ARTICLE

Serum Uric Acid and Blood Pressure in Children at

Cardiovascular Risk
AUTHORS: Francesca Viazzi, MD,a Laura Antolini, PhD,b,c
Marco Giussani, MD,d Paolo Brambilla, MD,d Sara Galbiati,
MD,b Silvana Mastriani, MD,e Andrea Stella, MD,b Roberto
Pontremoli, PhD,a Maria Grazia Valsecchi, PhD,b,c and
Simonetta Genovesi, MDb,e
aUniversity of Genoa and IRCCS Azienda Ospedaliera Universitaria
San Martino-IST Istituto Nazionale per la ricerca sul Cancro,
Genova, Italy; bDepartment of Health Science, and cCenter of
Biostatistics for Clinical Epidemiology, University of MilanoBicocca, Monza, Italy; dFamily Pediatrician, Milano, Italy; and
eNephrology Unit, San Gerardo Hospital, Monza, Italy

KEY WORDS
uric acid, children, hypertension, pre-hypertension, HOMA index,
obesity
ABBREVIATIONS
BPblood pressure
CIcondence interval
CVcardiovascular
DBPdiastolic BP
eGFRestimated glomerular ltration rate
HOMAHomeostasis Model Assessment
HThypertensive
NTnormotensive
NWnormal weight
OBobese
ORodds ratio
OWoverweight
PHprehypertensive
SBPsystolic BP
THtransiently elevated blood pressure
UAuric acid
WtHrwaist-to-height ratio
Drs Viazzi and Genovesi conceptualized and designed the study,
carried out the initial analyses, and drafted the initial
manuscript; Drs Antolini, Galbiati, and Valsecchi contributed to
analysis and interpretation of data, and reviewed the
manuscript; Dr Giussani designed the data collection
instruments, coordinated and supervised data collection, and
critically reviewed the manuscript; Dr Mastriani gave
a substantial contribution to acquisition of data and revised the
article critically; Drs Brambilla, Stella, and Pontremoli
contributed to interpretation of data and critically reviewed the
manuscript; and all authors approved the nal manuscript as
submitted.
(Continued on last page)

WHATS KNOWN ON THIS SUBJECT: Uric acid (UA) is associated

with hypertension in children, after body weight adjustment.
Whether the whole spectrum of variables, such as visceral
adiposity, insulin resistance, puberty, and renal function,
inuence the relationship between UA and blood pressure is
unknown.
WHAT THIS STUDY ADDS: In a cohort of children at relatively high
cardiovascular risk, the association between UA and blood
pressure levels is independent of several well-known factors
implicated in the development of hypertension, such as insulin
resistance, pubertal status, and renal function.

abstract
OBJECTIVES: Hyperuricemia has been shown to be a strong correlate
of hypertension in children. However, the complex interaction between
serum uric acid (UA), systemic blood pressure (BP), and possibly
confounding factors has been elucidated only in part.
METHODS: We evaluated ofce BP as well as clinical and biohumoral
parameters in a cross-sectional cohort of 501 children (280 boys and
221 girls) aged between 6 and 18 years (mean = 10.8 years)
consecutively referred for cardiovascular risk assessment.
RESULTS: Overall, 156 (31.1%) were normotensive, 122 (24.4%) showed
transient hypertension, 87 (17.4%) had prehypertension, and 136
(27.1%) had hypertension. Altogether 33.3% and 40.5% of the study
group were overweight or obese, respectively. There was a trend toward greater weight and waist circumference and higher BMI, Homeostasis Model Assessment index, and UA levels as the BP categories
rose. Moreover, the prevalence of pubertal children, obesity, and
waist-to-height ratio above 0.50 progressively increased from lower
to upper BP categories. After adjusting for puberty, gender, BMI
(z-score), Homeostasis Model Assessment index, and renal function,
UA was found to be directly related to systolic and diastolic BP values
(P = .03). Using normotensive children for comparison, the risk of
showing prehypertension or hypertension increased by at least 50%
for each 1 mg/dL UA increase (P , .01), whereas it doubled for
children in the top gender-specic UA quartile (P , .03).
CONCLUSIONS: Increased UA levels showed an independent predictive
power for the presence of higher BP levels among a cohort of children
at relatively high cardiovascular risk. Pediatrics 2013;132:e93e99

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e93

Serum uric acid (UA) was shown to be

a strong correlate of established hypertension in children.13 Preliminary
studies have also reported an association between hyperuricemia and nonsustained hypertension,4,5 and, recently,
a relationship between changes in serum UA over time and blood pressure
(BP) from childhood to adulthood has
been reported.6

Gerardo Hospital, Unit for Cardiovascular Risk Assessment in Children, because of evidence of elevated BP values
and/or because of positive family history of CV disease. The latter was dened as the presence in 1 or both of the
parents of at least 1 among the following: hypertension, type 2 diabetes,
dyslipidemia, early ischemic heart disease, and cerebrovascular disease.

These ndings have sparked growing

interest in the relationship between UA
and BP in children that may lead to
pathophysiological insights and greater
knowledge on the cause-effect relationship between these factors.7

None of these children were affected by

impaired glucose tolerance, diabetes,
or renal insufciency. Specic diagnostic
tests that are needed to rule out secondary hypertension were carried out
in all children. Children with secondary
forms of hypertension were excluded
from the study.

The complex interaction between serum

UA, BP changes,andotherwell-established
risk factors has been elucidated only in
part, and controversy remains as to
whether UA is an independent causal
factor or merely a marker of the development of hypertension.8 It has been
suggested that several factors, such as
age,9 puberty,10 obesity,11,12 insulin resistance,13 and impaired renal function,14 all of which are related to UA levels,
may play a role in the development of
hypertension. In 2 recent trials, serum
UA reduction by allopurinol or probenecid resulted in BP normalization in
children and adolescents with increased
BP levels, thus supporting a causative
role for UA in hypertension.15,16
The purpose of the current study was to
investigate the relationship between
serum UA and BP, as well as several
possibly confounding factors, such as
puberty, anthropometric parameters,
insulin resistance, and renal function in
a large group of children at relatively
high cardiovascular (CV) risk.

METHODS
Subjects
We studied a cohort of children aged
between 6 and 18 years (mean = 10.8
years), consecutively referred by their
primary care pediatricians to the San

e94

Informed consent was obtained from

the childrens parents, and the local ethical
committee approved the study protocol.
Denition of Terms and Groups
Height, weight (mobile digital scale
[SECA; Vogel & Halke GmbH, Hamburg,
Germany]; precision 100 g), and waist
circumference were measured with
the subjects in their underwear. BMI
was calculated as weight (kg)/height
(m2). BMI z-scores were calculated by
using the Centers for Disease Control
and Prevention charts (available at
http://www.cdc.gov/nchs/). Weight was
approximated to hectograms, whereas
height precision was 5 mm. Weight class
was dened according to the tables of
the International Obesity Task Force,17
distinguishing among normal weight
(NW), overweight (OW), and obese (OB).
Waist circumference was measured to
the nearest 0.1 cm by a nonelastic exible tape with the children in a standing
position. The tape was applied horizontally midway between the lowest rib
margin and the iliac crest. Waist-toheight ratio (WtHr) was calculated by
dividingwaistcircumferenceby height. A
cutoff of 0.5 was chosen to distinguish
between low and high WtHr category, as
suggested by several authors.1821

Pubertal stage was assessed by a medical examination and children were classied into 2 categories: prepubertal and
pubertal according to Tanner staging.22
BP was measured by using an aneroid
sphygmomanometer with the appropriate cuff for the childs upper arm
size. The sphygmomanometer was calibrated before starting the study and
once a month thereafter with a mercury
sphygmomanometer. Systolic BP (SBP)
was dened by the rst Korotkoff sound
(appearance of sounds) and diastolic
BP (DBP) was identied by the fth
Korotkoff sound (disappearance of
sounds). BP values were approximated
to the nearest 2 mm Hg. Measurements
were performed while children were
sitting with their back supported and
the cubital fossa supported at the heart
level, after a rest of at least 5 minutes.
BP was taken 3 times (35-minute
intervals) and SBP and DBP percentiles
were calculated according to the normograms recommended by the National High Blood Pressure Education
Program Working Group on High Blood
Pressure in Children and Adolescents.23
Each child was classied according to
the percentile of the mean of the 3
measurements as being normotensive
(NT) if both SBP and DBP percentiles
were ,90th; prehypertensive (PH) if the
SBP and/or DBP percentile was $90th
but both were ,95th; or hypertensive
(HT) if the SBP and/or DBP percentile
was $95th. Children who were referred
by family pediatricians because of evidence of elevated BP values, but whose
SBP and DBP percentiles were both
,90th percentile when BP was measured at the Cardiovascular Risk in
Children Unit, were classied as having
transiently elevated BP (TH). Family
history of hypertension was dened as
the presence of at least 1 parent with
hypertension.
Biochemical Parameters
Blood samples were taken from all
subjects after a 12-hour fasting period

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ARTICLE

to measure plasma glucose and insulin,

and serum UA, total cholesterol, triglycerides, and high-density lipoprotein
concentrations. Plasma glucose was
measured by a glucose oxidase method
and insulin was evaluated by chemiluminescent immunometric assay. Homeostasis Model Assessment (HOMA)
index was calculated by dividing the
product of plasma insulin (mU/mL) and
plasma glucose (mmol/L) by 22.5.24
Glomerular ltration rate was estimated (eGFR) by means of the updated
Schwartz formula using serum creatinine and height measurements and a k
constant of 0.413.25 Serum creatinine
level was measured by using the Jaffe
method referable to the standardized
reference measurement procedure
(isotope dilution mass spectrometry),
as recommended.
Statistical Methods

factors on the odds ratio (OR) of being

TH, PH, and HT with respect to NT in
3 separate models on the TH versus
NT, PH versus NT, and HT versus NT,
respectively.

10.8 years (SD = 2.4 years), 156 (31.1%)

were NT, 122 (24.4%) were TH, 87
(17.4%) were PH, and 136 (27.1%) were
HT. Among them, 33.3% and 40.5% were
OW or OB, respectively.

No data were missing for any of the

mentioned variables. All analyses and
graphics were conducted with the package R (available at http://cran.r-project.
org/).

Elevated BP (PH or HT) was found in

32.1% among 131 children with NW, in
42.5% among 167 OW and 54.2% among
203 OB. Table 1 reports the clinical
characteristics of study subjects on the
basis of the various BP categories. As
expected, there was a trend toward
higher BMI z-score and higher percentages of OW or OB, increasing WtHr, and
HOMA index as BP categories rose.
Moreover, the prevalence of pubertal,
OB, children whose WtHr was above
0.50 progressively increased from the
lower to the upper BP categories. Despite similarities in age, family history
of hypertension, renal function, fasting
serum glucose, and lipid prole, the
children showed a signicant rise in

RESULTS
Among 648 children consecutively referred to our outpatient clinic for CVrisk
assessment between November 2004
and March 2012, 147 were excluded (12
because they were ,6 years of age,
and 135 because data for 1 or more of
the variables included in the present
analyses were missing). In the resulting nal cohort of 501 subjects (55.9%
boys and 44.1% girls), mean age was

The cohort was categorized into groups

according to hypertension category,
weight class, and UA gender-specic
quartiles. The continuous variables were
described by mean and SD and compared
across groups by Fisher-Snecodor and
Students t tests. The categorical variables were described by the proportion
of subjects falling into each category.
Proportions were compared across
groups by the x 2 test. Box-plots were
used to describe the distribution of UA
according to hypertension category and
weight class based groups. Correlation
between continuous variables was
assessed by the Pearson correlation
coefcient. Multiple linear regression
was used to assess the inuence of age,
pubertal status, gender, BMI z-score (or
WtHr) and eGFR on UA. The impact of UA
was considered on SBP z-score and on
DBP z-score by a multiple linear regression model adjusting for age, pubertal status, gender, BMI z-score (or
WtHr), and HOMA index.

Age, y
10.5
Gender, boys, n (%)
83
Puberty, yes, n (%)
56
Weight, kg
45.8
Height, m
1.4
BMI, kg/m2
21.6
BMI, z-score
1.04
Weight class, n (%)
NW
61
OW
42
OB
53
WC, cm
71.8
WtHr, %
49.8
WtHr .50%, n (%)
78
SBP, mm Hg
108
DBP, mm Hg
64
SBP, z-score
0.40
DBP, z-score
0.20
Family history of HT, n (%) 50
Creatinine, mg/dL
0.52
eGFR, mL/min
116
UA, mg/dL
3.9
Glucose, mg/dL
83
Insulin, mM/L
10.8
HOMA indexb
2.23
Total cholesterol, mg/dL
168
HDL cholesterol, mg/dL
58
Triglycerides, mg/dL
68

Logistic regression models were used to

assess the impact of the aforementioned

Values are mean and SD unless otherwise indicated. HDL, high-density lipoprotein; WC, waist circumference.
a P , .05 was considered statistically signicant.
b HOMA index = plasma insulin (mU/mL) 3 plasma glucose (mmol/L)/22.5.

TABLE 1 Clinical Characteristics of Study Subjects According to BP Category (501 Children)

NT, n = 156;
31.1%

TH, n = 122;
24.4%

2.2
(53.2)
(35.9)
14.8
0.1
4.5
1.2

10.7
68
61
49.9
1.5
22.8
1.37

2.3
(55.7)
(50.0)
16.5
0.1
4.1
0.8

(39.1)
(26.9)
(34.0)
12.0
7.4
(50.0)
7.6
6.4
0.56
0.53
(32.1)
0.10
19.8
0.9
7.3
6.3
1.39
37.4
14.1
35.6

28
54
40
74.7
51.1
66
113
66
0.73
0.38
46
0.53
118
4.2
82
10.9
2.25
157
55
68

(23.0)
(44.3)
(32.8)
11.6
6.2
(54.1)
7.1
5.8
0.46
0.50
(37.7)
0.12
18.2
1.1
6.9
6.8
1.47
25.8
13.5
35.4

PH, n = 87;
17.4%
10.8
2.5
50
(57.5)
36
(41.4)
52.2
16.8
1.5
0.1
24.0
4.9
1.50
0.9
16
29
42
77.0
52.8
60
119
70
1.37
0.70
30
0.53
116
4.4
82
12.5
2.55
163
55
78

(18.4)
(33.3)
(48.3)
11.8
6.5
(69.0)
5.7
6.0
0.26
0.54
(34.5)
0.11
18.8
1.0
7.5
7.0
1.45
27.4
13.9
41.8

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HT, n = 136;
27.1%
11.1
79
69
56.7
1.5
25.3
1.57

2.6
(58.1)
(50.7)
20.4
0.1
6.0
0.9

26
42
68
79.3
53.6
86
130
74
2.14
1.03
50
0.55
114
4.6
84
14.0
2.93
163
54
74

(19.1)
(30.9)
(50.0)
13.8
7.7
(63.2)
10.5
9.5
0.37
0.76
(36.8)
0.13
20.5
1.1
6.7
8.6
1.87
27.8
12.2
39.1

P Valuea
.15
.85
.03
,.001
.19
,.001
,.001
,.001

,.001
,.001
.01
,.001
,.001
,.001
,.001
.92
.23
.63
,.001
.10
,.001
,.001
.03
.09
.10

e95

serum UA levels along with increasing

BP levels.
The distribution of UA levels based on
weight classes is shown in Fig 1. There
was a signicant trend in increasing UA
levels from NW to OB.
Univariate analysis showed that among
the whole study group, UAwas related to
age (r = 0.38, P , .001), pubertal stage
(t = 7.68, P , .001), BMI z-score (r =
0.29, P , .001), WtHr (r = 0.27, P ,
.001), eGFR (r = 0.22, P , .001), highdensity lipoprotein cholesterol (r =
0.26, P , .001), triglycerides (r = 0.23, P
, .001), and HOMA index (r = 0.29, P ,
.001).
The relationship between UA and these
correlates was further investigated by
means of multiple linear regression
analysis. A signicant and independent
association with UA values was shown
for age (b = 0.11, P , .001), gender (b =
0.11, P = .02), pubertal status (b = 0.35,
P = .001), BMI z-score (b = 0.34, P ,
.001), and eGFR (b = 0.006, P , .001).
Similar results were found when WtHr
was used in the model as a measure of
weight excess instead of BMI z-score.
HOMA index ceased to be signicantly
correlated to UA when included in this
model (data not shown).

Univariate analysis showed that among

the whole study group, UA was signicantly related to both systolic BP (SBP)
(z-score, r = 0.21, P , .001) and DBP
(z-score, r = 0.11, P = .02).
A multiple regression model showed
that the only variables signicantly
related to SBP (z-score) were BMI
(z-score) (P , .001), HOMA index (P = .02),
and serum UA (P = .03), whereas UA and
pubertal status were related to DBP
(z-score) (P = .03 and P = .02, respectively).
When WtHr was included in the multiple
linear regression model as a measure
of weight excess instead of BMI (z-score),
the only variables signicantly related
to SBP(z-score) were WtHr (P , .001)
and UA (P = .03), whereas WtHr was related to DBP (z-score) (P = .01). Including
eGFR in the statistical model yielded
superimposable results.
Mean UA level was 4.38 (SD = 1.14) in
boys and 4.15 (SD = 0.95) in girls (t test
statistic = 2.5, P = .01). Table 2 shows
the clinical characteristics of study
subjects on the basis of gender-specic
serum UA quartiles. It can be noticed
that, as UA quartiles increased, children
were more likely to be older, pubertal,
and OB. Moreover, there was a trend
toward higher BMI z-score, WtHr, BP

parameters, serum creatinine, and more

unfavorable HOMA index and lipid prole.
After adjusting for pubertal status,
gender, BMI z-score, and HOMA index,
the OR for the presence of HT among
the whole population was 1.40 (95%
condence interval [CI] 1.121.75, P ,
.01) for each 1 mg/dL increase in UA
and 1.67 (95% CI 1.002.82, P = .05) for
subjects in the IV UA quartile (.4.7 mg/
dL for girls; .5.0 mg/dL for boys). The
impact of UA was not found to be signicant when we compared children
with TH versus those with NT. Using NT
as comparison, the risk of being PH and
of being HT increased by at least 50%
(OR = 1.60 and P , .01, OR = 1.54 and P
, .01, respectively, Table 3) for each 1
mg/dL increase in UA, whereas it doubled (OR = 2.25, 95% CI 1.154.38, P =
.01 and OR = 2.04, 95% CI 1.123.73, P =
.02, respectively) for children in the IV
UA quartile. The relationship between
the distribution of BP categories and
UA quartiles is emphasized in Fig 2.
When WtHr was used instead of BMI
(z-score) as a measure of weight excess, the OR of being PH and of being HT
was 2.17, 95% CI = 1.104.28 (P = .03)
and 1.95, 95% CI = 1.063.60 (P = .03),
respectively. Including eGFR in the statistical model yielded almost superimposable results.

DISCUSSION
In this large group of children at relatively
highCVrisk,serum UAwasindependently
associated with BP levels across different
BP categories, from normotension to
transient and then prehypertension, up
to established hypertension.

FIGURE 1
Boxplot distribution of UA (mg/dL) in groups dened according to weight class in 501 subjects. Boxplot
explanation: upper horizontal line of box = 75th percentile; lower horizontal line of box = 25th percentile;
horizontal bar within box = median; square within box = mean; vertical lines out of the box = minimum
and maximum. The P value displayed is referred to the overall comparison.

e96

Although the association between mild

hyperuricemia and hypertension has
previously been described in several
studiesbothinadultsandinchildren,1,3,4,6,26
a relationship between UA and prehypertension has mainly been reported in
adults,27 with only a few, relatively small
studies carried out in children with white
coat and borderline hypertension.4,5,16

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ARTICLE

TABLE 2 Clinical Characteristics of Study Subjects on the Basis of UA Gender-Specic Quartiles

(501 Children)
I, n = 145;
28.9%
Age, y
9.7
Gender, boys, n (%)
78
Puberty, yes, n (%)
34
Weight, kg
39.3
Height, m
1.4
BMI, kg/m2
20.3
BMI, z-score
0.90
Weight class, n (%)
NW
64
OW
43
OB
38
WC, cm
67.3
WtHr, %
48.9
WtHr .50%, n (%)
59
SBP, mm Hg
112
DBP, mm Hg
66
SBP, z-score
0.93
DBP, z-score
0.49
Family history of HTN, n (%) 50
Creatinine, mg/dL
0.48
eGFR, mL/min
121
UA, mg/dL
3.1
Glucose, mg/dL
83
Insulin, mM/L
9.1
HOMA indexb
1.88
Total cholesterol, mg/dL
168
HDL cholesterol, mg/dL
60
Triglycerides, mg/dL
60

2.3
(53.8)
(23.4)
13.3
0.1
4.2
1.1

II, n = 118;
23.6%

III, n = 114;
22.7%

IV, n = 124;
24.8%

P Valuea

10.6
2.0
71
(60.2)
52
(44.1)
48.6
12.8
1.5
0.1
22.8
4.3
1.35
1.0

11.1
2.2
61
(53.5)
52
(45.6)
53.7
14.6
1.5
0.1
24.1
4.2
1.55
0.7

11.9
2.5
70
(56.5)
84
(67.7)
63.9
19.2
1.5
0.1
26.5
5.5
1.67
0.8

,.001
.70
,.001
,.001
,.001
,.001
,.001

(44.1)
33
(29.7)
39
(26.2)
46
10.9
74.8
6.8
51.7
(40.7)
73
10.8 116
7.6
67
0.87
1.06
0.69
0.50
(34.5)
39
0.10
0.53
20.4 115
0.4
4.0
6.1
82
5.5
11.3
1.14
2.33
36.4 161
13.2
57
26.5
64

(28.0)
17
(33.1)
50
(39.0)
47
10.5
77.2
6.9
52.2
(61.9)
69
10.4 118
7.5
69
0.79
1.20
0.64
0.56
(33.1)
43
0.09
0.54
18.0 116
0.2
4.6
7.6
84
6.6
13.0
1.44
2.73
27.1 163
14.1
53
36.5
77

(14.9)
17
(43.9)
35
(41.2)
72
10.1
83.9
6.3
54.6
(60.5)
89
8.7 123
6.8
71
0.70
1.32
0.60
0.69
(37.7)
44
0.11
0.59
19.1 111
0.2
5.7
7.4
83
7.9
15.0
1.76
3.10
27.1 160
11.6
50
35.9
85

(13.7)
(28.2)
(58.1)
12.7
7.7
(71.8)
14.0
10.0
0.88
0.76
(35.5)
0.13
18.6
0.7
7.6
8.0
1.73
30.0
12.6
46.1

,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
,.001
.08
.68
,.001
,.001
,.001
.33
,.001
,.001
.14
,.001
,.001

Values are mean and SD unless otherwise indicated.

UA gender-specic quartiles (#3.6 mg/dL, .3.6 mg/dL and #4.1, .4.1 mg/dL and #4.7 mg/dL, .4.7 mg/dL for girls, #3.6
mg/dL, .3.6 mg/dL and #4.3, .4.3 mg/dL and #5.0 mg/dL, .5.0 mg/dL for boys).
HDL, high-density lipoprotein; WC, waist circumference.
a P , .05 was considered statistically signicant.
b HOMA index = plasma insulin (mU/mL) 3 plasma glucose (mmol/L)/22.5.

TABLE 3 Effect of Pubertal Status, Gender, BMI, UA (as continuous measure), and HOMA index on
the risk of TH versus NT, PH versus NT, and HT versus NT
Variable

Puberty, Yes
Gender, boys
BMI, z-score
UA, mg/dL
HOMA indexb
a
b

TH versus NT, n = 278

PH versus NT, n = 243

a

HT versus NT, n = 292

a

OR

(95% CI)

OR

(95% CI)

OR

(95% CI)

Pa

1.97
1.11
1.53
1.17
0.82

(1.133.43)
(0.671.84)
(1.152.05)
(0.891.54)
(0.671.01)

.01
.69
,.01
.26
.06

1.09
1.15
1.43
1.60
0.96

(0.582.06)
(0.652.03)
(1.031.99)
(1.152.22)
(0.771.19)

.78
.64
.03
,.01
.70

1.47
1.29
1.44
1.54
1.06

(0.842.57)
(0.782.15)
(1.071.93)
(1.172.03)
(0.891.27)

.17
.32
.02
,.01
.50

P , .05 was considered statistically signicant.

HOMA index = plasma insulin (mU/mL) 3 plasma glucose (mmol/L)/22.5.

Although the clinical setting of our

study is cross sectional, it provides us
with an opportunity to investigate the
complex association between UA and
other variables (such as insulin resistance, obesity, puberty, and BP) in a
group of subjects in whom pathophysiological mechanisms and changes leading to the development of hypertension

are still at play. This is even more interesting in light of the recently reported nding that UA levels may be
a predictor of the future development of
hypertension in adults.6
The relationship between UA and BP that
we observed becomes clinically relevant
forhigherUAvalues,since children inthe
top UA quartile (ie, $5.0 mg/dL for boys

and $4.7 mg/dL for girls) showed

a twofold higher risk of being PH and HT
(Table 3, Fig 2). On the other hand, although a trend toward higher UA values
was present across all BP categories,
UA levels could not help identify children
with nonsustained hypertension.
The prevalence of OW and OB was relatively high in our study sample, as
expected on the basis of recruitment
criteria. Nonetheless, the association
between UA and BP persisted after
adjusting for BMI z-score and for WtHr,
a nding that clearly supports a pathogenetic role for serum UA in the early
phases of hypertension development.
With the aim of better elucidating the
role of UA in the development of essential hypertension, in the current
study we excluded patients with renal
insufciency and/or diabetes. However,
we analyzed the relationship between
UA and those parameters, such as eGFR
and HOMA index, which, even in the
range of normality, could be implicated
in the development of hypertension in
children.13 Even slightly elevated serum
UA levels have shown to be strong, independent predictors of the development
of type 2 diabetes in adult cohorts of
unselected general populations,28 as well
as of HT patients.29,30 Moreover, recent
data strongly support the hypothesis
that insulin resistance in children might
play a role in hypertension development
regardless of obesity and fat distribution.13 Other variables, such as puberty
and renal function,10,14 have also been
shown to bear an inuence on the link
between UA and BP in children.
To date, only a few studies have investigated the relationship of sexual
maturity1,2 and estimated renal function3,4,31 with UA and BP, and none have
taken insulin resistance into consideration. In the current study, HOMA index was found to be linearly related to
UA levels and increased along with UA
quartiles (Table 2), and BP categories
(Table 1). However, in multiple linear

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e97

concurrently collected and analyzed in

a group of referred children.

FIGURE 2
Distribution of BP categories according to UA quartiles. Stacked barplot of BP category in groups dened
according to UA quartiles (I = #3.6 mg/dL, II = .3.6 mg/dL and #4.1, III = .4.1 mg/dL and #4.7 mg/dL,
IV = .4.7 mg/dL for girls; I = #3.6 mg/dL, II = .3.6 mg/dL and #4.3, III = .4.3 mg/dL and # 5.0 mg/dL,
IV = .5.0 mg/dL for boys) in 501 subjects. Using the NTas comparison, the adjusted risk of being PH (OR
= 2.25, 95% CI 1.154.38, P = .01) and of being HT (OR = 2.04, 95% CI 1.123.73, P = .02) doubled for
children in IV UA quartile. The P value displayed refers to the overall comparison.

and logistic regression analysis, the

relationship between this marker of
insulin resistance and BP levels and
categories almost completely loses its
strength, whereas serum UA maintains
its independent link to BP. Although these
results cannot help to dene whether
serum UA is inuenced by BP elevation
and insulin resistance or vice versa, they
certainly point toward a complex relationship among these factors.
As for renal function, we found that eGFR
was similar in all BP categories, and the
addition of this variable to linear and
logistic regression analyses left the relationshipbetween UA and BP unchanged.
Even accounting for body mass and puberty, the independent role of UA variations on BP values did not decrease.
Our data conrm and expand those
previously reported by Loefer et al3 in
a large study conducted on a representative sample of adolescents in the
United States. In fact, we were fortunate
enough to obtain a larger study sample
from our records and therefore were
able to demonstrate an association
e98

between SBP as well as DBP and serum

UA levels even in a fully adjusted multivariate linear regression analysis.
Our study has both strengths and
weaknesses that deserve to be commented on. Among the former, the fact
that, unlike other previous large studies,3 the denition of elevated BP and
the allocation of children into different
BP categories was not based on a single physical examination. BP was measured in at least 2 different occasions:
previously by the family pediatrician
and then again in our clinic, and in both
cases the mean of 3 measurements was
used for analysis. To fully account for
age, gender, and height, according to
the tables published in the fourth report
on the diagnosis, evaluation, and treatment in children and adolescents,23 we
used BP z-scores rather than raw BP
values, which makes our observations
more reliable as compared with those
of a variety of previous reports.1,2,4,6,16
Furthermore, to the best of our knowledge, for the rst time several clinical
and biohumoral variables have been

Last, there are some limitations to our

study. First, given the cross-sectional
nature of its design, it would be inappropriate to derive denitive conclusions regarding the cause-effect
relationship between UA and BP levels,
even though the association we report
persisted even when several well-known
confounding factors were taken into
account. Second, the lack of a control
group may limit the implications of our
observations. Nevertheless, within the
context of childrenwith relatively high CV
risk, our data show a clear trend in the
BP-UA association along with progressively
worse BP categories, from transient
to established hypertension. Higher UA
levels show a signicant association with
the occurrence of higher BP levels even
among a cohort of children at relatively
high CV risk. Third, ambulatory blood
pressure monitoring was not performed
in our study and therefore we could not
classify any subject into the white-coat
hypertension or masked hypertension
category. However, there is a general
consensus in current pediatric literature
that diagnosis of hypertension in children
and adolescents be based on ofce BP
measures and not on ambulatory blood
pressure monitoring.

CONCLUSIONS
In children at relatively high CV risk, UA
shows a strong relationship with BP
values across different BP categories,
from normal BP to transient, up to preand nally to established hypertension.
The association between UA and BP
levels is independent of several wellknown factors potentially implicated in
the development of hypertension, such as
insulin resistance, pubertal stage, and
renal function. These data support the
need for further large, prospective, and
interventional studies to clarify the pathophysiological mechanisms underlying the
relationship between serum UA and BP.

VIAZZI et al

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ARTICLE

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(Continued from rst page)

www.pediatrics.org/cgi/doi/10.1542/peds.2013-0047
doi:10.1542/peds.2013-0047
Accepted for publication Apr 5, 2013
Address correspondence to Simonetta Genovesi, MD, Dipartimento di Scienze della Salute Universit degli Studi di Milano Bicocca Via Cadore 48, 20900, Monza (MB),
Italy. E-mail: simonetta.genovesi@unimib.it
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.
FUNDING: No external funding.

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e99

Serum Uric Acid and Blood Pressure in Children at Cardiovascular Risk

Francesca Viazzi, Laura Antolini, Marco Giussani, Paolo Brambilla, Sara Galbiati,
Silvana Mastriani, Andrea Stella, Roberto Pontremoli, Maria Grazia Valsecchi and
Simonetta Genovesi
Pediatrics 2013;132;e93; originally published online June 17, 2013;
DOI: 10.1542/peds.2013-0047
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2013 by the American Academy of Pediatrics. All
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Serum Uric Acid and Blood Pressure in Children at Cardiovascular Risk

Francesca Viazzi, Laura Antolini, Marco Giussani, Paolo Brambilla, Sara Galbiati,
Silvana Mastriani, Andrea Stella, Roberto Pontremoli, Maria Grazia Valsecchi and
Simonetta Genovesi
Pediatrics 2013;132;e93; originally published online June 17, 2013;
DOI: 10.1542/peds.2013-0047

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/132/1/e93.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2013 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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