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Hindawi Publishing CorporationInternational Journal o EndocrinologyVolume , Article ID ,pageshttp://dx.doi.org/.//

Research ArticleInflammatory Markers: C-Reactive Protein,Erythrocyte Sedimentation Rate, and Leukocyte Count in

Vitamin D Deficient Patients with and without ChronicKidney Disease

Ibrahim Yildirim,1 Ender Hur,1 and Furuzan Kokturk2

Division of Nephrology, Department of Internal Medicine, University of Bulent Ecevit, Zonguldak, urkey Department of Biostatistics, University of Bulent Ecevit, Zonguldak, urkey

Correspondence should be addressed to Ibrahim Yildirim; [email protected]

Received April ; Accepted June

Academic Editor: Hulya askapan

Copyright Ibrahim Yildirim et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Although some studies revealed a positive relationship between vitamin D3deciency and inammatory markers, there have been

also many studies that ailed to nd this relationship. Te aim o this large scaled study is to determine the association between

the level o plasma hydroxy vitamin D3 [-(OH) D3] and inammatory markers in the general population without chronickidney disease (CKD) and in patients with CKD. Participants with simultaneously measured inammatory markers and -(OH)D

3levels were retrospectively analyzed ( = 1897). Te incidence o all-cause inammation inection, hospitalization, chronic renal

ailure, and vitamin B deciency was evaluated. Te medians o serum creatinine levels in subjects without renal ailure werelower in -(OH) D

3decient group. Patients with CKD were more likely to have vitamin D

3deciency compared with normal

GFR. -(OH) D3levels were associated with a greater incidence o all-cause hospitalization, hypoalbuminemia, and vitamin B

deciency. However, there was no relationship between inammatory markers and vitamin D3

levels. In -(OH) D3

decientpatients, inammatory markers can be related to other inammatory and inectious status such as malnutrition and cachexia. Webelieved that there must be a relationship between vitamin deciency and inammatory markers due to other causes than low-(OH) D

3status.

1. Introduction

Te deciency o vitamin D3 is commonly associated withchronic kidney disease (CKD), and the prevalence o thishypovitaminosis increases as kidney unction declines [,].Several actors, such as aging, loss o appetite, and other ac-tors affecting cutaneous synthesis, such as low sun exposureand skin pigmentations [], have consistently been associatedwith low -hydroxyvitamin D [-(OH) D3] levels in thegeneral population. Tereore, it is common in the elderly,malnourished individuals, and some societies [].

Even though there is growing evidence to suggest thatvitamin D3 status is associated with the development andprogression o cardiovascular disease [,], diabetes [], andimmune system disorders [], there is limited inormation

about the association o -(OH) D3

deciency and inam-mation in the general population without CKD and in

patients with CKD.Studies examining the association between low -(OH)

D3levels and inammation inection are still popular. Tereare studies suggesting a relationshipbetween a lack o vitaminD3 and morbidity and also mortality as well []. Teresults o these studies were contradictory and conusing.Randomized controlled trials o vitamin D3supplementationhave shown incompatible results, with some trials suggestinga decrease [,] and other studies concluding no effect oninammatory biomarkers [].

Te potential relationship between the deciency o vita-min D3 and inection-inammation remains poorly under-stood. Tereore, the aim o present study is to examine the

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International Journal o Endocrinology

: Demographical data.

Patients with CKD

Gender (M/F) (/)

Outpatient (%) (.)

Hospitalized patient (all-cause) (%) (.)Te elderly group

years

years

> years

CKD: chronic kidney disease; M: male; F: emale; : the number oparticipants.

association between the level o plasma -(OH) D3

andinammatory markers in the general population withoutchronic kidney disease and in patients with CKD.

2. Methods

.. Study Population. Present study was conducted betweenJanuary , and April , in Bulent Ecevit Uni-

versity Hospital and patients with -(OH) D3 levelsand inammatory markers measured simultaneously wereincluded. Patients whose age under years, patients withprimary hyperparathyroidism and hypoparathyroidism, wereexcluded.Te study participants age,gender, and hospitaliza-tion data were recorded. Te clinical and laboratory data areshown in ables and. Te relationship between -(OH)D3 levels and serum creatinine, parathormone (PH), sen-sitive C-reactive protein (CRP), erythrocyte sedimentationrate (ESR), leucocyte count, platelet count, and hemoglobinconcentrations were evaluated as retrospectively in this studypopulation.

Serum -(OH) D3 levels vary depending on season;we categorized patients into two groups according to serum-(OH) D3 levels. Group was composed o vitamin D3decient ( g/L). Patients with vitaminD

3levelsbetween g/Land g/Lwere excluded rom the

analysis in order to avoid the effects o seasonal changes. Sothis intermediate group was not used in this study (Figure ).

Patients with known levels o CRP were grouped categor-ically as normal (CRP< mg/L; there was no inammationor inection) and as abnormal (CRP > mg/L; there wasimportant inammatory or inectious status). Likewise, toexamine the relationship between renal ailure and -(OH)D3 levels, participants were divided into categorical groups:the patients with and without renal ailure. CKD was denedaccording to serum creatinine levels. Study cases with serumcreatinine levels above . mg/dL or more than monthswere considered as patients with CKD.

Moreover, the participants in this study were also dividedinto two groups: ambulatory patients and hospitalizedpatients.

: Clinical and laboratory data.

Variable () MeanSD (MinMax)

Age (year) () 55 15()

-(OH) D(g/L) () 16 13()

Vit B (pg/mL) () . ()

PH (pg/mL) () 112 184()CRP (mg/L) () 12.9 26.7()

ESR (mm/h) () 29 21.7()

WBC (/g/L) () 7.7 3.5(.)

Hemoglobin (gr/dL) () 12.5 1.7(..)

Platelet (/g/L) () 264 82()

Albumin (gr/dL) () 4.13 0.58(..)

Vit B: vitamin B; PH: parathormone; CRP: C-reactive protein; ESR:erythrocyte sedimentation rate; WBC: white blood cells; SD: standarddeviation; Min: minimum; Max: maximum.

21g/L29%

40%

1021g/L

F : Distribution o -(OH) vitamin D3

levels in studypopulation.

Finally, vitamin B levels were measured in vitamin D3

decient and vitamin D3normal group, and then these twogroups were divided into subgroups o their own.

Primary endpoints are as ollows:

() determining the -(OH) D3

level in the generalpopulation and in patients with CKD;

() comparing the clinical and laboratory data regardinginammation with levels o -(OH) D3;

() evaluation o whether low and normal -(OH) D3

levels and inammation could explain this potentialassociation;

.. Biochemical Analysis. -HydroxyvitaminD3levels weremeasured by high perormance liquid chromatographic anal-ysis perormed with using a Zivak HPLC system (Gebze,urkey) using a commercial -OH vitamin D

3kit (Recipe,

Munich, Germany). Te reerence values were g/L orwinter, g/L or summer seasons. A deciency in -(OH) D3level was considered as below g/L.

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: Vitamin Ddecient and normal group medians in all outpatients participants.

(otal number) -(OH) D g/L

Median (MinMax) Median (MinMax)

Age ( = 1032) () () .

Albumin ( = 292) . (.) . () .

CRP ( = 554) . () . () .Creatinine ( = 770) . (.) . (.) .

PH ( = 655) . () () .

ESR ( = 716) () () .

WBC ( = 767) . (..) . (..) .

Vitamin B ( = 254) () () .

CRP:C-reactive protein;ESR: erythrocyte sedimentation rate; WBC: whiteblood cells; Min: minimum; Max: maximum. When hospitalized patientsincludedin the analysis; albumin and ESR gained signicance ( = 0.001, = 0.024, resp.)

Serum vitamin B andplasma PH levelswere measuredwith chemiluminescence method by Immulite (Diag-nostic Products Corp., LA, USA).

PH was measured by chemiluminescence with reerencevalues o g/L.

C-reactive protein was assayed with Dade Behring BNProSpec System using a nephelometric method.

Serum albumin levels and ESR were measured by routinelaboratory methods.

Leukocyte count, platelet count, and hemoglobin con-centrations were measured by Beckman Coulter LH hematology analyzer.

.. Statistical Analysis. Statistical analyses were perormedby SPSS . sofware (SPSS Inc., Chicago, IL, USA). Distri-bution o data was determined by Kolmogorov-Smirnov test.

Continuous variables were expressed as median (minimum-maximum) and categorical variables as requency and per-cent. Continuous variables were compared with the Mann-Whitney U test and categorical variables were comparedusing Pearsons Chi-square test. Linear relation between twocontinuous variables was evaluated by Spearman correlationanalysis.Pvalue o less than . was considered statisticallysignicant or all tests.

3. Results

A total o subjects were included in this retrospectivestudy. Patients that measured -(OH) D3levels under g/l

were (.%), the number o those between and g/Lwas (.%), andthe number o those over g/L was (.%), respectively, in the study group (Figure ).

Te difference between male and emale in -(OH) D3levels was statistically signicant ( < 0.001), and -(OH)D3levels were signicantly lower in emale [16.1 12.8()] than in male [19.2 12.9()]. For this reason, maleand emale patients were divided into groups according tothe presence o renal ailure. Te results are summarized inablesand.

Tere was no signicant correlation between ageand vita-min D

3deciency in our study population. Tere were lower

serum albumin levels in patients with vitamin D3deciency,

but this was not statistically signicant (able ). Medianserum creatinine levels were less in patients with vitaminD3deciency without renal ailure than in participants withnormal vitamin D

3levels without renal ailure (able ).

Serum albumin, CRP, ESR, and WBC levels had nosignicant relationship in groups that vitamin D

3deciency

and vitamin D3normal in male and emale patients withoutrenal ailure (ables ). Tere was no difference in thelevels o albumin, CRP, ESR, and WBC in women with renalinsufficiency, but there was signicant difference betweenlevels o serum albumin and ESR in male patients.

Te inammatory status measured by CRP showed nodifference with respect to the -(OH) D

3( = 0.318).

In CRP variable that was categorized as

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: (a) Vitamin D decient and normal group medians in subjects without renal ailure; (b) vitamin D decient and normal groupmedians in subjects with renal ailure.

(a)

-(OH) vitamin D g/L Median (Minmax) Median (MinMax)

Age ( = 706) () () .Albumin ( = 227) . (.) . () .

CRP ( = 401) . () . () .

Creatinine ( = 706) . (..) . (..) .

PH ( = 426) . () () .

ESR ( = 543) () () .

WBC ( = 605) . (..) . (..) .

CRP: C-reactive protein; PH: parathormone; ESR: erythrocyte sedimentation rate; WBC: white blood cells; Min: minimum; Max: maximum.

(b)

-(OH) D g/L Median Median

Age ( = 178) () . () .

Albumin ( = 109) . (..) . (..) .

CRP ( = 102) () () .

Creatinine ( = 178) . (..) . (..) .

PH ( = 121) . () () .

ESR ( = 106) () () .

WBC ( = 144) . (..) . (..) .

CRP: C-reactive protein; PH: parathormone; ESR: erythrocyte sedimentation rate; WBC: white blood cells; SD: standard deviation; Min: minimum; Max:maximum.

: Vitamin D levels in patients with inammation andwithout inammation.

-(OH) DMedian

(MinMax)

-(OH) D(MeanSD)

CRP mg/dL () 17.47 15.65

CRP total () 17.44 13.65

CRP: C-reactive protein; SD: standard deviation.

study population. Te incidence o vitamin D3

deciencyin all-cause hospitalized patients was more requent ( =0.000). Te prevalence o vitamin D3deciency in outpatients

was .% ( = 236) and in hospitalized patients was .%( = 7 7). Te number o subjects with normal vitamin D3was .% or outpatients ( = 274) and or hospitalizedpatients was .% ( = 37), respectively (able ). Moreoverage, ESR, WBC, and CRP medians had higher levels inhospitalized patients.

Finally, B levels were measured in patients. Teprevalence o low vitamin B ( pg/mL) was % ( = 1 4) in the group with vitaminD3deciency, whereas the prevalence o low vitamin B was.% ( = 108), and the prevalence o normal vitamin B(Number ) was .% ( = 102) in the normal vitamin D3

: Te requency o CRP, vitamin B, hospitalization, andrenal ailure in -(OH) vitamin D

deciency.

-(OH) D g/L,(%)

CRP mg/dL (.) (.)

otal .

Vit Bpg/mL (.) (.)

otal .

Albumin. g/dL () (.)

otal .

Outpatients (.) (.)

Inpatients (.) (.)

otal .

With CKD (.) ()

Without CKD (.) ()

otal .

CRP: C-reactive protein; CKD: chronic kidney disease.

group. Vitamin B deciency was more requently seen inpatients with vitamin D3deciency ( = 0.043) (able ).

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4. Discussion

Present study did not reect the true incidence o vitamin D3

deciency becausepatientswho are thought to lack o vitaminD3were included in this study. A limited number o studiesconducted in urkey have shown that vitamin D

3deciency

is a common issue during the all and winter in individuals,particularly or elderly. Te deciency o vitamin D

3is seen

in % o women in our country. Vitamin D3deciencyrates are % in the Middle East, % in Asia, %in Europe, and % in Latin America []. Female consti-tutes the majority o patients may be due to less exposure tothe sun and the higher prevalence o osteoporosis.

Tere was no signicant correlation between age andvitamin D deciency and that may be due to individualcharacteristics o the studied population. Tis relationship isshown in some other studies [, ]. But manystudies did notmentionedthe relationship between age andvitamin D levels.

In present study we did not nd a relationship betweenvitamin D3 deciency and inammatory markers, such as

CRP, ESR, and leukocyte counts. Some other studies mea-sured CRP was ound the relationship but in these studiesthe relatively small number o participants were the limitingactor [,]. In several studies were unknown accompany-ing diseases, and hospitalization rates [,]. Tere were nostudies evaluating ESR, and leukocyte counts were evaluatedin -(OH) D3deciency.

Sensitive CRP that was not measured is the limitation othe study. o resolve this drawback was categorized patientsaccording to the levelso CRP. Tereore we divided ourstudypopulations into subsets according to CRP levels. Firstly, wecounted the number o patients with and without vitamin D3deciency in CRP normal group. We ound no signicant

difference between two subgroups. Secondly, we separatedthe study population into CRP normal and signicantly highCRP groups. We ound no signicant difference between thelast subgroups again. Te reason or this classication wasto evaluate the requency o vitamin D

3deciency in out-

patients with important high level o CRP. Finally, we appliedcorrelation analysis between the level o CRP and -(OH)D3. But a relationship between the level o CRP and -(OH)D

3was not ound in all our analyses. In other words, we did

not observe an association between vitamin D deciency andCRP levels anyway.

Patients age, serum albumin, CRP, and ESR levels,leukocyte counts, and creatinine values were signicantly

different between ambulatory and hospitalized patients. Temedians o inammatory markers o hospitalized patientswere higher compared to those o ambulatory patients exceptalbumin levels. In addition, the requency o -(OH) D3deciency was higher once again in hospitalized patients.Tese also mean that -(OH) D3 deciency aggravatesall-cause diseases, which is associated with the course oinammation and inection but not CRP levels.

Te prevalence o vitamin D3deciency in patients with

CKD was more common at all stages in emale patients;however, it was more common at advanced stage in malepatients. Tis could be explained by a combination o actors,such as poor nutrition or a lack o skin synthesis due to low

sun exposure []. In CKD patients, dietary restriction andloss o appetite due to uremia or high levels o broblastgrowth actor may be stronger determining actors or -(OH) D3deciency.

In groups without renal ailure, creatinine values ovitamin D3 decient patients were lower than vitamin D 3

normal subjects. Vitamin D3 decient patients had higherPH values. Higher PH values were known and expectedto be higher among the vitamin D

3 decient patients [].

However, the low level o creatinine was not been describedpreviously, and this difference was statistically signicant.

In our study population, the levels o albumin were lowerin vitamin D3 decient patients than in vitamin D3 normalparticipations. However, this state did not reach statisticalsignicance. Tis also pointed out other studies []. It hasbeen reported decreased level o albumin in a large scaledstudy o Melamed et al. [].

In groups without renal ailure, low creatinine and albu-min levels might be associated with a nutritional disorder orother comorbid inammatory-inectious status. It is knownthat deciency o vitamin D

3and malnutrition wererelated to

each other. Some studies demonstrated that the replacemento vitamin D

3did not correct mortality []. Patients with

high mortality despite treatment with vitamin D3could haveother disorders. o clariy this state we evaluated another

vitamin such as vitamin B. Vitamin B deciency wasmore common in vitamin D3 decient patients. Multivita-min deciency was common in malnourished and elderlypatients, but there was no study that tested vitamin B levelsin vitamin D

3decient patient in the literature.

For more accurate assessment it is necessary to knowother actors that trigger inammation and inection instudies examining the relationship between vitamin D andinammatory markers. For example, when hospitalizedpatients are included in our analysis; all inammatory mark-ers gained signicance statistically.

In addition, the reason or the deciency o -(OH) D3

should be known in similar studies. However, there may beno relationship in encountered -(OH) D

3deciency due to

low sunlight exposure, and it could be expected in patientswith -(OH) D

3deciency due to malnutrition.

According to the results o our study, high levels o CRPin vitamin D decient patients might be related to otheractors such as inectious, inammatory status, malnutrition,cachexia, or multivitamin deciency. Tese actors and othersmay affect high morbidity and mortality in patients with

vitamin D3 deciency. Tereore, replacement o vitamin Dalone could be corrected only in patients with vitamin Ddecient patients in the oreground.

Conflict of Interests

Te authors declare that they have no competing interests.

Authors Contribution

Yildirim Ibrahim participated in concept, design, data col-lection, data analysis, data interpretation, and writing. Hur

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Ender participated in data interpretation and writing. Kok-turk Furuzan participated in data analysis.

Acknowledgment

Tis study was unded by University o Bulent Ecevit.

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