A large proportion of patients with chronic kidney disease (CKD) are vitamin D deficient (plasma 25-hydroxyvitamin D (25(OH)D) < 25 or 30 nmol/L per UK and US population guidelines) and this ...contributes to the development of CKD–mineral bone disease (CKD–MBD). Gaps in the evidence-base for the management of vitamin D status in relation to CKD–MBD are hindering the formulation of comprehensive guidelines. We conducted a systemic review of 22 RCTs with different forms of vitamin D or analogues with CKD–MBD related outcomes and meta-analyses for parathyroid hormone (PTH). We provide a comprehensive overview of current guidelines for the management of vitamin D status for pre-dialysis CKD patients. Vitamin D supplementation had an inconsistent effect on PTH concentrations and meta-analysis showed non- significant reduction (
P
= 0.08) whereas calcifediol, calcitriol and paricalcitol consistently reduced PTH. An increase in Fibroblast Growth Factor 23 (FGF23) with analogue administration was found in all 3 studies reporting FGF23, but was unaltered in 4 studies with vitamin D or calcifediol. Few RCTS reported markers of bone metabolism and variations in the range of markers prevented direct comparisons. Guidelines for CKD stages G1–G3a follow general population recommendations. For the correction of deficiency general or CKD-specific patient guidelines provide recommendations. Calcitriol or analogues administration is restricted to stages G3b–G5 and depends on patient characteristics. In conclusion, the effect of vitamin D supplementation in CKD patients was inconsistent between studies. Calcifediol and analogues consistently suppressed PTH, but the increase in FGF23 with calcitriol analogues warrants caution.
The field of vitamin D public health research has a pressing need to define sensitive and specific predictors of vitamin D status that can be used to determine whether an individual or population has ...a supply of vitamin D that is sufficient to meet requirements. The aim of this review is to highlight the considerations needed when evaluating evidence of the relations between vitamin D biomarkers and functional or health outcomes across the life cycle. It draws attention to the importance of distinguishing between biomarkers of supply, function, and outcome and of considering the many factors that could influence interpretation, such as life stage, ethnicity, body mass index, liver and kidney function, and dietary calcium and phosphorus intake. The vitamin D biomarkers that have shown the most utility to date are the plasma concentration of 25-hydroxyvitamin D (supply), the plasma concentration of parathyroid hormone (function), and the presence or absence of rickets (outcome). However, a single biomarker of vitamin D status or threshold value is unlikely to be valid in all situations. The field therefore needs research to refine existing biomarkers or establish new indicators that take the many factors into account and to identify useful functional biomarkers of vitamin D status for infants, children, women of reproductive age, and specific ethnic groups. However, evidence using the biomarkers currently available shows that frank vitamin D deficiency is a major public health problem in many parts of the world that requires urgent attention.
The demand for measurement of vitamin D metabolites for clinical diagnosis and to advance our understanding of the role of vitamin D in human health has significantly increased in the last decade. ...New developments in technologies employed have enabled the separation and quantification of additional metabolites and interferences. Also, developments of immunoassays have changed the landscape. Programmes and materials for assay standardisation, harmonisation and the expansion of the vitamin D external quality assurance scheme (DEQAS) with the provision of target values as measured by a reference measurement procedure have improved standardisation, quality assurance and comparability of measurements. In this article, we describe developments in the measurement of the commonly analysed vitamin D metabolites in clinical and research practice. We describe current analytical approaches, discuss differences between assays, their origin, and how these may be influenced by physiological and experimental conditions. The value of measuring metabolites beyond 25 hydroxyvitamin D (25(OH)D), the marker of vitamin D status, in routine clinical practice is not yet confirmed. Here we provide an overview of the value and application of the measurement of 1,25 dihydroxyvitamin D, 24,25 dihydroxyvitamin D and free 25OHD in the diagnosis of patients with abnormalities in vitamin D metabolism and for research purposes.
Context:
Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, ...considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD.
Objectives:
Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD.
Design:
This study used a cross-sectional design.
Setting:
The general community in the United States, United Kingdom, and The Gambia were included in this study.
Participants:
Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included.
Exposures:
Total 25OHD concentration, race, and DBP (GC) genotype exposures were included.
Outcome Measures:
Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures.
Results:
Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured by monoclonal assay, mean DBP in African-ancestry subjects was approximately 50% lower than in whites, whereas DBP measured by polyclonal DBP antibodies or proteomic methods was not lower in African-ancestry. Calculated f25OHD (using polyclonal DBP assays) correlated strongly with directly measured f25OHD (r = 0.80–0.83). Free 25OHD, measured or calculated from polyclonal DBP assays, reflected total 25OHD concentration irrespective of race and was lower in African Americans than in US whites.
Conclusions:
Previously reported racial differences in DBP concentration are likely from monoclonal assay bias, as there was no racial difference in DBP concentration by other methods. This confirms the poor vitamin D status of many African-Americans and the utility of total 25OHD in assessing vitamin D in the general population.
We found no racial or genetic differences in serum vitamin D binding protein. Free 25OHD, directly measured or calculated from DBP (using polyclonal antibodies), was low in Afro-Americans, compared to US whites or blacks from The Gambia.
Vitamin D is an important determinant of bone health at all ages. The plasma concentrations of 25-hydroxy vitamin D (25-OH D) and other metabolites are used as biomarkers for vitamin sufficiency and ...function. To allow for the simultaneous determination of five vitamin D metabolites, 25-OH D
3
, 25-OH D
2
, 24,25-(OH)
2
D
3
, 1,25-(OH)
2
D
3
, and 1,25-(OH)
2
D
2
, in low volumes of human plasma, an assay using ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) was established. Plasma samples were spiked with isotope-labeled internal standards and pretreated using protein precipitation, solid-phase extraction (SPE) and a Diels–Alder derivatization step with 4-phenyl-1,2,4-triazoline-3,5-dione. The SPE recovery rates ranged from 55% to 85%, depending on the vitamin D metabolite; the total sample run time was <5 min. Mass spectrometry was conducted using positive ion electrospray ionization in the multiple reaction monitoring mode on a quadrupole–quadrupole-linear ion trap instrument after pre-column addition of methylamine to increase the ionization efficiency. The intra- and inter-day relative standard deviations were 1.6–4.1% and 3.7–6.8%, respectively. The limit of quantitation for these compounds was determined to be between 10 and 20 pg/mL. The 25-OH D results were compared with values obtained for reference materials (DEQAS). In addition, plasma samples were analyzed with two additional Diasorin antibody assays. All comparisons with conventional methods showed excellent correlations (
r
2
= 0.9738) for DEQAS samples, demonstrating the high degree of comparability of the new UHPLC-MS/MS technique to existing methods.
Every tenth pregnancy is affected by hypertension, one of the most common complications and leading causes of maternal death worldwide. Hypertensive disorders in pregnancy include pregnancy-induced ...hypertension and preeclampsia. The pathophysiology of the development of hypertension in pregnancy is unknown, but studies suggest an association with vitamin D status, measured as 25-hydroxyvitamin D (25(OH)D). The aim of this study was to investigate the association between gestational 25(OH)D concentration and preeclampsia, pregnancy-induced hypertension and blood pressure trajectory. This cohort study included 2000 women. Blood was collected at the first (T1) and third (T3) trimester (mean gestational weeks 10.8 and 33.4). Blood pressure at gestational weeks 10, 25, 32 and 37 as well as symptoms of preeclampsia and pregnancy-induced hypertension were retrieved from medical records. Serum 25(OH)D concentrations (LC-MS/MS) in T1 was not significantly associated with preeclampsia. However, both 25(OH)D in T3 and change in 25(OH)D from T1 to T3 were significantly and negatively associated with preeclampsia. Women with a change in 25(OH)D concentration of ≥30 nmol/L had an odds ratio of 0.22 (p = 0.002) for preeclampsia. T1 25(OH)D was positively related to T1 systolic (β = 0.03, p = 0.022) and T1 diastolic blood pressure (β = 0.02, p = 0.016), and to systolic (β = 0.02, p = 0.02) blood pressure trajectory during pregnancy, in adjusted analyses. There was no association between 25(OH)D and pregnancy-induced hypertension in adjusted analysis. In conclusion, an increase in 25(OH)D concentration during pregnancy of at least 30 nmol/L, regardless of vitamin D status in T1, was associated with a lower odds ratio for preeclampsia. Vitamin D status was significantly and positively associated with T1 blood pressure and gestational systolic blood pressure trajectory but not with pregnancy-induced hypertension.
We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, ...associations between vitamin D status and pregnancy loss were studied.
Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week ≤ 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south-west Sweden at latitude 57-58°N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression.
T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD ≥ 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a ≥ 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery.
Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy.
Context:
Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response.
Objective:
We assessed which maternal and ...environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol.
Design:
Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy.
Setting:
Hospital antenatal clinics.
Participants:
A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks.
Interventions:
1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery.
Main Outcome Measure:
25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison).
Results:
25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean SD, 67.7 21.3 nmol/L) compared with placebo (43.1 22.5 nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = −0.81 95% confidence interval −1.39, −0.22), lower compliance with study medication (%) (β = −0.28 −0.072, −0.48), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 0.16, 0.40), and delivery in the winter vs the summer (β = −10.5 −6.4, −14.6) were independently associated with lower 25(OH)D at 34 weeks of gestation.
Conclusions:
Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.
Within the treatment arm of the MAVIDOS RCT, poorer 25(OH)D response to 1000IU/d cholecalciferol was associated with lower initial 25(OH)D, greater pregnancy weight gain and delivery in winter.
•We developed a mathematical model to predict longitudinally the population mean plasma 25(OH)D concentration during winter.•Predicted values closely matched plasma 25(OH)D concentrations as measured ...in the UK population.•Vitamin D intake required to maintain the population mean plasma 25(OH)D concentration at a predetermined concentration can be predicted from this model.
On a population basis, there is a gradual decline in vitamin D status (plasma 25(OH)D) throughout winter. We developed a mathematical model to predict the population winter plasma 25(OH)D concentration longitudinally, using age-specific values for 25(OH)D expenditure (25(OH)D3t1/2), cross-sectional plasma 25(OH)D concentration and vitamin D intake (VDI) data from older (70+ years; n=492) and younger adults (18–69 years; n=448) participating in the UK National Diet and Nutrition Survey. From this model, the population VDI required to maintain the mean plasma 25(OH)D at a set concentration can be derived. As expected, both predicted and measured population 25(OH)D (mean (95%CI)) progressively declined from September to March (from 51 (40–61) to 38 (36–41)nmol/L (predicted) vs 38 (27–48)nmol/L (measured) in older people and from 59 (54–65) to 34 (31–37)nmol/L (predicted) vs 37 (31–44)nmol/L (measured) in younger people). The predicted and measured mean values closely matched. The predicted VDIs required to maintain mean winter plasma 25(OH)D at 50nmol/L at the population level were 10 (0–20) to 11 (9–14) and 11 (6–16) to 13(11–16)μg/d for older and younger adults, respectively dependent on the month. In conclusion, a prediction model accounting for 25(OH)D3t1/2, VDI and scaling factor for the 25(OH)D response to VDI, closely predicts measured population winter values. Refinements of this model may include specific scaling factors accounting for the 25(OH)D response at different VDIs and as influenced by body composition and specific values for 25(OH)D3 t1/2 dependent on host factors such as kidney function. This model may help to reduce the need for longitudinal measurements.
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