Pulse Wave Velocity in End-Stage Renal Disease: Influence of [623437]

Pulse Wave Velocity in End-Stage Renal Disease: Influence of
Age and Body Dimensions
E´VA KIS, ORSOLYA CSEPREKA ´L, ZSO ´FIA HORVA ´TH, GA ´BOR KATONA, BERTALAN C. FEKETE, ERZSE ´BET HRAPKA,
ANDRA ´S SZABO ´, ATTILA J. SZABO ´, ANDREA FEKETE, AND GYO ¨RGY S. REUSZ
First Department of Pediatrics [E.K., O.C., Z.H., G.K., E.H., A.J.S., A.F., G.S.R.], First Department of Internal Medicine [B.C.F.],
Semmelweis University, Budapest, Hungary, 1083; Szenta ´gothai Ja ´nos Knowledge Center [A.S.], Budapest, Hungary, 1056
ABSTRACT: Arterial stiffness increases with age. This process is
accelerated by end-stage renal disease (ESRD). Pulse wave velocity(PWV) increases with arterial stiffness. In this study, PWV of 133healthy individuals (6–23 y of age) and 11 patients on dialysis wasmeasured to establish the normal values of PWV and to comparethem with those in ESRD. Age-matched (A-C) and height- andweight-matched (H/W-C) control groups were used. Thereafter,PWV was indexed to height and the data were reevaluated. The roleof the risk factors including serum calcium, phosphate, parathyroidhormone (PTH), and the time on dialysis was analyzed using a scoresystem. PWV correlated with age, weight, height, blood pressure, andheart rate. ESRD patients were smaller than A-C and older thanH/W-C. PWV of patients with ESRD did not differ from A-C;however, it was elevated in comparison to H/W-C. In both healthyand ESRD patients, the PWV/height ratio was independent of age.PWV/height was increased in ESRD. There was a correlation be-tween PWV/height and the risk factor score. Controls matched forheight and weight or PWV/height should be used in cases of growthfailure. A number of risk factors responsible for increased arterialstiffness are present in ESRD. (Pediatr Res 63: 95–98, 2008)
Cardiovascular disease is the leading cause of death among
patients with end stage renal disease (ESRD) (1). The
causes are multifactorial, and include alterations of calcium-phosphate homeostasis and lipid metabolism, chronic inflam-mation, systemic hypertension, and chronic anemia, leadingtogether to accelerated arteriosclerosis, atherosclerosis, and leftventricular hypertrophy (2–5). One consequence of changes inthe arterial wall composition in uremia is an increase in arterialwall stiffness. Valuable information on arterial properties such asstiffness can be obtained from noninvasive measurement of thepulse wave velocity (PWV) (6,7). Accelerated arteriosclerosiswas recently described in young adults with ESRD (8,9); data onPWV in uremic children is sparse (10).
As PWV is influenced by age, our aim was to a) establish
normal values for PWV in a healthy pediatric population andb) to compare it with children on dialysis. Blood pressure,calcium (Ca), phosphate (P), and parathyroid hormone (PTH)levels were also analyzed as known cardiovascular risk
factors.
PATIENTS AND METHODS
Patients with ESRD. Eleven patients receiving maintenance dialysis par-
ticipated in the study. The diagnoses leading to ESRD were (number ofpatients in parentheses): focal-segmental glomerulosclerosis (4), autosomalrecessive polycystic kidney disease (2), renal hypoplasia and vesicoureteralreflux (2), chronic glomerulonephritis (1), Alport syndrome (1), and juvenilenephronophthisis (1). Four children were treated with peritoneal dialysis andseven with hemodialysis. Two patients had transplants previously, but re-turned to dialysis due to chronic rejection.
Eight children were treated with an angiotensin-converting enzyme (ACE)
inhibitor, enalapril, and six with enalapril and a calcium channel blocker,amlodipine. They were normotensives on medication. Three patients hadnormal blood pressure without antihypertensive treatment.
Control population for PWV measurements. PWV was measured in 133
healthy children and young adults aged 6–23 y (13.01 /H110063.76 y). Using the
database of the 133 healthy controls, two subgroups of children consisting of11, respectively, were formed. One was adjusted to the patient’s age andgender (children with date of birth closest to the patient’s data were selected).The other was adjusted to the height, weight, and gender (children with heightand weight closest to the patient’s values were selected).
Furthermore, in search of a more universal technique of comparison, the
effect of indexing PWV to height (m), weight (kg), and BSA (body surfacearea, m
2) was assessed.
Control population for laboratory data. Leftover serum samples of 40
children evaluated for minor surgical interventions were used anonymously ascontrol for Ca, P, creatinine, and PTH.
Basic characteristics of the patients and the control groups are shown in
Table 1.
PWV measurements. PWV is the speed of travel of the pulse along an
arterial segment. Aortic PWV is defined as the distance of the sampling sitesdivided by the time difference between the rise delay of the distal andproximal pulse according to the R wave belonging to the ECG qRs complex.
PWV was measured by sequential recordings of the arterial pressure wave
at the carotid and femoral arteries and by measurement of the distance fromthe carotid sampling site to the suprasternal notch and from the suprasternalnotch to the femoral sampling site. Arterial pressure wave was recorded byapplanation tonometry (11) using the validated PulsePen device (DiaTecnes.r.l., Milan, Italy) interfaced with a computer. The probe was connected to ahand-held ECG-unit. Both pressure and electrocardiographic signals weretransmitted to a computer to be displayed and processed. The pulse wave wascalibrated by measuring BP immediately before the recordings. The speciallydesigned software provides absolute arterial pressure values, an assessment ofarterial pulse wave contours, an estimation of reflection waves, and measure-ments of PWV (12). We discarded recordings when the systolic or diastolicvariability of consecutive waveforms was /H1102210% or when the amplitude of the
pulse wave signal was /H1102180 mV.
Laboratory measurements. Ca, P, and creatinine were measured by rou-
tine laboratory methods on a Hitachi autoanalyzer. Intact (1-84) PTH (iPTH)was determined by immunochemiluminometric two-site assay (CIBA-
Received March 14; accepted August 10, 2007.
Correspondence: Gyo ¨rgy S. Reusz, M.D., Ph.D., First Department of Pediatrics,
Semmelweis University, Budapest, Bo ´kay u. 53, H-1083; e-mail: reusz@gyer1.sote.hu
The study was supported by the National Scientific Research Grants OTKA-T046155-
F048842-F042563, ETT 435/2006, the Semmelweis Foundation, and by the Szenta ´gothai
Ja´nos Knowledge Center (A.S.). A.F. is a recipient of the “Magyary” and A.J.S. is a
recipient of the “Bolyai” scholarship.
E´.K. and O.C. contributed equally to the manuscript.Abbreviations: ESRD, end-stage renal disease; PWV, pulse wave velocity;
UB, uremic burden0031-3998/08/6301-0095
PEDIATRIC RESEARCH Vol. 63, No. 1, 2008
Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A.
95

CORNING, Fernwald, Germany). The reference range of the assay is 9–60
pg/mL (13).
Evaluation of the effect of ESRD. To characterize the impact of the
persistent uremic environment—the “uremic burden” (UB)—we introduced ascoring system. High-normal serum calcium (Ca /H110222.2 mM), elevated serum
phosphate (P /H110221.8 mM), PTH ( /H11022180 pg/mL), and the time on dialysis
beyond 12 mo were scored as 1. Values below these limits were scored 0.
Statistical analysis. Data management was performed using the
STATISTICA7.1. software (StatSoft, Inc., Tulsa, OK). All data are pre-sented as mean (SD). Data were compared using ttest. Linear and multiple
linear regression analysis were performed for the assessment of possibleassociations between PWV and other variables. A pvalue/H110210.05 was
considered statistically significant.
The study conformed to the Helsinki declaration and was approved by the
Ethical Committee of the Semmelweis University. Parental informed consentwas obtained from all healthy children in the control group and from thepatients with ESRD participating in the study.
RESULTS
Healthy controls. The mean PWV of the 133 healthy children
(male: 60, female: 73) was 5.02 (0.89) m/s. There was a signif-icant linear correlation between PWV and age, height, weight,and systolic and diastolic blood pressure and a significant nega-tive correlation to the heart rate. Values of the individual corre-lations are shown in Table 2.
By multivariate analysis, only age remained the significant
determinant of PWV (Beta: 0.74, SE: 0.16, p/H110210.0001).
Patients with ESRD. As shown in Table 1, patients with
ESRD were significantly shorter and lighter than the age-matched controls. Further, they were significantly older thantheir height- and weight-matched healthy pairs.
The hemodynamic and laboratory parameters of the patient
and the control groups are shown in Table 3.
The PWV of the patients with ESRD did not differ signif-
icantly from the age-matched group. On the contrary, patientswith ESRD had significantly increased PWV compared withthe height/weight-matched control group.There was no difference between the blood pressure (ex-
pressed as Z-score) and heart rate parameters of the patientswith ESRD and either of the control groups.
Patients with ESRD had significantly elevated creatinine,
lower calcium, and increased phosphate and iPTH comparedwith the controls.
There was no significant correlation between the PWV and
any of the serum parameters measured.
Indexing PWV to weight or BSA did not suppress the age
dependence of the indexed variables ( r/H11005–0.55, p/H110210.001,
andr/H11005–0.41, p/H110210.001, respectively). However, age depen-
dence disappeared completely following indexing PWV to height(r/H110050.03, p/H11005NS).
Based on the novel parameter the PWV/height, the ESRD
group differed significantly from both age-matched control(A-C) and height/weight matched control (H/W-C) groups aswell as from the whole control group (ESRD: 4.02 /H110060.75 1/s
versus control: 3.27 /H110060.49 1/s; p/H110210.0001). There were no
differences between the PWV/height values of the A-C andH/W-C groups (Table 3).
The individual values of Ca, P, PTH, and time on dialysis as
well as PWV/height and the UB score are shown in Table 4.
The PWV/height values of the group with one or two risk
factors were significantly lower than those of patients withthree or four risk factors (3.46 /H110060.37 1/s versus 4.62/H110060.5
1/s;p/H110210.01, respectively).
Furthermore, a significant correlation could be shown be-
tween PWV/height and the UB score expressed as the sum ofthe individual risk factors ( r/H110050.61, p/H110210.05) (Fig. 1).
DISCUSSION
There is a continuous increase of PWV with age, due to
geometric and structural changes of the vessel walls duringgrowth and physiologic aging. This study confirmed the closecorrelation between PWV and age in children. Due to theclose relation between age, height, and weight during growth,only age remained the independent variable correlating withPWV in healthy children (14).
Uremia increases the risk of cardiovascular mortality due to
accelerated arteriosclerosis (15). The increase of PWV wasestablished as a useful measure to characterize arterial stiff-ness in adult hypertension and ESRD (16–18).
As described recently, premature vascular calcification is
already present in young patients with ESRD (19,20). Itseemed obvious that arterial dysfunction in children withTable 1. Clinical data of the patients with ESRD and the control groups
Gender m/fRRT Age Weight Height
HD/CAPD mean (SD), y mean (SD), kg mean (SD), m
ESRD 8/3 7/4 14.3 (4.1) 36.9 (15.5) 1.415 (0.206)
Control (age adjusted) 8/3 — 14.5 (4.3) 46.6 (15.6)* 1.562 (0.197)§Control (height/weight adjusted) 8/3 — 10.7 (2.6)** 36.7 (19.7) 1.409 (0.156)
RRT, renal replacement therapy; HD, hemodialysis; CAPD, chronic ambulatory peritoneal dialysis.
*p/H110210.05 vsESRD and height/weight-adjusted control.
**p/H110210.01 vsESRD and age-adjusted control.
§p/H110210.01 vsESRD and height/weight-adjusted control.
Table 2. Correlations between PWV and age, weight, height,
systolic, diastolic blood pressure, and heart rate in 133 healthy
children and young adults
Rp Value
Age 0.64 /H110210.00001
Weight 0.47 /H110210.00001
Height 0.53 /H110210.00001
RRsy 0.39 /H110210.0001
RRdia 0.21 /H110210.02
HR –0.35 /H110210.0001
RRsy, systolic blood pressure; RRdia, diastolic blood pressure; HR,
heart rate.96 KIS ET AL.

ESRD could be reflected in the changes of PWV. However,
our first analysis, i.e.when we used data of age-matched
healthy children, presented only a weak tendency of increasedPWV in uremia. At the same time, the analysis revealed thatthe patient group’s body dimensions (weight and height) weresignificantly below those of the controls, due to the deleteriouseffect of uremia on growth (21).
The use of controls matched by height or weight is a
well-established necessity in pediatrics. Bone mineral densityand blood pressure are examples where specific patient pop-ulations require a thoughtful selection of their control pairsrather than the automated use of age matched controls (22–25). Thus, using a height- and weight-matched control group,
we did indeed find a significantly increased PWV in ESRD,whereas the other hemodynamic parameters did not differsignificantly.
In the search of a universal measure of PWV in children, we
found that indexing PWV to height provides a parameterindependent of age. The PWV/height of the patients withESRD differed significantly not only from the control group,but also from both special subgroups ( i.e.from the age
matched on one hand and the height and weight matched onthe other).
Disturbed calcium and phosphate metabolism is among the
main factors leading to vascular calcification in uremic adults(26–28) and in children (29).
Compared with healthy controls, our patients had signifi-
cantly elevated creatinine, P, and PTH levels. To assess therelation between the UB and PWV/height, we established anarbitrary scoring system (the UB score) based on serum Ca, P,and PTH levels and the time spent on dialysis.
Although the choice of the score is arbitrary, the individual
elements used are well-established factors of cardiovascular
risk in adults as well as in children (19,20,30,31).
Using the scoring system, patients with one or two risk
factors had significantly lower PWV/height values than thoserating higher. There was also a significant correlation betweenPWV/height and scores of the individual patients.
The lack of direct correlation between those parameters and
PWV or PWV/height might be explained by the small samplesize and the cross-sectional nature of the present study: thesnapshot of the individual parameters does not necessarilyreflect the atherogenic burden inflicted during the long-lastingdevelopment of the end-stage renal disease.
As already mentioned, the small sample size and the cross-
sectional design of the study is a serious obstacle to a more-detailed analysis. As individual pediatric dialysis units have alimited number of patients compared with adult facilities, amulticenter prospective approach is needed to establish thebiologic significance of the results presented.
A confounding factor influencing arterial stiffness and PWV
might be the use of antihypertensive drugs. However, ACEinhibitors and vasodilators such as calcium channel blockersare known to decrease arterial stiffness and PWV viadelayed
return of the reflected wave from the periphery to the heartwhile decreasing its amplitude and systolic duration (32–34).Thus, our patients had increased PWV despite the possiblepositive effect of antihypertensive treatment. A withdrawal ofthe antihypertensive drugs was not considered for ethicalreasons.Table 3. Comparison of PWV, PWV/height, blood pressure, and heart rate values of patients with ESRD and the control groups adjusted
for age and for height and weight, and of the laboratory data
PWV PWV/height RRsy RRdia HR Creatinine Ca P PTH
m/s 1/s Z-score Z-score 1/min /H9262mol/L mmol/L mmol/L pg/mL
ESRD 5.72 (0.94) 4.10 (0.75) 0.74 (1.89) 0.67 (1.27) 79 (21) 745 (303) 2.21 (0.23) 2.35 (0.79) 618 (549)
Control (age adjusted) 5.01 (1.07) 3.17 (0.6)* 0.24 (0.75) 0.37 (0.36) 74 (11) 74 (13)§ 2.55 (0.13)* 1.35 (2.75)* 34 (5)§Control (height/weight adjusted) 4.56 (0.50)* 3.23 (0.49)* 0.46 (0.54) 0.44 (0.45) 84 (9)**
RRsy, systolic blood pressure; RRdia, diastolic blood pressure; HR, heart rate.
*p/H110210.01 vsESRD; ** p/H110210.02 vsage-adjusted controls; § p/H110210.001 vsESRD.
Table 4. Values of serum calcium, phosphate, PTH, time on
dialysis, PWV/height, and the score of the UB
Patient Se Ca Se P PTHTime
on dialysisPWV/
height
UB score (mmol/L) (mmol/L) (pg/mL) (mo) (1/s)
1 2.2 2.1 227 0 3.35 2
2 2.4 2.0 121 3 3.58 23 2.4 2.0 1588 3.5 5.11 34 2.4 2.5 315 5 4.78 35 2.5 1.8 170 5 3.86 16 2 3.1 692 11 3.65 27 2.2 0.7 108 14 2.86 18 2.2 3.6 197 42 4.49 39 2.3 3.0 1459 43 3.68 410 1.9 2.9 1010 73 4.78 311 1.8 2.2 912 78 4.94 3Mean 2.21 2.35 618 25.2 4.10SD 0.23 0.79 549 29.0 0.75
Individual elements of the UB score: Ca /H110222.2, P/H110221.8, PTH /H11022180, Time
on dialysis /H1102212 mo.
Figure 1. Correlation between the UB score and PWV/height, Y /H110050.4869 *
X/H110012.9031; R/H110050.61, p/H110210.05.97 PULSE WAVE VELOCITY AND UREMIA

In conclusion, this study demonstrates increased PWV as a
sign of increased arterial stiffness in children with ESRD. Italso points out the necessity of the use of appropriate controlsin special pediatric populations. Thus, controls matched forheight and weight should be used in cases of growth failure.Indexing PWV to height (PWV/height) provides a universalparameter to circumvent the problem of growth retardation.
Children with more risk factors involving calcium and
phosphate homeostasis have higher PWV/height, suggestingthe role of disturbed calcium metabolism.
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