Causes and Consequences of Increased Arterial Stiffness in Chronic Kidney Disease Patients

Fax +41 61 306 12 34E-Mail [email protected]

Review

Kidney Blood Press Res 2007;30:97–107 DOI: 10.1159/000100905

Causes and Consequences of Increased Arterial Stiffness in Chronic Kidney Disease Patients

Paul Gusbeth-Tatomir Adrian Covic

Dialysis and Renal Transplantation Center, Parhon University Hospital, Iasi , Romania

Introduction

End-stage renal disease (ESRD) patients treated by chronic dialysis have an impressive mortality, compara-ble with aggressive forms of cancer. More than half of this mortality is attributable to cardiovascular (CV) disease. CV morbidity and mortality is more prominent in young dialysis patients, who are at a more than 500 times high-er risk of dying from CV disease (CVD) compared to the non-renal population of the same age [1] . Taken together, CVD mortality is 10–30 times higher in patients treated by dialysis than in patients in the general population, de-spite stratification for sex, race, and the presence of dia-betes [2] . This huge CV burden, already starting in the early stages of chronic kidney disease (CKD), is due to both traditional and non-traditional/uremia-related risk factors. Some traditional factors like diabetes mellitus, hypertension, dyslipidemia or smoking are major deter-minants of the genesis of CKD, as well as contributors to the progression of renal disease (and CVD as well), long before ESRD is reached [3] . The contribution of non-tra-ditional risk factors to CV morbidity in renal patients is crucial. Endothelial dysfunction, vascular calcification and arterial stiffness are in this respect closely related. Along with the focal process of atherosclerosis (mainly affecting the intima of the arteries), the diffuse patho-logical phenomenon of arteriosclerosis (affecting mainly the media of large- and middle-sized arteries) is promi-

Key Words Arterial stiffness � Arteriosclerosis � Arterial calcification � End-stage renal disease � Chronic kidney disease � Hemodialysis � Renal transplantation

Abstract Cardiovascular (CV) morbidity and mortality is greatly en-hanced in patients with chronic kidney disease, compared to the non-renal population. One key element of this high CV burden appears to be arterial stiffness, as an expression of premature vascular aging. Increased arterial stiffness in renal patients may be a consequence of vascular calcification, chronic volume overload, inflammation, endothelial dys-function, oxidative stress and several other factors. The au-thors review briefly the main pathophysiological mecha-nisms leading to reduced arterial compliance. Increased arterial stiffness has significant clinical consequences: iso-lated systolic hypertension, left ventricular hypertrophy (and failure), and reduced myocardial perfusion. Better knowledge of the mechanisms of arterial functional and morphologic alteration may help in developing more re-fined therapeutic strategies aimed to reduce the high CV burden in chronic kidney disease. The potential therapeutic interventions – mainly the use of certain antihypertensive drugs and reduction of vascular calcification – are finally dis-cussed.

Copyright © 2007 S. Karger AG, Basel

Received: October 11, 2006 Accepted: February 2, 2007 Published online: March 19, 2007

Prof. Dr. Adrian Covic Dialysis and Renal Transplantation Center Parhon University Hospital Carol 1st Blvd Nr. 50, RO–6600 Iasi (Romania) Tel. +40 721 280 246, Fax +40 232 210 940, E-Mail [email protected]

© 2007 S. Karger AG, Basel1420–4096/07/0302–0097$23.50/0

Accessible online at:www.karger.com/kbr

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nent in ESRD patients. Arteriosclerosis, characterized by reduced arterial compliance (i.e. reduced elasticity of the arteries), is due to increased fibrosis, loss of elastic fibers and extensive vessel wall calcification. In response to di-rect injury, the hemodynamic burden and to atherogenic factors, the arterial wall alters its structure and function. The large arteries suffer dilatation of the arterial lumen and wall thickening due to the activation, proliferation and migration of vascular smooth muscle cells (VSMCs) and rearrangements of the extracellular matrix [4] . Chronic alterations in the mechanical forces – as seenin persistent hemodynamic overload and hypertension (highly prominent in CKD patients) – generate arterial remodeling by tensile and shear stress. Endothelial cells, by their strategic position at the wall/lumen interface, are considered ‘mechanosensors’ crucial for the conversion of physical forces into biochemical signals leading finally to vessel wall remodeling. The endothelium generates and expresses several substances responsible for arterial function, but also for structural changes of the vessel wall: nitric oxide, endothelins, adhesion molecules, and metalloproteinases [4] .

Arterial stiffness of large arteries has important clin-ical consequences: raised systolic blood pressure (BP), increased pulse pressure, left ventricular hypertrophy and reduced coronary perfusion (for a review, see Covic et al. [6] ). This review deals briefly with the pathophys-iology of arterial stiffness in ESRD patients, focusing on the major determinants and their recognition. Potential aggressive therapies addressing the main factors re-sponsible for increased arterial stiffness and vascular calcification may have a significant impact on the high CV burden.

Pathophysiology of Arterial Stiffness

Arterial stiffening is the result of a complex interac-tion ( fig. 1 ) between structural and functional changes in the vessel wall. These vascular changes, occurring main-ly in large arteries, are highly influenced by hemodynam-ic forces, as well as by several factors such as salt, hor-mones, the ‘uremic milieu’ and glucose. Widespread dis-eases like CKD, diabetes mellitus and hypertension

Hypertension

Chronic volume overload

Activation of the RAA axis

Endothelial dysfunction

Oxidative stress

F Formation of advancedglycation end-products

Chronic hyperglycemia andhyperinsulinemia

Lipid abnormalities

The ‘uremic milieu’

Disorders of calcium-phosphatemetabolism

F Vessel wall calcification

Functional and structural abnormalities of the vessel wall arterial stiffnessr

F SBP and PP

f Coronary perfusion

Left ventricular hypertrophy

F Incidence of acute CV events

F CV and overall mortality

Fig. 1. Pathogenic mechanisms and clinical consequences of increased arterial stiffness in chronic renal disease.

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potentate age-related vessel wall alterations, acting fre-quently in a negative synergistic manner [5, 6] .

Compliance of the vessel wall is highly dependent on the dynamic process of production and degradation of two major proteins: collagen and elastin. Impairment of this balance, for instance by the microinflammatory mi-lieu (highly prominent in renal disease), leads to exces-sive production of abnormal collagen and reduction of elastin synthesis. High BP or increased luminal pressure (as in partial atherosclerotic occlusion) also stimulates collagen production [7] . The consequence of these vessel wall alterations is an impressive increase in intima-media thickness and proliferation of VSMCs. Histological ex-amination of the stiff arteries reveals profound altera-tions: abnormal endothelial cells, increased collagen con-tent, altered elastin fibers, migration of VSMCs and mac-rophages in the intima. Cytokines, intracellular adhesion molecules, matrix metalloproteinases, and transforming growth factor- � are also found in high concentrations in the arterial wall [8] . Enhanced deposition of chondroitin sulfate, proteoglycans, and fibronectin thickens and stiff-ens the arterial wall as well [9] . Collagen and elastin, the two major proteins responsible for the structural integ-rity and the elasticity of the arterial wall, are regulatedby the catabolic effect of the matrix metalloproteases (MMPs). The main function of the MMPs is to degrade the extracellular matrix, resulting in structurally abnor-mal collagen and elastin molecules. Vascular cells, but also inflammatory cells produce various types of MMPs [10] . Various tissue inhibitors of MMPs are essential for controlling and fine tuning of the remodeling processes in the vessel wall [11] . Collagen molecules (crucial for the tensile strength of the vessel wall) are enzymatically cross-linked in order to provide their insolubility in re-spect to hydrolysis by several enzymes [12] . Breaks in the integrity of these intermolecular bonds determine the unraveling of the collagen matrix. Most importantly, col-lagen molecules, characterized by a low turnover, are highly susceptible to non-enzymatic glycation. Elastin is also stabilized by cross-linking; disruption of these cross-links determines the weakening of the elastin array. Ac-tivation of MMPs leads to frayed and broken elastin fi-bers [13, 14] ; this results in a predisposition to mineral-ization of the vessel wall due to calcium-phosphate salts deposition [13] , a phenomenon apparent at older ages and more prominent in CKD patients. In fact, artery calcifi-cation is a major contributor to arterial stiffness in CKD patients (to be discussed later).

Increased advanced glycation end products (AGEs) formation (a frequent feature of CKD and diabetes) plays

a central role in arterial stiffening. Collagen is predis-posed to non-enzymatic glycation, forming irreversible cross-links [15] . The structurally inadequate collagen is less susceptible to hydrolytic turnover and leads to stiffer vessel wall [16] . Similarly, the elastic matrix of the vessel wall is reduced by AGE cross-linking of elastin [17] . These alterations, observed ‘physiologically’ with aging, are more prominent in CKD (and extreme in dialysis pa-tients), where the accumulation of AGEs and their recep-tor is very important [18] . Through their receptor, AGEs stimulate inflammatory responses, increasing the forma-tion of free oxygen radicals, pro-inflammatory cytokines, growth factors, nuclear factor (NF)- � B, and vascular ad-hesion molecules [19] . The consequences of these altera-tions are endothelial dysfunction, impaired endothelial-mediated vasodilatation and elevated smooth vascular tone, angiogenesis and response to vascular injury, and change in the phenotype of the VSMCs [5, 20] . Therefore, reducing AGE generation may improve arterial compli-ance, as confirmed by studies in primates [21, 22] . In a broader sense, abnormalities of glucose metabolism are major determinants of arterial stiffness; insulin resis-tance is positively correlated with arterial stiffness. Hy-perinsulinemia and chronic hyperglycemia promote ves-sel wall hypertrophy and fibrosis by stimulating the para-crine activity of the renin-angiotensin-aldosterone (RAA) axis [23, 24] . Reduced glucose tolerance stimulates the non-enzymatic glycation of proteins, generating AGEs [25] . Endothelial dysfunction due to high LDL choles-terol and free fatty acid and hyperinsulinemia is also re-sponsible for increased arterial stiffness [5] .

Beyond the structural changes of the vessel wall, arte-rial stiffness is first of all deeply influenced by endothe-lial cell signaling and vascular tone. A recent investiga-tion by McEniery et al. [26] revealed a strong relationship between parameters of arterial stiffness (pulse wave ve-locity (PWV) and augmentation index) and global endo-thelial function, measured by means of pulse wave analy-sis after administration of sublingual nitroglycerin and inhaled albuterol. Furthermore, not only endothelial dys-function promotes arterial stiffness, but that also the op-posite may be true: the lack of arterial compliance may further promote endothelial impairment [5] . VSMC tone is altered by mechanostimulation (as in hypertension), due to the cell stretch and alterations in calcium cell bal-ance, as well as by the influence of several hormones/paracrine mediators such as endothelin, angiotensin II, nitric oxide and factors of oxidative stress [5] . Asymmet-rical dimethylarginine, reduced nitric oxide expression and increased expression of the nitric oxide synthase in-

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hibitor are linked to arterial stiffening [27] . The forma-tion of highly reactive oxygen species leads to an abnor-mal vascular tone [28] .

The most prominent hormone that modulates vascu-lar stiffness is possibly angiotensin II (Ang II). Ang II reduces elastin synthesis, promotes collagen formation, determines vascular hypertrophy and remodeling, and increases oxidant stress [29] . Furthermore, Ang II is a potent promoter of pro-inflammatory responses [30] . Al-dosterone, a hormone whose synthesis is mainly deter-mined by Ang II, also has a major impact on arterial stiff-ening by stimulating fibrosis and smooth muscle cell hy-pertrophy [31] . Therefore, strategies that interfere with the RAA axis may be particularly important for tackling increased arterial stiffness. High-salt diet decreases arte-rial compliance, especially in older individuals; salt re-striction may improve arterial stiffness in the elderly [32] . A high sodium load determines the hypertrophy of VSMCs and augments collagen and elastin production [33, 34] . Sodium also generates increased reactive oxygen production by reducing the nitric oxide production, stim-ulating asymmetrical dimethylarginine production and increasing NAPDH oxidase activity [35] . Finally, artery wall calcification is a major determinant of arterial stiff-ness both in the non-renal and, more prominently, in the renal population. The mechanisms of vascular calcifica-tion will be discussed below.

Pathophysiology of Arterial Stiffness in CKD Patients

The mechanisms for increased arterial stiffness in re-nal patients are not entirely defined, but may include ar-terial calcification, chronic volume overload, increased mechanical stress by hypertension, chronic microin-flammation, sympathetic overactivity, activation of the RAA axis, AGEs, lipid peroxidation and abnormalities of the nitric oxide system [4] . CKD is a state characterized by increased extracellular matrix collagen content and proliferation of VSMCs in the setting of paracrine and systemic activation of the RAA axis. Collagen and elastin in the vessel wall of renal subjects are severely altered by the increased generation of AGEs [36] and augmented carbonyl stress [37] . Chronic overhydration may play an important role in the large artery dysfunction in dialysis patients. Volume overload (frequently encountered in ESRD subjects) contributes to the high PWV associated with stiffened arteries. However, volume reduction by he-modialysis is not able to reverse/significantly decrease ar-

terial stiffness [38] , although an increased extracellular to intracellular fluid ratio is strongly associated with ar-terial stiffness [39] . Further studies have to determine if aggressive volume control in ESRD patients is able to re-verse to certain extent arterial stiffening.

Chronic inflammation, as assessed by serum levels of the C-reactive protein, is significantly associated with in-creased arterial stiffness in the general population [40] . The same strong relationship between stiffened arteries and the microinflammatory state has been recently found in ESRD patients on chronic hemodialysis [41] . The as-sociation between abnormalities of lipid metabolism and arterial function is controversial. An inverse correlation between PWV and HDL cholesterol levels has been re-ported [42, 43] . Efficient removal of LDL cholesterol by lipid apheresis and usage of vitamin E-coated hemodialy-sis membranes improves arterial stiffness and reduces the serum levels of several markers of inflammation [44] . The presence of generalized endothelial dysfunction in chron-ic uremic patients contributes significantly to the arterial alterations seen in dialysis patients. The endothelium in-fluences the mechanical and geometric properties of elas-tic arteries; removal of the endothelium causes an increase in arterial diameter [45] . In dialysis patients, decreased endothelial-dependent vasodilatation suggests a relation-ship between arterial and endothelial dysfunction [46] .

A central role among the structural changes with a strong impact on stiffness is played by vascular calcifica-tions (VC). Calcification of the vessel wall is the result not only of passive calcium-phosphate deposition, but also represents an active process, similar to bone formation –‘ossification’ of the vascular wall structure [47] . VC results from an imbalance between promoters and inhibitors of mineralization, sharing similarities with the process of skeletal mineralization. Different gene products seem to modulate the process of ectopic calcification: matrix G1a protein, fetuin, osteopontin and the osteoprotegerin re-ceptor activator of NF- � B (RANK)–RANK ligand com-plex [48] may play a crucial role on modulating the min-eral deposition in the vessel wall. In particular, serumfetuin, a potent in vitro inhibitor of calcification, isstrongly associated with valvular calcifications, but also with atherosclerosis, malnutrition and inflammation – a fatal triad in ESRD patients [49] . High levels of phosphate and/or calcium are directly activating genes related to an osteoblastic phenotype in the smooth muscle cells (for an excellent review, see Cozzolino et al. [47] ). Hyperphos-phatemia and increased calcium phosphate product ( 1 55 mg 2 /dl 2 ) are important and clinically evident contribu-tors to VC in ESRD patients [50] . Low levels of inhibitors

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of calcification also cause VSMC apoptosis; apoptotic cells and the vesicles resulting from programmed cell death form a nidus for the deposition of the calcium-phos-phate salt (mainly hydroxyapatite) [51] . In the healthy ves-sel, this process is actively inhibited by locally and sys-temically produced factors [52] . In the presence of a me-dium with high level of calcium and phosphate (as seen frequently in ESRD patients), exposed VSMCs suffer rap-id calcification [51] while increased intracellular phos-phate levels induce osteoblastic differentiation of vascular cells [53] . According to recent data, inflammation also contributes to the calcification process [54] . Furthermore, pro-inflammatory cytokines have been shown to enhance in vitro calcification of vascular cells [55] , suggesting a close relationship between inflammation and calcifica-tion. There seems to be a direct link between valvular cal-cification and inflammation in patients on dialysis [56] . Serum fetuin-A, an important circulating inhibitor of cal-cification, is significantly linked to with valvular calcifi-cation, atherosclerosis, malnutrition and inflammation, and is related to an increased mortality and CV events rate in dialysis patients. Arterial calcification is closely related to arterial stiffness: more calcified arteries obviously lose their elastic properties [57, 58] . Increased arterial calcifi-cation and stiffness may explain, at least in part, the huge morbidity and mortality in ESRD patients. Efforts to re-duce the burden of arterial calcifications in renal patients (by controlling the calcium-phosphate metabolism, avoid-ing excessive vitamin D load, usage of non-calcium-con-taining phosphate binders, etc.) may be the most impor-tant challenge for the nephrological community in the near future (see below).

Clinical Consequences of Increased Arterial Stiffness in Non-Renal Subjects

The pulsatile flow resulting from ventricular ejection is transformed by large arteries into a steady flow, thus reducing pressure variability in the arterial tree during the cardiac cycle. The arterial system has a remarkable buffering capacity; less than half of the stroke volume is forwarded directly to the peripheral tissues during sys-tole, while the reminder is stored in the aorta and the elastic-type large arteries. During the diastole, the elastic recoil of the aorta pushes the blood column forwards, providing a continuous perfusion of the tissues. The ef-ficiency of this conduit function of large arteries is depen-dent on the viscoelastic properties of the arterial wall and the geometry of the arteries (diameter and length) [59] .

The clinical consequences of reduced arterial compli-ance are important and deleterious. For stiff arteries, the process of elastic recoil of the aorta during diastole is im-paired, leading to increased afterload, left ventricular hy-pertrophy, reduced coronary (subendocardial) perfusion, and altered tissue supply with blood. The most obvious clinical consequence of arterial stiffness is altered BP profile; there is an isolated increase of systolic BP, while diastolic BP decreases, resulting in high pulse pressure (PP), as seen in the elderly [60] and in ESRD patients, even at younger ages. In the non-renal general popula-tion, PP is an independent CV risk factor after the age of 50 [60, 61] . The high CV risk is not seen in subjects with high PP due to increased stroke volume (athletes), but is observed in older patients with increased arterial stiffen-ing. While in younger patients, diastolic, systolic and mean BP are associated with decreased survival, in more elderly individuals, with stiffer arteries, high systolic BP, low diastolic BP and increased PP are related to a worse CV outcome [60–63] . However, in contrast to the effects of aging, the stiffened arterial wall in younger hyperten-sive individuals may not be essentially different from normotensive controls, hypertension-related wall hyper-trophy being at least in part reversible with the proper reduction of BP [5, 63] . Arterial stiffness has been in-creasingly recognized as a major determinant of morbid-ity in the non-renal population. Aortic stiffness is an in-dependent predictor of primary coronary events in pa-tients with essential hypertension and normal renal function [64, 65] . These findings may be easily explain-able by the fact that in stiffer arteries, diastolic recoil of the aorta is critically for adequate coronary perfusion [6] . Arterial stiffness is also a major determinant of CV mor-bidity and mortality in the hypertensive and the elderly non-renal subjects [66, 67] . The increase of PWV ( 1 13 m/s) is a potent predictor of CV death in hypertensive patients, even in the absence of clinically overt athero-sclerotic disease; another parameter expressing at least in part the increased arterial stiffness due to enhanced pulse wave reflection from the periphery – the augmentation index – is also a strong predictor of premature coronary artery disease in the non-renal population [68] .

Arterial Stiffness and Minor Renal Dysfunction

Even subtle renal dysfunction may be associated with increased arterial stiffness; in a large study in normoten-sive and untreated hypertensive humans with ‘normal’ serum creatinine, those in the lowest tertile of creatinine

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clearance (assessed by the Cockroft-Gault formula) had a more elevated PWV. This association was independent of BP, plasma cholesterol and glucose, as well as other classic CV risk factors. In untreated hypertensive pa-tients, common carotid compliance was positively and independently correlated with the creatinine clearance. Renal function had a high contribution to the total vari-ance of carotid compliance: 20% [69] . These results were confirmed by others; in treated hypertensives with serum creatinine ! 2.14 mg/dl ( ! 300 � mol/l), aortic PWV and serum creatinine were positively and independently cor-related. Other factors independently influencing PWV were age, the level of BP and the presence of diabetes mel-litus. Only ACE-I inhibitors among all antihypertensive drugs used in this study were associated by a lower PWV, underlining the importance of the RAA axis to the gen-esis of increased arterial stiffness [70] . This is in accord with data from a randomized trial in ESRD patients showing that just the use of ACE inhibition or a signifi-cant BP lowering determines the reduction of CV mortal-ity [71] . A longitudinal study in hypertensive patients [72] showed that arterial stiffness progresses more rap-idly with age in treated hypertensives than in untreated normotensive controls. From all factors known to in-crease PWV with age, the most important factor was baseline serum creatinine level. Furthermore, as renal function deteriorates, there is a stepwise progression of arterial stiffness, the highest reduction of arterial compli-ance being demonstrated in chronic uremic patients [73] .

Arterial Stiffness and Outcome in ESRD Patients

It has become evident that ESRD patients treated by dialysis have much stiffer arteries compared to the non-renal hypertensive population of same age and BP level. At least in younger patients, renal transplantation re-stores PWV to levels comparable to those seen in essen-tial hypertensive individuals [74] . Arterial stiffness has been identified as a major determinant of poor general and CV survival in ESRD patients as well. Dialysis pa-tients with stiffer arteries have an increased CV and gen-eral death rate [4] . The same is true for ESRD patients with extensive artery calcification [60] . Increased arte-rial stiffness determines an impressive impact on out-come in the renal population. In ESRD patients, any in-crease of the PWV index (measured PWV – theoretical PWV) by 1 m/s is associated with an increase of 14% in adjusted CV and overall mortality [75] . Safar et al. [76]

also underlined the very important fact that while aortic PWV is a strong predictor of all-cause and CV mortality, brachial BP is not – thus explaining, at least in part, the inverse epidemiology for BP in ESRD subjects.

Is Arterial Stiffness Treatable?

Unfortunately, large-scale randomized studies aiming to analyze the impact of different therapeutic strategies on arterial stiffness are still lacking. We rely to date rath-er on small-sized investigations in renal patients, as well as on some data from the non-renal population. The most consistent study is the recent CAFÉ (Conduit Artery Function Evaluation) trial in hypertensive patients with three additional risk factors were randomized to amlo-dipine 8 perindopril versus atenolol 8 diuretic [77] . De-spite similar reductions in brachial BP, central aortic sys-tolic BP and PP (as measures of stiffness in large arteries) were significantly more influenced in the amlodipine/perindopril group. Most importantly, the post-hoc de-fined composite outcome of total CV events and proce-dures and the development of renal impairment was sig-nificantly associated with central aortic PP. Furthermore, this may explain at least in part the better outcome seen in patients treated with amlodipine and ACE inhibitor seen in the parent study (ASCOT). The authors specu-lated that the central BP hypothesis might also explain the differential effects of BP-lowering agents on CV struc-ture and clinical outcomes in other recent trials like LIFE or HOPE [77] . These data confirm earlier suggestions that some antihypertensive drugs may be more efficient than others in terms of reducing arterial stiffness. Most studied are drugs that influence the RAA axis; ACE in-hibitors reduce PWV, whereas verapamil has no effect [78] . Compared to a thiazide diuretic, losartan signifi-cantly improves arterial stiffness [79] . Both ACE inhibi-tion and Ang II receptor blockade improve arterial com-pliance. Furthermore, the ‘dual’ blockade of the RAA axis is even more advantageous [80] . A significant reduc-tion of arterial stiffness is also obtained with low-dose perindopril with indapamide, when compared to the use of a � -blocker [81] . A recent study in hemodialysis pa-tients claims a BP-independent effect of ACE inhibition and angiotensin receptor blockade on arterial stiffness [82] . However, the beneficial impact of ACE inhibition may be limited to some but not all ESRD patients [71] , suggesting that in patients with severe structural and functional alterations of the vessel wall, inhibition of the RAA axis comes late. Experimental data suggest that di-

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rect inhibition of spironolactone may also significantly improve arterial stiffness [83] .

Further therapeutic promises come from the pleiotro-pic effects of statins. A placebo-controlled small-scale study in diabetic hemodialysis patients showed that a 6-month lipid-lowering therapy may significantly reduce arterial stiffness. Another well-conducted study in renal transplant recipients demonstrated a 300% improvement in endothelial-dependent vasodilatation after 12 months, this effect being sustained after 3 years [84] . However, the disappointing results of the 4-D study on outcome in di-alyzed diabetics treated with atorvastatin [85] suggest that therapeutic interventions should be directed pre-dominantly to the earlier phases of CKD. Further poten-tial therapeutic interventions aiming to reduce arterial stiffness (at least in the non-renal population) include the use of AGE inhibition [86] , endothelin blockade [87] , and flavonoids [88] . A recent study in ESRD patients [89] claims that regular exercise could improve arterial wave reflections, confirming thus the beneficial effect of phys-ical exercise on arterial compliance seen in the general population.

Finally, more specific interventions in the renal popu-lation may significantly improve arterial compliance. As shown by our group, the hemodialysis session improves arterial elasticity in some, but not all patients [90, 91] . Use of modern polysulfone membranes is clearly more bene-ficial than the older bioincompatible membranes in re-ducing arterial stiffness [92] . Vitamin E-coated dialysis membranes significantly improve arterial stiffness, prob-ably as a consequence of the antioxidant properties of the membrane [44] . Whether intensified (daily or long-hour) hemodialysis is beneficial in terms of reducing arterial stiffness is unknown to date. Inflammation is directly linked to arterial stiffness and calcification, as well as to CV and general mortality in ESRD; interestingly, the del-eterious effect of inflammation on arterial stiffness is more pronounced in patients not receiving ACE inhibi-tion [93] . Clearly, every effort should be made to reduce inflammation in renal patients.

Is Reduction/Prevention of Arterial Calcification the Key to the Improvement of Arterial Stiffness?

Coronary artery calcification (CAC) – assessed best by electron beam computed tomography (EBCT) – is associ-ated with atherosclerosis and predicts mortality in the general elderly population [94] . According to the Dallas Heart Study [95] , the occurrence and severity of calcified

coronary arteries is an early event in CKD, directly re-lated to the degree of renal function. Other than in the general population, coronary calcifications, present even at a young age in ESRD patients, worsen with longer di-alysis duration and progress rapidly. [96] . There is a strong relationship between calcifications of the coro-nary arteries and arterial stiffness [97] . Unfortunately, the effect of non-calcium-containing phosphate binders (CCPBs – see below) on arterial stiffness has not been studied extensively to date. In fact, there is only one small-scale study showing that the decrease of calcium load through therapy with the non-CCPB sevelamer hydro-chloride seems to be associated with a significant reduc-tion of arterial stiffness, in contrast to patients continued on CCPBs [98] . Survival of renal patients with arterial calcification is poor, being proportional to the extent of VC [99] . The major determinants of arterial calcification have been discussed above.

Major concerns regarding the high calcium load with CCPBs have driven research in order to find effective non-CCPBs. The Treat-to-Goal study [100] suggested that sevelamer, unlike calcium-based salts, significantly reduced CAC (assessed by EBCT) in hemodialysis pa-tients. These findings were subsequently confirmed by others in a randomized open-label trial [101] . However, heavy criticism concerning the results of the Treat-to-Goal study has emerged since the publication of these data. This study cannot inform us solely about the role of oral calcium ingestion in the pathogenesis of CVD [102] . This is due to the fact that the drugs used (sevelamer hy-drochloride and calcium carbonate/acetate) differ not only in their phosphate-binding and calcium-loading ca-pacities, but also in their lipid-lowering capacity; with sevelamer, there is a 35% reduction of LDL cholesterol [100] . Although the effect of sevelamer on the progres-sion on CAC was remarkable, the Treat-to-Goal study does not tell us how these marked improvements were achieved, since these CAC scores did not correlate with any parameter of the calcium-phosphate metabolism [102] . Furthermore, sevelamer may not be as effective as calcium salts in correcting hyperphosphatemia [103] .

More recent studies refined the early findings: the RIND study [104] in incident hemodialysis patients dem-onstrated that those subjects without evidence of coro-nary calcification at baseline showed little evidence of disease development over 18 months, regardless of the type of phosphate binder therapy. However, patients with evidence of at least mild calcification at baseline had sig-nificant progression, with a more rapid progression in subjects receiving a CCPB [104] . Though not published

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to date, the results of the DCOR study are now largely known at least to the nephrological community. This largest head-to-head randomized trial has compared clinical outcomes in patients randomized to alternative (sevelamer) phosphate binder therapy. The primary end-point (all-cause mortality) was inconclusive throughout the entire population during 1 3 years of follow-up; how-ever, all-cause mortality was significantly better (–22%) in elderly patients, this effect being apparent late during therapy. Furthermore, sevelamer therapy was also associ-ated with a reduced risk of hospitalization. Whether the arrest of VC progression seen with sevelamer translates into a benefit in order of CV and general outcome re-mains to be proven in further studies. Another effective phosphate binder, lanthanum carbonate, has not yet been studied regarding the improvement of CAC, as well as the reduction of arterial stiffness and of CV mortality in ESRD patients. Clearly, we urgently need well-conducted clinical trials in order to examine the impact of different therapeutic strategies in reducing arterial calcification (preferably also arterial stiffness) in renal patients.

Conclusions

Arterial stiffness is a potent CV risk factor both in the renal and non-renal population. Reduced arterial com-pliance is a consequence both hemodynamic changes of the large elastic arteries and the intrinsic viscoelastic properties of the vessel wall. Aging, diabetes mellitus, hy-pertension, but especially CKD (due to the particular ac-

cumulation of both traditional and non-traditional CV risk factors) are significantly associated by arterial stiff-ening. There are several structural and functional altera-tions leading to the impairment of the viscoelastic prop-erties of large arteries: vessel wall calcification, activation of the RAA axis, endothelial dysfunction, microinflam-mation, increased production of AGEs and products of lipid peroxidation. These abnormalities are more promi-nent in patients with CKD, being most severe in ESRD patients on dialysis. The clinical consequences of in-creased arterial stiffness in renal patients are isolated sys-tolic hypertension, left ventricular hypertrophy, and im-paired coronary perfusion. These may explain the im-pressive CV morbidity and mortality of renal patients as compared to non-renal subjects. One issue still to be clar-ified is the optimal measurement of arterial stiffness: along with the ‘classical’ parameters of arterial stiffness like PWV, the augmentation index or several sonogra-phy-derived parameters [6] , the newly described ambula-tory arterial stiffness index [105] may be of clinical value in measuring arterial compliance. Therapeutic strategies meant to prevent/reverse the functional and structural abnormalities of the arterial wall associated with arterial stiffening may significantly improve CV outcome in the renal population. A more efficient dialysis, prevention of chronic inflammation and volume overload, treatment with certain antihypertensive drugs and particularly pre-venting/reversing arterial calcification in renal patients may improve arterial compliance and therefore reduce the high CV burden in renal patients.

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