Hyperuricemia is Associated with Hypertension, Obesity, and Albuminuria

in Children with Chronic Kidney Disease

Damien G. Noone, MB, BCh, BAO, MRCPI1, and Stephen D. Marks, MD, MSc, MRCP, FRCPCH1,2

Objective To assess the prevalence and associations of hyperuricemia in a cohort of pediatric patients with
chronic kidney disease (CKD).
Study design This was an observational cross-sectional study of clinical and laboratory data in pediatric patients
being followed in a nephrology clinic. All patients with CKD were included. ORs and risk estimates of having stage
III-V CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) with hyperuricemia were
calculated. The relationships among eGFR, body mass index (BMI), and hyperuricemia were estimated using both
correlation and regression models.
Results A total of 116 children (61% male), aged 0.4-17 years, were included in the analysis. The prevalence
of hyperuricemia in those with an eGFR <60 mL/min/1.73 m2 was 70%. Children with hyperuricemia were more
likely to have an eGFR <60 mL/min/1.73 m2 than those with a normal urate level (OR, 4.6) and were more likely
to be hypertensive (OR, 2.1). Hyperuricemia was significantly associated with increased BMI, albuminuria, renal
dysfunction with reduced eGFR, and hypertension. Significant linear relationships between eGFR and urate
(P = .0001) and between BMI and urate (P = .0001) were detected.
Conclusions Hyperuricemia is common in pediatric patients with CKD and is associated with renal dysfunction,
hypertension, obesity, and albuminuria. Future prospective studies should be undertaken to further assess the role
of hyperuricemia in pediatric patients with CKD. (J Pediatr 2013;162:128-32).

U
rate is the final end product of purine metabolism and is reabsorbed across the proximal tubular cells via URAT 1, an
organic ion transporter.1 Hyperuricemia is relatively rare in children compared with adults, in whom it occurs most
commonly in association with gout. Inherited disorders of purine metabolism are much more likely to be the cause
of hyperuricemia in children, who have a higher fractional excretion of filtered urate (FEU) than adults (15%-30% vs
10%).2 A linear increase in plasma urate concentration is seen up to age 15 years with a decline in FEU. In fact, in children
with Lesch-Nyhan syndrome, who have a complete enzyme deficit of hypoxanthine-guanine phosphoribosyltransferase, lead-
ing to uric acid overproduction, serum urate concentration might not be elevated until puberty because of this increased FEU.3
The FEU rapidly increases to 85% once the glomerular filtration rate (GFR) drops below 30 mL/min/1.73 m2 in chronic kidney
disease (CKD).4 Other disorders of purine production leading to hyperuricemia in children include phosphoribosylpyrophos-
phate synthetase superactivity, adenine phosphoribosyltransferase deficiency, and hereditary xanthinuria.3 Hyperuricemia is
also seen in children with familial juvenile hyperuricemic nephropathy in association with mutations in the uromodulin gene.5
Data are emerging on the role of hyperuricemia in renal dysfunction, the metabolic syndrome, and hypertension in adults.
Whether hyperuricemia has a consequential or causal relationship with renal impairment remains to be fully elucidated. In
1997, the Modification of Diet in Renal Disease study reported uric acid to be a marker of, but not predictive of, declining renal
function.6 Subsequent large epidemiologic studies involving more than 50 000 subjects from Asia suggested that uric acid is an
independent risk factor for renal failure.7-9 Bellomo et al10 identified hyperuricemia as an independent risk factor for declining
GFR in healthy, normotensive individuals without diabetes or proteinuria, and reported that this decline was evident even in
those with serum uric acid levels within the normal range. The metabolic syndrome of obesity, hypertriglyceridemia, hyper-
tension, and insulin resistance is known to be associated with an increased risk of CKD, and it is now thought that hyperuri-
cemia actually may play a pivotal role in this increased risk, in association with a high-fructose diet.11-13 Hyperuricemia also has
been shown to be significantly associated with the metabolic syndrome and predictive of albuminuria, especially in patients
with diabetes.14

BMI Body mass index

BP Blood pressure
From the 1Department of Pediatric Nephrology, Great
CKD Chronic kidney disease Ormond Street Hospital for Children National Health
eGFR Estimated glomerular filtration rate Service Trust; and 2Nephro-Urology Unit, Institute of
FEU Fractional excretion of filtered urate Child Health, University College London, London, United
Kingdom
GFR Glomerular filtration rate
The authors declare no conflicts of interest.
RR Relative risk
SBP Systolic blood pressure 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.06.008

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 Vol. 162, No. 1  January 2013

The aims of the present study were to assess the prevalence

Results
of hyperuricemia in a cohort of pediatric patients being fol-
lowed in a pediatric nephrology clinic, and to further estab-
The study population comprised 117 children, including 71
lish relationships among serum urate level, renal function,
males (61%), aged 0.4-17 years (median, 6.5 years). One pa-
body mass index (BMI), blood pressure (BP), and protein-
tient with a uromodulin gene defect was excluded. None of
uria in this group.
the patients were prescribed allopurinol. Congenital anoma-
lies of the kidneys and urinary tract accounted for 63% of
Methods the diagnoses (Table). Formal GFR ranged from 8 to 149
mL/min/1.73 m2 (median, 59 mL/min/1.73 m2), and eGFR
This was a retrospective, cross-sectional study of clinical and
ranged from 7 to 146 mL/min/1.73 m2 (median, 60 mL/
laboratory data obtained at least twice in patients attending
min/1.73 m2). BMI ranged from 12.9 to 34.3 (median,
a pediatric nephrology clinic over a 6-year period between
16.8). Laboratory results included a urine
2004 and 2010. Anthropometric and BP measurements were
albumin:creatinine of 0.3-2256 mg/mmol (median, 59 mg/
also obtained for each child on at least 2 occasions, with the
mmol) and a serum urate level of 127-780 mmol/L (median,
number of antihypertensive medications noted in all patients
306 mmol/L), or 2.1-13.1 mg/dL (median, 5.1 mg/dL).
with CKD of any etiology. Exclusion criteria included acute
Serum uric acid level was positively associated with in-
kidney injury, any known uromodulin gene defects, and treat-
creased BMI (r = 0.44; P = .0001) and BMI z-score
ment with allopurinol. Laboratory data, including serum cre-
(r = 0.2: P = .02), albuminuria (r = 0.31; P = .0001), and el-
atinine, formal GFR and estimated GFR (eGFR), serum urate,
evated SBP (r = 0.24; P = .004) and inversely associated with
and urine albumin:creatinine, were recorded. The study was
renal dysfunction, as determined by eGFR (r = 0.44;
approved by Great Ormond Street Hospital and UCL Insti-
P = .0001) and formal GFR (r = 0.37; P = .01). The stron-
tute of Child Health Research Ethics Committee.
gest linear relationships were between urate and eGFR and
For this study, hyperuricemia was defined as a serum ur-
between urate and BMI (Figures 1 and 2).
ate level above the normal range for age- and sex-specific
ORs and 95% CIs were calculated to assess the relationship
values. The following pediatric reference ranges were used:
between high serum uric acid level and the risk of stage III-V
80-500 mmol/L for age 1-12 months, 120-320 mmol/L for
CKD (eGFR <60 mL/min/1.73 m2). Forty-seven of the 67
age 1-10 years, 160-470 mmol/L for boys aged 11-15 years,
children with an eGFR of <60 mL/min/1.73 m2 (70%) had
and 140-350 mmol/L for girls aged 11-15 years. Normal adult
hyperuricemia, compared with 34% (24 of 71) with an
ranges were used for those aged above 15 years.15 For the
eGFR >60 mL/min/1.73 m2 (relative risk [RR], 0.5; 95%
purpose of our analyses, we classified our children with an
CI, 0.3-0.7; P < .0001). Children with stage III-V CKD were
eGFR of $60 mL/min/1.73 m2 as stage I-II and those with
more likely to have hyperuricemia (OR, 4.6; 95% CI, 2.2-
an eGFR of <60 mL/min/1.73 m2 as stage III-V. Overweight
9.4; P < .0001). Of the 42 children classified as overweight,
was defined as a BMI above the 85th percentile for age and
27 (64%) had an elevated serum uric acid level, compared
sex, and obesity was defined as a BMI above the 95th percen-
with 43 of 97 (44%) with a normal BMI (RR, 0.6; 95% CI,
tile.16 Hypertension was defined as systolic BP (SBP) greater
0.3-0.9). Children with a BMI >85th percentile were more
than the 95th percentile for age, sex, and height or receipt of
likely to have hyperuricemia than those with a normal BMI
one or more antihypertensive agents (excluding the use of
(OR, 2.3; 95% CI, 1.1-4.8; P = .03). Thirty-five of the 57 chil-
angiotensin-converting enzyme inhibitors for proteinuria).
dren with hypertension (61%) had hyperuricemia, compared
Formal GFR was calculated using the iohexol method;
with 43% (36 of 83) who were normotensive (RR, 0.6; 95%
eGFR was calculated using a modified Schwartz formula.17
CI, 0.4-0.9). Children with hyperuricemia were more likely
Statistical Analyses
Data were analyzed using SPSS 17 (IBM, Armonk, New York).
Correlation among factors was assessed. The Pearson correla- Table. Diagnoses
tion coefficient (r) was used to estimate the nature and
Diagnosis Number (%)
strength of the relationships for normally distributed data,
Congenital anomalies of the kidneys and urinary tract 72 (63)
and the Spearman rank correlation (r) was used for other Aplasia/hypoplasia/dysplasia 26 (23)
data. ORs, 95% CIs, and risk estimates of stage III, IV, or V Dysplasia and reflux nephropathy 23 (20)
CKD (eGFR < 60 mL/min/1.73 m2) with hyperuricemia Obstructive uropathy 23 (20)
Glomerulonephritis 9 (8)
were calculated using the c2 test. The risks of being overweight Organ (nonrenal) transplant recipients 6 (5)
or hypertensive and having hyperuricemia were calculated as Focal and segmental glomerulosclerosis 4 (3)
well. The relationships among eGFR, BMI, and hyperurice- Polycystic kidney disease 4 (3)
Bilateral Wilms tumor 4 (3)
mia were further estimated using both simple and multiple Haemolytic uremic syndrome 2 (2)
linear regression, and predictive equations were derived. Lo- Chemotherapy-induced CKD 4 (3)
gistic regression was performed to further investigate the ef- Metabolic disorder 4 (3)
Preterm/neonatal complications 4 (3)
fects of urate, BMI, BP, and albuminuria as predictors of Other 4 (3)
more severe renal dysfunction (CKD stage III-V vs stage I-II).
129
THE JOURNAL OF PEDIATRICS  www.jpeds.com
Figure 1. Scatterplot of serum urate (mmol/L) by eGFR (mL/
min/1.73 m2), where r represents the correlation coefficient.
to have hypertension or to be receiving antihypertensive ther-
apy (OR, 2.1; 95% CI, 1-4.1; P = .03).
A significant linear relationship between eGFR and
urate was seen, with a regression coefficient of 0.08
(95% CI, 0.1 to 0.05; P = .0001); the equation is
eGFR = 87 (0.08  urate). This was also true for
formal GFR, where the regression coefficient was 0.07
(95% CI, 0.12 to 0.01; P = .01); the equation is
GFR = 81 (0.07  urate). A significant linear relationship
between urate and BMI was seen, with a regression coeffi-
cient of 13.1 (95% CI, 8.6-17.5; P = .0001); the equation
is urate = 91 + (13  BMI). A multiple regression model
was used to ascertain the effect of eGFR, BMI, albuminuria,
Figure 2. Scatterplot of serum urate (mmol/L) by BMI (kg/m2),
where r represents the correlation coefficient.
130
Vol. 162, No. 1
and SBP on urate; no collinearity among the variables was
seen. A significant model to predict serum urate emerged
based on BMI and eGFR (adjusted R2, 0.35; P < .001).
For the predictor variable eGFR, the beta was -2.2 (95%
CI, -3.1, - 1.4; P < .001) and for BMI, the beta was 12.9
(95% CI, 8.4, 17.4; P < .001); the predictive equation is ur-
ate = 243 + (12.9  BMI) -2.2 (eGFR).
Logistic regression analysis was conducted to predict the
odds of having CKD stage III-V as opposed to CKD stage
I-II, using urate, BMI, SBP, and albuminuria as predictor
variables. The Wald criterion demonstrated that urate and
BMI made significant contributions to the prediction
(P < .001 and .007, respectively), but that SBP and albumin-
uria were no longer significant in this model. When adjusting
for the other factors, each unit increase in serum uric acid
level increased the risk of stage III-V CKD (OR, 1.01; 95%
CI, 1.006-1.017), and each unit increase in BMI reduced
the risk of stage III-V CKD (OR, 0.845; 95% CI, 0.748-0.955).
Discussion
Hyperuricemia was present in 70% of children in our cohort
with stage III-V CKD, which was closely correlated with renal
dysfunction and increased BMI, elevated BP, and albumin-
uria. BMI and urate were the most significant predictors of
eGFR, with hyperuricemia and a lower BMI predictive of
worse CKD. eGFR and BMI accounted for 35% of the variance
in serum urate levels. Hyperuricemia in children may be sig-
nificant, particularly if it represents an evolving deleterious
process and increased cardiovascular risk, as has been sug-
gested in adult studies.7-9 We feel that monitoring serum urate
level in children with CKD is prudent, especially considering
recently published data showing that a decline in eGFR was
apparent even when uric acid was in the normal range.10
Animal models of CKD have provided evidence suggesting
that hyperuricemia can induce an afferent arteriolopathy
leading to glomerular hypertension, glomerulosclerosis, and
progressive CKD can be attenuated by treating the hyperuri-
cemia.18 Proving a causal role for urate in CKD progression
in human clinical studies has been more difficult, and most
of the existing evidence has come from large epidemiologic
studies.7-9 The largest of these studies involved a cohort
of 177 570 patients and identified elevated uric acid as a novel
independent risk factor for end-stage renal disease (hazard
ratio, 2.14).19 Although some studies have pointed to a possi-
ble independent role for uric acid in the progression of CKD,
others have suggested that it is a bystander, rising as the GFR
falls because uric acid is normally excreted renally.20 Studies
of hyperuricemia in pediatric CKD are lacking, however.
In our pediatric population, the likelihood of having hy-
peruricemia was significantly increased in those with hyper-
tension and receiving an antihypertensive agent. Another
area of controversy concerns the role of hyperuricemia in hy-
pertension and the role of hypertension in hyperuricemia.21
Experimental evidence suggests that hyperuricemia leads to
renal arteriolopathy and hypertension through a combination
of inhibited endothelial cell proliferation, renin angiotensin
Noone and Marks
January 2013
system activation, vascular smooth muscle cell proliferation,
and reduced endothelial nitric oxide levels.22-24 A recent sys-
tematic review and meta-analysis of 18 prospective cohort
studies identified an association between elevated uric acid
level and increased risk of incident hypertension.25 In addi-
tion, a novel study involving a homogeneous population of
516 Amish adults with hypouricemia secondary to a genetic
defect in the uric acid transporter GLUT9 found an associa-
tion between decreased uric acid levels and significant
reductions in BP.26 Modifying hyperuricemia before the es-
tablishment of this arteriolopathy may play a role in reducing
BP. Feig et al reported a very high correlation between hyper-
uricemia and essential hypertension in adolescents,27 and in
a randomized, double-blind, placebo-controlled crossover
trial showed that the reduction in serum uric acid level
from allopurinol therapy resulted in a significant reduction
in SBP of 6.9 mmHg (95% CI, 4.5 to 9.3 mmHg;
P = .009).28
Strict BP control and limitation of proteinuria with
angiotensin-converting enzyme inhibition can slow the pro-
gression of CKD.29 Hyperuricemia reduction also may
play a role in this multifactorial process.30 Losartan, an
angiotensin II receptor blocker, exerts a direct uricosuric ef-
fect by inhibiting URAT1.31 This uricosuric effect seems to
be limited to losartan, and a number of studies have shown
it to be effective in lowering urate levels in hypertensive sub-
jects.31,32 It may be a significant contributing factor to the ben-
efit seen from the combination of an angiotensin-converting
enzyme inhibitor and an angiotensin II receptor blocker in pa-
tients with CKD, hypertension, and proteinuria.33
Whether lowering serum urate can have an impact on
CKD progression remains to be demonstrated. The most
compelling evidence to date comes from a prospective ran-
domized trial involving 113 patients, in whom treatment
with allopurinol significantly reduced C-reactive protein,
slowed GFR decline, and was associated with a reduced risk
of cardiovascular morbidity.34 Allopurinol acts as a competi-
tive inhibitor of xanthine oxidase, blocking de novo hepatic
urate synthesis. Allopurinol may be especially useful, because
it has a direct antioxidant action and scavenges free radicals
and reactive oxygen species, major causes of endothelial dys-
function.35 Allopurinol increases xanthine and hypoxanthine
levels, and cases of xanthine nephrolithiasis secondary to al-
lopurinol treatment in pediatric patients have been re-
ported.36 There are other safety concerns with allopurinol,
especially in children with CKD, in whom it has been associ-
ated with hypersensitivity reaction and drug rash with eosin-
ophilia and systemic symptoms, as well as with an increased
risk for other dermatologic reactions, such as Stevens-
Johnson syndrome.37
Our observational cross-sectional study has estimated the
prevalence of hyperuricemia in a population not assessed
previously. The correlation with increasing BMI may simply
reflect increasing weight and age; however, the correlation
with BMI z-scores remained significant. Obviously, we can-
not conclude that hyperuricemia is causal in the declining re-
nal function in our cohort of children with CKD, but what is
Hyperuricemia is Associated with Hypertension, Obesity, and Albuminuria in Children with Chronic Kidney Disease
ORIGINAL ARTICLES
important is that hyperuricemia is very prevalent and appears
to be associated with reduced eGFR and increased BMI, ele-
vated BP, and albuminuria. n
We thank Dr Afif El-Khuffash, Mount Sinai Hospital and University
of Toronto, for statistical advice during the preparation of this
manuscript.
Submitted for publication Dec 15, 2011; last revision received Apr 25, 2012;
accepted Jun 4, 2012.
Reprint requests: Stephen D. Marks, MD, Department of Paediatric
Nephrology, Great Ormond Street Hospital for Children NHS Trust, London
WC1N 3JH, UK. E-mail: stephen.marks@gosh.nhs.uk
References
1. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH,
et al. Molecular identification of a renal urate anion exchanger that reg-
ulates blood urate levels. Nature 2002;417:447-52.
2. Sanchez Bayle M, Vazquez Martul M, Ecija Peiro JL, Garcia Vao C, Ramo
Mancheno C. Renal handling of uric acid in normal children by means
of the pyrazinamide and sulfinpyrazone tests. Int J Pediatr Nephrol 1987;
8:5-8.
3. Cameron JS, Moro F, Simmonds HA. Gout, uric acid and purine metab-
olism in paediatric nephrology. Pediatr Nephrol 1993;7:105-18.
4. Danovitch GM, Weinberger J, Berlyne GM. Uric acid in advanced renal
failure. Clin Sci 1972;43:331-41.
5. Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, et al.
A cluster of mutations in the UMOD gene causes familial juvenile hyper-
uricemic nephropathy with abnormal expression of uromodulin. J Am
Soc Nephrol 2003;14:2883-93.
6. Hunsicker LG, Adler S, Caggiula A, England BK, Greene T, Kusek JW,
et al. Predictors of the progression of renal disease in the Modification
of Diet in Renal Disease Study. Kidney Int 1997;51:1908-19.
7. Satirapoj B, Supasyndh O, Chaiprasert A, Ruangkanchanasetr P,
Kanjanakul I, Phulsuksombuti D, et al. Relationship between serum
uric acid levels with chronic kidney disease in a Southeast Asian popu-
lation. Nephrology (Carlton) 2010;15:253-8.
8. Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance
of hyperuricemia on the early detection of renal failure in a cohort of
screened subjects. Hypertens Res 2001;24:691-7.
9. Tomita M, Mizuno S, Yamanaka H, Hosoda Y, Sakuma K, Matuoka Y,
et al. Does hyperuricemia affect mortality? A prospective cohort study of
Japanese male workers. J Epidemiol 2000;10:403-9.
10. Bellomo G, Venanzi S, Verdura C, Saronio P, Esposito A, Timio M. As-
sociation of uric acid with change in kidney function in healthy normo-
tensive individuals. Am J Kidney Dis 2010;56:264-72.
11. Cirillo P, Sato W, Reungjui S, Heinig M, Gersch M, Sautin Y, et al. Uric
acid, the metabolic syndrome, and renal disease. J Am Soc Nephrol 2006;
17:S165-8.
12. Johnson RJ, Sanchez-Lozada LG, Nakagawa T. The effect of fructose on
renal biology and disease. J Am Soc Nephrol 2010;21:2036-9.
13. Nakagawa T, Cirillo P, Sato W, Gersch M, Sautin Y, Roncal C, et al. The
conundrum of hyperuricemia, metabolic syndrome, and renal disease.
Intern Emerg Med 2008;3:313-8.
14. Jalal DI, Rivard CJ, Johnson RJ, Maahs DM, McFann K, Rewers M, et al.
Serum uric acid levels predict the development of albuminuria over 6
years in patients with type 1 diabetes: findings from the Coronary Artery
Calcification in Type 1 Diabetes study. Nephrol Dial Transplant 2010;25:
1865-9.
15. Holt RCL, Connell JE, Addison GM. Reference data for paediatric ne-
phrology. In: Webb NJA, Postlethwaite RJ, eds. Clinical paediatric
nephrology. 3rd ed. New York: Oxford University Press; 2003. p.
493-509.
16. Barlow SE. Expert Committee recommendations regarding the preven-
tion, assessment, and treatment of child and adolescent overweight
and obesity: summary report. Pediatrics 2007;120:S164-92.
131
THE JOURNAL OF PEDIATRICS  www.jpeds.com
17. Gonzalez Celedon C, Bitsori M, Tullus K. Progression of chronic renal
failure in children with dysplastic kidneys. Pediatr Nephrol 2007;22:
1014-20.
18. Sanchez-Lozada LG, Tapia E, Soto V, Avila-Casado C, Franco M,
Wessale JL, et al. Effect of febuxostat on the progression of renal disease
in 5/6 nephrectomy rats with and without hyperuricemia. Nephron
Physiol 2008;108:69-78.
19. Hsu CY, Iribarren C, McCulloch CE, Darbinian J, Go AS. Risk factors for
end-stage renal disease: 25-year follow-up. Arch Intern Med 2009;169:
342-50.
20. Feig DI. Uric acid: a novel mediator and marker of risk in chronic kidney
disease? Curr Opin Nephrol Hypertens 2009;18:526-30.
21. Mazzali M, Kanbay M, Segal MS, Shafiu M, Jalal D, Feig DI, et al. Uric acid
and hypertension: cause or effect? Curr Rheumatol Rep 2010;12:108-17.
22. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al.
Elevated uric acid increases blood pressure in the rat by a novel crystal-
independent mechanism. Hypertension 2001;38:1101-6.
23. Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuri-
cemia induces a primary renal arteriolopathy in rats by a blood pressure-
independent mechanism. Am J Physiol Renal Physiol 2002;282:F991-7.
24. Sanchez-Lozada LG, Tapia E, Santamaria J, Avila-Casado C, Soto V,
Nepomuceno T, et al. Mild hyperuricemia induces vasoconstriction
and maintains glomerular hypertension in normal and remnant kidney
rats. Kidney Int 2005;67:237-47.
25. Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and inci-
dent hypertension: a systematic review and meta-analysis. Arthritis
Care Res (Hoboken) 2011;63:102-10.
26. Parsa A, Brown E, Weir MR, Fink JC, Shuldiner AR, Mitchell BD, et al.
Genotype-based changes in serum uric acid affect blood pressure. Kid-
ney Int 2011;81:302-7.
27. Feig DI, Johnson RJ. Hyperuricemia in childhood primary hypertension.
Hypertension 2003;42:247-52.
132
Vol. 162, No. 1
28. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure
of adolescents with newly diagnosed essential hypertension: a random-
ized trial. JAMA 2008;300:924-32.
29. Wuhl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, et al.
Strict blood pressure control and progression of renal failure in children.
N Engl J Med 2009;361:1639-50.
30. Rinat C, Becker-Cohen R, Nir A, Feinstein S, Shemesh D, Algur N, et al.
A comprehensive study of cardiovascular risk factors, cardiac function
and vascular disease in children with chronic renal failure. Nephrol
Dial Transplant 2010;25:785-93.
31. Hamada T, Ichida K, Hosoyamada M, Mizuta E, Yanagihara K,
Sonoyama K, et al. Uricosuric action of losartan via the inhibition of ur-
ate transporter 1 (URAT 1) in hypertensive patients. Am J Hypertens
2008;21:1157-62.
32. Dang A, Zhang Y, Liu G, Chen G, Song W, Wang B. Effects of losartan
and irbesartan on serum uric acid in hypertensive patients with hyperur-
icaemia in Chinese population. J Hum Hypertens 2006;20:45-50.
33. Zaffanello M, Franchini M, Fanos V. New therapeutic strategies with
combined renin-angiotensin system inhibitors for pediatric nephropa-
thy. Pharmacotherapy 2008;28:125-30.
34. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J,
Rincon A, et al. Effect of allopurinol in chronic kidney disease progres-
sion and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388-93.
35. George J, Struthers AD. Role of urate, xanthine oxidase and the effects of
allopurinol in vascular oxidative stress. Vasc Health Risk Manag 2009;5:
265-72.
36. Sikora P, Pijanowska M, Majewski M, Bienias B, Borzecka H,
Zajczkowska M. Acute renal failure due to bilateral xanthine urolithiasis
in a boy with Lesch-Nyhan syndrome. Pediatr Nephrol 2006;21:1045-7.
37. Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety,
and efficacy for hyperuricemia in gout. Curr Rheumatol Rep 2009;11:
135-40.
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