Sympathetic Overactivity in Chronic Kidney Disease: Consequences and Mechanisms

Abstract

The incidence of chronic kidney disease (CKD) is increasing worldwide, with more than 26 million people suffering from CKD in the United States alone. More patients with CKD die of cardiovascular complications than progress to dialysis. Over 80% of CKD patients have hypertension, which is associated with increased risk of cardiovascular morbidity and mortality. Another common, perhaps underappreciated, feature of CKD is an overactive sympathetic nervous system. This elevation in sympathetic nerve activity (SNA) not only contributes to hypertension but also plays a detrimental role in the progression of CKD independent of any increase in blood pressure. Indeed, high SNA is associated with poor prognosis and increased cardiovascular morbidity and mortality independent of its effect on blood pressure. This brief review will discuss some of the consequences of sympathetic overactivity and highlight some of the potential pathways contributing to chronically elevated SNA in CKD. Mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and to date, not completely understood. Identification of the mechanisms and/or signals leading to sympathetic overactivity in CKD are crucial for development of effective therapeutic targets to reduce the increased cardiovascular risk in this patient group.

Keywords: angiotensin II; asymmetric dimethylarginine; blood pressure; cardiovascular disease; hypertension; muscle sympathetic nerve activity; nitric oxide; oxidative stress; sympathetic outflow.

Figure 1

Original record of muscle sympathetic nerve activity (MSNA) in a normal subject and a renal failure patient on hemodialysis, demonstrating significantly greater resting MSNA in the dialysis patient. The bottom two panels display a portion of the neurogram and simultaneous electrocardiogram from the patient on hemodialysis showing that the renal failure patient has a burst of MSNA with every cardiac cycle. (Modified from Converse et al. [11] with permission).

Figure 2

Muscle sympathetic nerve activity (MSNA) expressed as burst frequency (bursts (bs)/min, A) and burst incidence (bs/100 heartbeats (hb), B) in subjects grouped according to their estimated glomerular filtration rate (eGFR), with the highest quartile of eGFR in group I and lowest quartile of eGFR in group IV. With decreasing eGFR, there is a significant and progressive increase in resting MSNA in chronic kidney disease (CKD) patients. * p < 0.05 significant difference between quartiles. (From Grassi et al. [13] with permission).

Figure 3

Mean arterial pressure (MAP) responses during 8-h continuous systemic infusion of the nitric oxide synthase (NOS) inhibitor l-nitroarginine methyl ester (l-NAME) in rats with sympathectomy (open circles) and without sympathectomy (closed circles). Although no difference was observed in the initial increase in MAP (removal of endothelium-mediated dilation), sympathectomy attenuated the sustained hypertensive response to l-NAME, demonstrating a sympathetic contribution to the blood pressure raising effects of systemic NOS inhibition. * p < 0.05 vs. control. (From Sander et al. [75] with permission).

Figure 4

Average mean arterial pressure, heart rate, and renal sympathetic nerve activity during continuous systemic infusion of asymmetric dimethylarginine (ADMA; an endogenous NOS inhibitor) in baroreceptor-intact (A) and baroreceptor-denervated animals (B). In comparison with barointact animals, barodenervated animals show a significant increase in renal SNA indicating frank sympathoexcitation in response to systemic ADMA infusion. * p < 0.05 vs. baseline; ^† p < 0.05 vs. baroreceptor intact. (From Augutyniak et al. [87] with permission.)

Figure 5

Schematic illustration depicting the effects of elevated ADMA in the brainstem and the peripheral circulation. Reduced dimethylarginine dimethylaminohydrolase (DDAH) activity and renal clearance of ADMA leads to elevated plasma ADMA concentrations in chronic kidney disesase (CKD). Elevated ADMA in the brainstem inhibits NOS and reduces central nitric oxide (NO) production, contributing to higher central sympathetic outflow. This greater SNA results in peripheral vasoconstriction. When prolonged, the sympathetic overactivity leads to a host of other deleterious consequences as outlined in the text of the review. In the periphery, elevated ADMA inhibits NOS and decreases NO, thereby reducing endothelium-mediated vasodilation. Greater sympathetically-mediated vasoconstriction and lower endothelium-mediated vasodilation contributes to increased vascular tone and higher blood pressure. ROS, reactive oxygen species; eNOS, endothelial nitric oxide synthase; NE, norepinephrine. ⱶ- denotes inhibition. (See text for further details).