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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: Curr Opin Nephrol Hypertens. 2013 Jul;22(4):377–382. doi: 10.1097/MNH.0b013e3283621408

Impact of new vitamin D data on future studies and treatment

Ishir Bhan 1, Hector Tamez 1, Ravi Thadhani 1
PMCID: PMC3984907  NIHMSID: NIHMS565284  PMID: 23666416

Abstract

Purpose of review

This review evaluates recently published data on clinical effects of vitamin D supplementation, focusing on randomized, placebo-controlled trials and nontraditional actions on the cardiovascular and immune systems.

Recent findings

Several randomized trials evaluating vitamin D therapy have recently emerged, in both the general population and in individuals with chronic kidney disease (CKD). In the former, measurable effects on cardiovascular risk factors have not been detected, with the possible exception of a modest reduction in blood pressure. Studies aimed at boosting immunity have demonstrated efficacy only in specific, high-risk populations. In CKD, the benefits of nutritional vitamin D appear largely limited to earlier stages of disease. Benefits of active vitamin D agents, outside of their known effects on mineral metabolism, have also thus far eluded detection. One possible exception that has accumulated supportive evidence is the link between active vitamin D analogs and decreased proteinuria. Large-scale clinical trials, now underway, will be critical to understanding of the potential benefits and hazards of vitamin D treatment.

Summary

New trials evaluating the effects of vitamin D supplementation have failed to reveal any robust clinical benefits beyond its known actions on mineral and bone disease.

Keywords: cardiovascular disease, chronic kidney disease, immunity, vitamin D

INTRODUCTION

Vitamin D is unique among vitamins: it can be acquired through diet, typically from fortified foods or supplements, or generated through cutaneous synthesis following sunlight exposure. A combination of ultraviolet B radiation (UVB) and heat catalyzes conversion of 7-dehydrocholesterol to D3 (cholecalciferol). D3 is relatively inactive without further metabolism. The largely unregulated hydroxylation at the 25th position, predominantly in the liver, yields 25-hydroxyvitamin D [25(OH)D]. With its long half-life, 25(OH)D is the most stable and widely used measure of vitamin D status, despite having relatively weak affinity for the vitamin D receptor. The CYP27B1 enzyme (1α-hydroxylase), primarily located in the kidney, converts 25(OH)D to the active vitamin, 1,25-dihydroxyvitamin D (1,25(OH)2D).

Renal CYP27B1 activity declines along with glomerular filtration rate (GFR) in advancing chronic kidney disease (CKD). Circulating 1,25(OH)2D levels consequently decrease, resulting in reduced absorption of intestinal calcium, hypocalcemia and secondary hyperparathyroidism. Replacement of active vitamin D with calcitriol or one of its analogues has thus become standard therapy in CKD, aimed at normalizing serum calcium and mitigating bone disease caused by secondary hyperparathyroidism.

Several observational and mechanistic studies have suggested that vitamin D’s actions may be more broad reaching, and more significant, than originally appreciated. Most tissues in the body express vitamin D receptors [1]. In 2003, Teng et al. [2] found that patients with end-stage renal disease (ESRD) on hemodialysis who received paricalcitol had a more favorable survival profile when contrasted with their calcitriol-treated counterparts. A follow-up study showed similar benefit in patients who received any form of active vitamin D vs. nonsupplemented patients [3]. Although numerous studies have echoed these findings, these have largely been retrospective and observational and thus prone to residual confounding effects [4–9].

Animal data on vitamin D has been encouraging. Further investigation into potential beneficial effects on both cardiac function and immunity is particularly relevant as cardiovascular and infectious disease represent the leading causes of morbidity and mortality in ESRD. However, the dearth of prospective interventional studies has tempered initial enthusiasm for vitamin D supplementation. A recent Institute of Medicine report emphasized that data supporting the widespread use of vitamin D for disease prevention and treatment is scant. One high-profile trial aimed at reducing falls and fractures with high dose vitamin D found that treatment in fact increased the risk [10]. Now, new interventional studies are emerging, both in the general and CKD populations.

CLINICAL TRIALS IN THE GENERAL POPULATION

Several recent studies have attempted to establish whether vitamin D supplementation has definite effects on cardiovascular diseases (CVD). In a clinical trial of 305 postmenopausal women, researchers randomized patients to one of two arms of cholecalciferol (400 or 1000 IU per day) or matching placebo for 1 year and examined markers of cardiovascular risk including lipids, apolipoproteins, measures of insulin resistance, inflammatory biomarkers, and blood pressure [11▪]. Despite the broad range of markers, only small, clinically insignificant differences in apo B100 were detected. Interestingly, significant seasonal variation of blood pressure by 6.6 mmHg (lower in summer) was observed across all arms. Seasonal variation in 25(OH)D levels did not explain these findings, suggesting that season itself may have confounded interpretation of previous data linking vitamin D and blood pressure. Critics might point out that the vitamin D dosage was relatively low: the mean 25(OH)D in the high-dose group reached only 30.4 ng/ml after 12 months of treatment, barely clearing the 30 ng/ml threshold many use to define sufficiency. One could also speculate that the relatively healthy population in this trial had little room to improve. Indeed, many have argued that early trials should focus on high-risk populations to maximize the chance of observing a benefit.

A second trial included 114 ambulatory women with intermediate 25(OH)D levels (10–60 ng/ml) treated with cholecalciferol (2500 IU) and evaluated the changes in vascular function using flow-mediated vasodilatation (FMD, a measure of endothelial function), carotid–femoral pulse-wave velocity, and aortic augmentation (measures of arterial stiffness), all of which are predictors of cardiovascular risk [12]. 25(OH)D levels below 30 ng/ml were associated with higher BMI, blood pressure, C-reactive protein (CRP), and FMD. Treatment with cholecalciferol resulted in a 16 ng/ml increase in 25(OH)D, but no difference in any of the outcomes measures was observed between arms. Supplementation effect did not depend on baseline levels, nor was there any observed change in blood pressure. This study reinforces the possibility that previously reported benefits associated with higher 25(OH)D levels from observational studies may have been misinterpreted. Rather than 25(OH)D levels per se, other factors that correlate with both 25(OH)D levels and outcomes may be the key mediators.

Not all interventional trials have been negative. Investigators from Denmark randomized 130 hypertensive patients to 3000 IU of cholecalciferol vs. daily placebo for 20 weeks, and evaluated ambulatory blood pressure and arterial stiffness as measures of cardiovascular health [13▪]. Unlike prior long-term studies, this focused trial limited vitamin D repletion to winter (October–March). There was a nonsignificant decrease in 24-h blood pressure in the cholecalciferol arm. However, restricting the analysis to individuals with baseline levels of 25(OH)D less than 32 ng/ml, the blood pressure reductions were significant (4 mmHg systolic and 3 mmHg diastolic). Measurement of central SBP by applanation tonometry revealed significant reductions in the cholecalciferol arm by 5 mmHg. Although predictable changes in 25(OH)D and parathyroid hormone (PTH) were observed, changes in renin, angiotensin, and aldosterone were not evident. Measures of arterial stiffness were also unchanged. Nonetheless, the study raised the possibility that targeting high-risk individuals may be necessary to observe meaningful clinical changes.

Enhancing immunity, particularly in the CKD population, represents another relevant and promising target for vitamin D therapy that experimental evidence supports. Monocytes and macrophages carry their own inducible 1α-hydroxylase, and vitamin D supplementation appears to boost production of cathelicidin, an antimicrobial peptide with broad-ranging antibacterial properties [14,15]. Despite encouraging observational data and clear biological rationale, recent interventional studies have been less encouraging.

One study of 322 obese individuals who received either 40 000 or 20 000 IU of cholecalciferol weekly or placebo over a year found no association between 25(OH)D and inflammatory markers such as IL-6 and TNF-α [16]. Even after combining the low and high-dose cholecalciferol groups, no effect of on IL-6 was discovered. The one significant difference between groups was an increased CRP level compared with placebo. Similarly, in the Vitamin D and Acute Respiratory Infection Study (VIDARIS) in New Zealand, high-dose monthly cholecalciferol therapy failed to prevent the development of upper respirator tract infections, or affect missed work days, duration of symptoms, or severity of illness [17▪▪].

Instead of focusing on a low-risk healthy population, one trial studied infants less than 1 year old (n = 3046) in Afghanistan, a country with the third highest mortality rate for young children and near-universal vitamin D deficiency [18▪▪]. Infants were randomized to either 100 000 IU cholecalciferol three times per year or matching placebo. Following intervention, radiographically confirmed first pneumonias were similar in both arms. Further analysis led to some concerning findings, including a higher death rate in the vitamin D arm (4.2 per 1000 vs. 3.4 in the placebo arm), though this difference was neither statistically significant nor a primary outcome. Additionally, children in the vitamin D group had a statistically significant increase in repeat episodes of radiographically confirmed pneumonia [hazard ratio (HR) 1.69; P = <0.0001]. When non-confirmed pneumonias were also included, the risk was diminished (HR 1.06) but remained statistically significant (P = 0.04).

Insofar as findings in CVD and infections may depend on the population and outcomes studied, heterogeneity has also been observed in outcomes trials. In contrast to the above negative studies, a double-blinded trial of 247 Mongolian children was promising [19▪]. Children were randomized to daily doses of unfortified or fortified milk (300 IU of cholecalciferol) during the winter. Median baseline 25(OH)D level was profoundly low at 7 ng/ml. The rate of the primary outcome (acute respiratory infection) was halved in the group receiving vitamin D [rate ratio of 0.52 (95% confidence interval: 0.31–0.89)], with no differential effect based on baseline 25(OH)D level. Although the median 25(OH)D level at study completion was considerably higher in the intervention arm, it remained low at 19 ng/ml. This raises the question as to whether population selection plays a role. Another group randomized 95 patients being treated for pulmonary tuberculosis to cholecalciferol (four doses of 100 000 IU) vs. placebo, and found that treatment with vitamin D was associated with faster smear conversion and normalization of white cell counts [20]. Although vitamin D may not be a universal panacea for infectious disease, some signals suggest a potentially important role in specific circumstances and populations.

CLINICAL TRIALS IN CHRONIC KIDNEY DISEASE

Although interventional studies of vitamin D in CKD are scarcer than those in the general population, recent trials have emerged that shed light on potential effects in this vulnerable group. In one trial, 46 patients with stage 2–3 CKD were randomized to high dose cholecalciferol (50 000 IU weekly for 12 weeks, then every other week) or placebo for one year while tracking several cytokines including tumor necrosis factor, IL-6, monocyte chemo-attractant protein-1 (MCP-1), interferon-γ-induced protein-10 and neutrophil gelatinase associated lipocalin at baseline, 12 weeks and 1 year [21]. MCP-1 was correlated with baseline 25(OH)D levels and decreased 18% by 12 weeks in the intervention arm. The decrease in MCP-1 correlated with the increase in 25(OH)D during this timeframe. Despite these intriguing results, the reduction in MCP-1 did not persist at 1 year. Similarly PTH levels decreased after 12 weeks, but did not remain significantly reduced at 1 year [22]. This lack of persistence could be due to a decline in 25(OH)D levels despite continued treatment or due to other compensatory changes with ongoing exposure to supplementation (e.g. changes in vitamin D metabolism). Another study randomized 52 patients with CKD (half on chronic hemodialysis) to either 40 000 IU cholecalciferol or placebo weekly for 8 weeks [23]. Although 25(OH)D levels rose in treated patients, 1,25(OH)2D levels did not increase in the dialysis patients, likely reflecting the loss of 1α-hydroxylase activity that coincides with falling GFR.

Data regarding comparison of different nutritional vitamin D repletion regimens are scarce. The Dialysis Infection and Vitamin D In New England study (DIVINE; NCT00892099) is randomizing 120 incident hemodialysis patients to one of two ergocalciferol arms (50 000 IU weekly or 50 000 IU monthly) or to placebo over 12 weeks and following the response in serum 25(OH)D levels. Secondary outcomes include hospitalizations, changes in cytokines and immunologically active proteins such as cathelicidin.

Given that conversion of 25(OH)D to 1,25(OH)2D is impaired in CKD, several trials have studied calcitriol (or its analogs). The VITAL trial found that addition of 2 μg per day paricalcitol to an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker reduced albuminuria in patients with diabetic nephropathy [24]. Two more recent studies have added support to this model of vitamin D action. In one Chinese study, 50 patients with IgA nephropathy and urinary protein excretion more than 0.8 g per day were randomly assigned to either 0.5 mu;g calcitriol twice weekly or no calcitriol for 48 weeks [25▪]. All patients had received a renin–angiotensin system (RAS) inhibitor for at least 3 months. Protein excretion increased 21% in the control group and decreased 19% in the calcitriol group. Reduction in proteinuria of at least 15% was achieved in 29% of controls vs. 65% in the intervention arm. An open-label study evaluated paricalcitol for proteinuria in 48 patients with at least 0.5 g per day of urinary protein despite anti-RAS therapy after the addition of 1 mu;g per day of oral paricalcitol for 6 months [26]. Mean 24-h urinary protein measurements were halved, falling from 1.23 to 0.61 g. Three months after stopping paricalcitol, urinary protein returned to pretreatment values. Collectively, these data support a role for active vitamin D analogs in the control of proteinuria.

Not all studies of active vitamin D agents have demonstrated consistent beneficial effects in the CKD population. The multinational PRIMO trial (NCT00497146) evaluated the effect of 2 mu;g per day paricalcitol on left ventricular hypertrophy (LVH) in 227 patients with Stage 3b and 4 CKD [27▪▪]. Patients had mild-to-moderate LVH on echocardiogram at baseline. After 48 weeks of treatment, no difference in left ventricular mass index (primary outcome) or in echocardiographic measurements of diastolic function were detected. However, there was an attenuated rise of B-type natriuretic peptide (BNP) and a lower number of cardiovascular hospitalizations in the paricalcitol group compared with placebo. A posthoc analysis demonstrated that paricalcitol reduced the left atrial volume index compared with placebo [28▪]. The atrial reverse remodeling correlated with the changes in BNP. Future studies will need to focus on a population at high-risk for hospitalization, such as patients with advanced heart failure. Another small crossover trial in 22 patients with borderline fasting glucose evaluated glucose tolerance, insulin sensitivity, and insulin responsiveness and found no effect of paricalcitol on these measures. However, 1,25(OH)2D and 25(OH)D were decreased, while FGF-23 and 24,25(OH)2D, an inactive metabolite of vitamin D, were increased [29]. These findings raise the question of whether active vitamin D analogs might have deleterious effects on vitamin D metabolism while increasing FGF-23, a hormone that has been linked to increased mortality in ESRD [29].

FUTURE DIRECTIONS

Despite the wealth of new information that has emerged, additional trials of both nutritional vitamin D and active vitamin D analogs are still needed. Fortunately, several large trials with a range of outcomes are now underway (Table 1). In addition, new frontiers in vitamin D biology are emerging. Recent data from our group suggests that traditional measures of vitamin D status may need to be revisited to account for levels of vitamin D binding protein (VDBP) and albumin, both of which can bind circulating vitamin D. In one model, unbound vitamin D and vitamin D bound relatively weakly to albumin (collectively termed ‘bioavailable vitamin D’) is free to bind to its receptor, while VDBP-bound is relatively inactive. In healthy young individuals bioavailable 25(OH)D, but not total 25(OH)D levels, correlated with bone density [30]. Similarly, only bioavailable 25(OH)D was associated with serum calcium and PTH in dialysis patients [31]. Future studies will need to validate these findings in other populations. In addition to new assays, new treatments are also emerging. Inhibitors of 24-hydroxylase, the enzyme that catabolizes both 25(OH)D and 1,25(OH)2D, may prove useful adjuncts to current therapies [32].

Table 1.

Randomized trials of vitamin D currently underway

Name Country Population Dose Main outcome Current state Results expected
DIVINE United States 120 incident hemodialysis adults (vitamin D <32 ng/ml) 50 000 IU D2 weekly or 50 000 IU D2 monthly or placebo Vitamin D2 >32 ng/ml, cathelicidin and cytokines levels Finalizing recruiting NCT00892099 2013
VITAL United States 20 000 adults (men >50 and women >55 years old) 2000 IU D2 or placebo Cardiovascular disease and cancer Recruiting NCT01169259 2016
DOHealth 8 European cities 2150 adults (>70 years old) 2000 IU D2 or placebo Bone fractures, infection, blood pressure, cognition and lower extremity function Recruiting NCT01745263 2017
VIDA New Zeeland 18 000 adults (>50 years old) 200 000 D3 once (and every June) and 100 000 D3 monthly or placebo Cardiovascular disease, respiratory disease in COPD, bone fractures Finalizing recruiting ACTRN12611000402943 2017
FIND Finland 18 000 adults (men >60 and women >65 years old) 3200 D3 daily, 1600 D3 daily or placebo Cardiovascular disease, cancer and diabetes mellitus Recruiting NCT01463813 2019
VIDAL United Kingdom 20 000 adults (65–85 years old) 100 000 IU D3 monthly, placebo or open control Mortality, morbidity (infections, doctor’s visits, cancer) and vitamin D levels Recruiting (pilot of 1600 participants) ISRCTN46328341 2020
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CONCLUSION

After years of observational studies linking vitamin D to improved outcomes, the results of randomized trials of vitamin D supplementation are finally emerging in the literature and point to decidedly mixed results. Although select high-risk populations with specific disorders may benefit from vitamin D supplementation, broad effects on CVD, immunity, and other nontraditional actions are not supported by current data. Large-scale randomized trials, currently underway, will provide important guidance for treatment practices. In the interim, no established justification exists for the use of nutritional vitamin D analogs in dialysis patients or for using any form of vitamin D for actions outside of mineral metabolism. A prominent exception relevant to patients with CKD may be to control proteinuria, in which several trials have demonstrated a beneficial effect. Trials that target specific populations will likely have the greatest likelihood of demonstrating tangible effects.

KEY POINTS.

  • Initial randomized trials of vitamin D are now emerging, but generally have failed to demonstrate broadly applicable health benefits beyond known effects on bone disease.

  • Widespread use of vitamin D for nontraditional indications is not supported by current data.

  • Important large-scale randomized trials are now underway and will yield valuable additional information in years to come.

Acknowledgments

We are indebted to Kathy Lucchesi, Ph.D., R.Ph. for her critical reading of the article, helpful discussions, and feedback of the article.

Footnotes

Conflicts of interest

R.I.T. has a research grant from Abbott Laboratories and is a consultant to Fresenius Medical Care North America and Diasorin. I.B. and H.T. have no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000).

  • 1.Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. doi: 10.1056/NEJMra070553. [DOI] [PubMed] [Google Scholar]
  • 2.Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446–456. doi: 10.1056/NEJMoa022536. [DOI] [PubMed] [Google Scholar]
  • 3.Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16:1115–1125. doi: 10.1681/ASN.2004070573. [DOI] [PubMed] [Google Scholar]
  • 4.Shoji T, Shinohara K, Kimoto E, et al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant. 2004;19:179–184. doi: 10.1093/ndt/gfg513. [DOI] [PubMed] [Google Scholar]
  • 5.Melamed ML, Eustace JA, et al. Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int. 2006;70:351–357. doi: 10.1038/sj.ki.5001542. [DOI] [PubMed] [Google Scholar]
  • 6.Tentori F, Hunt WC, Stidley CA, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 2006;70:1858–1865. doi: 10.1038/sj.ki.5001868. [DOI] [PubMed] [Google Scholar]
  • 7.Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006;70:771–780. doi: 10.1038/sj.ki.5001514. [DOI] [PubMed] [Google Scholar]
  • 8.Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med. 2008;168:397–403. doi: 10.1001/archinternmed.2007.110. [DOI] [PubMed] [Google Scholar]
  • 9.Shoben AB, Rudser KD, de Boer IH, et al. Association of oral calcitriol with improved survival in nondialyzed CKD. J Am Soc Nephrol. 2008;7:1613–1619. doi: 10.1681/ASN.2007111164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815–1822. doi: 10.1001/jama.2010.594. [DOI] [PubMed] [Google Scholar]
  • 11▪.Wood AD, Secombes KR, Thies F, et al. Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. J Clin Endocrinol Metab. 2012;97:12. doi: 10.1210/jc.2012-2126. This study of 305 postmenopausal women randomized to two doses of vitamin D (400 or 1000 IU daily) or placebo found no change in biomarkers. The study reports seasonal variation of blood pressure (lowest in the summer) [DOI] [PubMed] [Google Scholar]
  • 12.Gepner AD, Ramamurthy R, Krueger DC, et al. A prospective randomized controlled trial of the effects of vitamin D supplementation on cardiovascular disease risk. PLOS ONE. 2012;7:8. doi: 10.1371/journal.pone.0036617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13▪.Larsen T, Mose FH, Bech JN, et al. Effect of cholecalciferol supplementation during winter months in patients with hypertension: a randomized, placebo-controlled trial. Am J Hypertens. 2012;25:1215–1222. doi: 10.1038/ajh.2012.111. Danish randomized trial of 130 hypertensive patients to either 3000 IU of cholecalciferol or placebo for 12 weeks found a decrease in 24-h blood pressure monitoring only in vitamin D deficient patients (<32 ng/ml) [DOI] [PubMed] [Google Scholar]
  • 14.Liu PT, Stenger S, Li H, Wenzel L, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–1773. doi: 10.1126/science.1123933. [DOI] [PubMed] [Google Scholar]
  • 15.Bhan I, Camargo CA, Wenger J, et al. Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J Allergy Clin Immunol. 2011;127:1302–1340. doi: 10.1016/j.jaci.2010.12.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Beilfuss J, Berg V, Sneve M, et al. Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects. Cytokine. 2012;60:870–874. doi: 10.1016/j.cyto.2012.07.032. [DOI] [PubMed] [Google Scholar]
  • 17▪▪.Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012;308:7. doi: 10.1001/jama.2012.12505. Randomized, double blind, placebo-controlled trial of 322 healthy adults found that high-dose vitamin D (200 000 IU once, then 100 000 monthly afterwards) did not reduce incidence or severity of upper respiratory tract infections. [DOI] [PubMed] [Google Scholar]
  • 18▪▪.Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet. 2012;379:9. doi: 10.1016/S0140-6736(11)61650-4. Randomized trial of 1524 Afghan children (<1 year old) to 100 000 IU of cholecalciferol or placebo found no effect of vitamin D on the prevention of pneumonia. This study targeted a very high-risk population for infections, with high prevalence of vitamin D deficiency. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19▪.Camargo CA, Ganmaa D, Frazier AL, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012;130:9. doi: 10.1542/peds.2011-3029. Randomized trial including 744 severely vitamin D deficient Mongolian children who received either unfortified or fortified (300 IU of cholecalciferol) milk found that vitamin D supplementation reduced the risk of acute respiratory infections. [DOI] [PubMed] [Google Scholar]
  • 20.Coussens AK, Wilkinson RJ, Hanifa Y, et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci USA. 2012;109:15449–15454. doi: 10.1073/pnas.1200072109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Alvarez JA, Zughaier SM, Law J, et al. Effects of high-dose cholecalciferol on serum markers of inflammation and immunity in patients with early chronic kidney disease. Eur J Clin Nutr. 2013;67:264–269. doi: 10.1038/ejcn.2012.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Alvarez JA, Law J, Coakley KE, et al. High-dose cholecalciferol reduces parathyroid hormone in patients with early chronic kidney disease: a pilot, randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2012;96:672–679. doi: 10.3945/ajcn.112.040642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Marckmann P, Agerskov H, Thineshkumar S, et al. Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D. Nephrol Dialysis Transplant. 2012;27:3523–3531. doi: 10.1093/ndt/gfs138. [DOI] [PubMed] [Google Scholar]
  • 24.de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543–1551. doi: 10.1016/S0140-6736(10)61032-X. [DOI] [PubMed] [Google Scholar]
  • 25▪.Liu LJ, Lv JC, Shi SF, et al. Oral calcitriol for reduction of proteinuria in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis. 2012;59:67–74. doi: 10.1053/j.ajkd.2011.09.014. This study enrolled 50 patients with IgA nephropathy and proteinuria and randomized the patients to calcitriol (0.5 μg twice weekly) or no therapy for 48 weeks. Results echoed the VITAL study results, showing reduced proteinuria with active vitamin D therapy compared with placebo. [DOI] [PubMed] [Google Scholar]
  • 26.De Nicola L, Conte G, Russo D, et al. Antiproteinuric effect of add-on paricalcitol in CKD patients under maximal tolerated inhibition of reninangiotensin system: a prospective observational study. BMC Nephrol BioMed Central. 2012;13:150. doi: 10.1186/1471-2369-13-150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27▪▪.Thadhani RI, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674–684. doi: 10.1001/jama.2012.120. Multinational trial that randomized 227 patients to paricalcitol (2 μg daily) or placebo found no effect of paricalcitol on left ventricular hypertrophy (primary outcome). However, paricalcitol therapy decreased cardiovascular hospitalizations and attenuated the rise of BNP. [DOI] [PubMed] [Google Scholar]
  • 28▪.Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164:902–912. doi: 10.1016/j.ahj.2012.09.018. Posthoc analysis of the PRIMO randomized trial that showed a decrease in left atrial volume index with paricalcitol therapy (over 48 weeks) compared with placebo. Reverse atrial remodeling correlated with BNP changes. [DOI] [PubMed] [Google Scholar]
  • 29.Gutiérrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–592. doi: 10.1056/NEJMoa0706130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Powe CE, Ricciardi C, Berg AH, et al. Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship. J Bone Miner Res. 2011;26:1609–1616. doi: 10.1002/jbmr.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Bhan I, Powe CE, Berg AH, et al. Bioavailable vitamin D is more tightly linked to mineral metabolism than total vitamin D in incident hemodialysis patients. Kidney Int. 2012;82:84–89. doi: 10.1038/ki.2012.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys. 2012;523:9–18. doi: 10.1016/j.abb.2011.11.003. [DOI] [PubMed] [Google Scholar]

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