Mechanisms of sympathetic overactivity in patients with chronic renal failure: a role for chemoreflex activation?

Hypertension affects the majority of patients with chronic renal disease and is one of the leading causes of end-stage renal disease. Moreover, hypertension is the major factor of progression of diabetic and non-diabetic renal disease. This is particularly true in patients with non-insulin-dependent diabetes mellitus, accounting for the majority of patients entering chronic renal replacement therapy. Many factors have been identified that cause hypertension in chronic kidney disease. During the last decade, activation of the sympathetic nervous system has been established as a substantial cause of hypertension in patients with renal disease. However, a number of issues related to the patterns and causes of this adrenergic abnormality remain largely unaddressed. Some of these will be focused on here, also in the light of the results of the study by Hering et al. [1] who present interesting observations on the contribution of tonic chemoreflex activation to heightened sympathetic nerve activity occurring in chronic renal disease. How early is the sympathetic activaction in the clinical course of renal failure? Direct and indirect measures of sympathetic activity agree that an adrenergic overdrive is common in advanced phases of chronic renal failure. However, little information is available on how early in the clinical course of the disease this neurogenic abnormality takes place [2]. The question has both pathophysiological and clinical relevance because the demonstration that, in the early phases of the disease, adrenergic drive is already increased may suggest that: (i) neurogenic mechanisms participate at the development as well as at the progression of the disease; and (ii) therapeutic interventions should be targeted on this variable. Recent findings by our group suggest that this may be the case because, in a group of patients with mild renal failure (creatinine clearance between 60 and 90 ml/min), we found that muscle sympathetic activity is already increased compared to a group of healthy control subjects, thus paralleling data obtained some years ago in mild heart failure [3]. What are known causes of sympathetic activation in chronic renal failure? A series of elegant animal studies performed by Vito Campese et al. [4] have demonstrated that afferent signals arising from the diseased kidneys are responsible for the centrally mediated excitation of efferent sympathetic nerve fibers [4]. The authors were able to show that afferent denervation of the diseased kidneys was sufficient to abolish the increase in efferent sympathetic nerve activity. The degree of renal disease appears to be of minor importance. Similar results were obtained in 5/6-nephrectomized rats and in rats who had received an intrarenal injection of a small amount of phenol without impairment of renal function [5]. These animal studies are in line with human studies showing normalization of efferent sympathetic nerve activity after bilateral nephrectomy [6]. What are the mechanisms causing activation of afferent nerves in diseased kidneys? The major factors causing activation of renal afferents in renal disease are alterations of mechanoreceptor activity resulting from scarring and fibrosis, chemoreceptor activation likely due to ischemia with subsequent endogeneous adenosine release and activation of the renin–angiotensin–aldosterone system, and reduced availability of nitric oxide in the kidneys. The latter has multiple causes, including importantly decreased nitric oxide synthase (NOS) activity resulting from the accumulation of endogeneous NOS inhibitors in chronic renal failure. Together with increased oxidative stress in the diseased kidneys, this could contribute to chemoreceptor activation [7,8]. Besides nitric oxide bioavailability in the kidneys, brain nitric oxide also may be crucial for the regulation of sympathetic outflow in renal disease, nitric oxide deficiency in the hypothalamus and brain stem causing tonic increase of sympathetic outflow. However, in uremic animals, brain NOS activity is increased, possibly as a compensatory mechanism [9]. On the other hand, in renal failure, an accumulation of endogenous inhibitors of the nitric oxide synthase is generally observed. For example, asymmetric dimethyl-arginine (ADMA) is such an inhibitor. Mallamaci et al. [10] have demonstrated a strong relationship between plasma norepinephrine and ADMA in patients with end-stage renal disease. Therefore, it is conceivable that alterations of nitric oxide bioavailability contribute to the enhanced sympathetic outflow in chronic renal failure. Which novel mechanisms of sympathetic activation in chronic renal disease emerge? In this issue of the journal, Hering et al. [1] report that, in patients with chronic renal disease, deactivation of arterial chemoreceptors by breathing of 100% oxygen significantly decreases muscle sympathetic nerve activity (MSNA). This occurred despite many patients being treated with antihypertensive drugs known to reduce sympathetic nerve activity, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers [11]. In healthy control subjects, MSNA did not change on breathing 100% oxygen. These observations suggest tonic arterial chemoreceptor activation in patients with chronic renal disease. Arterial chemoreceptor activation appears to contribute to the increased sympathetic drive of patients with chronic renal failure. Peripheral chemoreceptor hypersensitivity has been shown to determine cardiovascular prognosis in patients with heart failure [12]. This interesting observation raises the issue of the potential mechanisms involved in arterial chemoreceptor activation in patients with renal disease. A study in anesthetized cats by Hatcher et al. [13] suggests that sympathetic firing per se may induce a tonic carotid chemoreceptor activation. Thus, in patients with chronic renal disease, the generally observed tonic activation of the sympathetic nervous system may cause tonic carotid chemoreceptor activation, which may lead to a vicious circle. An important stimulus for chemoreceptor activation is anemia [14]. Patients with chronic renal disease suffer in general from anemia. The collective studied by Hering et al. [1] had significantly reduced hemoglobin levels compared to the control collective. In parallel, oxygen saturation was significantly reduced in patients with renal disease. Although, in the sample of 12 patients, there was no significant relationship between hemoglobin levels and the hyperoxia-induced decrease in MSNA, and a decrease in MSNA with oxygen supplementation was also observed in a subgroup of patients with a baseline oxygen saturation not different from control subjects, a possible effect of anemia on chemoreflex activation cannot be ruled out. Recently, Frank et al. [15] studied the effect of erythropoeitin therapy on MSNA in hemodialysis patients. Despite a sustained increase in hemoglobin levels for at least 5 months, there was no decrease in sympathetic drive in the dialysis patients. However, with chronic anemia, there may be structural alterations of arterial chemoreceptors [16], requiring a more prolonged correction of anemia to allow restitution of chemoreceptor function. Therefore, the observation of Hering et al. [1] warrants further studies assessing a possible effect of anemia correction on arterial chemoreceptor activation on MSNA in patients with chronic renal disease and anemia. The study by Hering et al. [1] may underline the importance of anemia management in patients with renal disease. In these patients, anemia is a major risk factor associated with substantially increased cardiovascular morbidity and mortality. Correction of anemia by therapy with iron and recombinant erythropoeitin has been shown to substantially improve cardiovascular prognosis [17]. Importantly, the results obtained by Hering et al. [1] in patients with chronic renal disease contrast with findings obtained in patients with heart failure. As observed in renal disease, there is a tonic activation of sympathetic nerve activity in heart failure [3]. However, in patients with heart failure, hyperoxia failed to reduce sympathetic nerve traffic, as shown by Andreas et al. [18]. Therefore, under normoxia, tonic activation of arterial chemoreceptors does not appear to contribute to heightened sympathetic nerve activity in patients with heart failure as seen in patients with renal failure. This raises the possibility of specific chemoreceptor activation in renal disease. Beecroft et al. [19] recently reported an increased chemo-responsiveness in patients suffering from both end-stage renal disease and sleep apnea. Possibly, uremia-related toxins may contribute to the tonic arterial chemoreceptor activation observed in renal failure by Hering et al. [1]. It is conceivable that, in conditions of hypoxia, patients with renal failure display a particularly profound increase in sympathetic nerve activity. Conclusions A tonic increase in sympathetic outflow is commonly observed in patients with renal disease. Activation of afferent sympathetic nerves in the diseased kidneys is a major factor contributing to this phenomenon. Hering et al. [1] report that tonic chemoreceptor activation also may contribute to increased sympathetic drive in renal disease. Sympathetic overactivity in renal disease can be reduced by blockers of the renin–angiotensin–aldosterone system, by adrenoreceptor blockers and by substances inhibiting central sympathetic outflow, such as imidazolines [11]; however, sympathetic outflow remains elevated. Correction of chemoreflex activation, possibly by effective anemia management, may additionally improve sympathetic dysregulation in patients with renal disease and improve their outcome. Further studies investigating this issue are warranted.