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Perit Dial Int 27(Supplement_2): 293-297
2007
© 2007 International Society for Peritoneal Dialysis
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Part 9: Miscellaneous Complications and Pathophysiologic Mechanisms

SYMPATHETIC HYPERACTIVITY—A HIDDEN ENEMY IN CHRONIC KIDNEY DISEASE PATIENTS

Peter J. Blankestijn

Department of Nephrology, University Medical Center, Utrecht, Netherlands

Correspondence to: P.J. Blankestijn, Department of Nephrology, Room F03.226, University Medical Center, PO Box 85500, Utrecht 3508 GA Netherlands. P.J.Blankestijn{at}umcutrecht.nl


   ABSTRACT
TOP
 ABSTRACT
CLINICAL RELEVANCE
 TREATMENT
 UNRESOLVED ISSUES
 CONCLUSIONS
 REFERENCES
 

Chronic kidney disease is often characterized by the presence of sympathetic hyperactivity. The aim of this brief review is to summarize available knowledge on the pathogenesis of sympathetic hyperactivity and to discuss its clinical relevance, the consequences of this knowledge for the choice of treatment, and the yet unresolved issues.

KEY WORDS: Chronic kidney disease; renal hypertension; sympathetic activity; angiotensin II.

Chronic kidney disease (CKD) is often characterized by the presence of sympathetic hyperactivity. Comprehensive reviews by my group (1–5) and others (6–8) are published elsewhere.

The application of microneurography has greatly enhanced knowledge about sympathetic activity in kidney patients. This technique can measure true sympathetic nerve activity [muscle sympathetic nerve activity (MSNA)]. This MSNA, usually measured in the peroneal nerve, represents the centrally originated postganglionic sympathetic nerve activity directed to resistance vasculature. The technique is highly reproducible, technically difficult, but very suitable to study effects of interventions such as medication and diet (9).

Chronic kidney disease patients both on and not yet on hemodialysis have elevated MSNA (10–17). Hemodialysis patients have higher MSNA than do patients not on dialysis (Neumann J et al., unpublished observations). Data on peritoneal dialysis are not currently available.

Bilaterally nephrectomized hemodialysis patients have MSNA comparable to controls, providing definite proof that the signal that commands the central nervous system to increase sympathetic outflow is generated in the diseased kidneys (10). Renal transplant patients with good renal graft function exhibit MSNA identical to that of hemodialysis patients (11). Bilateral nephrectomy in these transplant patients resulted in a MSNA level not different from that in control subjects. Unilateral nephrectomy for the purpose of transplantation did not affect MSNA (12).

Experimental studies found that even a limited renal lesion not affecting GFR results in neurogenic hypertension, which is reduced or prevented by renal denervation [summarized in (1–5)]. The sympathetic hyperactivity is meant to restore kidney perfusion. Circulating angiotensin II (AngII), which is usually increased in CKD patients, can increase MSNA, which indicates an effect of AngII on the central nervous system. Further, on the peripheral level, AngII enhances noradrenaline secretion by stimulating prejunctional receptors [summarized in (1–5)].

In human renovascular hypertension, angioplasty resulted in a decrease of AngII levels and MSNA alike (18). Angiotensin converting-enzyme (ACE) inhibitors and AngII receptor blockers both reduce MSNA (14–16). Changes in fluid status in healthy controls and in CKD patients result in parallel changes in plasma renin activity and MSNA (12). These observations support the idea that overactivity of the renin–angiotensin system and the sympathetic nervous system have a cause-and-effect relationship or a common origin.

Evidence also suggests that yet other mechanisms are involved (1–5). The nitric oxide system is a natural antagonist of catecholamines. It is inhibited by the endogenous inhibitor of NO synthase asymmetrical dimethylarginine (ADMA), which causes an increase in vascular resistance and blood pressure (19). In hemodialysis patients, ADMA is a strong predictor of poor clinical outcome (20,21). Noradrenaline and ADMA levels exhibit a positive relationship, suggesting cause and effect (22).

Additional factors that are able to increase sympathetic activity include sleep apnea, smoking, and obesity. Dialysis patients also often suffer from sleep apnea. Nocturnal hemodialysis has been shown to reduce the number of sleep apnea periods (23).

In summary, the data indicate that, in humans, the diseased kidneys are key players in the pathogenesis of increased MSNA. And it is kidney disease or injury rather than failure that predisposes for the presence of sympathetic hyperactivity. My group's hypothesis is that kidney ischemia, possibly combined with other factors, is of critical importance in this pathogenesis (Figure 1).


Figure 1
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  		Figure 1 — Schematic representation of kidney involvement in the pathogenesis of sympathetic hyperactivity. Existing minimal kidney damage (not necessarily affecting kidney function) results in areas of ischemia. Increased plasma levels of angiotensin II (AngII) or increased afferent renal nerve activity, or both, stimulate the central nervous system to increase central sympathetic outflow, resulting in sodium retention and vasoconstriction that are meant to restore kidney perfusion.

 

   CLINICAL RELEVANCE
TOP
 ABSTRACT
 CLINICAL RELEVANCE
TREATMENT
 UNRESOLVED ISSUES
 CONCLUSIONS
 REFERENCES
 
Hypertension: Toward the end of the 1970s, a profound decline in blood pressure had already been reported in hypertensive hemodialysis patients after administration of the ganglion blocker debrisoquine, as compared with only a moderate effect in normotensive patients (24). Blood pressure in CKD patients correlated with MSNA, and blood pressure reduction with the use of chronic ACE inhibitors or AngII receptor blockers correlated with the decrease of MSNA (13,14).

Cardiovascular Outcomes: Sympathetic hyperactivity is related to left ventricular hypertrophy (25–27). Also, in CKD patients, a positive relationship is observed between noradrenaline levels and the risk of having left ventricular hypertrophy (28), and patients with left ventricular hypertrophy generally have a poorer prognosis (29). Sympathetic activity contributes to the development of other forms of organ damage independent of its effect on blood pressure (30). It is associated with heart failure, arrhythmias, and in experimental conditions, with atherogenesis. Plasma noradrenaline is an independent predictor for all-cause mortality and cardiovascular events in hemodialysis patients without overt heart failure (31).

Kidney Damage: Experimental evidence suggests that catecholamines are involved in the development of kidney injury, also independent of their effect on blood pressure (2). These effects include vascular and glomerular injury. In subtotally nephrectomized rats, a low dose of moxonidine (also of alpha and beta blockers) ameliorates renal damage without affecting blood pressure (32,33). In normotensive humans with diabetes, moxonidine reduced albuminuria without affecting blood pressure (34).


   TREATMENT
TOP
 ABSTRACT
 CLINICAL RELEVANCE
 TREATMENT
UNRESOLVED ISSUES
 CONCLUSIONS
 REFERENCES
 
Based on the pathophysiologic mechanisms outlined here, it seems logical that treatment should include an ACE inhibitor or an AngII receptor blocker, combined with diuretics (or ultrafiltration in case of dialysis patients) to maintain normovolemia.

We reported that enalapril, losartan, and eprosartan reduce MSNA by 20% – 25% (14–16). The tested agents did not differ in efficacy. Mean arterial pressure was reduced by 15%. Interestingly, heart rate slightly but significantly decreased with eprosartan, suggesting that cardiac inotropic sympathetic activity was also inhibited (16). However, sympathetic hyperactivity (at least MSNA) was not normalized. Therefore, we added moxonidine, which is a centrally acting sympatholytic agent, to chronic treatment with eprosartan. Blood pressure and MSNA were both reduced to levels identical to that of controls (16).

The ACE inhibitors appear to be most effective in reducing left ventricular hypertrophy, and they are associated with improved survival independently of their effect on blood pressure [reviews in (1–5)]. In dialysis patients with dilated cardiomyopathy, the addition of carvedilol to the standard therapy regimen reduced cardiovascular morbidity and mortality as compared with placebo (35). In dialysis patients with heart failure, the addition of an AngII receptor blocker to standard therapy (including an ACE inhibitor) reduced mortality (36).

Nocturnal home dialysis lowers blood pressure, peripheral resistance, and plasma noradrenaline levels (37). We found that by increasing the frequency of hemodialysis from 3 x 4 hours to 6 x 2 hours weekly, MSNA was decreased, accompanied by a decrease in peripheral resistance, but without an effect on renin activity (38). Whether this result was caused by an improvement of the balance of sympatho-stimulating and sympatho-inhibiting factors is unknown. For instance, ADMA levels are reduced by hemodialysis treatment (39), and removal is likely to be more efficient with frequent dialysis. Further, standard hemodialysis with ultrafiltration causes sympathetic activation. This activation is likely to less pronounced with frequent dialysis.


   UNRESOLVED ISSUES
TOP
 ABSTRACT
 CLINICAL RELEVANCE
 TREATMENT
 UNRESOLVED ISSUES
CONCLUSIONS
 REFERENCES
 
Although sympathetic hyperactivity has now been recognized as a cardiovascular or renal risk factor (or both) in CKD patients (40), many issues are still unclear.

Defining the "optimal" dose of ACE inhibitors or AngII receptor blockers is more difficult than previously thought. The currently recommended and commercially licensed maximal doses are based on the potential of these agents to lower blood pressure. However, experimental evidence has shown that the intrarenal renin–angiotensin system is compartmentalized from the systemic renin–angiotensin system (41). The kidney renin–angiotensin system is not inhibited by plasma concentrations of ACE inhibitors reached with current doses. Comprehensive reviews of combining these therapies are summarized elsewhere (42,43).

Dual therapy—that is, combining ACE inhibitors and AngII receptor blockers—usually results in a greater reduction in blood pressure and proteinuria. In a recent study (44), an ACE inhibitor and an AngII receptor blocker were adjusted to reach identical blood pressure values in all treatment arms (ACE inhibitor alone, AngII receptor blocker alone, and combination therapy). The risk of reaching an endpoint (end-stage kidney disease or doubling of serum creatinine) was lower with combination therapy than with the respective monotherapies.

No "official" guidelines exist with respect to the use of dual therapy. However, it is attractive to hypothesize that "more intense" inhibition of the renin–angiotensin system or the combination of agents that interfere with the renin system with newer beta blockers or centrally acting sympatholytic agents will result in more effective inhibition of sympathetic hyperactivity, translating into an improvement of meaningful cardiovascular clinical endpoints. However, no such studies exist. That fact is especially relevant because we found that, despite treatment with a usual dose of an ACE inhibitor or AngII receptor blocker, the unfavorable relationship between sympathetic hyperactivity and outcome remained (45).

Future studies need to address several questions:

If the state of NO deficiency characteristic in CKD indeed means that even normal sympathetic activity may cause harm to patients, these patients might benefit from this treatment as well.

The optimal regimen with respect to combining medication and dialysis schedule is unclear. Studies in peritoneal dialysis are totally lacking. A very recent study suggests that statin therapy also reduces MSNA (46). The mode of action of this sympatholytic effect is unclear. Whether statins also lower MSNA when combined with ACE inhibitors or AngII receptor blockers (or both) is also unclear.


   CONCLUSIONS
TOP
 ABSTRACT
 CLINICAL RELEVANCE
 TREATMENT
 UNRESOLVED ISSUES
 CONCLUSIONS
REFERENCES
 
Chronic kidney disease is often characterized by the presence of sympathetic hyperactivity, which contributes to the development of cardiovascular organ damage and possibly also kidney failure progression. Experimental and clinical evidence both suggest that kidney ischemia plays a central role in the pathogenesis. In their currently recommended and commercially licensed maximal dosages, ACE inhibitors and AngII receptor blockers reduce but do not normalize sympathetic hyperactivity. The addition of other sympatholytic agents such as moxonidine or newer beta blockers may result in further inhibition of sympathetic hyperactivity. Finally, available evidence suggests that increasing the dialysis dose also results in inhibition of sympathetic hyperactivity.


   ACKNOWLEDGMENTS
 
These studies were supported by the Dutch Kidney Foundation (Nierstichting Nederland), grant numbers C95.1489, C97.1684, C98.1750, and KC 24.


   REFERENCES
TOP
 ABSTRACT
 CLINICAL RELEVANCE
 TREATMENT
 UNRESOLVED ISSUES
 CONCLUSIONS
 REFERENCES
 

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