Vitamin D Status and Clinical Outcomes in Acute Respiratory Distress Syndrome: A Secondary Analysis From the Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury (ALVEOLI) Trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a highly morbid condition that has limited therapeutic options. Optimal vitamin D status has been linked to immunological effects that may benefit critically ill patients. Therefore, we investigated whether admission 25-hydroxyvitamin D levels (25OHD) are associated with clinical outcomes in ARDS patients. METHODS: We performed a secondary analysis of data from a randomized, controlled trial comparing oxygenation strategies in 549 patients with ARDS (NCT00000579). Baseline 25OHD was measured in stored plasma samples. We investigated the relationship between vitamin D status and ventilator-free days (VFD) as well as 90-day survival, using linear regression and Cox proportional hazard models, respectively. Analyses were adjusted for age, race, and Acute Physiology and Chronic Health Evaluation III score. RESULTS: Baseline 25OHD was measured in 476 patients. 90% of these individuals had 25OHD <20 ng/ml and 40% had 25OHD <10 ng/ml. Patients with 25OHD <20 ng/ml were likely to be ventilated for 3 days longer than patients with levels ≥20 ng/ml (ß 3.41; 95%CI 0.42-6.39: P = 0.02). Patients with 25OHD <10 ng/ml were likely to be ventilated for 9 days longer (ß 9.27; 95%CI 7.24-11.02: P < 0.001) and to have a 34% higher risk of 90-day mortality (HR 1.34; 95% CI 1.06-1.71: P = 0.02) compared to patients with levels >10 ng/ml. CONCLUSIONS: In patients with ARDS, vitamin D status is associated with duration of mechanical ventilation and 90-day mortality. Randomized, controlled trials are warranted to determine whether vitamin D supplementation improves clinical outcomes in ARDS patients.

Acute Homeostatic Changes Following Vitamin D2 Supplementation.

CONTEXT: Changes in vitamin D binding protein (DBP) concentrations and catabolism of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D (24,25D) after vitamin D2 supplementation may alter concentrations and bioavailability of circulating 25-hydroxyvitamin D (25D). OBJECTIVE: Examine acute changes in vitamin D metabolism and bioavailability after vitamin D2 supplementation. METHODS: Study design was secondary analysis of a single-arm interventional study. Thirty consenting volunteers were treated with five 50,000 IU oral doses of ergocalciferol over 2 weeks. Main outcome measures included concentrations of DBP, vitamin D metabolites, and bioavailable 25-hydroxyvitamin D (25D) in pre- and posttreatment serum samples. RESULTS: After supplementation, 25D2 (mean ± standard deviation) increased from 1.4 ± 0.9 ng/mL to 45.3 ± 16.5 ng/mL (P < 0.0001), and 25D3 levels decreased from 26.8 ± 9.9 ng/mL to 19.7 ± 8.2 ng/mL (P < 0.0001). Total 25D (25D2 plus 25D3) increased from 28.2 ± 10.0 ng/mL to 65.0 ± 21.1 ng/mL (152.2% ± 102.5%; P < 0.0001). DBP and total 24,25D concentrations increased 39.1% ± 39.4% (165.6 ± 53.8 µg/mL to 222.0 ± 61.1 µg/mL; P < 0.0001) and 31.3% ± 48.9% (3.9 ± 2.0 ng/mL to 4.7 ± 2.1 ng/mL; P = 0.0147), respectively. In contrast to total 25D, bioavailable 25D increased by 104.4% ± 99.6% (from 5.0 ± 2.0 ng/mL to 8.7 ± 2.7 ng/mL; P < 0.001), and 1,25D increased by 32.3% ± 38.8% (from 45.5 ± 10.7 pg/mL to 58.1 ± 13.0 pg/mL; P = 0.0006). There were no changes in calcium or parathyroid hormone (P > 0.05 for both). CONCLUSION: Changes after vitamin D2 supplementation involve acute rise in serum DBP and 24,25D, both of which may attenuate the rise in bioavailable 25D and 1,25D.

Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial.

OBJECTIVES: To compare changes in vitamin D status and cathelicidin (LL-37) levels in septic ICU patients treated with placebo versus cholecalciferol. DESIGN: Randomized, placebo-controlled, trial. SETTING: Medical and surgical ICUs of a single teaching hospital in Boston, MA. PATIENTS: Thirty adult ICU patients. INTERVENTIONS: Placebo (n = 10) versus 200,000 IU cholecalciferol (n = 10) versus 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained at baseline (day 1) and on days 3, 5, and 7, to assess total 25-hydroxyvitamin D, as well as vitamin D-binding protein and albumin to calculate bioavailable 25-hydroxyvitamin D. Plasma LL-37 and high-sensitivity C-reactive protein levels were also measured. At baseline, median (interquartile range) plasma 25-hydroxyvitamin D was 17 ng/mL (13-22 ng/mL) and peaked by day 5 in both intervention groups. Groups were compared using Kruskal-Wallis tests. Relative to baseline, on day 5, median change in biomarkers for placebo, 200,000 IU cholecalciferol, and 400,000 IU cholecalciferol groups, respectively, were as follows: 1) total 25-hydroxyvitamin D, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25-hydroxyvitamin D, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37: -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity C-reactive protein levels did not differ between groups. A positive correlation was observed between bioavailable 25-hydroxyvitamin D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25-hydroxyvitamin D and LL-37. CONCLUSIONS: High-dose cholecalciferol supplementation rapidly and safely improves 25-hydroxyvitamin D and bioavailable 25-hydroxyvitamin D levels in patients with severe sepsis or septic shock. Changes in bioavailable 25-hydroxyvitamin D are associated with concomitant increases in circulating LL-37 levels. Larger trials are needed to verify these findings and to assess whether optimizing vitamin D status improves sepsis-related clinical outcomes.

Nutritional vitamin D supplementation in dialysis: a randomized trial.

BACKGROUND AND OBJECTIVES: Vitamin D (25-hydroxyvitamin D; 25[OH]D) deficiency is common in patients initiating long-term hemodialysis, but the safety and efficacy of nutritional vitamin D supplementation in this population remain uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This randomized, placebo-controlled, parallel-group multicenter trial compared two doses of ergocalciferol with placebo between October 2009 and March 2013. Hemodialysis patients (n=105) with 25(OH)D levels ≤32 ng/ml from 32 centers in the Northeast United States were randomly assigned to oral ergocalciferol, 50,000 IU weekly (n=36) or monthly (n=33), or placebo (n=36) for a 12-week treatment period. The primary endpoint was the achievement of vitamin D sufficiency (25[OH]D >32 ng/ml) at the end of the 12-week treatment period. Survival was assessed through 1 year. RESULTS: Baseline characteristics were similar across all arms, with overall mean±SD 25(OH)D levels of 21.9±6.9 ng/ml. At 12 weeks, vitamin D sufficiency (25[OH]D >32 ng/ml) was achieved in 91% (weekly), 66% (monthly), and 35% (placebo) (P<0.001). Mean 25(OH)D was significantly higher in both the weekly (49.8±2.3 ng/ml; P<0.001) and monthly (38.3±2.4 ng/ml; P=0.001) arms compared with placebo (27.4±2.3 ng/ml). Calcium, phosphate, parathyroid hormone levels, and active vitamin D treatment did not differ between groups. All-cause and cause-specific hospitalizations and adverse events were similar between groups during the intervention period. Lower all-cause mortality among ergocalciferol-treated participants was not statistically significant (hazard ratio, 0.28; 95% confidence interval, 0.07 to 1.19). CONCLUSIONS: Oral ergocalciferol can increase 25(OH)D levels in incident hemodialysis patients without significant alterations in blood calcium, phosphate, or parathyroid hormone during a 12-week period.

Prospective study of vitamin D status at initiation of care in critically ill surgical patients and risk of 90-day mortality.

OBJECTIVES: 1) To characterize vitamin D status at initiation of critical care in surgical ICU patients and 2) to determine whether this vitamin D status is associated with the risk of prolonged hospital length of stay, 90-day readmission, and 90-day mortality. DESIGN: Prospective cohort study. SETTING: A teaching hospital in Boston, MA. PATIENTS: Hundred surgical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mean (± SD) serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were 17 ± 8 ng/mL and 32 ± 19 pg/mL, respectively. Mean calculated bioavailable 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were 2.5 ± 2.0 ng/mL and 6.6 ± 5.3 pg/mL, respectively. Receiver-operating characteristic curve analysis demonstrated that all of four vitamin D measures predicted the three clinical outcomes; total 25-hydroxyvitamin D was not inferior to the other measures. Median (interquartile range) hospital length of stay was 11 days (8-19 d). Poisson regression analysis, adjusted for biologically plausible covariates, demonstrated an association of total 25-hydroxyvitamin D with hospital length of stay (incident rate ratio per 1 ng/mL, 0.98; 95% CI, 0.97-0.98). The 90-day readmission and mortality rates were 24% and 22%, respectively. Even after adjustment for biologically plausible covariates, there remained significant associations of total 25-hydroxyvitamin D with readmission (odds ratio per 1 ng/mL, 0.84; 95% CI, 0.74-0.95) and mortality (odds ratio per 1 ng/mL, 0.84; 95% CI, 0.73-0.97). CONCLUSIONS: Serum 25-hydroxyvitamin D levels within 24 hours of ICU admission may identify patients at high risk for prolonged hospitalization, readmission, and mortality. Randomized trials are needed to assess whether vitamin D supplementation can improve these clinically relevant outcomes in surgical ICU patients.

Impact of new vitamin D data on future studies and treatment.

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.

Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship.

Studies examining the relationship between total circulating 25-hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D-binding protein (DBP), the major carrier protein for 25(OH)D, may alter the biologic activity of circulating vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College-Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual-energy X-ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin-bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for vitamin D supplementation in vitamin D-deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.

Dietary vitamin D intake in advanced CKD/ESRD.

In healthy individuals, vitamin D produced in the skin or derived from nutritional sources is converted to 25-hydroxyvitamin D (25[OH]D) in the liver, and then 1,25-dihydroxyvitamin D (1,25[OH](2)D) by 1 alpha-hydroxylase in the kidney. Chronic kidney disease (CKD) is accompanied by a progressive decline in the ability to produce 1,25(OH)(2)D; thus, replacement of this hormonal form of vitamin D has been the focus of therapeutic interventions to prevent and treat complications such as hypocalcemia, and secondary hyperparathyroidism. New research suggests that conversion of 25(OH)D to 1,25(OH)(2)D outside of the kidney may have important biological roles beyond those traditionally ascribed to vitamin D. 25(OH)D levels have increasingly been linked to important clinical outcomes in CKD. This article reviews vitamin D metabolism, emerging new roles for vitamin D, and data surrounding the potential importance of nutritional sources of vitamin D in the management of patients with CKD.

Klotho variants and chronic hemodialysis mortality.

Patients with end-stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)-23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF-23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ESRD. We tested the association between 12 single nucleotide polymorphisms (SNPs) in the Klotho gene and mortality in a cohort of ESRD patients during their first year on hemodialysis (n = 1307 white and Asian). We found a significant association between the CC genotype of one tag SNP, rs577912, and increased risk for 1-yr mortality (RR, 1.76; 95% CI, 1.19-2.59; p = 0.003). This effect was even more marked among patients who were not treated with activated vitamin D supplementation (HR, 2.51; 95% CI, 1.18-5.34; p = 0.005). In lymphoblastoid cell lines derived from HapMap subjects, the CC genotype was associated with a 16-21% lower Klotho expression compared with the AA/AC genotype. Our data suggest that a specific Klotho variant (rs577912) is linked to survival in ESRD patients initiating chronic hemodialysis and that therapy with activated vitamin D may modify this risk.

Design and implementation of an application and associated services to support interdisciplinary medication reconciliation efforts at an integrated healthcare delivery network.

Confusion about patients' medication regimens during the hospital admission and discharge process accounts for many preventable and serious medication errors. Many organizations have begun to redesign their clinical processes to address this patient safety concern. Partners HealthCare, an integrated delivery network in Boston, Massachusetts, has answered this interdisciplinary challenge by leveraging its multiple outpatient electronic medical records (EMR) and inpatient computerized provider order entry (CPOE) systems to facilitate the process of medication reconciliation. This manuscript describes the design of a novel application and the associated services that aggregate medication data from EMR and CPOE systems so that clinicians can efficiently generate an accurate pre-admission medication list. Information collected with the use of this application subsequently supports the writing of admission and discharge orders by physicians, performance of admission assessment by nurses, and reconciliation of inpatient orders by pharmacists. Results from early pilot testing suggest that this new medication reconciliation process is well accepted by clinicians and has significant potential to prevent medication errors during transitions of care.