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Journal of Hypertension:
doi: 10.1097/HJH.0b013e3281a7369e
Editorial commentaries

Adrenergic overdrive: a ‘not-so-sympathetic’ risk factor in renal failure patients

Jordan, Jensa; Grassi, Guidob

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aFranz Volhard Clinical Research Center and Department of Nephrology, HELIOS Klinikum Berlin and Medical Faculty of the Charité, Berlin, Germany

bClinica Medica, Università Milano-Bicocca, Ospedale San Gerardo, Monza (Milan) Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Milano, Italy

Correspondence to Professor Jens Jordan, Franz Volhard Clinical Research Center, HELIOS Klinikum Berlin and Medical Faculty of the Charité Wiltbergstrasse 50, 13125 Berlin, Germany Tel: +49 30 941 72220; fax: +49 30 941 72265; e-mail: jens.jordan@charite.de

Patients with impaired renal function are exposed to an unacceptably high cardiovascular risk [1]. Even subtle renal impairment profoundly increases cardiovascular morbidity and mortality. The prognosis is much worse in patients with end-stage renal disease requiring dialysis. The clinical goal should be to halt the progression to end-stage renal disease, and improve cardiovascular risk in patients who have already progressed. Unfortunately, even with optimal care, many patients with mild to moderate renal failure progress to end-stage renal disease. Furthermore, treatments that effectively reduce cardiovascular risk in most patients appear to be of limited value in patients with the disease. Cholesterol-lowering therapy with atorvastatin was largely ineffective in this regard [2]. Other risk factors may be more amenable to therapy. The sympathetic nervous system could hold promise. In the present issue of the journal, Blankestijn et al. [3] provide intriguing data on a novel treatment approach ameliorating sympathetic activity in dialysis patients.

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Sympathetic function in renal failure

Sympathetic nerve traffic is profoundly increased in many patients with chronic renal disease [4,5]. Surprisingly, sympathetic activity is also increased in patients who successfully underwent renal transplantation [5]. Thus, sympathetic activation cannot be solely explained by uraemia. Instead, the stimulus eliciting central nervous sympathetic activation may be generated within the diseased kidney itself. The idea is supported by the observation that sympathetic activity is within the normal range in transplant patients whose native kidney had been removed [5]. Similarly, sympathetic activity is normal in nephrectomized dialysis patients [4]. The nature of the afferent signal sustaining sympathetic activity is a matter of ongoing research. Earlier studies in animals suggested that renal afferent nerves may be excited by chemical signals [6]. Phenol injection into the lower pole of one kidney, which elicits a local inflammatory response and scarring, increases centrally generated sympathetic activity [7]. Generation of reactive oxygen species in the brain appears to be involved [8]. Renin–angiotensin–aldosterone system activation within the kidney or the brain may also contribute to sympathetic activation. Angiotensin-converting enzyme inhibition reduced sympathetic activity in patients with chronic renal failure [9]. Local ischaemia within the kidney may stimulate renal afferents through increased production of active metabolites, such as adenosine [10].

A less-appreciated mechanism that may raise sympathetic activity in patients with end-stage renal disease is sleep apnea syndrome. Sleep apnea is rather common in haemodialyis patients [11]. At least in patients with intact renal function, sleep apnea may trigger sustained sympathetic activation [12].

Sympathetic activation promotes renal failure progression. There are at least three pieces of evidence to support this idea. First, in patients with different levels of disease severity, the level of sympathetic activation has been shown to parallel the degree of renal dysfunction [13]. Second, sympatholytic drug treatment attenuates albumin excretion in animals and in patients with diabetic nephropathy [14,15]. Finally, sympatholytic treatment prevents glomerulosclerosis in experimental hypertension [16]. Selective renal sympathetic denervation also improves renal failure progression [17]. The latter observation is consistent with a direct effect of the sympathetic nervous system on renal failure progression. Indeed, the kidney is densely innervated by autonomic, predominantly adrenergic, efferent neurones [18]. In animals, electrical renal nerve stimulation increases renin–angiotensin system activity, sodium reabsorption, and renal vascular resistance in a graded fashion. All these mechanisms could conceivably contribute to renal failure progression.

Sympathetic activation in renal failure does not only involve the kidney. Plasma norepinephrine concentrations are also positively correlated with left ventricular mass in these patients [19]. Furthermore, plasma norepinephrine concentration was an independent predictor of death of any cause as well as fatal and nonfatal cardiovascular events [20]. Nevertheless, correlations do not prove causality.

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Reversibility of renal failure-related adrenergic overdrive

How can sympathetic activity be reduced in renal failure patients? Patients with sleep apnea may respond to treatment with a continuous positive airway pressure device [21]. Beta-adrenoreceptor blockers and medications that inhibit the renin–angiotensin system are used in many patients and may attenuate some, but not all, sympathetic responses. Sympatholytic drugs, such as clonidine and moxonidine, effectively suppress centrally-generated sympathetic activity. It is unlikely that these medications will be tested in outcomes trials in larger numbers of patients with end-stage renal failure. First, these drugs are now generic and pharmaceutical companies will not pursue the issue further. Second, recent experience in heart failure patients dampened the enthusiasm for sympatholytic medications. Moxonidine treatment increased mortality in heart failure patients [22]. The profound suppression in circulating norepinephrine suggested that the drug could have been substantially overdosed [23].

The study by Blankestijn et al. [3] suggests that certain dialysis regimens may also reduce sympathetic activity. The authors tested the hypothesis that short, daily haemodialysis reduces sympathetic activity compared to standard thrice-daily haemodialysis. The total haemodialysis duration was identical with both interventions. The authors applied the microneurography technique to record postganglionic muscle sympathetic nerve activity in the leg in their patients. They obtained measurements in patients who had been receiving standard haemodialysis. The patients then commenced short daily haemodialysis and were studied again after 6 months. To exclude a time-related effect on sympathetic activity, a subset of patients was switched back to thrice-weekly dialysis and studied for a third time. Short daily haemodialysis substantially reduced sympathetic neural outflow. The response was associated with a reduction in blood pressure through systemic vasodilation. The authors suggested that the sympatholytic response may be explained only in part by more effective dialysis. Another possible explanation is that volume status fluctuates less with daily compared to thrice-weekly haemodialysis. The average ultrafiltration volume that was removed during each dialysis session was 2.4 l with standard and 1.5 l with short daily haemodialyis. Large reductions in plasma volume could raise sympathetic activity through baroreflex mechanisms or through worsened renal perfusion.

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Perspectives

Thus far, it has not been shown that reduced sympathetic activity improves the prognosis in end-stage renal disease. Nevertheless, the data strongly suggest that the sympathetic nervous system provides a promising target for therapeutic interventions. To attenuate sympathetic nervous system activation, thrice-weekly standard haemodialysis may not be enough; additional strategies could prove necessary. Nonetheless, Blankestijn et al. [3] provide novel new data to address this issue in a collection of patients commonly ignored by the hypertension community. The study deserves an ‘A’ grade for effort. However, the effort could extend above and beyond the usual endeavour. The therapeutic approach could be coupled with other measures, including renin–angiotensin system blockade [24]. Were methods available to reduce renal afferent signalling, further therapies might be available [25]. One target not addressed by the current study is renalase, a catecholamine-metabolizing hormone from the kidney [26,27]. In any event, there is clearly enough work that remains to be done.

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References

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17 Hamar P, Kokeny G, Liptak P, Krtil J, Adamczak M, Amann K, et al. The combination of ACE inhibition plus sympathetic denervation is superior to ACE inhibitor monotherapy in the rat renal ablation model. Nephron Exp Nephrol 2007; 105:E124–E136.

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22 Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, et al. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003; 5:659–667.

23 Swedberg K, Bristow MR, Cohn JN, Dargie H, Straub M, Wiltse C, et al. Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure. Circulation 2002; 105:1797–1803.

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