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NDT Advance Access first published online on January 25, 2007
This version published online on March 8, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl750
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Spatial inhomogeneity of common carotid artery intima media is increased in dialysis patients

Marc M. H. Hermans1, Jeroen P. Kooman1, Vincent Brandenburg2, Markus Ketteler2, Jan G. M. C. Damoiseaux3, Jan W. Cohen Tervaert3, Isabel Ferreira4,9, Pieter L. Rensma5, Ulrich Gladziwa6, Abraham A. Kroon7, Arnold P. G. Hoeks8, Coen D. A. Stehouwer9 and Karel M. L. Leunissen1

1Department of Internal Medicine and Nephrology, Academic Hospital Maastricht, Maastricht, Netherlands, 2Department of Nephrology and Clinical Immunology, University Hospital RWTH, Aachen, Germany, 3Department of Clinical and Experimental and Immunology, Academic Hospital Maastricht, Maastricht, 4Department of Clinical Epidemiology and Medical Technology Assessment, Academic Hospital Maastricht, Maastricht, Netherlands, 5Department of Internal Medicine and Nephrology, Elisabeth Hospital Tilburg, Netherlands, 6University of Witten-Herdecke,Witten, Germany, 7Department of Internal Medicine and Vascular Medicine, Academic Hospital Maastricht, Maastricht, 8Department of Biophysics, Maastricht University and 9Department of Internal Medicine, Academic Hospital Maastricht, Maastricht, Netherlands

Correspondence and offprint requests to: Marc M. H. Hermans, MD, Department of internal medicine and nephrology, Academic Hospital Maastricht, PO box 5800, 6202 AZ Maastricht, The Netherlands. Email: mherm{at}sint.azm.nl



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Structural abnormalities of the common carotid artery (CCA), as assessed by ultrasound techniques, are related to cardiovascular outcome in dialysis patients. An increased intima media thickness (IMT) of the CCA may both represent a reaction to a haemodynamic burden as well as atherosclerosis. With a new ultrasound technique CCA-IMT and IMT-inhomogeneity, a novel parameter of spatial variance of the IMT, were measured and related to traditional and non-traditional risk factors.

Methods. In a cross-sectional study, we included 134 dialysis patients, aged 61 ± 13 years (103 on haemodialysis, 31 on peritoneal dialysis) and 41 controls, aged 60 ± 8 years. Age, sex, pulse pressure, diabetes, prevalent cardiovascular disease (CVD) and height were included in the basic multiregression analysis. Ultrasound examination of the CCA was performed. We also measured serum fetuin-A, high-sensitivity C-reactive protein (hsCRP), antibodies to oxidized low density lipoproteins (anti-oxLDL antibodies), calcium, phosphate, albumin and parathyroid hormone.

Results. Compared with controls, dialysis patients had a greater CCA-IMT (670 µm vs 590 ± 10 µm; P = 0.002) and a greater CCA-IMT inhomogeneity (11.0 vs 8.1%; P = 0.013). Dialysis patients with CVD had a greater CCA-IMT (734 µm vs 631µm; P = 0.001) and IMT-inhomogeneity (13.2 vs 9.7; P = 0.008) compared with patients without CVD. IMT-inhomogeneity strongly correlated with IMT (R = 0.65, P < 0.0001). In multiregression analysis, serum fetuin-A and anti-oxLDL antibodies correlated with IMT-inhomogeneity but not with IMT. HsCRP neither correlated with IMT-inhomogeneity nor with IMT.

Conclusion. The present study shows that CCA-IMT and IMT-inhomogeneity were increased in dialysis patients compared with controls. Although CCA-IMT and IMT-inhomogeneity are related, the different associations between both measurements and non-traditional risk factors show that they are distinct entities.

Keywords: atherosclerosis; Carotid wall intima-medial thickness; calcification; Ultrasound; Dialysis patients; Cardiovascular risk factors



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Cardiovascular mortality is greatly increased in dialysis patients, the mean risk of cardiovascular death being thirty times higher than in the general population [1].

Structural abnormalities of the large arteries as assessed by echographic techniques in dialysis patients are related to cardiovascular outcome [2]. An increased intima media thickness of the common carotid artery (CCA-IMT), is considered to be a marker of atherosclerosis [3]. However, only values >900 µm are considered to represent atherosclerosis [4]. Moreover, in dialysis patients only IMT values >1.0 mm predicted cardiovascular mortality [2]. Despite their greatly increased cardiovascular risk, several studies have shown that in most dialysis patients CCA-IMT values are well <1.0 mm [5–8]. In some studies, even no difference in CCA-IMT between patients and controls was observed [6–8]. Among other reasons, this may be due to the relative insensitivity of the commonly used measurement techniques, which either assess IMT at a single point, or average IMT thickness along an arterial segment [9]. The latter method may be more sensitive than single-point measurement, but advanced lesions (atheroma) and fully developed plaques tend to be localized at specific sites [10], which is obscured by averaging over relatively long arterial segments.

Recently, a new technique has been developed which is able to detect local inhomogeneities in the IMT by assessing the spatial variance of IMT over an arterial segment [11]. Application of this technique might increase the sensitivity of IMT measurements and enable the detection of focal atherosclerotic lesions at an earlier stage in the development. Local inhomogeneities of CCA-IMT have not yet been assessed in dialysis patients, or in other patient populations with cardiovascular disease. Given the greatly increased prevalence of cardiovascular disease (CVD) in dialysis patients, it would appear rational to study this novel parameter in this population.

CVD in dialysis patients is related to traditional and non-traditional risk factors [12]. Both C-reactive protein (CRP) [13] and fetuin-A, a potent circulating calcification inhibitor [14,15], are non-traditional risk factors related to cardiovascular mortality in dialysis patients. Moreover, in dialysis patients, a higher CRP is associated with a greater CCA-IMT [16], and a lower serum fetuin-A is associated with greater coronary artery calcification [17]. Oxidative stress, as measured by the presence of IgG antibodies to oxidized low-density lipoproteins (anti-oxLDL antibodies), is associated with atherosclerosis in the general population [18,19], but its role as a non-traditional risk-factor in uraemic patients is less clear [20].

The aim of the present study was to study the difference in CCA-IMT and inhomogeneities in CCA-IMT between dialysis patients and controls. Secondly, the associations between the IMT and inhomogeneity measurements and several traditional risk factors, as well as anti-oxLDL antibodies, serum fetuin-A levels and hsCRP were studied.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects and study design
We performed a cross-sectional study in 134 stable, all but two Caucasian, dialysis patients, undergoing haemodialysis (HD; n = 103, 77%) or peritoneal dialysis (PD; n = 31, 23%), from three dialysis centres.

End-stage renal disease (ESRD) patients were eligible when they had been on dialysis for more than 3 months. Patients with an underlying malignancy, infection or heart failure were excluded.

The age- and sex-matched control group (n = 41) consisted of spouses and healthy staff members. Controls had to have a negative cardiovascular medical history including hypertension. CVD was defined as the presence or history of ischaemic heart disease, peripheral vascular disease and/or a cerebrovascular event. Hypertension was defined as a blood pressure ≥140 mmHg systolic and/or ≥90 mmHg diastolic according to the JNC VII criteria [21] and/or the current use of anti-hypertensive medication. In controls, renal function was estimated by the modified MDRD formula in millilitre per minute and expressed per 1.73 m2 body surface area [22]. Fasting plasma glucose levels ≥7.0 mmol/l were considered diagnostic for diabetes mellitus.

All participants gave their written informed consent. The study protocol was designed in adherence to the declaration of Helsinki and approved by the ethical committees of the participating centres.

Carotid artery properties
Structural properties of the carotid artery were obtained by one trained vascular sonographer and assessed with the use of a 7.5 MHz linear array transducer connected to an ultrasound scanner (Picus, Esaote, Maastricht, the Netherlands). The method has been described previously [11,23] but was adapted for this study. In short, using standard B-mode the right common carotid artery and the bifurcation were scanned for plaques; hereafter the region of interest (2–3 cm proximal to the carotid flow divider) was identified. The ultrasound system was then switched to fast B-mode with a considerably lower echo line density (14 lines covering 16.4 mm), favouring a substantially higher frame update rate (671 Hz). The radio frequency (RF) signal of the echo system was captured for a time segment of 5 s by a 12 bit data acquisition system with a conversion frequency of 33 MHz and stored on hard disk for further processing. Off-line, the RF data were recalled and transformed to a complex format using the Hilbert transform, facilitating the computation of the instantaneous echo-amplitude as function of depth and echo line position which results in an echo image where the amplitude is retained on a linear scale (Figure 1). For this study only the images coincident with the R-top of the simultaneously recorded ECG were used for further analysis. The adventitia-media and lumen-intima echo transitions of the posterior wall were identified manually, resulting in estimates for the IMT (p,b) as function of echo-line position p and beat b. Subsequently the IMT was averaged over all considered beats. The processing procedure is completed with the computation of the average and the SD of the estimated IMT over echo-line position. The SD of the spatial distribution of the IMT is used as a measure for the spatial inhomogeneity. Lumen diameter (LD) was calculated from interadventitial diameter (IAD) and IMT as LD = IAD – (2 x IMT).


Figure 1
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  		Fig. 1. B-mode images of the common carotid artery showing a 60-yr old healthy control with a homogeneous aspect of the intima media (A) and a 63-yr old dialysis patient with an inhomogeneous aspect of the intima media with arrows indicating ‘lesions’ of the intima media (B).

 
Feasibility of measurements
Of the 134 dialysis patients, CCA-IMT measurement was successful in 128 patients (96%). Measurement failure was due to a poor visualization quality of the CCA-IMT, mostly in obese patients. Two patients were excluded from analysis because of missing blood samples.

Blood pressure measurement
Brachial systolic and diastolic pressures were assessed at 3 min intervals with a radial artery tonometrical device (CBM 7000, Colin Medial Instruments, San Antonio, Texas, USA) on the right arm or in the case of a right-sided dialysis shunt, on the left arm. Mean arterial pressure (MAP) was calculated from the mean of three systolic and diastolic pressures as diastolic pressure + pulse pressure/3, with pulse pressure defined as the difference between systolic and diastolic pressure.

Laboratory analysis
In the patient group, serum calcium (Ca), phosphate (P), albumin and cholesterol were measured using standard laboratory techniques. In the HD group, samples were taken at the start of a short-interval haemodialysis. Time-averaged values of Ca, P and albumin were calculated as the mean of the routine 6 weekly measurements of the previous 6 months. Calcium concentration was calculated after correction for albumin. Intact parathyroid hormone (iPTH) was measured by a two-site chemiluminescence immunoassay (Nichols Institute Diagnostics B.V.; Nijmegen; The Netherlands).

In both groups, hsCRP and fetuin-A were measured by nephelometry. Serum was harvested by centrifugation of clotted blood. Serum samples were stored at –80°C prior to analysis. Serum analysis for hsCRP were performed by means of particle enhanced immunonephelometry using a standard ‘CardioPhase hsCRP’ for ‘BNII’ (Dade Behring Holding GmbH, D-65835 Liederbach, Germany). CRPI or CRPII assay protocols were used when appropriate. Interday precision controls revealed coefficience of variance (CV) <6%.

The nephelometry method for fetuin-A employs the same high specifity antibody as the ELISA method [14,24] and has been described elsewhere [25]. Briefly, the measurement has been evaluated in a side-by-side comparison with immunoblot analysis to exclude cross-reactivity of the antibodies with other serum proteins and proteolytic fragments of fetuin-A. Cross-reaction with fetuin-B was excluded. The assay linear measurement range of human fetuin-A is 0.05 g/l up to 3.5 g/l. The within-run precision obtained from a 20-fold measurement of identical samples yielded a CV of 7.75%. The day-to-day precision obtained from repetitive measurements of control serum was determined as a CV of 8.2%.

Anti-oxLDL antibody measurement has been previously described [26]. Briefly, LDL was isolated from the plasma of a healthy subject in a potassium bromide discontinuous gradient according to Redgrave et al. [27]. The low density lipoprotein (LDL) content was determined according to Lowry et al. [28]. Malondialdehyde modification (MDA-LDL) was used to oxidize LDL. Specific IgG anti-oxLDL antibodies in patient serum were detected by ELISA and wells were deferentially coated with MDA-LDL and native LDL. Results are expressed as mean anti-oxLDL levels in optical density (OD) and were calculated by subtracting binding to native LDL from binding to oxLDL.

Statistical analysis
Normally distributed variables are expressed as mean ± SD, and non-normally distributed variables as median and inter-quartile range (IQR), with P < 0.05 indicating significance. Non-normally distributed variables were log-transformed for further analysis. Differences in mean values between groups were compared with t-tests for continuous and with chi-squared tests for categorized variables. Univariate and multiple linear regression analyses were used to investigate the association between traditional and non-traditional risk factors and IMT and IMT-inhomogeneity. Multiple linear models used to investigate the association between non-traditional risk factors and CCA-IMT and CCA inhomogeneity were first adjusted for age, sex, pulse pressure, diabetes, cardiovascular disease and height (model 1). We then investigated the potential confounding and/or mediating effects of inflammation, oxidative stress, calcium–phosphate metabolism and fetuin-A, by adding log-hsCRP, anti-oxLDL antibodies, Ca, P and Ca x P product and fetuin-A to the initial model (models 2–4). Finally, confounding and/or mediation effect of IMT in the associations with IMT-inhomogeneity was investigated by adding IMT to the regression model of the IMT-inhomogeneity analysis (model 5).



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
The characteristics of the dialysis group and the controls are shown in Table 1. Baseline laboratory values of the dialysis patients are shown in Table 2. The major causes of stage 5 chronic kidney disease were diabetes in 17%, nephrosclerosis in 38%, and glomerulonephritis in 18% of the patients. Compared with controls, dialysis patients had a larger CCA-lumen diameter, CCA-IMT and IMT-inhomogeneity (Table 2). Compared with dialysis patients without prevalent CVD, patients with CVD had a greater IMT (734 ± 17 vs 631 ± 136 µm; P = 0.001) and a greater IMT-inhomogeneity (13.2 ± 9.1 vs 9.7 ± 5.4%; P = 0.008) of the common carotid artery (Figures 2 and 3). An ROC analysis showed an area under the curve for the prediction of prevalent CVD of 0.63 (95% CI 0.53–0.74: P = 0.012) for IMT-inhomogeneity and of 0.68 (95% CI 0.58–0.78: P = 0.001) for IMT.


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  		Table 1. Characteristics of dialysis patients (HD and PD) and controls

 

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  		Table 2. Baseline laboratory characteristics of dialysis patients (n = 126)

 

Figure 2
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  		Fig. 2. Box plot showing mean intima media thickness (IMT, micrometres) and IMT-inhomogeneity (%) with 95% CI in patients and controls.

 

Figure 3
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  		Fig. 3. Box plot showing CCA-IMT and IMT-inhomogeneity values in 126 dialysis patients with and without CVD.

 
Association between IMT and IMT-inhomogeneity in dialysis patients
After adjustment for age, sex, pulse pressure, diabetes, cardiovascular disease and height, IMT and IMT-inhomogeneity strongly correlated (ß = 0.59; P < 0.001).

Associations between traditional and non-traditional risk factors with IMT and IMT-inhomogeneity (Table 3)
Traditional risk factors
Univariate analyses identified age, pulse pressure, diabetes and prior CVD as positive correlates of both carotid IMT and IMT-inhomogeneity. Body height was an inverse correlate of IMT inhomogeneity only (Table 3). In a multiple regression model including all these variables, only age remained independently associated with both IMT (ß = 0.48; P < 0.001) and IMT-inhomogeneity (ß = 0.21; P = 0.04).


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  		Table 3. Univariate associations between traditional and non-traditional risk factors and carotid intima–media thickness (IMT) and carotid IMT-inhomogeneity in dialysis patients (n = 126)

 
Non-traditional risk factors
Univariate analyses identified Fetuin-A as an inverse correlate of both carotid IMT and IMT-inhomogeneity; anti-oxLDL antibodies were positively and significantly associated with IMT-inhomogeneity only and hsCRP was positively and (borderline) significantly associated with carotid IMT only (Table 4).


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  		Table 4. Associations between fetuin-A, log hsCRP and log anti-oxLDL, and carotid intima media thickness (IMT) and IMT-inhomogeneity in dialysis patients (n = 126)

 
In multiple regression models adjusted for age, sex, pulse pressure, diabetes, CVD and body height, fetuin-A was inversely and anti-oxLDL was positively and significantly associated with IMT-inhomogeneity but not to IMT (Table 4; model 1). This significant association persisted after further adjustment for markers of inflammation (log-hsCRP), oxidative stress (log-anti-oxLDL) or fetuin-A, and calcium-phosphate metabolism (Ca, P, Ca x P product) (models 2–4). Adding IMT to the model resulted in a decrease in the strength of the association between fetuin-A or anti-oxLDL and IMT-inhomogeneity, which nevertheless remained significant (model 5). Log-hsCRP was neither related to IMT nor to IMT-inhomogeneity.

Additional analyses
The results did not change materially after additional adjustments for dialysis modality, dialysis vintage or adequacy. Also additional adjustment for the use of anti-hypertensive or lipid lowering drugs did not materially change the results.



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
The present study has two main findings. First, not only IMT but also IMT-inhomogeneity (a new parameter of spatial variance of the IMT over a given length) of the CCA is increased in dialysis patients compared with controls. Secondly, although strongly correlated, IMT and IMT-inhomogeneity seem to represent different entities given the different set of independent correlates identified: IMT was primarily associated with age, diabetes and prior CVD whereas IMT-inhomogeneity was primarily determined by decreased levels of fetuin-A and anti-oxLDL.

Carotid IMT is used as a surrogate marker for cardiovascular disease in different populations.

However, it has become clear that IMT does not merely represent atherosclerosis, but is also a reaction to haemodynamic changes [29]. In the dialysis population with a large haemodynamic burden caused by fluid overload and arterioveneous shunts, IMT values are even more difficult to interpret. In spite of the hemodynamic burden, some authors, including our group, did not find a difference in CCA-IMT between patients and controls [6,8]. In the present study, IMT values in dialysis patients were greater than in controls. This contrasting finding may be due to differences in measurement techniques: instead of a single-point assessment or averaging of the IMT over a longer segment, we measured IMT at 14 adjacent points simultaneously of an artery segment of 16.4 mm. This results in a higher accuracy and sensitivity of the measurements. Due to the new technique it is difficult to compare the absolute IMT values of this study with other studies. We believe that measuring IMT at a single point may, in the case of increased inhomogeneity, yield less reliable results.

This is the first study to report results on CCA IMT-inhomogeneity measurements in a study population. The greater IMT-inhomogeneity observed in dialysis patients may represent early changes in the structural properties of the arterial wall, which is in line with the increased frequency of plaques among these patients as compared with controls [7,8]. A large number of these plaques are heavily calcified [7] and Stenvinkel et al. [15] recently showed that ESRD patients with plaques had a lower serum fetuin-A level [15]. Fetuin-A, a calcification inhibitor [30], was also negatively correlated with IMT-inhomogeneities in our study. However, whether inhomogeneities are precursors of plaques cannot be concluded from our cross-sectional data.

Both IMT and IMT-inhomogeneities were higher in dialysis patients with prevalent CVD. IMT-inhomogeneity therefore could be a potential marker for CVD. Future prospective studies investigating whether IMT-inhomogeneity may serve as a marker for cardiovascular disease are warranted.

In the present study we show that carotid artery IMT and IMT-inhomogeneity strongly correlate. However, they should not be interpreted interchangeably, given the different set of potential determinants identified. Indeed, IMT may reflect thickness of the medial (rather than the intima) layer that could, for instance, result from adaptations to the high haemodynamic burden characteristic of dialysis patients. IMT-inhomogeneity represents a structural change over a given length of the arterial wall. Our findings suggest that these local changes may be caused by an increased calcification process caused by a lower serum fetuin-A level or accelerated atherosclerosis due to an increase in lipid peroxidation represented by higher IgG anti-oxLDL antibody levels (adaptations likely to occur at the intima layer). We thus conclude that despite their strong relationship, IMT and IMT-inhomogeneities may be markers of distinct arterial wall adaptation processes to risk factor exposure in dialysis patients.



   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors are indebted to Jan Meinders who contributed substantially to the subject of this article but unfortunately passed away. They were also are indebted to Jeroen Hameleers for his technical support and Ruud Theunissen for his laboratory assistance.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 11. 7.06
Accepted in revised form: 16.11.06


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