DOI: 10.1542/peds.

2008-0634
2009;123;791 Pediatrics
Farah N. Ali, Lester M. Arguelles, Craig B. Langman and Heather E. Price
Epidemic
Vitamin D Deficiency in Children With Chronic Kidney Disease: Uncovering an

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ARTICLE
Vitamin D Deciency in Children With Chronic
Kidney Disease: Uncovering an Epidemic
Farah N. Ali, MD
a,b
, Lester M. Arguelles, PhD
c
, Craig B. Langman, MD
a,b
, Heather E. Price, MS
a,b
a
Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
b
Divisions of Pediatrics and of Kidney Diseases, Childrens Memorial Hospital, Chicago, Illinois;
c
The Mary Ann & J. Milburn Smith Child Health Research Program, Childrens Memorial Hospital, Chicago, Illinois
The authors have indicated they have no nancial relationships relevant to this article to disclose.
Whats Known on This Subject
There are no data in the literature about levels of 25(OH)D and CKD in children. Guide-
lines suggest measuring these levels, but they are without substantiation.
What This Study Adds
We provide a rationale and substantive data on vitamin D sufciency, insufciency, and
deciency in a large group of children with CKD and provide a rm foundation for
recommendations for measurement of 25(OH)D.
ABSTRACT
BACKGROUND. Vitamin D deciency in children adversely affects bone development by
reducing mineralization. Children with chronic kidney disease are at risk for altered
bone development from renal osteodystrophy and concomitant vitamin D deciency.
The pediatric Kidney Disease Outcomes Quality Initiative guidelines suggest mea-
suring serum 25-hydroxyvitamin D (25[OH]D) levels if serum parathyroid hormone
levels are above the target range for chronic kidney disease stages 2 and beyond, but
the magnitude of vitamin D deciency in children with chronic kidney disease is not
well studied.
OBJECTIVES. The purpose of this work was to determine whether children with chronic
kidney disease had vitamin D deciency, to evaluate whether the prevalence of
vitamin D deciency changed over time, and to examine seasonal and ethnic
differences in 25(OH)D levels.
METHODS. 25(OH)D levels in children with chronic kidney disease (stages 15) were
measured over a 10-year period from 1987 to 1996. Data were also collected for a
contemporary group of patients from 2005 to 2006.
RESULTS. The prevalence of vitamin D deciency ranged from 20% to 75% in the
decade studied. There was a signicant trend for decreasing 25(OH)D levels over the
decade, both at the group and individual levels. Seasonal variation was noted. In our
contemporary population with chronic kidney disease, the mean 25(OH)D level was
21.8 ng/mL; we found a prevalence of vitamin D deciency of 39%. Black and
Hispanic patients had lower levels of 25(OH)D than white patients.
CONCLUSIONS. Children with chronic kidney disease have great risk for vitamin D deciency, and its prevalence was
increasing yearly in the studied decade. Contemporary data show that vitamin D deciency remains a problem
in these children. Sunlight exposure and ethnicity play a role in levels of 25(OH)D. Our data support the recent
pediatric Kidney Disease Outcomes Quality Initiative guidelines for measurement of 25(OH)D levels in children
with chronic kidney disease and secondary hyperparathyroidism. Pediatrics 2009;123:791796
T
HE PATHWAY OF vitamin D metabolism involves a series of related synthetic reactions. Vitamin D (cholecalciferol)
is synthesized in the skin from its precursor 7-dehydrocholesterol through isomerization under the effects of
UV-B from sun exposure. This compound then undergoes 2 subsequent hydroxylations, the rst of which takes place
in the liver at the carbon-25 position through the actions of 25-hydroxylase. Six cytochrome P450 enzymes have
been reported to catalyze this reaction, including CYP2R1.
1
The second major hydroxylation occurs in the kidney
proximal tubule, where 25-hydroxyvitamin D (25[OH]D) is further modied by a 1--hydroxylase, CYP27B1, to
form 1,25(OH)2 vitamin D. 1,25(OH)2 vitamin D is the major regulator for intestinal calcium and phosphorus
absorption and has vital actions in maintaining serum calcium and phosphorus levels. Ultimately, it is vitamin D
adequacy that guarantees optimal skeletal mineralization. Vitamin D deciency in children, then, adversely affects
bone development by reducing mineralization.
2
Children with chronic kidney disease (CKD) are at risk for impaired bone from renal osteodystrophy and
concomitant vitamin D deciency as part of the entity CKD-mineral and bone disorder.
35
Vitamin D deciency is
www.pediatrics.org/cgi/doi/10.1542/
peds.2008-0634
doi:10.1542/peds.2008-0634
Key Words
CKD-mineral and bone disorder, renal
osteodystrophy, rickets, secondary
hyperparathyroidism, osteomalacia
Abbreviations
25(OH)D25-hydroxyvitamin D
CKDchronic kidney disease
KDOQIKidney Disease Outcomes Quality
Initiative
PTHparathyroid hormone
iPTHintact parathyroid hormone
Accepted for publication Jun 16, 2008
Address correspondence to Craig B. Langman,
MD, Feinberg School of Medicine,
Northwestern University, Childrens Memorial
Hospital, 2300 Childrens Plaza, Box 37,
Chicago, IL 60614. E-mail: c-langman@
northwestern.edu
PEDIATRICS (ISSNNumbers: Print, 0031-4005;
Online, 1098-4275). Copyright 2009 by the
American Academy of Pediatrics
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dened by inadequate 25(OH)D levels. The pediatric
National Kidney Foundation Kidney Disease Outcomes
Quality Initiative (KDOQI) guidelines
6
suggest measur-
ing serum 25(OH)D levels if serum parathyroid hor-
mone (PTH) levels are above the target range for CKD
stages 2 and beyond, but the magnitude of vitamin D
deciency in children with CKD is not well studied.
25(OH)D levels 32 ng/mL have dened vitamin D
insufciency, because population-based data have dem-
onstrated the association of secondary hyperparathy-
roidism at levels below this cutoff.
7
A similar relationship
between 25(OH)D and PTH was demonstrated in
healthy adolescents.
8
Vitamin D deciency occurs with
25(OH)D levels 15 ng/mL.
6
The objective of our study, then, was to determine the
extent of vitamin D deciency/insufciency in children
with CKD. Thus, we chose to evaluate a cohort over a
past decade (19871996), before KDOQI and the routine
use of vitamin D supplementation, as well as a contem-
porary population (20052006) that followed the publi-
cation of KDOQI guidelines. We found extensive vita-
min D deciency/insufciency in both.
MATERIALS ANDMETHODS
Decade Data
25(OH)D levels in ambulatory pediatric patients with
CKD, stages 1 through 5, were measured under clinical
care over a 10-year period from 1987 to 1996 (n
1992). We studied 1074 patients, and 403 patients
(38%) had repeat levels over the decade. When a given
patient had more than one 25(OH)D level measured in 1
year, we analyzed the rst data point available for each
year. Usual clinical care at that time did not include
supplementation with ergocalciferol.
Simultaneous measurements of intact PTH (iPTH) and
25(OH)D were evaluated over the 5-year period from
1992 to 1996 (n 1492). We limited our analysis to
those children with a 25(OH)D 32 ng/mL (80 nM) and
iPTH between 0 and 100 pg/mL to reduce the inuence
of severe secondary hyperparathyroidism as CKD ad-
vances into stage 5. The iPTH levels were measured
using a second generation immunoradiometric assay,
9
and 25(OH)D levels were measured as described previ-
ously
9
using a competitive binding protein radioreceptor
immunoassay.
Contemporary Data
A random sample of an additional 88 patients with CKD
who had 25(OH)D levels measured during 2005 to 2006
was also studied. From this population, we obtained data
regarding CKD staging based on the Schwartz formula
for estimated glomular ltration rate, ethnicity, and un-
derlying cause of CKD. We excluded those patients with
nephrotic syndrome and those on ergocalciferol supple-
mentation from study. In the contemporary data analy-
sis, we measured iPTH by a chemiluminescence method
(Immulite 2000, Siemens Medical Solutions Diagnostics,
Los Angeles, CA), and 25(OH)D was measured by a
radioimmunoassay (DiaSorin, Stillwater, MN).
10
Statistics
Our initial descriptive analysis for the decade data
used analysis of variance methodology and Cochrans
linear trend test. Next, we generated spaghetti plots of
25(OH)D concentrations among those with 2 time
points to examine the individual trend, that is, the slope,
of 25(OH)D concentrations across time. Then, we gen-
erated a penalized spline from generalized additive mod-
els
11
to determine the appropriateness of linear terms for
the covariate of time in the regression model. Because
these were longitudinal data, where multiple measures
within an individual are likely correlated, we used ran-
dom-effects regression models to account for these corre-
lations. Because we were also interested in the variance in
individual slopes, we partitioned a within-subjects model:
yij b0i b1iTimeij eij and a between-subjects model:
b0j 0 0i; b1i 1 1i.
The within-subject model shows that the ith individ-
uals 25(OH)D at time j is inuenced by the initial level,
b0j, and the time trend, b1i. The between-subjects model
shows that ith individuals initial 25(OH)D level is de-
termined by the population level at time 0, 0, plus the
unique contribution by that individual, 0i, and it also
shows the ith individuals slope across time is deter-
mined by the population slope of time, 1, plus the
unique contribution to the slope by individual i, 1i. The
statistical signicance of these random effects can be
determined by a likelihood ratio
2
test.
12
Finally, we modeled the prevalence of 25(OH)D de-
ciency across time with a Poisson model. Penalized
splines were generated by using the software package R:
A Language and Environment for Statistical Computing
(R Foundation for Statistical Computing, Vienna, Aus-
tria). SAS 8.2 (SAS Institute Inc, Cary, NC) was used to
run the random effects and Poisson models in proc
mixed and proc genmod, respectively.
The relationship between 25(OH)D and PTH was
studied with linear regression, after log transformation
of the data because of positively skewed data points, and
Pearson product moment correlation. Seasonal variation
was analyzed with analysis of variance on ranks. P val-
ues .05 were considered statistically signicant. Statis-
tical software packages used for these tests included both
SigmaStat 3.1 and SYSTAT 10 (SPSS Inc, Chicago, IL).
This study was conducted with institutional review
board approval, wherein the requirement for informed
consent was waived.
RESULTS
Decade Data
Yearly mean 25(OH)D levels ranged from 11.6 to 30.2
ng/mL (n 79336 per year), with median levels rang-
ing from 10.5 to 24.6 ng/mL from 1987 to 1996 (Fig 1).
There were differences between the yearly mean values
over the decade (F 25.75; P .001).
The prevalence of vitamin D deciency, dened as a
25(OH)D level of 15 ng/mL (37.5 nM), ranged from
20% to 75% in the decade studied (Fig 2). There were
differences between the yearly values (F 311.59; P
.001), and, in addition, increasing prevalence of
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25(OH)D levels 15 ng/mL was noted from the begin-
ning to the end of the decade (P .001).
The 25(OH)D concentrations decreased rather lin-
early over time. We examined spaghetti plots of the
individual slopes over time and found that individual
trends tended to decrease over time, when analyzing
those subjects with 2 time points and those with 6
time points.
A random-effects regression model for the 25(OH)D
concentration over time showed that subjects had
25(OH)D concentrations of 17.5 ng/mL on average, con-
centrations decreased 0.06 ng/mL each month on aver-
age, and the effect of time was signicant (P .0001).
However, we noted that the individual heterogeneity in
25(OH)D concentration at time 0 was quite large, where
the SD was 7.5 ng/mL.
Similarly, the average decrease over time was
0.007, the estimate SD of the slope was 0.08 (the
square root of 0.007), and, thus, 95% of the individual
slopes would fall between 0.07 (1.96*0.08) 0.22
to 0.09. Because the interval includes 0, this means that
some individuals did not decrease over time. Finally, the
covariance between the intercept and slope terms was
0.5, which, when expressed as a correlation, is 0.86
and is rather high. Interestingly, this term means that
those who had a higher 25(OH)D concentration at time
0 were likely to have a higher negative slope or more
extreme decrease.
To evaluate the relationship between 25(OH)D and
iPTH, we limited our analysis to those children with a
25(OH)D 32 ng/mL (80 nM) and iPTH between 0 and
100 pg/mL, likely with CKD stages 1 to 4, to reduce the
inuence of severe secondary hyperparathyroidism as
CKD advances into stage 5 (Fig 3). Of the 1492 PTH
values, the mean level was 29.866, with an SD of
19.421. We found a small but highly signicant inverse
relationship between PTH and 25(OH)D (n 1492
paired observations; R 0.109; P .001).
Interestingly, seasonal variation in 25(OH)D levels
was noted (P .001) in our patients with CKD (Fig 4),
with summer-fall values greater than winter-spring. An-
alyzing only 1 measurement per patient, the patients
who had levels drawn in the summer-to-fall time period
from July through December had signicantly higher
values of 25(OH)D than those who had levels drawn in
the winter-to-spring time periods from January through
June (P .05).
Contemporary Data
We analyzed contemporary data (20052006) in 88
patients with CKD stages 1 to 5 and found the mean
25(OH)D level of 21.8 ng/mL and median level of 17.7
ng/mL quite similar to those in the decade study. The
FIGURE 2
Prevalence of severe 25(OH)Ddeciency indecade data of childrenwithCKD. There were
differences between the yearly values (F 311.59; P .001), and a trend (P .001) of
increasing prevalence of 25(OH)D levels 15 ng/mL was noted over the decade.
FIGURE 3
iPTHlevels are inversely related to 25(OH)Dlevels (R 0.109; P .001). Our analysis was
limited to values of 25(OH)D32 ng/mL and iPTHlevels between 0 and 100 pg/mL. The
solid line represents the regression line, and the dashed lines represent the 95% con-
dence intervals around the regression.
FIGURE 1
Differences inyearly 25(OH)Dlevels indecade data of childrenwithCKD. The box denotes
25th to 75th percentiles; the line in box is the median; and black circles denote the 5th
and 95th percentiles. For the individual years in the decade 19871996: n 79, n 100,
n148, n144, n254, n220, n246, n154, n311, andn336. Meanlevels
ranged from 11.6 to 30.2 ng/mL (data not shown). There were differences between the
yearly mean values over the decade (F 25.75; P .001).
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prevalence of deciency in this contemporary study
group was 39%, and the majority, 72%, had levels
32 ng/mL. When we analyzed these data according
to ethnicity, we found that 68% (n 13) of black
patients had levels of 15 ng/mL and 90% (n 26) of
Hispanic (Spanish-speaking) patients of varying an-
cestry had levels 32 ng/mL. A total of 53% (n 16)
of whites were either decient or insufcient. The
mean levels of 25(OH)D in blacks and Hispanics were
17 and 18 ng/mL, respectively, which were signi-
cantly lower than the mean level of 28 ng/mL found
in whites (P .05).
DISCUSSION
The classic endocrine action of vitamin D lies in the
regulation of intestinal calcium and phosphorus absorp-
tion, to maintain both normal serum calcium and phos-
phorus levels and, ultimately, to guarantee adequate
skeletal mineralization. In children with normal kidney
function, deciency of vitamin D leads to the classical
ndings of rickets and undermineralization of the skel-
eton.
CKD forces an additional constraint to maintain nor-
mal vitamin D metabolism, because the kidney proximal
tubule is the site of 1,25(OH)2D production. In adults,
progressive loss of kidney function (estimated glomular
ltration rate) leads to lower serum levels of
1,25(OH)2D and eventual secondary hyperparathyroid-
ism.
13
As such, measuring 25(OH)D levels may be criti-
cal, because having inadequate substrate available for
conversion to 1,25(OH)2D will only exacerbate this
deciency in our patients with CKD.
14
Decient
1,25(OH)2D leads to secondary hyperparathyroidism.
Thus, keeping normal levels of 25(OH)D is important to
ensure maximal capacity for renal and extrarenal pro-
duction of 1,25(OH)2D.
Controlling the secondary hyperparathyroidism that
occurs as part of renal osteodystrophy is a mainstay in
the therapy of these children to repair their bone and
mineral disturbances,
15
but vitamin D likely has impor-
tance beyond the maintenance of skeletal integrity. In
adults, it has been shown that muscle weakness and
bone pain scores improved after treatment with 50 000
units of ergocalciferol weekly for 4 weeks.
16
A prospec-
tive study of 25(OH)D3 therapy in pediatric patients
with moderate CKD demonstrated an increase in the
mean growth velocity of the group into the normal
range after 1 year, as well as a correlation between
pretherapy and 1-year therapy values of growth velocity
and serum 25(OH)D3 concentration.
17
There is increasing literature documenting numerous
nonclassical or nonendocrine actions of vitamin D as
well. Vitamin D is involved in the regulation of the
immune system and autoimmune disease,
2
and solar
UV-B radiation and, thus, vitamin D have been associ-
ated with reduced risk of multiple cancers.
18
Vitamin D is
involved in cardiovascular disease and regulating blood
pressure through renin. Hypertensive patients exposed
to UV-B radiation had normalization of their blood pres-
sures as their 25(OH)D levels increased in 1 study,
19
and
1,25(OH)2D is known to be a potent downregulating
factor for renin messenger RNA in the kidneys.
20
Although there remains controversy over what opti-
mal levels of 25(OH)D should be, one index of normalcy
is in relation to the prevention of the onset of secondary
hyperparathyroidism. Based on data from Chapuy et al
7
in a population of normal urban adults, vitamin D in-
sufciency is thought to occur at levels of 25(OH)D 32
ng/mL, because elevations of PTH were noted once lev-
els fell below this threshold value. A similar relationship
was demonstrated in healthy adolescents in Boston,
Massachusetts.
8
Our ndings also support this observa-
tion in children with CKD.
Although there are few existing data available in chil-
dren, several studies report suboptimal 25(OH)D levels
in adults with CKD. LaClair et al
21
conducted a study in
adult patients with moderate-to-severe CKD, not on
dialysis, across 12 latitudes in the United States. Of the
201 subjects studied, they found a mean 25(OH)D level
of 19.4 ng/mL. Only 29% with moderate CKD and 17%
with severe CKD were sufcient in their vitamin D sta-
tus. A recent cross-sectional study in 1814 unselected
outpatients with CKD from across the United States
found that 50% of subjects had inadequate 25(OH)D
levels, with a 12% prevalence of frank deciency in this
population.
13
A study in 104 adult hemodialysis patients
reported 51% of the sampled population having a level
of 30 ng/mL.
22
In this study, 25(OH)D levels 20
ng/mL were associated with low bone turnover on tran-
siliac bone biopsy.
22
Shah et al
16
studied 29 adult perito-
neal dialysis patients and found that 97% had levels 15
ng/mL.
Our decade data, chosen from an era that predated
KDOQI and the routine use of ergocalciferol supplemen-
tation, has shown rampant vitamin D deciency among
children with CKD. Our randomly chosen contemporary
cohort, which is representative of the current patients at
our institution, demonstrated similar levels of de-
ciency, even with excluding nephrotic patients who
have been found previously to have a higher likelihood
of vitamin D deciency.
23
FIGURE 4
Seasonal variation in 25(OH)D levels in decade data of children with CKD. Seasonal vari-
ation was noted (P .001), with July to December having higher levels of 25(OH)D
than January to June (P .05). The year 1996 was used as a representative sample.
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In addition, the ndings in our study validate previ-
ous knowledge that increased content of melanin does in
fact decrease vitamin D production in the skin,
24
because
we found more vitamin D deciency in Hispanic and
black children with CKD. This is a problem that affects
healthy children and adolescents, especially those with
darkly pigmented skin,
25,26
but may be an extra threat to
optimal bone health in such patients with underlying
CKD with altered vitamin D metabolism.
The nding of increasing prevalence of vitamin D
deciency over the decade studied is noteworthy. This
nding was demonstrated both at the individual level,
because those with 2 time points tended to have de-
clining 25(OH)D, as well as at the group level. Several
factors may have contributed to this nding. There may
have been a referral bias in that physicians increasingly
ordered 25(OH)D levels on patients whom they sus-
pected were at higher risk for vitamin D deciency.
There may have been some changes in sunlight expo-
sure during that decade, perhaps through increasing use
of sunscreen preparations or less outdoor time, for this
population of children. In addition, Chicago, Illinois, has
signicantly lower vitamin D-producing UV radiance
than lower-latitude sites; in fact, at times, the winter
solar noon irradiance at lower-latitude locations exceeds
the summer values recorded in Chicago.
27
Our study has some limitations. It would have been
useful to have had dietary and supplement information
and for the decade group to have data regarding racial
background and underlying diagnoses. However, in the
contemporary group in which those on ergocalciferol
supplements and nephrotic patients were excluded, we
found similar 25(OH)D levels to the decade group,
which supports the ndings from the decade group.
CONCLUSIONS
To date there has been a paucity of published data for
children with CKD examining the extent of nutritional
vitamin D deciency. Our data over time and extent of
CKD serve to illustrate that 25(OH)D deciency is a
signicant problem for this population of children. Al-
though another decade has passed since this data set was
collected, a contemporary population of similar children
with CKD at the same institution and city demonstrates
that vitamin D deciency still remains an issue.
In addition, we have shown that sunlight exposure
plays a role in levels of 25(OH)D in children with CKD,
because we observed seasonal variation, although it is
noteworthy that the median levels were always insuf-
cient. Black and Hispanic children are possibly at even
greater risk of severe deciency. Our data support the
pediatric KDOQI guideline for the measurement of
25(OH)D levels in children with CKD, to reduce the
effects of vitamin D deciency as an important compo-
nent of their renal osteodystrophy, now termed CKD-
mineral and bone disorder.
4
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THIS QUESTION HAS BEEN ASKED AND ANSWERED
A top exec quits a major autism group because she doesnt think vaccines
cause the disorder. The warfare over vaccines and autism is heating up yet
again. This week, Alison Singer, the executive vice president of communica-
tions and awareness at Autism Speaks, one of the nations leading autism
advocacy groups, announced her resignation, citing a difference of opinion
over the organizations policy on vaccine research. Dozens of credible scien-
tic studies have exonerated vaccines as a cause of autism, she wrote in a
statement. I believe we must devote limited funding to more promising
avenues of autism research. Singer, who has an 11-year-old daughter with
autism, joined the organization when it launched in 2005. Singer praised
Autism Speaks and its founders, Bob and Suzanne Wright, but said she could
no longer work for a group that supports spending limited resources on
vaccine research. Calling Singers resignation disappointing and sad, Bob
Wright says more authoritative research needs to be conducted on the safety
of vaccines given to children under 2. We all know that autism has genetic
causes, but its highly associated with environmental factors we cant get our
hands around, says Wright. Vaccines fall into that category. Newsweeks
Claudia Kalb spoke with Alison Singer about her resignation.
Excerpt:
Newsweek: What do you believe the science shows?
Singer: There are more than a dozen studies that show no causal link
between the MMR [measles-mumps-rubella] vaccine and autism, and
thimerosol [a mercury-containing vaccine preservative] and autism. Over
and over, the science has shown no causal link between vaccines and autism.
My feeling is that if there was an unlimited pot of money at the NIH [National
Institutes of Health] from which to fund autism science then it would be ne
to say lets study it more. But we dont have that. We have very limited
resources and every dollar we spend looking where we know the answer isnt
is a dollar we dont have to spend where we might actually nd new answers.
In general, yes, more research is always better than less. But again, we have
limited dollars to spend and we have to use our limited money wisely in ways
that are likely to yield new information for families.
Kalb C. Newsweek.com. January 16, 2009
Noted by DLS, MD
796 ALI et al
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DOI: 10.1542/peds.2008-0634
2009;123;791 Pediatrics
Farah N. Ali, Lester M. Arguelles, Craig B. Langman and Heather E. Price
Epidemic
Vitamin D Deficiency in Children With Chronic Kidney Disease: Uncovering an

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