the number of peer - reviewed publications with the term ' vitamin d ' in their title or abstract has increased greatly since the early 2000s1 ) . pubmed currently lists over 25,000 publications from 1950 to the present . in the 1960s , fewer than 100 papers on ' vitamin d ' were published per year ; however , in 2010 , this rate of publication reached approximately 2,500 papers per year . this expansion of research over recent decades has resulted in a dramatic increase in our understanding of additional biological actions of vitamin d on various systems including pancreas -cell function , immune , cardiovascular , muscle , and brain systems , and control of the cell cycle . an interesting relationship exists between mortality in ischemic heart disease and geographic latitude in european countries2 ) , which shows an increase in the mortality of heart diseases with increase in latitude . additionally , serum 25-hydroxyvitamin d ( 25(oh)d ) levels have been shown to be higher in healthy subjects at lower latitudes2 ) . phosphate is absorbed from the diet in the gut , stored in the skeleton , and excreted by the kidneys ; 1,25-dihydroxyvitamin d ( 1,25(oh)2d ) stimulates absorption of phosphate from the diet3 ) . fibroblast growth factor ( fgf)-23 increases renal phosphate clearance , suppresses synthesis of 1,25(oh)2d , and may decrease parathyroid hormone ( pth ) . pth increases renal phosphate clearance and stimulates synthesis of 1,25(oh)2d4 ) . in chronic kidney disease ( ckd ) patients , ionizing calcium ( ica ) is decreased secondary to phosphate retention and decrease in 1,25(oh)2d . phosphate retention increases fgf-23 , which , in conjunction with its cofactor , klotho protein , decreases the activity of 1-hydroxylase and increases 24-hydroxylase , thus decreasing the levels of circulating 1,25(oh)2d . decreases in the vitamin d receptor ( vdr ) , calcium sensor receptor , and klotho - fgfr1 receptor complex in the parathyroid gland aggravate the development of the secondary hyperparathyroidism in ckd patients4 ) . apart from hyperparathyroidism , calcium and phosphate imbalance and vitamin d deficiency also contribute to vascular calcification . a cross - sectional study by gracia - canton et al . has reported an independent negative association between serum levels of 25(oh)d and vascular calcification in 210 patients with stage 4 and 5 ckd5 ) . plain x - ray images of pelvis , hands , and lateral lumbar spines from all subjects were studied for calculation of semi - quantitative vascular calcification scores , as described by adragao6 ) and kauppila7 ) . adragao scores revealed only 47 patients ( 22.4% ) without vascular calcification and 120 patients ( 57.1% ) with scores higher than 35 ) . kauppila scores revealed only 29 patients ( 13.8% ) without aortic calcifications and 114 patients ( 54.3% ) with scores higher than 75 ) . higher vascular calcification scores were related to older age , diabetes , history of cardiovascular disease ( cvd ) , and lower levels of 25(oh)d5 ) . only one - fifth of patients had adequate levels of 25(oh)d , whereas a half had vitamin d insufficiency , and a quarter had vitamin deficiency ( fig . vitamin d is a multifunctional hormone that can affect many essential biological functions , ranging from immune regulation to mineral ion metabolism . calcitriol or 1,25(oh)2d is the active form of vitamin d , formed by dual hydroxylation in the liver and kidney . figure 2 shows a simplified diagram of the different stages of vitamin d synthesis8 ) . vitamin d2 ( ergocalciferol ) , which is absorbed mainly from food , and vitamin d3 ( cholecalciferol ) , produced in the skin by photolytic cleavage of 7-dehydrocholesterol , is transported to the liver and converted to 25(oh)d , the major circulating metabolite of vitamin d. the final activation step , 1-hydroxylation , occurs primarily , but not exclusively , in the kidney , forming 1,25(oh)2d8 ) . vdrs are operational in at least 38 tissues of the body . in these target tissues , vdr functions in the cell nucleus as a transcriptional factor influencing approximately 3% of the human genome , and in the plasma membrane caveolae as a modulator of signal transduction pathways ( fig . the activity of the vdr conformational ensemble ( with 2 ligand pockets ) can generate either genomic or rapid biological responses . in this model , one shape ( 6-s - trans ) of the conformationally flexible 1,25(oh)2d can interact with vdr localized in the cell nucleus to generate genomic responses via regulation of gene transcription , whereas a different shape ( 6-s - cis ) of 1-25(oh)2d binds to the second ligand pocket of the vdr associated with caveolae of the plasma membrane to generate rapid responses1 ) . non - calciotropic actions involve activation of vdrs by locally produced 1,25(oh)2d in a number of tissues in a paracrine and autocrine fashion9 ) . experimental studies have shown that vitamin d treatment reduces neurohormonal activation , inhibits inflammation , and suppresses ventricular hypertrophy10 ) . the recent workshop consensus for vitamin d nutritional guidelines estimated that approximately 50% and 60% of the older populations in north america and the rest of the world , respectively , do not have satisfactory vitamin d status11 ) . reasons for this remain unclear but are probably related to factors such as urbanization , demographic shifts , decreased outdoor activity , air pollution , global dimming , and decrease in cutaneous production of vitamin d with age . epidemiological investigations in many countries have shown high prevalence of unsatisfactory vitamin d status ( table 1)12 - 15 ) . in particular , the 2008 korea national health and nutrition examination survey ( knhanes ) found vitamin d insufficiency in 47.3% of male and 64.5% of female subjects15 ) . the outpatient cross - sectional cohort study conducted by levin et al . a decrease in 1,25(oh)2d levels was above the range of glomerular filtration rate ( gfr ) values even in the early stage of ckd16 ) . similarly , significant inverse correlations were observed among serum phosphate , fgf-23 and pth levels , and gfr in patients with stage 1 to 3 ckd17 ) . it is consistent with the previous data that 25(oh)d deficiency worsens with the progression of ckd . therefore , the kidney disease : improving global outcomes ( kdigo ) clinical practice guidelines have recommended annual measurement of 25(oh)d and have also recommended that the level should be maintained at 30 ng / ml or higher in patients with any stage of ckd19 ) . melamed et al . tested the association of low 25(oh)d levels with all - cause , cancer , and cvd mortality in 13,331 nationally representative adults from the third national health and nutrition examination survey ( nhanes iii ) linked mortality files20 ) . in this cross - sectional multivariate analysis , increasing age , female sex , non - white race / ethnicity , diabetes , current smoking , and higher body mass index were all independently associated with higher odds of 25(oh)d deficiency , whereas greater physical activity , vitamin d supplementation , and non - winter season showed an inverse association20 ) . in multivariate models , compared with the highest quartile , being in the lowest quartile for 25[oh]d levels ( < 17.8 ng / ml ) was associated with a 26% increased rate of all - cause mortality ( mortality rate ratio , 1.26 ; 95% ci , 1.08 - 1.46 ) and a population attributable risk of 3.1%20 ) . the prospective cohort study by dobnig et al . , which enrolled patients undergoing diagnostic coronary angiography with normal kidney function showed a similar result with regard to relationships between endogenous 25(oh)d and 1,25(oh)2d levels and all - cause and cardiovascular mortality21 ) . multivariate - adjusted hazard ratios ( hrs ) for patients with lower levels of 25(oh)d were two times higher for all - cause mortality and cardiovascular mortality21 ) . a meta - analysis of randomized controlled trials by autier and gandini showed that intake of ordinary doses of vitamin d supplements appears to be associated with decreases in total mortality rates22 ) . they have identified 18 independent randomized controlled trials , including 57,311 participants . the relative risk for mortality from any cause was 0.93 ( 95% ci , 0.87 - 0.99)22 ) . have reported on vitamin d supplementation in ckd by meta - analysis23 ) . among observational studies and randomized controlled trials , significant improvement was observed in serum 25(oh)d levels , along with an associated decline in pth levels23 ) . however , included studies were mostly of low to moderate quality and did not show beneficial effects on hard clinical endpoints23 ) . reported on the benefit of activated vitamin d treatment in patients with predialysis ckd24 ) . the incidence rate for mortality and combined death and dialysis initiation was significantly lower in treated than in untreated patients . one prospective cohort study of incident dialysis patients in the netherlands ( the necosad ) revealed an association of vitamin d deficiency in dialysis patients with an adverse health outcome , in particular , with short - term cardiovascular mortality25 ) . . reported on a historical cohort study of activated injectable vitamin d and hemodialysis survival26 ) . during a 2-year observational period , 37,173 patients on hemodialysis received activated injectable vitamin d , and 13,864 did not . at 2 years , the mortality rate was 13.8/100 person - years in the group that received injectable vitamin d , compared with 28.6/100 person - years in the non - vitamin d group ( p < 0.001 ) . the incidence of cardiovascular - related mortality was 7.6/100 person - years in the injectable vitamin d group , compared with 14.6/100 person - years in the non - vitamin d group ( p < 0.001 ) . the study by wolf et al . also showed that , although low vitamin d levels were associated with increased mortality , significant interactions were noted among vitamin d levels , subsequent active vitamin d therapy , and survival27 ) . compared with patients with the highest 25(oh)d or 1,25(oh)2d levels who received therapy , untreated deficient patients showed a significantly increased risk for early mortality27 ) ( table 2 ) . in summary , vitamin d deficiency is common not only in ckd patient but also in the general population . reduced vdr activation occurs early in ckd . decreased vdr activation is a major pathophysiological factor in the development of secondary hyperparathyroidism and also contributes to ckd morbidity and mortality .
mineral metabolism abnormalities , such as low 1,25-dihydroxyvitamin d ( 1,25(oh)2d ) and elevated parathyroid hormone ( pth ) , are common at even higher glomerular filtration rate than previously described . 
 levels of 25-hydroxyvitamin d ( 25(oh)d ) show an inverse correlation with those of intact pth and phosphorus . 
 studies of the general population found much higher all - cause and cardiovascular ( cv ) mortality for patients with lower levels of vitamin d ; this finding suggests that low 25(oh)d level is a risk factor and predictive of cv events in patients without chronic kidney disease ( ckd ) . 
 25(oh)d/1,25(oh)2d becomes deficient with progression of ckd . 
 additionally , studies of dialysis patients have found an association of vitamin d deficiency with increased mortality . 
 restoration of the physiology of vitamin d receptor activation should be essential therapy for ckd patients .