Nephrology Dialysis Transplantation

NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2006 21(3):729-735; doi:10.1093/ndt/gfi196

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Original Articles: Dialysis and Transplantation

Increased arterial stiffness in children on haemodialysis

Adrian Covic¹, Nicoleta Mardare¹, Paul Gusbeth-Tatomir¹, Ovidiu Brumaru², Cristina Gavrilovici², Mihaela Munteanu², Octavian Prisada¹ and David J. A. Goldsmith³

¹ Dialysis and Transplantation Center, ‘C.I. Parhon’ University Hospital, Iai, Romania, ² Nephrology and Dialysis Unit, ‘Sf. Maria’ Children Hospital, Iai, Romania and ³ Adult Renal Unit, Guy's Hospital, London, UK

Correspondence and offprint requests to: Adrian Covic, MD PhD, Professor of Nephrology, C.I. Parhon University Hospital, Carol 1st Blvd, No. 50, Iasi 700503, Romania. Email: acovic{at}xnet.ro

	Abstract

Top Abstract Introduction Subjects and methods Results Discussion References

 
Background. Measures of aortic stiffness—aortic pulse wave velocity (PWV) and augmentation index (AIx)—have been shown to be powerful predictors of survival in adult haemodialysis (HD) patients. Very few data have been reported regarding arterial stiffness in paediatric renal populations.

Methods. PWV and aortic AIx were determined from contour analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCor device in 14 children on HD (age = 14.1 years) and in 15 age, height matched children controls.

Results. Pre-HD AIx (29.7±15.4%) and PWV (6.6±1.0 m/s) were significantly higher compared with children controls (8.3±8.0% and 5.4±0.6 m/s, respectively, P<0.0001). The only significant difference between normal and HD children was BP level: 103/61 vs 114/72 mmHg, P<0.05. In children of HD patients, a multiple linear regression model including BP, age, height, weight, Ca and P levels as independent variables accounted for 57% of the variability in AIx. Dialysis had no impact on AIx (post-HD: 28.5±12.7%) or on PWV (post-HD: 6.7±0.8 m/s).

Conclusions. We show, in this first-ever report of increased arterial stiffness in children on dialysis, that end-stage renal disease is associated with abnormalities in arterial wall elastic properties, comparable with adult levels, even in childhood. Most importantly, the absence of a discernible amelioration with dialysis implies that purely structural and not functional alterations lie behind the increased arterial stiffness.

Keywords: arterial stiffness; haemodialysis; haemodynamic; intimamedia thickness; paediatric patients

	Introduction

Top Abstract Introduction Subjects and methods Results Discussion References

 
Cardiovascular complications—the main cause of death in end-stage renal disease (ESRD) adults—are present in a disproportionately large incidence and prevalence in children with chronic kidney disease (CKD), compared with normal controls [1]. This increase in cardiovascular morbidity and even mortality in children and adolescents with ESRD, has been attributed to classical cardiovascular risk factors (hypertension, dyslipidaemia), as well as to the presence of hyperhomocysteinaemia, inflammation, and NO-synthetase inhibitors—causing endothelial dysfunction and vascular damage.

Clinical and epidemiological studies have shown that structural and functional changes in large arteries are a major contributing factor to the high mortality recorded in adult uraemic patients [2]. Recognised hallmarks of CKD are: a dramatic increase in arterial stiffness, a high prevalence of surrogate, early markers of athero-/arteriosclerosis (increased carotid intimamedia thickness—IMT) and of sub-clinical (carotid plaques) or clinically overt atheromatous disease [3]. Currently, surrogate markers of increased arterial stiffness (such as pulse wave velocity—PWV), increased peripheral arterial reflectivity (such as augmentation index—AIx) or atheromatous disease (carotid IMT) are amongst the most powerful predictors of morbidity and mortality in pre-dialysis, dialysis and even renal transplant subjects [1,4–7].

Post-mortem findings suggest that atherosclerosis starts early in children and adolescents with ESRD; furthermore very recent findings demonstrated that CKD is associated with morphologic alterations of the large arteries as early as in the second decade of life [8,9]. Increased arterial stiffness and decreased distensibility have been demonstrated only recently in a few selected children populations: with vasculitis or connective tissue diseases [10–14], with intrauterine growth retardation or born from hypertensive parents [15–17] and, most importantly, with hypercholesterolaemia or obesity [18–22]. Similarly, children with a clustering of risk factors for atherosclerotic disease have significantly greater IMT and/or abnormal endothelial function compared with normal controls [19,23].

Although well described in adults, comparably few data exist in children, assessing arterial stiffness and IMT, to demonstrate that the prevailing metabolic milieu in (moderate-to-severe) chronic renal failure favours an increased rate of vascular damage. Groothof et al. [24] analysing in 2002, 130 young adult Dutch patients with onset of ESRD between age 0 to 14 described a significantly reduced arterial wall distensibility and increased stiffness, but similar IMT, compared with controls. More recently, arterial distensibility was found to be comparable with controls in paediatric renal transplant recipients [25,26]. In addition, only two other studies in children with renal impairment describe a significant increase of carotid IMT, providing also information regarding possible determinants and consequences on left ventricular changes [8,9].

This study describes for the first time arterial stiffness parameters (PWV), peripheral arterial reflective properties (AIx – see Subjects and methods) and carotid IMT, in a paediatric dialysis population, comparatively to well-matched controls. These data represent the baseline assessment for a longitudinal analysis, in which patients will be re-analysed yearly while on dialysis and following transplantation. Changes (progression) in baseline vascular parameters will be correlated with survival and changes in left ventricular structure and function. Additional objectives of the present report were to evaluate baseline determinants for the arterial wall structure abnormalities seen in uraemic children, and to assess whether, similar to adults with ESRD, abnormalities in PWV and AIx are improved following a HD session.

	Subjects and methods

Top Abstract Introduction Subjects and methods Results Discussion References

 
Study population
After institutional ethical approval and informed consent, all dialysis patients from the St Mary's Hospital Iasi paediatric renal unit were studied. The causes of renal failure for the 18 dialysis children included (14 on haemodialysis and 4 on continuous ambulatory peritoneal dialysis) were: reflux nephropathy—10 patients, chronic glomerulonephritis—5 patients, Alport syndrome—1 patient, nephrolithiasis—1 patient, chronic pielonephritis—1 patient. All haemodialysis patients were treated with three 4 h dialysis sessions per week, using Fresenius F5 dialysers. Dialysis duration was between 1 month and 6 years. Only one of the HD children had residual renal function (diuresis 300 ml/24 h). Antihypertensive drugs were used by 13 (72.2%) of 18 patients, of whom 12 (66.6%) used ACE inhibitors, 8 (44.4%) beta-blockers, 1 (5.5%) calcium channel blockers and 4 (22.2%) central agonists.

The study consisted of two parts: (1) in the first part we assessed the differences in arterial stiffness between children on dialysis and controls; (2) in the second part we evaluated the influence of a single haemodialysis session on the vascular stiffness parameters (AIx, PWV). Therefore measurements were performed before and after the mid-week HD session.

For both groups, baseline data on height and weight were recorded at the time of vascular studies. Blood pressure was also measured at the time of vascular studies at the non-fistula arm in HD children and at the left brachial artery in controls, by sphygmomanometry (mean of three readings taken after 10 min of semi-recumbence with an appropriate size-cuff) and the value was used in the analysis.

For the HD children, information about the cause and duration of chronic renal disease and biochemical parameters were retrieved from charts. Haemoglobin, total serum proteins, serum calcium and phosphate were determined each month (mid-week pre-dialysis values); PTH was assessed every 3 months. For the study we used time-averaged serum calcium, phosphate, calcium–phosphate product, serum total proteins and haemoglobin (mean of the previous 6 monthly values) and iPTH (mean of the two values obtained in the 6 months preceding the study) (Table 1).

View this table: [in this window] [in a new window]   Table 1. Comparison between children on dialysis and controls: demographic and biochemical parameters

 
Pulse wave velocity and augmentation index
PWV and AIx were determined from contour analysis of arterial waveforms recorded by applanation tonometry (AtCor® device, PWV Inc., Westmead, Sydney, Australia) using a highly reproducible technique previously described elsewhere [27,28]. All measurements were taken in duplicate and averaged. Briefly, PWV was computed from carotid and femoral artery waveforms recorded consecutively, an ECG gated-signal simultaneously recorded, and standard anthropometrical distances ((sternal notch to arterial femoral site distance) – (sternal notch to carotid site distance)), as required by the AtCor® software.

For the AIx, carotid artery applanation tonometry was performed and normalized AIx was used in the statistical analysis. AIx was calculated as the difference between the second and the first systolic peak measured on the aortic pressure waveform divided by the pulse wave height (similarly to [27]). All augmentation indices were corrected for a standard heart rate of 75 bpm by the AtCor® software. PWV and AIx measurements were performed 2 h after the morning first drain in CAPD subjects, 1 h pre-dialysis (mid-week dialysis session) in HD patients, and 1 h after the HD session. Prior to the study the intra-observer error for AIx and PWV were determined in 10 healthy children and in 10 ESRD subjects: all results were <1.2% with the same experienced investigator.

Carotid ultrasound
Children were examined after at least 10 min of rest by a single well-trained investigator (blinded to the PWA results) using a Kretz SA 9900 (Kretztechnik AG, Zipf, Austria), equipped with a 12 MHz linear probe for the B-mode ultrasound scanning of the carotid arteries. The investigative protocol involved examination of the carotid artery in both transverse and longitudinal planes. Since the ultrasonographic parameters may be considerably influenced by the volume status, all measurements were performed 1 h before the mid-week HD session. The carotid ultrasound images were recorded on tape and one of the investigators, blinded to patient type performed the IMT measurements. IMT was defined as the distance between the leading edges of the lumen–intima interface and the media–adventitia interface of the far wall. The scans with the far wall image were frozen at diastole. The carotid arteries were assessed 1 to 2 cm proximal to the bifurcation over a range of 1 cm of the far wall. The measured values from right and left artery were averaged, and the mean was taken to analysis. The intra-observer technical error of measurement calculated from repeated measurements of 10 subjects was <4%. Blood pressure (BP) was measured before starting the ultrasound examination.

Echocardiography
Echocardiographic studies were performed according to the guidelines of the American Society of Echocardiography, using a Kretz SA 9900 (Kretztechnik AG, Zipf, Austria), with a multi-frequency curved array transducer (2–4 MHz) allowing M-mode, two-dimensional, and pulsed Doppler measurements. The same experienced paediatric cardiac sonographer performed all measurements. Left ventricular end diastolic diameter (EDD), interventricular wall thickness during diastole (IVST), and posterior wall thickness during diastole (PWT) were measured by M-mode. From these measurements, the left ventricular mass (LVM) was calculated according to the following formulae: LVM (g) = 0.8 {1.05[(EDD + IVST + PWT)³ – (EDD)³]} [29]. Since we analysed a paediatric population with ESRD, LVM was normalized similarly to Mitsnefes et al. [29]: LVM index (LVMI) [mass divided by height raised to a power of 2.7 (g/m^2.7)]. Systolic function was assessed by measuring the left ventricular shortening fraction and systolic dysfunction was defined as a shortening fraction less than 28%.

Statistical analysis
All values are expressed as mean±SD unless stated in the text. All parameters in HD and control children were normally distributed. Independent sample t-test was used to assess differences between groups and paired t-test was performed to evaluate the pre- to post-dialysis differences on blood pressure and arterial stiffness parameters. Univariate correlations between variables were assessed using the Pearson's coefficient of correlation test. Significant determinants identified from these analyses were studied in a stepwise multiple regression model using the F statistic. Multiple regression analysis: all potential (physiologically meaningful) determinants of PWV and AIx were investigated in a univariate screening procedure. Variables associated with PWV/AIx with a level of significance <0.15 were included. Variables were forced in the model using a stepwise procedure. A P<0.05 for the final model was used. Data were analysed using the SSPS 13.0 for Windows software (SPSS Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and methods Results Discussion References

 
Comparison between dialysis children and healthy controls
Dialysis and control children were well matched as age, height, weight and body mass index (BMI) (Table 1). Significant differences were recorded in BP and Hb levels: as expected, dialysis children were more anaemic and had a higher BP. There were no differences in heart rate or in other potentially relevant biochemical parameters (Table 1). Also, there were no significant differences between children on haemodialysis and those treated by CAPD.

Arterial stiffness, left ventricular structure, and carotid artery changes in dialysis children vs controls
Compared with controls, children on dialysis had significantly higher PWV and greater AIx (Table 2), reflecting that even at this age, uraemia is associated with stiffer arteries. The highest PWV (8.03 m/s) and highest AIx (55%) were recorded in a 16-year-old girl and in a 12-year-old boy, respectively. There were also other profound changes in the large arterial structure, as demonstrated by significantly higher carotid IMT in dialysis compared with controls. The highest IMT (0.7 mm) was recorded in a 11-year-old girl. Finally, ESRD children had thicker left ventricular (LV) walls and greater LVMI, but not a larger LV diameter (Table 2). There were no significant differences in arterial stiffness, IMT or LV echocardiographic data between CAPD and HD children.

View this table: [in this window] [in a new window]   Table 2. Arterial stiffness, left ventricular structure and carotid artery ultrasound parameters in dialysis children: a comparison with matched controls

 
Potential determinants of AIx and PWV in dialysis children and normal controls
Dialysis children
In univariate analysis, AIx was significantly associated with age, height and weight, both before and after a dialysis session (Table 4). PWV was only significantly associated with the mean CaxP product and with mean P levels (see Subjects and methods).

View this table: [in this window] [in a new window]   Table 4. Univariate analysis for PWV in normal children

 

View this table: [in this window] [in a new window]   Table 3. Univariate analysis for AIx and PWV in dialysis children

 
Normal children (controls)
In univariate analysis, only PWV was significantly associated with age, weight and height (Table 5).

View this table: [in this window] [in a new window]   Table 5. Comparison between pre-dialysis and post-dialysis HD status

 
Dialysis children – multiple regression analysis for AIx
In univariate analysis, the following variables were associated with AIx (P<0.15): age, height, weight, SBP and DBP. These were considered for the multivariate analysis. In addition, heart rate, known from the study of Wilkinson et al. [30] to influence AIx, was added to the model. The significance of this model was P = 0.0001. After adjustment for all the above variables, age remained the only significant predictor (P<0.001), while all other variables included in the model were not significant. The model predicts 68.6% of the variance in AIx.

In order to further clarify the significance of the difference in AIx between the two groups and its independence from important variables such as age and blood pressure, a separate multiple regression analysis was performed including all 33 children (dialysis plus controls). The subgroup type (patient on dialysis or control) was added as one of the predictor variables. Dialysis children have stiffer arteries since patient status (control or dialysis) remained a significant predictor in this model (P<0.001).

Dialysis children – multiple regression analysis for PWV
In univariate analysis, the only variables associated with PWV (P<0.15) were the mean P level and the mean Ca x P product. These were considered for the multivariate analysis. In addition, variables known to have an effect on PWV from the paper of O’Rourke and Mancia [31] were introduced in the multiple regression analysis model: age, height, SBP, DBP, PP. The significance of this model was P = 0.023. In the multivariate analysis, after adjustment for parameters found significant in the univariate analysis, mean phosphate level remained the only statistically significant predictor for PWV (P<0.05). Only 28.2% of the variance in PWV is predicted by the model.

Again, in order to further clarify the significance of the difference in PWV between the two groups and its independence from important variables such as age and BP, a separate multiple regression analysis was performed including all 33 children (dialysis plus controls). The subgroup type (patient on dialysis or control) was added as one of the predictor variables. Dialysis children have stiffer arteries since patient status (control or dialysis) remained a significant predictor in this model (P<0.002).

Normal children (controls) – multivariate analysis
In univariate analysis, the following variables were associated with PWV (P<0.15): age, height, weight. These were considered for the multivariate analysis. The significance of this model was P = 0.0001. 66.4% of the variance in PWV is predicted by the model. Weight remained the only significant predictor, while coefficients for all other variables included in the model were non-significant.

Influence of a HD session on arterial stiffness parameters PWV and AIx
In contrast with data from adult populations, there was no identifiable impact of a HD session on PWV and AIx (Table 3). There was no relationship between changes in AIx or PWV and HD children's ultrafiltration volume or ultrafiltration rate.

Potential relevance of AIx and PWV in dialysis children
LVMI in dialysis children correlated only with post-HD AIx (r = 0.643, P = 0.023). No relationship was found with PWV, IMT, BP levels (current or time-averaged) or with other determinants biochemical variables.

	Discussion

Top Abstract Introduction Subjects and methods Results Discussion References

 
As far as we know, this is the first report on arterial wall properties in a cohort of children with ESRD on dialysis. In this study, we aimed to evaluate the extent of large arteries wall changes in dialysis children compared with well-matched controls, to assess the impact of a single haemodialysis session and to explore clinical determinants that could be associated with arterial damage.

We found that, compared with controls, children on dialysis have already significant arterial wall structural abnormalities, and as a consequence, stiffer large arteries (as reflected by a PWV 22% greater than in controls) and increased reflective properties of the peripheral arterial sites (as reflected by an AIx 257% greater than in controls). These results suggest that even at this age, uraemia has a profound impact on arterial structure and function, and these children are at risk for accelerated atherosclerosis and arteriosclerosis. In adults, two highly reproducible markers of arterial stiffness – aortic PWV and AIx – have been shown to be the strongest predictors of cardiovascular mortality in HD patients: for each increase of 1 m/s in PWV the all-cause mortality-adjusted odds ratio was 1.39 (95%CI; 1.19–1.62); similarly, for each 10% increase in AIx, the risk ratio was 1.51 (95%CI; 1.23–1.86) for all-cause mortality [5,6]. Shoji et al. demonstrated that increased arterial stiffness is the most important contributor to the excessive cardiovascular mortality rate seen in diabetic ESRD patients [32].

It is not immediately clear if structural and functional arterial wall abnormalities are already present in children with ESRD. Until now we have only indirect evidence: recently, in a Dutch cohort study of the Late Effects of Renal Insufficiency in Children (LERIC) including 130 young adults with ESRD since childhood, Groothof et al. [24] reported a low arterial wall distensibility, and a high incremental modulus of elasticity in all patients compared with age-matched and gender-matched healthy controls. The increase in the carotid incremental modulus of elasticity and the stiffness parameters were both associated with ESRD, independent of other determinants. However, although these data show that abnormalities of the arterial wall usually associated with older age are present in young renal subjects (mean age at investigation 29 years), the mean duration of RRT of 18.1 years, (range 6.2 to 30 years with a mean duration of dialysis of 4.5 years), supports only speculations of the potential changes present in dialysis children, since it is possible that uraemia only multiplies the natural, age-related increase in PWV and AIx [33]. Oh et al. [34] also found an increase in IMT of the carotid artery in 39 patients with ESRD since childhood and a very similar mean age at the time of investigation and total duration of ESRD. Proof of increased IMT in children, as a consequence of uraemia and abnormalities in calcium–phosphate metabolism was provided by a large study including 55 children with stages 2 to 4 CKD, 37 on dialysis and 34 after renal transplantation [8].

Our data show that highly abnormal arterial wall elastic properties and increased IMT may be found, on average, as early as age 14 years in dialysis children (consistent with the age of subjects with the most profound abnormalities – see Results). Although of very similar age, differences in the methodology of evaluation of the arterial wall elastic properties, cannot directly compare stiffness parameters in dialysis children with the successful renal transplant cohorts reported by Mitsnefes et al. [26], to speculate if some of these changes might be reversible. In fact, the magnitude of changes seen in our cohort of dialysis children is impressive, since they are close(r) to previous data from our group obtained in dialysis adults with the same methodology (and investigators): PWV = 6.6 m/s comparatively with 7.1 m/s in HD and 6.6 m/s in renal transplant adults; AIx = 29.7% comparatively with 27.9% in HD and 15.9% in renal transplant adults [35]. To add to a potentially grim picture, stiffness parameters were not (favourably) influenced by a HD session, as seen in adults [27]. Furthermore, all study patients had individual IMT values greater than the theoretical values as determined from a regression equation derived from 60 healthy children and no dyslipidaemia or hypertension [IMT in millimetres = (0.009 x age in years) + 0.35] [36].

In non-renal children populations multivariate analysis identified the following variables independently associated with arterial stiffness: age [10,13], birth weight [15,16], BMI–obesity [18–22], BP levels [13,16], and serum hs-CRP. In adults, mechanisms for increased stiffness in patients with uraemia are not fully defined, but include chronic fluid overload, arterial calcifications, micro-inflammation, sympathetic nervous system overactivity, activation of the renin–angiotensin–aldosterone (RAA) system, increased lipid oxidation, and abnormalities of the nitric oxide system [2]. In renal transplant children, worse distensibility significantly correlated with a higher daytime systolic BP load [26]. In the present children, dialysis population indices of arterial stiffness were independently associated only with age (for AIx) and mean time-averaged phosphorus level (PWV), in multiple regression linear models including age, height, weight, SBP and DBP, mean Ca, phosphate levels and the mean CaxP product. Vascular calcifications (in subjects with abnormal Ca–P homeostasis) may be the hallmark and the central pathophysiologic step of the deleterious effect exerted by the uraemic milieu on the arterial tree. This is in line with the high incidence of (coronary) calcifications seen in young adults with ESRD since childhood as found by Oh et al. [34] and with data from our group in adults directly linking PWV and AIx with EBCT-derived arterial calcifications [37]. As mentioned, Litwin et al. [8] recently found that in children with various degrees of renal impairment carotid IMT correlated with mean past serum Ca x P product, the cumulative dose of calcium-based phosphate binders, and the time-averaged calcitriol dose. These predictors accounted for 32% of the total variation of carotid IMT.

The consequences of arterial wall changes
In contrast to adult populations (see above) there are no data to support the prognostic deleterious importance of increased stiffness and surrogate atherosclerotic markers – IMT, in ESRD children on dialysis. We provide cross-sectional evidence of a relationship between LVMI and AIx – a composite parameter. Of note, other recognised determinants of LV mass like the BP or Hb levels were not associated in this cohort with the LVMI. A higher AIx is a consequence of both more rigid arteries and of more reflective peripheral arterial sites. Physiologically, a higher AIx induces an increase in the pulsatile pressure load of the cardiac left ventricle. The direct consequences are left ventricular hypertrophy, an increase in systolic BP, and a decrease in diastolic BP. The combination of a higher demand for coronary flow as a result of the left ventricular hypertrophy and the reduced supply due to a decrease in diastolic BP leads to an increased susceptibility to coronary ischaemia.

Limitations of the present study derive from the small number of subjects. However, paediatric dialysis populations are currently limited due to the high transplantation rate. All 18 dialysis subjects from the Iasi renal unit were studied; in the largest comparable study, there were only 37 children on dialysis. The case–control design and the detailed examination of the cardiovascular status, in a population considered free of other confounders associated with age, supports the importance of the uraemic milieu in the pathogenesis of early and accelerated arterio/atherosclerosis.

In conclusion, we demonstrate for the first time that in children, ESRD is associated with significant arterial wall structural abnormalities – increased IMT, reflected in stiffer large arteries and increased reflective properties of the peripheral arterial sites, not corrected by a dialysis session. These results suggest that even at this age, uraemia has a profound impact on arterial structure and function, leading to cardiac hypertrophy and ultimately increased cardiovascular morbid-mortality.

Conflict of interest statement. None declared.

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Received for publication: 1. 7.05
Accepted in revised form: 9. 9.05

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