabetic and non-diabetic ESRD patients. Nephrol Dial Transplant. 2001;16(3):566–73. Mylonopoulou M, Tentolouris N, Antonopoulos S, Mikros S, Katsaros K, Melidonis A, et al. Heart rate variability in advanced chronic kidney disease with or without diabetes: midterm effects of the initiation of chronic haemodialysis therapy. Nephrol Dial Transplant. 2010;25(11):3749–54. doi:10.1093/ndt/gfq226. Chan CT, Chertow GM, Daugirdas JT, Greene TH, Kotanko P, Larive B, et al. Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) daily trial. Nephrol Dial Transplant. 2014;29(1):168–78. doi:10. 1093/ndt/gft212. Zilch O, Vos PF, Oey PL, Cramer MJ, Ligtenberg G, Koomans HA, et al. Sympathetic hyperactivity in haemodialysis patients is reduced by short daily haemodialysis. J Hypertens. 2007;25(6): 1285–9. doi:10.1097/HJH.0b013e3280f9df85. Korejwo G, Hermann A, Zdrojewski Z, Debska-Slizien A, Rutkowski B. Improved autonomic function after kidney transplantation. Transplant Proc. 2002;34(2):601–3. Yang YW, Wu CH, Tsai MK, Kuo TB, Yang CC, Lee PH. Heart rate variability during hemodialysis and following renal transplantation. Transplant Proc. 2010;42(5):1637–40. doi:10.1016/j. transproceed.2010.01.062. Heidbreder E, Schafferhans K, Heidland A. Disturbances of peripheral and autonomic nervous system in chronic renal failure: effects of hemodialysis and transplantation. Clin Nephrol. 1985;23(5):222–8.

Autonomic dysfunction in chronic liver disease.

Cardiovascular Autonomic Dysfunction in Mild and Advanced Parkinson's Disease.

Cardiovascular Autonomic Dysfunction in Patients of Nonalcoholic Fatty Liver Disease.

Baroreflex dysfunction in chronic kidney disease.

10. Cardiovascular Risk in Chronic Kidney Disease.

Liver enzymes serum levels in patients with chronic kidney disease on hemodialysis: a comprehensive review.

Invited review: autonomic dysfunction in peripheral nerve disease.

Male Sexual Dysfunction and Chronic Kidney Disease.

Statins in chronic kidney disease: cardiovascular risk and kidney function.

Cardiovascular autonomic dysfunction in multiple sclerosis: a meta-analysis.

Chronic kidney disease and cardiovascular complications.

Cardiovascular autonomic dysfunction: diagnosis and prognosis.

Autonomic dysfunction in chronic persistent dizziness.

The link between chronic kidney disease and cardiovascular disease.

Thyroid dysfunction and dyslipidemia in chronic kidney disease patients.

Erectile dysfunction in chronic kidney disease: From pathophysiology to management.

Subclinical cardiopulmonary dysfunction in stage 3 chronic kidney disease.

Hypertension: understanding baroreflex dysfunction in chronic kidney disease.

Autonomic dysfunction in essential hypertension: A systematic review.

Cardiovascular risk prediction in people with chronic kidney disease.

Cardiorespiratory fitness and cardiovascular burden in chronic kidney disease.

Cardiovascular Autonomic Dysfunction in Patients with Morbid Obesity.

Clinical trials: cardiovascular benefits of paricalcitol in chronic kidney disease.

Wine and Cardiovascular Health: A Comprehensive Review.