A. Guerin B. Pannier G. London
Service de Néphrologie, Centre Hospitalier Manhes, Fleury Mérogis, France
Epidemiological as well as clinical studies have shown that regardless of the severity of renal impairment the cardiovascular mortality in renal disease patients is very high compared to the general population. In uremia, cardiovascular disease is a combination of atherosclerosis, characterized by the presence of highly calcified plaques, and arteriosclerosis, an arterial wall alteration in response to both hemodynamic changes and humoral modifications such as inflammation or calcium-phosphate imbalance. Vascular endothelium, recognized as a large and complex endocrine organ strategically located between the wall of the blood vessel and the blood stream, could be the link between these two processes evolving during the same course.
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Epidemiological and clinical studies have shown that end-stage renal disease (ESRD) patients die from cardiovascular disease much younger than people in the general population. Age-adjusted cardiovascular mortality is about 30 times higher in ESRD than in the general population. In the National Institutes of Health Hemodialysis Study, prevalence of cerebrovascular disease, peripheral arterial disease or coronary heart disease was respectively 19, 23 and 40% , However, cardiovascular complications are also a cause of mortality in patients during the course of chronic renal failure before dialysis. It is only recently that mild renal insufficiency was associated with an increased cardiovascular risk, as some proatherogenic factors are present in early or mild renal insufficiency. It is important to keep in mind that regardless of how renal disease severity is classified (degree of urine albuminuria or proteinuria, glomer-
ular filtration rate, or presence of ESRD), 10-year mortality for severe renal abnormality is extraordinarily high (107 per 1,000 person-years) compared with that predicted by Framingham data with multiple risk factors (25 per 1,000 person-years) .
Moreover, cardiovascular disease in uremia is a combination of atherosclerosis and arteriosclerosis leading to uremic cardiomyopathy. Atherosclerosis, a primary intimal disease characterized by the presence of plaques and occlusive lesions, is the most frequent cause of cardiovascular complications. However, many of these complications occur in the absence of clinically significant atherosclerotic disease . Arterial wall alteration is not only the response to direct injury or to the presence of atherogenic factors, it is also involved in the response to hemodynamic burden modifications . The structural modifications induced by hemodynamic alterations are changes in arterial lumen and/or arterial wall thickness .
Atherosclerosis is characterized by the presence of plaques, focal and patchy in its distribution. It occurs preferentially in medium-sized conduit arteries, coronary, iliac, femoral arteries and less often in muscular arteries in the arm or internal mammary. In ESRD, these plaques are characterized by the intensity of calcifications.
There is growing evidence that inflammation probably plays a key role in the initiation and progression of the atherosclerotic process, and atherosclerosis has been consequently defined as an inflammatory disease . A high percentage of chronic kidney disease (CKD) patients have serological evidence of an activated inflammatory response [7, 8]. Serum levels of C-re-active protein appear to reflect the generation of proinflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-a (TNF-a), all of which have been reported to be markedly elevated in ESRD patients and also to predict mortality [8-11]. The causes of this phenomenon are multifactorial, including the decreased renal clearance and increased synthesis of proinflammatory cytokines, comorbidities such as diabetes or chronic heart failure and the atherosclerotic process per se , the accumulation of advanced glycation end-products  and other factors related to the dialytic procedure such as vascular access infections, membrane bioincompatibility, and contaminated dialysate. However, it is very difficult to distinguish whether chronic inflammation is a cause or a consequence of cardiovascular disease and it is still an open question. Currently, no treatments for the management of chronic inflammation in CKD are recognized, but attention has been paid to all of the factors that can maintain or enhance inflammation in CKD.
Hyperhomocysteinemia, which is now recognized as a proatherogenic factor and as an independent predictor of cardiovascular disease in the general population, is present from the earliest stage of CKD and increases inversely with the reduction in renal function . Hyperhomocysteinemia has many causes in CKD including decreased activity of the remethylation cycle, decreased serum folate and vitamin B intake and decreased renal clearance of homocysteine. Homocysteine may increase oxidative stress, decrease nitric oxide (NO) availability and produce endothelial dysfunction , The intravenous administration of acetylcysteine, a thiol-containing antioxidant, reduces the plasma homocysteine level and probably improves endothelial function in ESRD patients . Although an association between hyperhomocys-teine levels and cardiovascular events has been proven, particularly in CKD, the cause has not yet been demonstrated.
Numerous data suggest that CKD is a prooxidant state as shown by the increase in a number of oxidative stress markers in CKD patients . In renal failure, oxidative stress imposes damage on DNA (8-oxo-OH-deoxyguano-sine), proteins (carbonyl compounds, advanced oxidation protein products), carbohydrates (advanced glycation end-products) and lipids (oxidized LDL). Oxidative stress involves the increased production of free radicals which can exhaust endogenous antioxidant and lead to vascular injury. The activity of multiple oxidases, including Nox oxidases, nitric oxide synthase, xanthine oxidase, cytochrome P450, cyclooxygenase and mitochondria can contribute to the generation of oxidant species in the vessel wall . On the other hand, in hemodialysis patients oxidative stress is commonly attributed to the recurrent activation of polymorphonuclear neutrophils and monocytes, closely related to membrane biocompatibility, generating the cascade of highly reactive oxygen species (ROS)  (fig. 1). The repetitive enhancement of ROS production associated with complement activation and overexpression of adhesive molecules in circulating leukocytes could promote endothelial cell membrane lipid peroxidation leading to endothelial dysfunction. Moreover, activity of the glutathione system has been shown to be significantly decreased in hemodialysis patients. This diminution begins early in the course of chronic renal failure and steadily progresses as renal function decreases . The data concerning other oxidant-scavenging molecules such as superoxide dismutase, ceruloplas-min or transferrin appear less clear. The role of vitamin C is still a matter of debate and vitamin E concentration is normal in the plasma and decreased in erythrocytes and mononuclear cells .
The imbalance between free radical formation and neutralization which deteriorate over time may be the causative factor for the activation of an in-
flammatory cascade by a variety of potential stimulators in uremia and dialysis. A common signaling occurs via the generation of oxygen free radicals, activation of the transcription factor nuclear factor-kB (NF-kB) and induction of a number of genes such as adhesion molecules, cytokines, chemokines and matrix proteins . NF-kB is also involved in the proliferation of vascular smooth muscle cells which is a crucial event in the formation of atherosclerosis tissue . Moreover, recent studies indicate that proinflammatory cytokines may also have direct atherogenic properties. IL-6 is a stimulant of adhesion molecule-1 but also contributes to the development of atherosclerosis through various mechanisms reviewed recently by Yudkin et al. . TNF-a has been shown to promote in vitro calcification of vascular cells  or to cause endothelial dysfunction .
Hypertension appears to promote vascular dysfunction associated with increased scavenging of NO by superoxide anion that seems to originate from an initial activation of Nox oxidases through increased pressure and angioten-
sin II . There is strong experimental evidence of a role for angiotensin II in increasing oxidative stress, particularly in hypertension . Accordingly, in transgenic rat harboring human renin and angiotensinogen genes, Mervaala et al.  showed that experimentally induced oxidative stress was normalized by treatment with valsartan.
Markers of oxidative stress have been correlated with impaired endothelial function or the presence of carotid plaques and intima-media thickness in some studies [29-31]. Recent studies suggested that carotid intima-media thickness is an independent predictor of cardiovascular mortality in the he-modialysis population [32, 33] but the arterial changes could occur early in the course of renal disease . The Secondary Prevention with Antioxidants of Cardiovascular Disease in End-Stage Renal Disease (SPACE) trial has demonstrated positive results on the improvement in cardiovascular outcomes in hemodialysis patients with a history of cardiovascular disease with oral vitamin E supplementation . The prospective study with acetylcysteine administered as an antioxidant in 134 hemodialysis patients showed reduced composite cardiovascular endpoints . Despite these results, there is currently no evidence that increased oxidative stress contributes to the increased cardiovascular morbidity and mortality in CKD patients.
Other targets of ROS are lipids, the oxidation of which is associated with increased cardiovascular risks. First, the process of lipid peroxidation itself generates more free radical and ROS which increase the potential to do harm. Second, the lipid peroxidation is the first step in the generation of oxidized LDL (ox-LDL) which is implicated in atherogenesis. These modified lipids can induce the expression of adhesion molecules, chemokines, proinflammatory cytokines and other mediators of inflammation in macrophages and vascular wall cells. Some studies showed that ESRD patients had a higher level of anti ox-LDL antibody than healthy subjects .
More recently, Shoji et al.  were able to demonstrate, for the first time, that the serum level of antibody to ox-LDL was an independent predictor of cardiovascular mortality in ESRD patients. On the contrary, the same team showed an inverse association between intima-media thickness of carotid and femoral arteries suggesting an antiatherogenic role of antibody to ox-LDL . ox-LDL and antibodies to ox-LDL play a pivotal but still controversial role in the development of atherosclerosis. Atherogenic ox-LDL increases progressively during the development of renal failure, suggesting that the oxidation of LDL may be associated with endothelial injury and atherogenesis in these patients . Therefore, van den Akker et al.  studied the effect of statins on the level of these drugs in a small group of hemodialysis patients. They showed a significant decrease of ox-LDL, but there was no significant change of IgG and IgM autoantibodies to ox-LDL.
During the same course, and not independently of the atherosclerosis process, arterial remodeling accompanies the growing hemodynamic burden and humoral abnormalities associated to chronic uremia . Evidence that enhanced tensile stress is relevant to the pathogenesis of atherosclerosis comes from the observation that atherosclerotic plaques are virtually confined to systemic arteries where tensile stress is high. Moreover, the role of shear stress is demonstrated by the predilection of atherosclerosis for sites, characterized by flow pattern and shear stress disturbances, like bending or branching.
The mechanical signals for arterial remodeling associated with hemody-namic overload are the cyclic tensile stress or shear stress [43, 44]. This includes the chronic alterations of mechanical forces which lead to the changes in the geometry and the composition of the vessel wall; changes which may be considered as an adaptative response to long-lasting changes in blood flow and pressure. The quality of the responsiveness of the arterial wall to mechanical stimuli is tightly dependent on the presence of an intact endothelium [45, 46],
Experimental and clinical data indicate that acute and chronic augmentations of arterial blood flow induce proportional increases in the vessel lumen diameter, whereas decreasing flow reduces arterial inner diameter . It is activation of the endothelium, strategically situated at the blood vessel-wall interface, which transforms physical forces into biochemical signals through the generation of vasoactive substances.
The conduit function of arteries is to supply an adequate blood flow to peripheral organs. Their physiological adaptability is highly efficient and acute diameter changes are dependent on the endothelium which responds to alterations in shear stress. In chronic overload, the arterial diameters are enlarged and baseline arterial conductance is increased .
The role of arteries is also to dampen the pressure and flow oscillations resulting from intermittent ventricular ejection and to transform the pulsatile flow of arteries into a steady flow required in peripheral tissue. The efficiency of the conduit function depends on the viscoelastic properties of the arterial wall as well as the diameter and length of the arteries. The viscoelastic property is best described in term of stiffness (S) . Arterial stiffness can be evaluated by ultrasonography or by measuring the pulse wave velocity (PWV) over a given arterial segment. PWV increases with arterial stiffness .
Arterial Stiffness and Blood Pressure Changes: Cardiovascular
In uremic patients, the arterial system of CKD and ESRD patients undergoes remodeling that is characterized by dilatation and to a lesser degree arterial intima-media hypertrophy of central elastic type, capacitive arteries and wall hypertrophy of peripheral muscular type conduit arteries [34, 48, 50]. Large arteries, like the aorta or common carotid artery, are enlarged in CKD before the onset of dialysis and ESRD patients in comparison with age-, sex-and pressure-matched control subjects [51, 52]. In ESRD patients, this remodeling is associated with arterial stiffening related to alterations of the intrinsic properties of the arterial wall materials including those free of atherosclerosis [48, 53, 54]. Nevertheless, according to Laplace's law , the wall-to-lumen ratio should increase in order to normalize tensile stress. This increase was not observed in ESRD patients whose wall-to-lumen ratio in large conduit arteries was not related to pressure changes. This observation suggests that conduit arteries could have limited capacity to hypertrophy in response to a combined flow and pressure load.
In ESRD patients, the arterial remodeling is associated with arterial stiffening due to the alterations of the intrinsic properties of arterial wall material. Contrary to the arterial distensibility measurements in essential hypertensive patients in whom distensibility is increased, in ESRD arterial hypertrophy is accompanied by alteration in the intrinsic elastic properties of the vessel wall (incremental modulus, Einc). The observation that the incremental modulus of elasticity is increased in ESRD patients, i.e. a decrease distensibility, strongly favors altered intrinsic elastic properties or major architectural abnormalities like those seen in experimental uremia and the arteries of uremic patients, namely fibroelastic intimal thickening, increased extracellular matrix and high calcium content with extensive medial calcifications [54-56]. Recent data indicate that mediacalcosis and extensive calcifications of the arterial tree are an important factor accounting for the increased of arterial stiffening [55, 56]. Phosphate retention and poorly controlled calcium phosphate balance play an important role in the pathogenesis of these arterial changes. And aortic PWV was found to be associated with an increased serum phosphorus, high calcium phosphate product and the total dose of calcium-based phosphate binder . Arterial calcifications and arterial stiffening in ESRD patients are associated with the presence of systemic microinflammation, as evaluated by serum C-reactive protein levels. The association of dyslipidemia and arterial calcification in CKD is controversial, being found negative or positive  .
Postischemic flow debt repayment (%)
Fig. 2. Correlation between postischemic flow debt repayment and aortic PWV (personal data).
Postischemic flow debt repayment (%)
Fig. 2. Correlation between postischemic flow debt repayment and aortic PWV (personal data).
An association between arterial alterations and lipid abnormalities was found only irregularly. An inverse relationship between PWV and HDL cholesterol was shown [53, 58] and a positive relationship was described between carotid intima-media thickness and IDL or LDL cholesterol.
Arterial stiffening in CKD and ESRD patients is associated with an increase in systolic pressure and/or pulse pressure. The mechanism responsible for the alterations of the arterial pressure has been depicted by London et al. . Epidemiological studies have shown that pulse pressure is associated with risk of death in patients undergoing hemodialysis . A recent study demonstrated that arterial stiffening and increased wave reflections are per se independent predictors of all-cause and cardiovascular death in ESRD patients .
In recent years the vascular endothelium has been recognized as a large and complex endocrine organ. Endothelium-derived NO is critically involved in the regulation of a wide variety of vascular functions: vasodilatory, antiproliferative and antithrombogenic. Nevertheless, under conditions of increased oxidative stress, as in ESRD, NO may be involved in vascular damage atherosclerosis and probably arteriosclerosis , but the results on the vasodilatory effects of NO in ESRD remain controversial. As shown experimentally, the endothelium influences the mechanical and geometric properties of large arteries . Some studies measuring flow-mediated vasodilatation, a surrogate marker in the evaluation of endothelial function, found an impaired endothelial function in CKD and ESRD [64, 65]. The altered hyperemic response is correlated to arterial remodeling parameters and to aortic stiffness (fig. 2, also personal data). Moreover, endothelial cell dysfunction is associated to all-cause mortality . Aside many other causes, circulating endothelial derived mi-croparticles are tightly associated with endothelial dysfunction and arterial dysfunction in ESRD .
The vascular complications in ESRD are ascribed to two different but associated mechanisms, namely atherosclerosis and arteriosclerosis. Endotheli-um, the body's largest organ strategically located between the wall of blood vessels and the bloodstream, could be the link between the two faces of the arterial alteration underlying many common physiological molecules and reactions.
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Service de Néphrologie, Centre Hospitalier F-H Manhes 8 Grande Rue, FR-91712 Fleury Mérogis (France) Tel. +33 1 6925 6458/+33 06 0325 3079 Fax +33 1 6925 6525, E-Mail [email protected]
Section II - Arterial Stiffness, Atherosclerosis and End-Organ Damage
Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 199-211
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