the deficiency of vitamin d3 is commonly associated with chronic kidney disease ( ckd ) , and the prevalence of this hypovitaminosis increases as kidney function declines [ 1 , 2 ] .
several factors , such as aging , loss of appetite , and other factors affecting cutaneous synthesis , such as low sun exposure and skin pigmentations , have consistently been associated with low 25-hydroxyvitamin d [ 25-(oh ) d3 ] levels in the general population .
therefore , it is common in the elderly , malnourished individuals , and some societies .
even though there is growing evidence to suggest that vitamin d3 status is associated with the development and progression of cardiovascular disease [ 5 , 6 ] , diabetes , and immune system disorders , there is limited information about the association of 25-(oh ) d3 deficiency and inflammation in the general population without ckd and in patients with ckd .
studies examining the association between low 25-(oh ) d3 levels and inflammation infection are still popular .
there are studies suggesting a relationship between a lack of vitamin d3 and morbidity and also mortality as well [ 912 ] .
randomized controlled trials of vitamin d3 supplementation have shown incompatible results , with some trials suggesting a decrease [ 13 , 14 ] and other studies concluding no effect on inflammatory biomarkers .
the potential relationship between the deficiency of vitamin d3 and infection - inflammation remains poorly understood .
therefore , the aim of present study is to examine the association between the level of plasma 25-(oh ) d3 and inflammatory markers in the general population without chronic kidney disease and in patients with ckd .
present study was conducted between january 1 , 2008 and april 25 , 2012 in bulent ecevit university hospital and 1897 patients with 25-(oh ) d3 levels and inflammatory markers measured simultaneously were included .
patients whose age under 18 years , patients with primary hyperparathyroidism and hypoparathyroidism , were excluded .
the relationship between 25-(oh ) d3 levels and serum creatinine , parathormone ( pth ) , sensitive c - reactive protein ( crp ) , erythrocyte sedimentation rate ( esr ) , leucocyte count , platelet count , and hemoglobin concentrations were evaluated as retrospectively in this study population .
serum 25-(oh ) d3 levels vary depending on season ; we categorized patients into two groups according to serum 25-(oh ) d3 levels .
g / l ) population , and group 2 was composed of vitamin d3 normal group ( > 21 
g / l and 20  g / l were excluded from the analysis in order to avoid the effects of seasonal changes .
patients with known levels of crp were grouped categorically as normal ( crp < 6 
mg / l ; there was no inflammation or infection ) and as abnormal ( crp > 30 
mg / l ; there was important inflammatory or infectious status ) . likewise , to examine the relationship between renal failure and 25-(oh ) d3 levels , participants were divided into categorical groups : the patients with and without renal failure .
study cases with serum creatinine levels above 1.3  mg / dl for more than 3 months were considered as patients with ckd . moreover ,
the participants in this study were also divided into two groups : ambulatory patients and hospitalized patients .
finally , vitamin b12 levels were measured in vitamin d3 deficient and vitamin d3 normal group , and then these two groups were divided into subgroups of their own .
primary endpoints are as follows : determining the 25-(oh ) d3 level in the general population and in patients with ckd;comparing the clinical and laboratory data regarding inflammation with levels of 25-(oh ) d3;evaluation of whether low and normal 25-(oh ) d3 levels and inflammation could explain this potential association ; determining the 25-(oh ) d3 level in the general population and in patients with ckd ; comparing the clinical and laboratory data regarding inflammation with levels of 25-(oh ) d3 ; evaluation of whether low and normal 25-(oh ) d3 levels and inflammation could explain this potential association ; 25-hydroxyvitamin d3 levels were measured by high performance liquid chromatographic analysis performed with using a zivak hplc system ( gebze , turkey ) using a commercial 25-oh vitamin d3 kit ( recipe , munich , germany ) .
l for summer seasons . a deficiency in 25-(oh ) d3 level was considered as below 10 
serum vitamin b12 and plasma pth levels were measured with chemiluminescence method by immulite 2000 ( diagnostic products corp . ,
c - reactive protein was assayed with dade behring bn prospec system using a nephelometric method .
leukocyte count , platelet count , and hemoglobin concentrations were measured by beckman coulter lh 780 hematology analyzer .
continuous variables were expressed as median ( minimum - maximum ) and categorical variables as frequency and percent .
continuous variables were compared with the mann - whitney u test and categorical variables were compared using pearson 's chi - square test .
patients that measured 25-(oh ) d3 levels under 10  g / l were 598 ( 31.5% ) , the number of those between 10 and 21  g / l was 751 ( 39.5% ) , and the number of those over 21  g / l was 550 ( 28.9% ) , respectively , in the study group ( figure 1 ) .
the difference between male and female in 25-(oh ) d3 levels was statistically significant ( p < 0.001 ) , and 25-(oh ) d3 levels were significantly lower in female [ 16.1  12.8 ( 3121 ) ] than in male [ 19.2  12.9 ( 3201 ) ] . for this reason , male and female patients were divided into groups according to the presence of renal failure .
there was no significant correlation between age and vitamin d3 deficiency in our study population .
there were lower serum albumin levels in patients with vitamin d3 deficiency , but this was not statistically significant ( table 3 ) .
median serum creatinine levels were less in patients with vitamin d3 deficiency without renal failure than in participants with normal vitamin d3 levels without renal failure ( table 4 ) .  
serum albumin , crp , esr , and wbc levels had no significant relationship in groups that vitamin d3 deficiency and vitamin d3 normal in male and female patients without renal failure ( tables 14 ) .
there was no difference in the levels of albumin , crp , esr , and wbc in women with renal insufficiency , but there was significant difference between levels of serum albumin and esr in male patients .
the inflammatory status measured by crp showed no difference with respect to the 25-(oh ) d3 ( p = 0.318 ) . in crp variable that was categorized as < 6  mg / l and 6  mg / l
, there was no significant difference between crp categories and 25-(oh ) d3 levels ( p = 0.728 ) .
the results are summarized in table 5 . in crp variable that was categorized as < 6  mg / l and 30  mg / l
, there was no significant difference between these crp categories and 25-(oh ) d3 levels ( p = 0.635 ) ( table 6 ) .
then , all participants were included in the study , both 25-(oh ) d3 and crp variables taken as a numerical , and correlation analysis was performed .
there was no correlation between the two groups ( r = 0.03 , p = 0.335 ) .
the difference between men and women crp levels was statistically significant ( p = 0.013 ) .
crp and vitamin d3 levels in men and women were different ; therefore , similar analyses were repeated in men and women groups .
median crp in vitamin d3 deficient group and vitamin d3 normal group showed no significant difference in the male and female patients .
there was a weak positive correlation between age and crp ( r = 0.21 , p < 0.001 ) .
when 25-(oh ) d3 and crp variables are taken as categorical variables and analyzing the relationships between variables , no significant correlation was found ( p = 1.000 ) .
the prevalence of vitamin d3 deficiency in patients with renal failure had a higher number ( p = 0.000 ) ( table 6 ) .
this frequency were not statistically significant in male patients except advanced - stage renal failure ( creatinine < 3.8  mg / dl ) , ( p = 0.148 ) .
the frequency of vitamin d deficiency was evaluated between outpatient and hospitalized patients groups in this study population .
the incidence of vitamin d3 deficiency in all - cause hospitalized patients was more frequent ( p = 0.000 ) .
the prevalence of vitamin d3 deficiency in outpatients was 46.3% ( n = 236 ) and in hospitalized patients was 67.5% ( n = 77 ) .
( n = 274 ) and for hospitalized patients was 32.4% ( n = 37 ) , respectively ( table 6 ) .
moreover age , esr , wbc , and crp medians had higher levels in hospitalized patients .
the prevalence of low vitamin b12 ( < 160  pg / ml ) was 68% ( n = 30 ) , and the prevalence of normal vitamin b12 level ( > 160  pg / ml ) was 32% ( n = 14 ) in the group with vitamin d3 deficiency , whereas the prevalence of low vitamin b12 was 51.4% ( n = 108 ) , and the prevalence of normal vitamin b12 ( number 30 ) was 48.6% ( n = 102 ) in the normal vitamin d3 group .
vitamin b12 deficiency was more frequently seen in patients with vitamin d3 deficiency ( p = 0.043 ) ( table 6 ) .
present study did not reflect the true incidence of vitamin d3 deficiency because patients who are thought to lack of vitamin d3 were included in this study .
a limited number of studies conducted in turkey have shown that vitamin d3 deficiency is a common issue during the fall and winter in individuals , particularly for elderly .
vitamin d3 deficiency rates are 8084% in the middle east , 6065% in asia , 5055% in europe , and 50% in latin america [ 1618 ] .
female constitutes the majority of patients may be due to less exposure to the sun and the higher prevalence of osteoporosis .
there was no significant correlation between age and vitamin d deficiency and that may be due to individual characteristics of the studied population .
but many studies did not mentioned the relationship between age and vitamin d levels . in present study
we did not find a relationship between vitamin d3 deficiency and inflammatory markers , such as crp , esr , and leukocyte counts .
some other studies measured crp was found the relationship but in these studies the relatively small number of participants were the limiting factor [ 20 , 21 ] .
in several studies were unknown accompanying diseases , and hospitalization rates [ 9 , 22 ] .
there were no studies evaluating esr , and leukocyte counts were evaluated in 25-(oh ) d3 deficiency .
sensitive crp that was not measured is the limitation of the study . to resolve this drawback was categorized patients according to the levels of crp
firstly , we counted the number of patients with and without vitamin d3 deficiency in crp normal group .
secondly , we separated the study population into crp normal and significantly high crp groups .
the reason for this classification was to evaluate the frequency of vitamin d3 deficiency in out - patients with important high level of crp .
finally , we applied correlation analysis between the level of crp and 25-(oh ) d3 .
but a relationship between the level of crp and 25-(oh ) d3 was not found in all our analyses . in other words
, we did not observe an association between vitamin d deficiency and crp levels anyway .
patients ' age , serum albumin , crp , and esr levels , leukocyte counts , and creatinine values were significantly different between ambulatory and hospitalized patients .
the medians of inflammatory markers of hospitalized patients were higher compared to those of ambulatory patients except albumin levels . in addition , the frequency of 25-(oh ) d3 deficiency was higher once again in hospitalized patients .
these also mean that 25-(oh ) d3 deficiency aggravates all - cause diseases , which is associated with the course of inflammation and infection but not crp levels .
the prevalence of vitamin d3 deficiency in patients with ckd was more common at all stages in female patients ; however , it was more common at advanced stage in male patients .
this could be explained by a combination of factors , such as poor nutrition or a lack of skin synthesis due to low sun exposure . in ckd patients , dietary restriction and loss of appetite due to uremia or high levels of fibroblast growth factor 23
may be stronger determining factors for 25-(oh ) d3 deficiency . in groups without renal failure ,
higher pth values were known and expected to be higher among the vitamin d3 deficient patients .
however , the low level of creatinine was not been described previously , and this difference was statistically significant . in our study population ,
the levels of albumin were lower in vitamin d3 deficient patients than in vitamin d3 normal participations .
it has been reported decreased level of albumin in a large scaled study of melamed et al . .
in groups without renal failure , low creatinine and albumin levels might be associated with a nutritional disorder or other comorbid inflammatory - infectious status .
it is known that deficiency of vitamin d3 and malnutrition were related to each other .
multivitamin deficiency was common in malnourished and elderly patients , but there was no study that tested vitamin b12 levels in vitamin d3 deficient patient in the literature . for more accurate assessment
it is necessary to know other factors that trigger inflammation and infection in studies examining the relationship between vitamin d and inflammatory markers .
for example , when hospitalized patients are included in our analysis ; all inflammatory markers gained significance statistically .  
in addition , the reason for the deficiency of 25-(oh ) d3 should be known in similar studies .
however , there may be no relationship in encountered 25-(oh ) d3 deficiency due to low sunlight exposure , and it could be expected in patients with 25-(oh ) d3 deficiency due to malnutrition .   according to the results of our study , high levels of crp in vitamin d deficient patients might be related to other factors such as infectious , inflammatory status , malnutrition , cachexia , or multivitamin deficiency .
these factors and others may affect high morbidity and mortality in patients with vitamin d3 deficiency .
therefore , replacement of vitamin d alone could be corrected only in patients with vitamin d deficient patients in the foreground .
 although some studies revealed a positive relationship between vitamin d3 deficiency and inflammatory markers , there have been also many studies that failed to find this relationship . 
 the aim of this large scaled study is to determine the association between the level of plasma 25 hydroxy vitamin d3 [ 25-(oh ) d3 ] and inflammatory markers in the general population without chronic kidney disease ( ckd ) and in patients with ckd . 
 participants with simultaneously measured inflammatory markers and 25-(oh ) d3 levels were retrospectively analyzed ( n = 1897 ) . 
 the incidence of all - cause inflammation infection , hospitalization , chronic renal failure , and vitamin b12 deficiency was evaluated . 
 the medians of serum creatinine levels in subjects without renal failure were lower in 25-(oh ) d3 deficient group . 
 patients with ckd were more likely to have vitamin d3 deficiency compared with normal gfr . 
 25-(oh ) d3 levels were associated with a greater incidence of all - cause hospitalization , hypoalbuminemia , and vitamin b12 deficiency . 
 however , there was no relationship between inflammatory markers and vitamin d3 levels . in 25-(oh ) 
 d3 deficient patients , inflammatory markers can be related to other inflammatory and infectious status such as malnutrition and cachexia . 
 we believed that there must be a relationship between vitamin deficiency and inflammatory markers due to other causes than low 25-(oh ) d3 status . 
1. Introduction
2. Methods
3. Results
4. Discussion