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DOI: 10.1542/peds.2008-06342009;123;791Pediatrics

Farah N. Ali, Lester M. Arguelles, Craig B. Langman and Heather E. Price

EpidemicVitamin D Deficiency in Children With Chronic Kidney Disease: Uncovering an

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ARTICLE

Vitamin D Deficiency in Children With ChronicKidney Disease: Uncovering an Epidemic

Farah N.Ali,MDa,b, LesterM. Arguelles, PhDc, Craig B. Langman,MDa,b, Heather E. Price,MSa,b

aFeinberg School of Medicine, Northwestern University, Chicago, Illinois; bDivisions of Pediatrics and of Kidney Diseases, Childrens Memorial Hospital, Chicago, Illinois;cThe Mary Ann & J. Milburn Smith Child Health Research Program, Childrens Memorial Hospital, Chicago, Illinois

The authors have indicated they have no financial 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 sufficiency, insufficiency, and

deficiency in a large group of children with CKD and provide a firm foundation for

recommendations for measurement of 25(OH)D.

ABSTRACT

BACKGROUND. Vitamin D deficiency in children adversely affects bone development byreducing mineralization. Children with chronic kidney disease are at risk for altered

bone development from renal osteodystrophy and concomitant vitamin D deficiency.

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 deficiency in children with chronic kidney disease is notwell studied.

OBJECTIVES. The purpose of this work was to determine whether children with chronic

kidney disease had vitamin D deficiency, to evaluate whether the prevalence of

vitamin D deficiency 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 acontemporary group of patients from 2005 to 2006.

RESULTS. The prevalence of vitamin D deficiency ranged from 20% to 75% in thedecade studied. There was a significant 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 deficiency 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 deficiency, and its prevalence wasincreasing yearly in the studied decade. Contemporary data show that vitamin D deficiency 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

THE PATHWAY OFvitamin 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 ofUV-B from sun exposure. This compound then undergoes 2 subsequent hydroxylations, the first of which takes placein 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 modified 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 Dadequacy that guarantees optimal skeletal mineralization. Vitamin D deficiency 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 deficiency as part of the entity CKD-mineral and bone disorder.35 Vitamin D deficiency 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 2009by the

AmericanAcademy of Pediatrics

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defined by inadequate 25(OH)D levels. The pediatricNational Kidney Foundation Kidney Disease Outcomes

Quality Initiative (KDOQI) guidelines6 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

deficiency in children with CKD is not well studied.25(OH)D levels 32 ng/mL have defined vitamin D

insufficiency, 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 inhealthy adolescents.8 Vitamin D deficiency occurs with

25(OH)D levels 15 ng/mL.6

The objective of our study, then, was to determine the

extent of vitamin D deficiency/insufficiency in children

with CKD. Thus, we chose to evaluate a cohort over apast 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 deficiency/insufficiency in both.

MATERIALSANDMETHODS

Decade Data

25(OH)D levels in ambulatory pediatric patients with

CKD, stages 1 through 5, were measured under clinicalcare 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 first data point available for eachyear. 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 tothose children with a 25(OH)D 32 ng/mL (80 nM) and

iPTH between 0 and 100 pg/mL to reduce the influence

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-

ously9 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 dataregarding CKD staging based on the Schwartz formula

for estimated glomular filtration 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-

els11 to determine the appropriateness of linear terms forthe 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:

yijb0i b1iTimeij eijand 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 jis influenced 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 theunique 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 significance of these random effects can bedetermined by a likelihood ratio 2 test.12

Finally, we modeled the prevalence of 25(OH)D de-

ficiency 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 procmixed and proc genmod, respectively.

The relationship between 25(OH)D and PTH wasstudied 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. Pval-

ues .05 were considered statistically significant. 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 30.2ng/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 deficiency, defined as a25(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 individualtrends 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 had25(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 significant (P .0001).

However, we noted that the individual heterogeneity in

25(OH)D concentration at time 0 was quite large, wherethe 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 between0.07 (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 thatthose who had a higher 25(OH)D concentration at time

0 were likely to have a higher negative slope or moreextreme decrease.

To evaluate the relationship between 25(OH)D and

iPTH, we limited our analysis to those children with a25(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

influence 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 of19.421. We found a small but highly significant 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 significantly higher

values of 25(OH)D than those who had levels drawn in

the winter-to-spring time periods from January throughJune (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

FIGURE2

Prevalenceof severe25(OH)Ddeficiency indecadedataof childrenwithCKD.Therewere

differences between the yearly values (F 311.59;P .001), and a trend (P .001) of

increasing prevalence of 25(OH)D levels15 ng/mL was noted over the decade.

FIGURE3

iPTH levelsare inverselyrelated to 25(OH)D levels (R 0.109; P .001).Our analysis was

limitedto valuesof 25(OH)D32ng/mLand iPTH levels between0 and100 pg/mL.The

solid line represents the regression line, and the dashed lines represent the 95% confi-

dence intervals around the regression.

FIGURE1

Differences inyearly25(OH)Dlevelsin decadedataof children withCKD.Theboxdenotes

25th to 75th percentiles; the line in box is the median; and black circles denote the 5th

and95thpercentiles.For theindividual years in thedecade19871996:n79, n100,

n148,n144,n254,n220,n246,n154,n311,and n336.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 deficiency in this contemporary studygroup was 39%, and the majority, 72%, had levels32 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 deficient or insufficient. The

mean levels of 25(OH)D in blacks and Hispanics were

17 and 18 ng/mL, respectively, which were signifi-

cantly lower than the mean level of 28 ng/mL found

in whites (P .05).

DISCUSSIONThe 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, deficiency of vitamin D leads to the classical

findings 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 glomularfiltration 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 thisdeficiency in our patients with CKD.14 Deficient

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. Inadults, 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 normalrange after 1 year, as well as a correlation between

pretherapy and 1-year therapy values of growth velocityand serum 25(OH)D3 concentration.17

There is increasing literature documenting numerous

nonclassical or nonendocrine actions of vitamin D aswell. 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 bloodpressure 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.20Although 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 al7

in a population of normal urban adults, vitamin D in-sufficiency 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 findings 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 levelsin adults with CKD. LaClair et al21 conducted a study in

adult patients with moderate-to-severe CKD, not ondialysis, 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 sufficient in their vitamin D sta-

tus. A recent cross-sectional study in 1814 unselectedoutpatients with CKD from across the United States

found that 50% of subjects had inadequate 25(OH)D

levels, with a 12% prevalence of frank deficiency in this

population.13 A study in 104 adult hemodialysis patients

reported 51% of the sampled population having a levelof 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 al16 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 deficiency among

children with CKD. Our randomly chosen contemporary

cohort, which is representative of the current patients atour institution, demonstrated similar levels of defi-

ciency, even with excluding nephrotic patients who

have been found previously to have a higher likelihood

of vitamin D deficiency.23

FIGURE4

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 findings in our study validate previ-ous knowledge that increased content of melanin does in

fact decrease vitamin D production in the skin,24because

we found more vitamin D deficiency 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 finding of increasing prevalence of vitamin D

deficiency over the decade studied is noteworthy. This

finding 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 finding. 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 deficiency.

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, hassignificantly 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 beenuseful 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, wefound similar 25(OH)D levels to the decade group,

which supports the findings from the decade group.

CONCLUSIONS

To date there has been a paucity of published data for

children with CKD examining the extent of nutritionalvitamin D deficiency. Our data over time and extent of

CKD serve to illustrate that 25(OH)D deficiency is a

significant problem for this population of children. Al-

though another decade has passed since this data set was

collected, a contemporary population of similar childrenwith CKD at the same institution and city demonstrates

that vitamin D deficiency 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 isnoteworthy that the median levels were always insuffi-

cient. Black and Hispanic children are possibly at even

greater risk of severe deficiency. Our data support the

pediatric KDOQI guideline for the measurement of

25(OH)D levels in children with CKD, to reduce theeffects of vitamin D deficiency as an important compo-

nent of their renal osteodystrophy, now termed CKD-

mineral and bone disorder.4

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tific 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 ourhands 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 fine

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 isntis a dollar we dont have to spend where we might actually find 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.

KalbC. Newsweek.com. January 16, 2009

Noted by DLS, MD



8/8

DOI: 10.1542/peds.2008-0634

2009;123;791PediatricsFarah N. Ali, Lester M. Arguelles, Craig B. Langman and Heather E. Price

EpidemicVitamin D Deficiency in Children With Chronic Kidney Disease: Uncovering an

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