Department of Internal Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA
Introduction
The endothelium is a functional barrier between vessel wall and blood stream that for a long time has been regarded as a relatively inert container for blood. However, the last 20 years, researchers have found an extraordinary variety of important endothelial functions, including control of coagulation, fibrinolysis, vascular tone, growth, and immune response. The endothelium modulates vascular tone by releasing a number of vasoactive substances including nitric oxide (NO). It is now clear that dysfunction of the endothelium disturbs the physiological protective regulatory balance, which is a critical factor in the atherosclerotic disease progression. Thus, endothelial dysfunction occurs in many diseases/disorders associated with an increased cardiovascular risk, such as essential hypertension [1], dyslipidaemia [2], smoking [3] and mental stress [4].
The significant burden of atherosclerotic cardiovascular disease (CVD) in end-stage renal disease (ESRD) has been recognized since more than 25 years [5]. The increased incidence of CVD is probably the result of a high prevalence of both traditional risk factors (such as hypertension, dyslipidaemia, and smoking) and non-traditional risk factors (such as inflammation, oxidative stress, advanced glycation end products, and homocysteine). C-reactive protein (CRP), a sensitive and objective marker of one non-traditional risk factor, inflammation, has been shown to be associated to CVD in both predialysis [6] and dialysis [7] patients populations.
Endothelial dysfunction is a prominent feature of ESRD
Recently, several studies have shown that impaired endothelium-dependent vasodilation is a prominent feature in patients with moderate renal impairment [8], as well as in patients with advanced renal impairment treated by haemodialysis [9] or peritoneal dialysis [10]. The reason(s) why ESRD patients have signs of endothelial dysfunction are not fully understood but are probably multifactorial (Table 1). It could be speculated that various factors associated with ESRD, such as increased oxidative stress, hyperhomocysteinaemia, dyslipidaemia, hyperglycaemia, hypertension, retention of L-arginine inhibitors (ADMA) all may be important contributors. However, Annuk et al. [8] could recently show that the occurrence of traditional risk factors, such as hypertension, hypercholesterolaemia, and diabetes mellitus, could not explain the impairment of endothelial function in patients with moderate renal impairment. As they found a correlation between creatinine clearance and endothelial function, they concluded that renal impairment per se is related to impaired endothelial function. Thus, based on their findings, it could be speculated that one, or several non-traditional risk factors (such as homocysteine, advanced glycation end products, and inflammation) associated with reduced renal function might adversely affect endothelial function. In this respect, it is of interest that recent results from various non-renal patient groups show inflammation to be associated with endothelial dysfunction. Consequently, as inflammation has been shown to be a common feature in both predialysis and dialysis patients [11] it could be speculated that endothelial dysfunction may be one important intermediate phenotype in the relationship between inflammation and CVD in ESRD patients.
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Strong relation between inflammation and endothelial dysfunction in non-renal patient groups
A large number of recent epidemiological and observational studies have suggested an association between infection or inflammation on the one hand and risk of CVD on the other [12]. It is, therefore, of interest that exposure of endothelial cells to pro-inflammatory cytokines leads to expression of cell-surface adhesion molecules [13] and impairs endothelium-dependent vascular relaxation [14]. Taken together, these experimental data suggest that the inflammatory response may provide a link between systemic inflammation and CVD. Indeed, recently Fichtlscherer et al. [15] demonstrated an inverse correlation between CRP and forearm blood flow responses to acetylcholine in males with documented coronary artery disease. It should be noted that in this study decreasing CRP levels over time was associated with a normalization of endothelium-mediated forearm blood-flow responses after 3 months. In addition, other studies have shown that CRP is an independent determinant of endothelium-dependent vascular function in both coronary heart disease patients [16] and in healthy subjects [17]. Results presented by Cleland et al. [17] further expand our knowledge by showing a relationship between low-grade inflammation and basal endothelial NO synthesis. It should be pointed out that not only observational but also experimental studies have been able to demonstrate an association between inflammation and endothelial dysfunction in humans. In fact, in a recent study, Hingorani et al. [18] assessed the inflammatory response to Salmonella typhi vaccination in 12 healthy subjects and found that the vaccination resulted not only in a mild inflammatory reaction but also in a transient and profound dysfunction of the arterial endothelium.
Indirect evidence of a link between inflammation and endothelial dysfunction has also been found in type-1 diabetic patients by Schalkwijk et al. [19] who observed an inverse relation between CRP and endothelium-derived proteins, such as von Willbrand factor and adhesion molecules (ICAM-1). No study has yet been published in which markers of inflammation have been correlated to endothelial function in ESRD patients, as directly measured by forearm blood flow response, in ESRD patients. However, as an indirect marker of endothelial function (ICAM-1) has been found to correlate with CRP in predialysis patients [20] it seems conceivable to speculate that chronic inflammation may be associated with endothelial dysfunction in ESRD patients as well.
Various infections cause endothelial dysfunction
The cause of inflammation in ESRD patients may be multifactorial but it is probable that various chronic infectious processes contribute. Recent evidence suggests the participation of chronic Chlamydia pneumonia infection in the pathogenesis of atherosclerosis in both the general population [21] and ESRD patients [22,23]. It is, therefore, of interest that Liuba et al. [24] have shown that repeated C. pneumonia infections impairs endothelial function in apolipoprotein E-knockout mice. Importantly, recent evidence suggests that also other persistent infections may contribute to endothelial dysfunction in humans. In a preliminary study Prasad et al. [25] have shown that prior infection with cytomegalovirus, hepatitis A virus, herpes simplex virus type 1, C. pneumonia and Helicobacter pylori are risk factors for coronary endothelial dysfunction. Moreover, in HIV infection, dysfunctional or injured endothelial cells potentiate tissue injury and inflammation and accelerate the development of CVD [26]. Finally, Channon et al. [27] have shown that recombinant adenovirus triggers an early inflammatory response and that it is the inflammatory response that causes functional endothelial injury.
Is tumour necrosis factor- (TNF-
) the key mediator of endothelial dysfunction?
As strong correlations are found between CRP and endothelial function it seems reasonable to speculate that CRP per se may affect endothelial function. Indeed, CRP has recently been shown to induce adhesion molecule expression in the presence of serum suggesting a direct pro-inflammatory effect on human endothelial cells [28]. However, CRP is also relevant as a distal surrogate marker of various pro-inflammatory cytokines, which also may affect endothelial function. In fact, several lines of evidence suggest that the pro-inflammatory cytokine TNF- plays a key role in inducing endothelial dysfunction. First, in clinically stable heart transplant patients a strong positive relation between plasma TNF-
levels and the vascular response to acetylcholine has been documented [29]. Second, Bhagat and Vallance [14] have shown that whereas infusion of TNF-
alone impaired endothelial function in healthy subjects, infusion of IL-6 did not. In addition, another study has shown that administration of TNF-
depresses endothelium-dependent relaxation in vivo [30]. Finally, cell culture experiments have shown that TNF-
reduces the half-life of mRNA encoding for endothelial NO synthase [31]. A key role for TNF-
in mediating endothelial dysfunction is of interest not only because markedly elevated serum levels of TNF-
have been documented in ESRD patients [32] but also because we now have access to targeted anti-TNF therapies, such as etanercept. Thus, new effective treatment strategies may emerge for ESRD patients in the future. The exact mechanism(s) by which various pro-inflammatory mediators, such as TNF-
, cause endothelial dysfunction are not yet known. However, Kessler et al. [33] have shown that pro-inflammatory mediators induce NO synthase expression in cultures of endothelial cells and decreased expression of cytochrome P450 enzymes, both of which are probable candidates for synthesis of endothelium-derived hyperpolarizing factor (EDHF).
Anti-inflammatory treatment strategies improve endothelial function
Whereas a number of different treatment strategies (Table 2), such as ACE-inhibitors, statins, antioxidants, folic acid and nutritional supplements (L-arginine) have been shown to improve endothelial function in various non-renal patient groups, data on the effects of various anti-inflammatory treatment strategies on endothelial function are scarce. Bhagat and Vallance [14] showed that administration of hydrocortisone (100 mg) and high-dose aspirin (1000 mg) prevented cytokine induced endothelial dysfunction in healthy controls, whereas low-dose aspirin (75 mg) did not. Further evidence for a positive effect of anti-inflammatory treatment of endothelial function can be derived from a recent study in which it was shown that treatment of primary systemic vasculitis with steroids and/or cyclophosphamide was associated with a normalization of endothelial function [34].
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Conclusion
The endothelium can no longer be viewed as a static physical barrier that simply separates blood from tissue. It is evident that disturbed endothelial function may be an early marker of an ongoing atherosclerotic process. Thus, endothelial dysfunction has increasingly been recognized to play an important role in a number of conditions associated with a high prevalence of atherosclerotic CVDs, including ESRD. The identification of elevated CRP as a transient independent risk factor for endothelial dysfunction might provide an important clue to link a systemic marker of inflammation to progression of atherosclerotic disease. Available evidence suggests that low-grade inflammation is accompanied by a decreased bioavailability of endogenous NO and that TNF- may play a key role in these events. Thus, randomized longitudinal studies are now needed to investigate whether or not various anti-inflammatory treatment strategies (such as anti-TNF treatment) improve endothelial function in ESRD patients and, more importantly, also decrease the unacceptable high cardiovascular mortality rate in this patient group.
Notes
Correspondence and offprint requests to: Peter Stenvinkel, MD, University of California Davis, Department of Internal Medicine, Division of Nephrology, TB136, Davis CA 95616, USA. Email: peter-stenvinkel{at}klinvet.ki.se
References