NEPHROLOGY - REVIEW

Arterial stiffness in dialysis patients: where are we now?

Mehmet Kanbay • Baris Afsar •

Paul Gusbeth-Tatomir • Adrian Covic

Received: 29 July 2009 / Accepted: 26 October 2009 / Published online: 19 November 2009

� Springer Science+Business Media, B.V. 2009

Abstract Patients with end-stage renal disease

treated by chronic dialysis have an impressive

mortality, which more than half of this mortality is

attributable to cardiovascular disease. Despite strat-

ification for sex, race, and the presence of diabetes,

cardiovascular disease mortality is 10–30 times

higher in dialysis patients compared to general

population. In dialysis patients, both atherosclerosis

(mainly affecting the intima of the arteries) and

arteriosclerosis (affecting predominantly the media

of large- and middle-sized arteries diffusely) are

highly prominent. 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. Arte-

riosclerosis is closely related to arterial stiffness. A

generally accepted mechanistic view is that an

increase in arterial stiffness causes a premature return

of reflected waves in late systole, increasing central

pulse pressure, thus systolic. An increased arterial

stiffness can increase the risk of stroke through

several mechanisms, including an increase in central

pulse pressure, influencing arterial remodeling both at

the site of the extracranial and intracranial arteries,

increasing carotid wall thickness, and the develop-

ment of stenosis and plaques, and the likelihood of

plaque rupture. Very importantly, it was also sug-

gested that arterial stiffness itself independently plays

a role in exacerbating chronic kidney disease pro-

gression. This review deals briefly with the definition

of arterial stiffness, methods of measuring arterial

stiffness and pathophysiology of arterial stiffness, and

factors related with arterial stiffness.

Keywords Arterial stiffness �Chronic kidney disease

Introduction

Patients with end-stage renal disease (ESRD) treated

by chronic dialysis have an impressive mortality, and

more than half of this mortality is attributable to

cardiovascular disease (CVD). Despite stratification

for sex, race, and the presence of diabetes, CVD

mortality is 10–30 times higher in dialysis patients

compared to general population [1]. Thus, it is

thought that apart from traditional risk factors/

uremia-related risk factors also play an important

role for the development of CVD. Emerging risk

factors include malnutrition, inflammation, oxidative

M. Kanbay (&) � B. Afsar

Department of Internal Medicine, Section of Nephrology,

Fatih University School of Medicine, Gokkusagi

Mahallesi 16. Cadde, No ? 16/21, Cevizlidere/Cankaya,

Ankara, Turkey

e-mail: mkanbay@fatih.edu.tr; drkanbay@yahoo.com

P. Gusbeth-Tatomir � A. Covic

Department of Nephrology Clinic and Dialysis and

Transplantation Center, ‘‘C. I. PARHON’’ University

Hospital, Iasi, Romania

123

Int Urol Nephrol (2010) 42:741–752

DOI 10.1007/s11255-009-9675-1

stress, endothelial dysfunction, vascular calcification

(VC), and arterial stiffness. In dialysis patients, both

atherosclerosis (mainly affecting the intima of the

arteries) and arteriosclerosis (affecting predomi-

nantly the media of large- and middle-sized arteries

diffusely) are highly prominent. Arteriosclerosis

characterized by reduced arterial compliance (AC)

(i.e., reduced elasticity of the arteries) is due to

increased fibrosis, loss of elastic fibers, and extensive

vessel wall calcification [2]. Arteriosclerosis is

closely related to arterial stiffness. Increased stiffness

of large arteries has important clinical consequences:

raised systolic blood pressure (BP), increased pulse

pressure, left ventricular hypertrophy, and reduced

coronary perfusion [3]. A generally accepted mech-

anistic view is that an increase in arterial stiffness

causes a premature return of reflected waves in late

systole, increasing central pulse pressure, thus sys-

tolic BP. SBP increases the load on the left ventricle

(LV), increasing myocardial oxygen demand [4]. An

increased arterial stiffness can increase the risk of

stroke through several mechanisms, including an

increase in central pulse pressure (PP), influencing

arterial remodeling both at the site of the extracranial

and intracranial arteries, increasing carotid wall

thickness and the development of stenosis and

plaques [5, 6], and the likelihood of plaque rupture

[7]. Very importantly, it was also suggested that

arterial stiffness itself independently plays a role in

exacerbating chronic kidney disease progression [8].

Indeed, a large number of pathophysiological condi-

tions were associated with increased arterial stiffness.

For an extensive review, see Laurent et al. [4] .

This review deals briefly with the definition of

arterial stiffness, methods of measuring arterial

stiffness and pathophysiology of arterial stiffness,

and factors related with arterial stiffness.

Definition of arterial stiffness

Arteries are a unique system of distensible conduits

that contain the pulsatile output of the heart and

provide continuous flow to the tissues. During systole,

the transmitted flow of blood from the heart generates

a pressure wave that is propagated to all arteries of the

body. Pressure wave travels quickly at 5–15 m/s;

which is much faster than the speed of blood flow. On

arrival at branch points, pressure wave is reflected and

returned to the heart. The behavior of the pulse wave

is dependent on the ventricular contraction and the

compliance of the vascular system [9]. With the

influence of various factors such as age, high blood

pressure, and diabetes, the walls of large conduit

arteries undergo intense remodeling processes leading

to alteration in the viscoelastic properties. The result

is a diffuse process of arteriosclerosis, characterized

by stiffer arteries or, in other terms, reduced arterial

elasticity or compliance. Clinical consequences of

increased stiffness are higher SBP, lower diastolic BP,

and widened PP. All three changes are known as

major determinants for high CV morbidity and

mortality [3]. As arteries become stiffer, macroscopic

and microscopic changes are observed. Macroscopi-

cally, the arteries appear tortuous and dilated. Micro-

scopically, there is a loss of the orderly elastic

lamellae and disorganized thickening of the media

with glycosaminoglycan deposition, fibrosis, and

calcification. In the extreme, there is a medial necrosis

and aneurysm formation [9]. The causes and conse-

quences of arterial stiffness are shown in Fig. 1.

Methods to measure arterial stiffness

Ideally, such methods need to be safe, non-invasive,

quick, inexpensive, reliable, and reproducible; and

their results should correlate with the extent of

atherosclerotic disease and have high positive and

negative predictive values. The measurements should

integrate the deleterious effects of all genetic and

environmental cardiovascular (CV) risk factors in the

years of exposition [10]. Although several studies have

previously addressed the methodological issues con-

cerning the various indices of arterial stiffness cur-

rently available, and their clinical applications,

clinicians and researchers still report difficulties in

selecting the most appropriate methodology for their

specific use [4]. In clinical studies, several methods to

measure arterial stiffness have been investigated

including pulse wave velocity (PWV), systemic arte-

rial compliance (SAC), and augmentation index (AIx),

which are mostly used in clinical practice (Fig. 2).

A. Pulse wave velocity

Pulse wave velocity is defined as the speed of travel

of the pressure pulse along an arterial segment and

742 Int Urol Nephrol (2010) 42:741–752

123

can be obtained for any arterial segment accessible to

palpation. To measure PWV, continuous pulse wave

signals are recorded with pressure tonometers posi-

tioned over the arterial pulses [9]. Measurement of

PWV is generally accepted as the most simple, non-

invasive, robust, and reproducible method to deter-

mine arterial stiffness. Carotid-femoral PWV is a

direct measurement, and it corresponds to the widely

accepted propagative model of the arterial system [4].

The excellent reproducibility is demonstrated for

PWV, with intraobserver and interobserver variability

less than 5% [11]. Some limitations should be

underlined. The femoral pressure waveform may be

difficult to record accurately in patients with meta-

bolic syndrome, obesity, diabetes, and peripheral

artery disease. In the presence of aortic, iliac, or

proximal femoral stenosis, the pressure wave may be

attenuated and delayed. Abdominal obesity, particu-

larly in men, and large bust size in women can make

distance measurements inaccurate [12].

B. Augmentation index

The Augmentation index is derived from the arterial

pressure waveform and is a composite of the forward

pressure wave created by ventricular contraction and a

reflected wave. Waves are reflected from the periph-

ery, mainly at branch points. In elastic vessels, because

PWV is low, reflected wave tends to arrive back at the

aortic root during diastole. In the case of stiff arteries,

PWV rises, and the reflected wave arrives back at the

central arteries earlier, adding to the forward wave and

augmenting the systolic pressure. This phenomenon

can be quantitated through the AIx [4, 9].

Figure 2 demonstrates the schematic representa-

tion of AIx where the height of the late systolic peak

(P1) above the inflection (P2) defines the augmenta-

tion pressure, and the ratio of augmentation pressure

to PP defines the AIx (in percent), [6].

Measurement can be obtained directly from either

carotid artery or ascending aorta or using a transfer

Arteriosclerosis

Atherosclerosis

Systolic BP

Diastolic BP

Left ventricle hypertrophy Decompansated LVH

Ischemic heart disease

Peripheral artery disease

Decreased coronary reserveDecreased coronary perfusion

Cardiac failure

Volume overload

Cerebrovascular disease

Renal failure

Arteries becomes tortuous and dilated. Loss of elastic lamellae Disorganized thickening of the media Glycosaminoglycan deposition, Fibrosis Calcification

Medial necrosis and aneurysm formation

Widened PP

Reduced arterial elasticityor compliance

Death

Fig. 1 The causes and consequences of arterial stiffness

Int Urol Nephrol (2010) 42:741–752 743

123

function to derive aortic pressure waveforms from

recorded radial artery waveforms [13].

C. Arterial compliance

Arterial compliance is a measure of the elastic nature

of the arterial system, and it represents the relation-

ship between change in volume and change in

pressure during diastole. The AC requires measure-

ment of volumetric blood flow and associated driving

pressure to derive an estimated compliance over the

total systemic arterial tree. A hand-held Doppler flow

velocimeter placed on the suprasternal notch at the

base of the neck is used to estimate arterial blood

flow. Aortic driving pressure is estimated by appla-

nation tonometry of the right common carotid artery

using a non-invasive pressure transducer [9].

D. Arterial distensibility

Arterial distensibility (AD) is a quantitative evalua-

tion of arterial stiffness [14].

The distension of an artery refers to the change in

diameter during systole relative to diastole. Lower

distension suggests regional arterial stiffening. Ultra-

sound measurements of the distal common carotid

artery or aorta during the cardiac cycle can be used to

determine wall displacement and, thus, artery disten-

sion [9].

E. Ambulatory arterial stiffness index

It is the newly described method derived from

ambulatory blood pressure measurements [15].

Ambulatory arterial stiffness index (AASI) is a

Pressure tonometer

C=DxV

AC = Ad/R(Pes–Pd)

AIx = (DP/PP) X 100

PWV = D/Dt (m/s)

Fig. 2 Methods of measuring arterial stiffness

744 Int Urol Nephrol (2010) 42:741–752

123

method that aims to characterize the relationship of

systolic to diastolic BP during the day. By plotting

the individual values of systolic and diastolic BP

measurements obtained through 24-h non-invasive

ambulatory BP monitoring, the authors calculated the

regression slope of diastolic BP on systolic BP. The

slope was assumed as a global measure of AC, and its

reciprocal (1 minus the slope), named AASI, was

taken as a measure of arterial stiffness [16].

F. Arterial stiffness index

The Arterial stiffness index (ASI) is a quantitative

marker for arterial stiffness by measuring the volu-

metric changes of brachial artery in a computerized

oscillometry device [17]. ASI was proved to be

significantly correlated with aortic stiffness measured

by PWV and could serve as a reliable and convenient

method for arterial stiffness [18, 19]. However,

Kocak et al. [20] did not find a significant correlation

between FMD% and carotid-intima media thickness

in their peritoneal dialysis patient cohort. They

speculated that one possible explanation for their

results is that each method measures a different

aspect and stage of atherosclerosis.

G. X-ray vascular calcification score

Vascular calcifications were evaluated at baseline by

a single observer blind to clinical data, in plain X-ray

of pelvis and hands. Pelvis films were divided into

four sections by two imaginary lines: a horizontal line

over the upper limit of both femoral heads and a

median vertical line over the vertebral column [21].

The presence of VC in each section was rated as 1

and its absence as 0.

H. Cardiovascular magnetic resonance

This imaging modality also permits contemporaneous

visualization of large arteries and direct measurement

of aortic function, providing an integrated assessment

of both ventricular and vascular function in one

examination. Aortic distensibility (AD), the relative

change in aortic size throughout the cardiac cycle

relative to blood pressure, is readily assessed with

cardiovascular magnetic resonance [22].

Pathogenesis of arterial stiffness

The mechanisms for increased arterial stiffness in

renal patients are not entirely defined but may include

arterial calcification, chronic volume overload,

increased mechanical stress by hypertension, chronic

microinflammation, sympathetic overactivity, activa-

tion of the RAA axis, AGEs, lipid peroxidation, and

abnormalities of the nitric oxide system [23]. First of

all, it is important to note that even mild deterioration

in kidney function is a risk factor for the development

of arterial stiffness. Mourad et al. [24] investigated the

possibility that even mild deterioration in renal

function may cause increased arterial stiffness. In

1,290 subjects with normal BP or essential hyperten-

sion, they found that patients with the lowest tertile of

creatinine clearance (CrCl; but still normal serum

creatinine level) had a greater PWV, and this associ-

ation was independent of BP and other classic CV risk

factors. The negative association between PWV and

CrCl is stronger in subjects younger than 55 years.

Furthermore, a large longitudinal study of patients

with essential hypertension showed that the serum

creatinine level is a major determinant of accelerated

progression of aortic stiffness in treated patients with

hypertension [25]. 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 [26] and

augmented carbonyl stress [27]. Volume overload

(frequently encountered in ESRD subjects) also con-

tributes to the high PWV associated with stiffened

arteries [2]. However, volume reduction by hemodi-

alysis is not able to reverse/significantly decrease

arterial stiffness [28], although an increased extracel-

lular to intracellular fluid ratio is strongly associated

with arterial stiffness [29]. Further studies have to

determine if aggressive volume control in patients

with ESRD is able to reverse to certain extent arterial

stiffening. In patients with ESRD on chronic hemod-

ialysis, a strong relationship between stiffened arteries

and the microinflammatory state has been found [30].

In another study, Cheng et al. [31] demonstrated that

C-reactive protein is inversely correlated with PVW in

continuous ambulatory dialysis patients.

An inverse correlation between PWV and HDL

cholesterol levels has been reported [32]. Efficient

Int Urol Nephrol (2010) 42:741–752 745

123

removal of LDL cholesterol by lipid apheresis and

usage of vitamin E-coated hemodialysis membranes

improves arterial stiffness and reduces the serum

levels of several markers of inflammation [33].

Another important factor which is related with

increased in CKD is the presence of VC. VC results

from an imbalance between promoters and inhibitors

of mineralization, sharing similarities with the pro-

cess of skeletal mineralization. Different gene prod-

ucts seem to modulate the process of ectopic

calcification: matrix G1a protein, fetuin, osteopontin,

and the osteoprotegerin receptor activator of NF-KB

(RANK)–RANK ligand complex [34]. In particular,

serum fetuin, a potent in vitro inhibitor of calcifica-

tion, is strongly associated with valvular calcifica-

tions, but also with atherosclerosis, malnutrition, and

inflammation—a fatal triad in patients with ESRD

[35]. High levels of phosphate and/or calcium are

directly activating genes related to an osteoblastic

phenotype in the smooth muscle cells [36]. Hyper-

phosphatemia and increased calcium phosphate prod-

uct ([55 mg2/dl2) are important and clinically

evident contributors to VC in patients with ESRD

[37]. Low levels of inhibitors 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 phosphate

salt (mainly hydroxyapatite). In the presence of a

medium with high level of calcium and phosphate (as

seen frequently in patients with ESRD ), exposed

VSMCs suffer rapid calcification [38]. According to

previous data, inflammation also contributes to the

calcification process [39]. Furthermore, pro-inflam-

matory cytokines have been shown to enhance in

vitro calcification of vascular cells [40], suggesting a

close relationship between inflammation and calcifi-

cation. There seems to be a direct link between

valvular calcification and inflammation in patients on

dialysis [41]. Arterial calcification is closely related

to arterial stiffness: more calcified arteries obviously

lose their elastic properties [42, 43]. Indeed, in

dialysis patients, studies persistently showed a

positive correlation between VC and arterial stiffness.

Guerin et al. [44] showed that the presence of VCs in

large arteries was associated with increased arterial

stiffness in dialysis patients. Furthermore, in pro-

spective studies, the same group showed that both

increased arterial stiffness and large-artery

calcifications were major predictors of general and

CV mortality in renal patients [45, 46]. Fang et al.

[47] found that elevated pulse pressure is associated

with an increased risk of all-cause and cardiovascular

death in patients on peritoneal dialysis. They con-

cluded that recognition of this characteristic as an

important predictor of mortality suggests that one

goal of antihypertensive therapy in patients with PD

should be to decrease elevated pulse pressure.

Moreover, Ogawa et al. [48] showed that arterioscle-

rosis assessed by stiffness parameter beta is associ-

ated with atherosclerotic changes of carotid arteries

and with the presence of silent cerebral infarction in

patients with HD . Haydar et al. [49] found that PWV

strongly correlates with total calcification scores

assessed by means of EBCT, even after correction

for age, dialysis therapy duration, prescribed dose of

calcium-containing phosphate binders, and microin-

flammatory status. Recently, in hemodialysis

patients, it was demonstrated that aortic stiffness

(assessed by PWV) was associated with bone activity.

London et al. [50] showed that patients with

adynamic bone disease were characterized by signif-

icantly higher aortic PWV. They also showed that in

patients with adynamic bone disease, significant

positive correlations between Ca dosage and aortic

calcification scores or aortic PWV were observed. In

their multivariate analysis, aortic PWV is indepen-

dently and positively associated with Ca dosage

(p \ 0.0001) and negatively with bone activity

(p = 0.03). They suggest that the positive associa-

tions between Ca load and PWV were stronger in

patients with adynamic bone disease (ABD), indicat-

ing that the presence of ABD conferred significantly

greater influence of Ca load on aortic calcifications

and stiffening. The presence of an active bone was

associated with lower aortic stiffness and better aortic

capacitive function.

Factors related with arterial stiffness

in end-stage renal disease

Apart from well-defined risk factors for the develop-

ment of arterial stiffness (e.g, hyperphosphatemia,

hyperparathyroidism, and hypercalcemia), other risk

factors also present that are thought to play a role for

the development of arterial stiffness.

746 Int Urol Nephrol (2010) 42:741–752

123

Malnutrition

Protein-energy malnutrition is a common problem in

patients with ESRD and is a powerful predictor of

morbidity and mortality [51]. Gu et al. [52] demon-

strated in 124 patients on peritoneal dialysis that

patients with malnutrition exhibited a significantly

higher PWV than those classified as well nourished by

subjective global assessment (p \ 0.05). They also

found that, in multivariate regression analysis, albu-

min, handgrip strength SGA, and bioelectrical imped-

ance analysis phase angle were each independently

associated with PWV after adjustment (p \ 0.0001).

Fetuin-A

This glycoprotein is a potent calcification inhibitor, and

absence of fetuin in fetuin-A knock-out mice results in

massive extra-osseous calcification [53]. Fetuin-A, a

negative acute-phase reactant, plays a pivotal role in the

inhibition of Cax P precipitation [54]. Moreover, low

fetuin-A levels were found to be related to increased

VCs in dialysis patients [55]. To determine whether

fetuin-A deficiency in dialysis patients is an indepen-

dent predictor for the development of vascular stiffness

as a consequence of VC in dialysis patients, Hermans

et al. [56] conducted a study in dialysis patients. They

could not identify fetuin-A as an independent predictor

of aortic stiffness as measured with PWV, and AI.

Sigrist et al. [57] also did not demonstrate any

relationship between fetuin-a and VC. However, we

believe that more studies are needed to determine the

relationship between fetuin-A and VC and its relation-

ship with arterial stiffness in dialysis patients.

Beta-blockers

Sigrist et al. [58] found that use of beta-blockers was

also associated with the progression of VC. Blockers

inhibit the beta adrenoreceptors in the heart and

peripheral vasculature and may promote VC through

modulating sympathetic activity and trophic effects

on peripheral vasculature. VC in patients with HD is

associated with reduced baroreflex sensitivity.

Asymmetric dimethylarginine

Wilkinson et al. [59] speculated that the endogenous

NO synthesis inhibitor asymmetric dimethylarginine

(ADMA) might participate in the pathogenesis of

arterial stiffness. Previous studies showed that he-

modialysis reduces ADMA levels and to improve

central pressure waveform [60, 61]. Recently, Soveri

et al. [62] examined the changes in ADMA levels and

central arterial pressure waveform during HD in 32

patients with HD. They found that HD reduced both

AIx (19%; p = 0.003) and ADMA levels (17%;

p \ 0.001). The magnitudes of changes in AIx and

ADMA during HD were correlated (r = 0.44;

p = 0.045). They suggest that the reduction in

ADMA level seen after HD is associated with

improvement in the central arterial pressure wave-

form, suggesting involvement of nitric oxide in the

regulation of arterial stiffness in patients with HD.

Homocysteine

The effect of homocysteine on arterial stiffness is

controversial. Plasma homocysteine levels were

independently correlated with arterial stiffness as

measured by lower limb PWV in patients with ESRD

[63]. Nevertheless, reducing plasma homocysteine

levels by folic acid did not change the carotid artery

stiffness in patients with ESRD [64]. Tsai et al. [65]

examined the independent association between

homocysteine and arterial stiffness in 109 hemodial-

ysis patients. Their multiple regression analyses

showed that plasma homocysteine had significant

associations with arterial stiffness index (ASI) and

with pulse pressure. They suggest that homocysteine

might cause increase arterial stiffness by enhancing

the growth of vascular smooth muscle cells, by

impairing cell growth and function of endothelium,

by inducing oxidative effect, and by reducing elastic

lamina tissue.

Bone mineral metabolism

Derangements in bone mineral metabolism are spec-

ulatively playing a role in the increased arterial

stiffness in hemodialysis patients. Indeed, some stud-

ies have demonstrated a correlation between PWV and

low bone mineral density [66, 67]. Toussaint et al. [68]

report cross-sectional data on 48 patients with CKD

(GFR 17–55 ml/min), assessing the associations

between VC, arterial stiffness, and bone mineral

density in chronic kidney disease. The authors did

not show any correlation between bone mineral

Int Urol Nephrol (2010) 42:741–752 747

123

density and PWV. As the evidence for associations

between arterial stiffness and bone mineral density

strengthens, focus must be shifted to understanding the

mechanism for these processes.

Hepatitis C

Adam et al. [69] conducted a study to analyze the

relationship between hepatitis c infection, arterial

stiffness, and insulin resistance in hemodialysis

patients. Thirty-seven HCV (?) and 30 HCV (-)

HD patients were enrolled. Arterial stiffness was

measured by ‘‘stiffness index b’’ and the elastic

modulus.’’ The authors found that insulin resistance

was associated with stiffness index b (r = ?0.547,

p = 0.001) and elastic modulus (r = ?0.532,

p = 0.001) only in HCV (?) patients. However, the

investigators did not find any difference between

seropositive and seronegative patients in terms of

‘‘stiffness index b’’ and ‘‘elastic modulus.’’ They

concluded that no direct effect of HCV infection on

arterial stiffness could be sustained.

Fibroblast growth factor-23

Fibroblast growth factor-23 (FGF23) is a secreted,

bone-derived factor that plays a fundamental role in

the regulation of phosphate and vitamin D metab-

olism [70]. FGF23 levels are elevated at later stages

of CKD as a response to persistent hyperphospha-

temia [71]. Circulating concentration of FGF-23

increases as renal function declines in patients with

chronic kidney disease, but does not change in

response to variation in phosphate intake in healthy

volunteers [72]. Gutierrez et al. [73] recently

demonstrated that FGF23 is independently associ-

ated with mortality in incident hemodialysis patients

although the mechanistic causes remain unknown.

Until recently, the association between FGF23 and

vascular function in ESRD patients was not known.

Mirza et al. [74] very recently demonstrated that

both in patients with and without renal failure

circulating FGF23 is independently associated with

increased arterial stiffness. Circulating fibroblast

growth factor-23 is associated with vascular dys-

function in the community. They suggest that further

research should be carried for determining the exact

role of fibroblast growth factor-23 for the develop-

ment of CVD.

Magnesium

Numerous studies now provide strong suggestive

evidence for a protective role of Mg in VC,

arrhythmias, and atherosclerosis in patients with

ESRD. These studies also suggest that serum Mg

concentrations in dialysis patients are independently

associated with PTH levels which is an independent

risk factor for VC. Previous studies allow us to

speculate on the possible salutary role of increasing

plasma levels of Mg to facilitate the healing of

vascular injuries, to prevent atherosclerosis, hyper-

tension, arrhythmia, and chronic myocardial ische-

mia. Magnesium-based compounds have an

additional further advantage of being very much

cheaper to use than some newer alternatives [75, 76].

Perspectives and conclusion

Raised blood pressure measured at the brachial site

is thought to be a major CV risk factor in the general

population. However, central BP (as opposed to

peripheral, brachial BP) is determined by several

factors other than those listed by classical textbooks

(i.e., cardiac output and peripheral vascular resis-

tance), such as the stiffness of conduit arteries and

the timing and magnitude of pressure wave reflec-

tions [3]. This nuance is crucial to any investigation

of BP therapy, as there is an intense discussion on

potential advantages of the BP-lowering therapy

beyond BP lowering. Recent publications have

suggested that central aortic pressures may be

independent predictors of CV outcomes. Recen-

tly,this has been confirmed first by a large prospec-

tive investigation – the CAFE study. The authors of

CAFE study showed that certain drugs (in this case,

the calcium channel blocker amlodipine ± perindop-

ril combination) are more favorable in reducing

central BP (i.e., arterial stiffness) than others (aten-

olol ± thiazide). They suggest that BP-lowering

drugs can have substantially different effects on

central aortic pressures and hemodynamics despite a

similar impact on brachial BP. Moreover, central

aortic pulse pressure may be a more important

determinant of clinical outcomes, and differences in

central aortic pressures may be a potential mecha-

nism to explain the different clinical outcomes. The

results of this study are groundbreaking, and as a

748 Int Urol Nephrol (2010) 42:741–752

123

result of the knowledge obtained from the CAFE

trial, clinicians should try to choose the antihyper-

tensive drug that achieves the best balance between

central and brachial BP in any particular patient.

Today, it was well demonstrated in several studies

that the independent predictive value of aortic

stiffness has been demonstrated after adjustment to

classical CV risk factors, including brachial pulse

pressure. This indicates that aortic stiffness has a

better predictive value than each of classical risk

factors. In addition, aortic stiffness retains its

predictive value for CVD events after adjustment

to the Framingham risk score, suggesting that aortic

stiffness has an added value to a combination of CV

risk factors. One reason may be that aortic stiffness

integrates the damage of CV risk factors on the

aortic wall over a long period of time, whereas BP,

glycemia, and lipids can fluctuate over time, and

their values, recorded at the time of risk assessment,

may not reflect the true values damaging the arterial

wall. Arterial stiffness attenuation may reflect the

true reduction of arterial wall damage, whereas BP,

glycemia, and lipids can be normalized in a few

weeks by using antihypertensive, antidiabetic, and

lipid-lowering drugs, leading to a strong reduction in

CV risk scores, but without yet any improvement of

atherosclerotic lesions and arterial stiffness, which

requires a long-lasting correction of biochemical

abnormalities. A temporal dissociation is thus

expected between the improvement of CV risk

factors and a still high arterial stiffness. A direct

answer to the issue of the predictive value of aortic

stiffness attenuation for the reduction of CV events

has not yet been afforded in the general population

widely [4]. Although there are indirect clues,

whether the reduction in central PP is associated

with a concomitant reduction in CV events, inde-

pendently of the normalization of classical CV risk

factors remains to be demonstrated. Thus, one major

goal of future clinical research will be to confirm

these data in large, well-designed trials. If the results

of these future trials do demonstrate a more favor-

able impact of some antihypertensives on central

blood pressure and on major CV end-points, it will

lead to a major shift in our understanding of BP, our

treatment of it, and also the way we measure blood

pressure. Arterial stiffness assessment (by applana-

tion tonometry or other methods) would become

mandatory in any clinical setting.

Thus, as mentioned earlier, there are many factors

that play a role for the development of arterial

stiffness. Some of them are unique to dialysis

patients, and some of them are also present in general

population. Our current knowledge does not enable

us to know exactly to what extend these factors play a

role for the development of arterial stiffness.

Although important research is going on, we still do

not know the answers to important questions. How do

these risk factors work, how they interact with each

other, at what stage can we stop the process? Finally,

which might be the protective factors related to

arterial stiffness prevention?

References

1. Foley RN, Parfrey PS, Sarnak MJ (1998) Clinical epide-

miology of cardiovascular disease in chronic renal disease.

Am J Kidney Dis 32:S112–S119

2. Gusbeth-Tatomir P, Covic A (2007) Causes and conse-

quences of increased arterial stiffness in chronic kidney

disease patients. Kidney Blood Press Res 30:97–107

3. Covic A, Gusbeth-Tatomir P, Goldsmith DJ (2005) Arte-

rial stiffness in renal patients: an update. Am J Kidney Dis

45:965–977

4. Laurent S et al (2006) Expert consensus document on

arterial stiffness: methodological issues and clinical

applications. Eur Heart J 27:2588–2605

5. Boutouyrie P, Bussy C, Hayoz D, Hengstler J, Dartois N,

Laloux B, Brunner H, Laurent S (2000) Local pulse pres-

sure and regression of arterial wall hypertrophy during

long term antihypertensive treatment. Circulation 101:

2601–2606

6. Zureik M, Ducimetiere P, Touboul PJ, Courbon D, Boni-

thon-Kopp C, Berr C, Magne C (2000) Common carotid

intima-media thickness predicts occurrence of carotid

atherosclerotic plaques longitudinal results from the ageing

vascular study (EVA) study. Arterioscler Thromb Vasc

Biol 20:1622–1629

7. Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT

(1993) Distribution of circumferential stress in ruptured

and stable atherosclerotic lesions: a structural analysis with

histopathological correlation. Circulation 87:1179–1187

8. Taal MW, Sigrist MK, Fakis A, Fluck RJ, McIntyre CW

(2007) Markers of arterial stiffness are risk factors for

progression to end-stage renal disease among patients with

chronic kidney disease stages 4 and 5. Nephron Clin Pract

107:c177–c181

9. Zoungas S, Asmar RP (2007) Arterial stiffness and

cardiovascular outcome. Clin Exp Pharmacol Physiol 34:

647–651

10. Celermajer DS (1998) Noninvasive detection of athero-

sclerosis. N Engl J Med 339:2014–2015

11. Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B,

Brisac AM, Target R, Levy BI (1995) Assessment of

Int Urol Nephrol (2010) 42:741–752 749

123

arterial distensibility by automatic pulse wave velocity

measurement. Validation and clinical application studies.

Hypertension 26:485–490

12. Van Bortel LM, Duprez D, Starmans-Kool MJ, Safar ME,

Giannattasio C, Cockcroft J, Kaiser DR, Thuillez C (2002)

Applications of arterial stiffness, Task Force III: recom-

mendations for user procedures. Am J Hypertens 15:445–

452

13. McEniery CM, Yasmin HallIR, Qasem A, Wilkinson IB,

Cockcroft JR (2005) Normal vascular aging: differential

effects on wave reflection and aortic pulse wave velocity:

the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll

Cardiol 46:1753–1760

14. Nichols WW, O’Rourke MF (1998) Vascular impedance.

In: Nichols WW, O’Rourke MF (ed) McDonald’s blood

flow in arteries: theoretical, experimental and clinical

principles. 4th edn. London: Edward Arnold, pp 54–97,

243–283, 347–395

15. Ratto E, Leoncini G, Viazzi F, Vaccaro V, Falqui V, Pa-

rodi A, Conti N, Tomolillo C, Deferrari G, Pontremoli R

(2006) Ambulatory arterial stiffness index and renal

abnormalities in primary hypertension. J Hypertens 24:

2033–2038

16. Schillaci G, Parati G, Pirro M, Pucci G, Mannarino MR,

Sperandini L, Mannarino E (2007) Ambulatory arterial

stiffness ındex ıs not a specific marker of reduced arterial

compliance. Hypertension 49:986–991

17. Vogel RA, Benitez RM (2000) Noninvasive assessment of

cardiovascular risk: from Framingham to the future. Rev

Cardiovasc Med 1:34–42

18. Komai N, Ohishi M, Morishita R, Moriguchi A, Kaibe M,

Matsumoto K, Rakugi H, Higaki J, Ogihara T (2002)

Arterial stiffness index: a new evaluation for arterial

stiffness in elderly patients with essential hypertension.

Geriatric Geront Int 15:199–205

19. Hiramatsu K, Oiwa A, Shigematsu S et al (2004) A novel

arterial stiffness index (ASI) as a marker of arteriosclero-

sis. Am J Hypertens 17:131A

20. Kocak H, Gumuslu S, Sahin E, Ceken K, Ermis C, Gocmen

AY, Yakupoglu G, Ersoy FF, Suleymanlar G, Tuncer M

(2009) Relationship between carotid artery intima-media

thickness and brachial artery flow-mediated dilation in

peritoneal dialysis patients. Int Urol Nephrol 41(2):409–

416

21. Adragao T, Pires A, Birne R, Curto JD, Lucas C,

Goncalves M, Negrao AP (2009) A plain X-ray vascular

calcification score is associated with arterial stiffness and

mortality in dialysis patients. Nephrol Dial Transplant

24(3):997–1002

22. Mark PB, Doyle A, Blyth KG, Patel RK, Weir RA,

Steedman T, Foster JE, Dargie HJ, Jardine AG (2008)

Vascular function assessed with cardiovascular magnetic

resonance predicts survival in patients with advanced

chronic kidney disease. J Cardiovasc Magn Reson 10(1):39

23. London GM, Marchais SJ, Guerin AP, Metivier F (2002)

Impairment of arterial function in chronic renal disease:

prognostic impact and therapeutic approach. Nephrol Dial

Transplant 12:13–15

24. Mourad JJ, Pannier B, Blacher J et al (2001) Creatinine

clearance, pulse wave velocity, carotid compliance and

essential hypertension. Kidney Int 59:1834–1841

25. Benetos A, Adamopoulos C, Bureau JM et al (2002)

Determinants of accelerated progression of arterial stiff-

ness in normotensive subjects and in treated hypertensive

subjects over a 6-year period. Circulation 105:1202–1207

26. Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman

AM, Korbet SM, Barth RH, Winston JA, Fuh H, Manogue

KR et al (1994) Reactive glycosylation end-products in

diabetic uremia and treatment of renal failure. Lancet

343:1519–1522

27. Miyata T, de Strihou C, Kurokawa K, Baynes JW (1999)

Alterations in nonenzymatic biochemistry in uremia: origin

and significance of ‘carbonyl stress’ in long-term uremic

complications. Kidney Int 55:389–399

28. Tycho Vuurmans JL, Boer WH, Bos WJ, Blankestijn PJ,

Koomans HA (2002) Contribution of volume overload and

angiotensin II to the increase pulse wave velocity of he-

modialysis patients. J Am Soc Nephrol 13:177–183

29. Lin YP, Yu WC, Hsu TL, Ding PY, Yang WC, Chen CH

(2003) The extracellular fluid-to-intracellular fluid volume

ratio is associated with large-artery structure and function

in hemodialysis patients. Am J Kidney Dis 42:990–999

30. Kobayashi S, Okamoto K, Maesato K, Moriya H, Ohtake T

(2005) Important role of blood rheology in atherosclerosis

of patients with hemodialysis. Hemodial Int 9:268–274

31. Cheng LT, Tang LJ, Chen HM, Tang W, Wang T (2008)

Relationship between serum albumin and pulse wave

velocity in patients on continuous ambulatory peritoneal

dialysis. Vasc Health Risk Manag 4(4):871–876

32. London GM, Marchais SJ, Safar ME, Genest AF, Guerin

AP, Metivier F, Chedid K, London AM (1990) Aortic and

large artery compliance in end-stage renal failure. Kidney

Int 37:137–142

33. Nakamura T, Kawagoe Y, Matsuda T, Takahashi Y,

Sekizuka K, Ebihara I, Koide H (2003) Effects of LDL

apheresis and vitamin E-modified membrane on carotid

atherosclerosis in hemodialyzed patients with arterioscle-

rosis obliterans. Kidney Blood Press Res 26:185–191

34. Moe SM, Reslerova M, Ketteler M, O’Neill K, Duan D,

Koczman J, Westenfeld R, Jahnen-Dechent W, Chen NX

(2005) Role of calcification inhibitors in the pathogenesis

of vascular calcification in chronic kidney disease. Kidney

Int 67:2295–2304

35. Wang AY, Woo J, Lam CW, Wang M, Chan IH, Gao P,

Lui SF, Li PK, Sanderson JE (2005) Associations of serum

fetuin-A with malnutrition, inflammation, atherosclerosis

and valvular calcification syndrome and outcome in peri-

toneal dialysis patients. Nephrol DialTransplant 20:1676–

1685

36. Cozzolino M, Brancaccio D, Gallieni M, Slatopolsky E

(2005) Pathogenesis of vascular calcification in chronic

kidney disease. Kidney Int 68:429–436

37. Goldsmith DJ, Covic A, Sambrook PA, Ackrill P (1997)

Vascular calcification in long-term hemodialysis patients

in a single unit: a retrospective analysis. Nephron 77:37–43

38. Reynolds JL, Joannides AJ, Skepper JN, Mc-Nair R,

Schurgers LJ, Proudfoot D, Jahnen-Dechent W, Weissberg

PL, Shanahan CM (2004) Human vascular smooth muscle

cells undergo vesicle-mediated calcification in response to

changes in extracellular calcium and phosphate concen-

trations: a potential mechanism for accelerated vascular

calcification in ESRD. J Am Soc Nephrol 15:2857–2867

750 Int Urol Nephrol (2010) 42:741–752

123

39. Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL

(2002) Monocyte/macrophage regulation of vascular cal-

cification in vitro. Circulation 105:650–655

40. Tintut Y, Patel J, Parhami F, Demer LL (2000) Tumor

necrosis factor- alpha promotes in vitro calcification of

vascular cells via the cAMP pathway. Circulation 102:

2636–2642

41. Wang AY, Woo J, Wang M, Sea MM, Ip R, Li PK, Lui SF,

Sanderson JE (2001) Association of inflammation and

malnutrition with cardiac valve calcification in continuous

ambulatory peritoneal dialysis patients. J Am Soc Nephrol

12:1927–1936

42. Haydar AA, Hujairi NM, Covic AA, Pereira D, Rubens M,

Goldsmith DJ (2004) Coronary artery calcification is

related to coronary atherosclerosis in chronic renal disease

patients: a study comparing EBCT-generated coronary

artery calcium scores and coronary angiography. Nephrol

Dial Transplant 19:2307–2312

43. Kullo IJ, Bielak LF, Turner ST, Sheedy PF 2nd, Peyser PA

(2006) Aortic pulse wave velocity is associated with the

presence and quantity of coronary artery calcium. A

communitybased study. Hypertension 47:174–179

44. Guerin AP, London GM, Marchais SJ, Metivier F (2000)

Arterialstiffening and vascular calcifications in end-stage

renal disease. Nephrol Dial Transplant 15:1014–1021

45. London GM, Blacher J, Pannier B, Guerin AP, Marchais

SJ, Safar ME (2001) Impact of aortic stiffness attenuation

on survival of patients in endstage renal failure. Circulation

103:987–992

46. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM

(2001) Arterial calcifications, arterial stiffness, and car-

diovascular risk in end-stage renal disease. Hypertension

38:938–942

47. Fang W, Yang X, Bargman JM, Oreopoulos DG (2009)

Association between pulse pressure and mortality in

patients undergoing peritoneal dialysis. Perit Dial Int

29(2):163–170

48. Ogawa T, Shimada M, Ishida H, Matsuda N, Fujiu A,

Ando Y, Nitta K (2009) Relation of stiffness parameter

beta to carotid arteriosclerosis and silent cerebral infarction

in patients on chronic hemodialysis. Int Urol Nephrol

41(3):739–745

49. Haydar AA, Covic A, Colhoun H, Rubens M, Goldsmith

DJ (2004) Coronary artery calcification and aortic pulse

wave velocity in chronic kidney disease patients. Kidney

Int 65:1790–1794

50. London GM, Marchais SJ, Guerin AP, Boutouyrie P,

Metivier F, de Vernejoul MC (2008) Association of bone

activity, calcium load, aortic stiffness, and calcifications in

ESRD. J Am Soc Nephrol 19:1827–1835

51. Bossola M, Muscaritoli M, Tazza L, Giungi S, Tortorelli

A, Rossi Fanelli F, Luciani G (2005) Malnutrition in he-

modialysis patients: what therapy? Am J Kidney Dis

46:371–386

52. Gu Yue, Cheng Li-Tao, Chen Hui-Min, Sun Xiao-Yan,

Tang Li-Jun, Guo Li-Juan, Axelsson Jonas, Wang Tao

(2008) Strong association between nutritional markers and

arterial stiffness in continuous ambulatory peritoneal

dialysis patients. Blood Purif 26:340–346

53. Schafer C, Heiss A, Schwarz A et al (2003) The serum

protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is

a systemically acting inhibitor of ectopic calcification. J

Clin Invest 112:357–366

54. Jahnen-Dechent W, Schinke T, Trindl A, Muller-Esterl W,

Sablitzky F, Kaiser S, Blessing M (1997) Cloning and

targeted deletion of the mouse fetuin gene. J Biol Chem

272:31496–31503

55. Moe SM, Chen NX (2005) Inflammation and vascular

calcification. Blood Purif 23:64–71

56. Hermans MM, Brandenburg V, Ketteler M, Kooman JP,

van der Sande FM, Gladziwa U, Rensma PL, Bartelet K,

Konings CJ, Hoeks AP, Floege J, Leunissen KM (2006)

Study on the relationship of serum fetuin-A concentration

with aortic stiffness in patients on dialysis. Nephrol Dial

Transplant 21:1293–1299

57. Sigrist MhairiK, Taal MaartenW, Bungay Peter, Christo-

pher W (2007) McIntyre progressive vascular calcification

over 2 years ıs associated with arterial stiffening and

ıncreased mortality in patients with stages 4 and 5 chronic

kidney disease. Clin J Am Soc Nephrol 2:1241–1248

58. Chesterton LJ, Sigrist MK, Bennett T, Taal MW, McIntyre

CW (2005) Reduced baroreflex sensitivity is associated

with increased vascular calcification and arterial stiffness.

Nephrol Dial Transplant 20:1140–1147

59. Hermans MM, Vermeer C, Kooman JP, Brandenburg V,

Ketteler M, Gladziwa U, Rensma PL, Leunissen KM,

Schurgers LJ (2007) Undercarboxylated matrix GLA pro-

tein levels are decreased in dialysis patients and related to

parameters of calcium-phosphate metabolism and aortic

augmentation ındex. Blood Purif 25:395–401

60. Wilkinson IB, Franklin SS, Cockcroft JR (2004) Nitric

oxide and the regulation of large artery stiffness: from

physiology to pharmacology. Hypertension 44:112–116

61. Kielstein JT, Boger RH, Bode-Boger SM, Schaffer J,

Barbey M, Koch KM, Frolich JC (1999) Asymmetric

dimethylarginine plasma concentrations differ in patients

with endstage renal disease: Relationship to treatment

method and atherosclerotic disease. J Am Soc Nephrol

10:594–600

62. Mardare NG, Goldsmith DJ, Gusbeth-Tatomir P, Covic A

(2005) Intradialytic changes in reflective properties of the

arterial system during a single hemodialysis session. He-

modial Int 9:376–382

63. Wikstrom IngaSoveriLarsLindBjorn, Zilmer Mihkel, Zil-

mer Kersti, Fellstrom Bengt (2007) Improvement in central

arterial pressure waveform during hemodialysis ıs related

to a reduction in asymmetric dimethylarginine (ADMA)

levels. Nephron Clin Pract 106:c180–c186

64. Blacher J, Demuth K, Guerin AP, Safar ME, Moatti N,

London GM (1998) Influence of biochemical alterations on

arterial stiffness in patients with end-stage renal disease.

Arterioscler Thromb Vasc Biol 18:535–541

65. van Guldener C, Lambert J, ter Wee PM, Donker AJ,

Stehouwer CD (2000) Carotid artery stiffness in patients

with end-stage renal disease: no effect of long-term

homocysteine-lowering therapy. Clin Nephrol 53:33–41

66. Tsai JC, Kuo HT, Chiu YW, Hwang SJ, Chuang HY,

Chang JM, Chen HC, Lai YH (2005) Correlation of plasma

homocysteine level with arterial stiffness and pulse pres-

sure in hemodialysis patients. Atherosclerosis 182:121–127

67. London GM, Guerin AP, Verbeke FH, Pannier B, Bou-

touyrie P, Marchais SJ, Metivier F (2007) Mineral

Int Urol Nephrol (2010) 42:741–752 751

123

metabolism and arterial functions in end-stage renal dis-

ease: potential role of 25-hydroxyvitamin D deficiency. J

Am Soc Nephrol 18:369–373

68. Raggi P, Bellasi A, Ferramosca E, Block GA, Muntner P

(2007) Pulse wave velocity is inversely related to vertebral

bone density in hemodialysis patients. Hypertension

49:1278–1284

69. Toussaint ND, Lau KK, Strauss BJ, Polkinghorne KR, Kerr

PG (2008) Associations between vascular calcification,

arterial stiffness and bonemineral density in chronic kidney

disease. Nephrol Dial Transplant 23(2):586–593

70. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R,

Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Ya-

mashita T (2004) FGF-23 is a potent regulator of vitamin D

metabolism and phosphate homeostasis. J Bone Miner Res

19:429–435

71. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R,

Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T

(2001) Cloning and characterization of FGF23 as a caus-

ative factor of tumor-induced osteomalacia. Proc Natl

Acad Sci USA 98:6500–6505

72. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson

KB (2003) Circulating concentration of FGF-23 increases

as renal function declines in patients with chronic kidney

disease, but does not change in response to variation in

phosphate intake in healthy volunteers. Kidney Int 64(6):

2272–2279

73. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA,

Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner

H, Wolf M (2008) Fibroblast growth factor 23 and mor-

tality among patients undergoing hemodialysis. N Engl J

Med 359:584–592

74. Mirza MA, Larsson A, Lind L, Larsson TE (2009) Circu-

lating fibroblast growth factor-23 is associated with vas-

cular dysfunction in the community. Atherosclerosis 205:

385–390

75. Tzanakis IP, Oreopoulos DG (2009) Beneficial effects of

magnesium in chronic renal failure: a foe no longer. Int

Urol Nephrol 41(2):363–371

76. Turgut F, Kanbay M, Metin MR, Uz E, Akcay A, Covic A

(2008) Magnesium supplementation helps to improve

carotid intima media thickness in patients on hemodialysis.

Int Urol Nephrol 40(4):1075–1082

752 Int Urol Nephrol (2010) 42:741–752

123